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A Set of Dynamic Programming Algorithms for Haplotype Block Partitioning and Tag SNP Selection via programming algorithms developed for haplotype block partitioning and tag SNP selection, with a focus to map genes on a fine scale. Single nucleotide polymorphism (SNP) markers are preferred over
Sun, Fengzhu - Sun, Fengzhu
Grouping preprocess for haplotype inference from SNP and CNV data
NASA Astrophysics Data System (ADS)
The method of statistical haplotype inference is an indispensable technique in the field of medical science. The authors previously reported Hardy-Weinberg equilibrium-based haplotype inference that could manage single nucleotide polymorphism (SNP) data. We recently extended the method to cover copy number variation (CNV) data. Haplotype inference from mixed data is important because SNPs and CNVs are occasionally in linkage disequilibrium. The idea underlying the proposed method is simple, but the algorithm for it needs to be quite elaborate to reduce the calculation cost. Consequently, we have focused on the details on the algorithm in this study. Although the main advantage of the method is accuracy, in that it does not use any approximation, its main disadvantage is still the calculation cost, which is sometimes intractable for large data sets with missing values.
Shindo, Hiroyuki; Chigira, Hiroshi; Nagaoka, Tomoyo; Kamatani, Naoyuki; Inoue, Masato
Optimal Tag SNP Selection for Haplotype Reconstruction Jin Jun and Ion Mandoiu
Optimal Tag SNP Selection for Haplotype Reconstruction Jin Jun and Ion Mandoiu Abstract. In this poster, we propose optimum tag single nu- cleotide polymorphism (SNP) selection methods based on integer the con- flated SNP information in the so called genotype. Haplotypes are currently inferred from
Mandoiu, Ion
Efficient Algorithms for SNP Genotype Data Analysis using Hidden Markov Models of Haplotype Diversity Justin Kennedy University of Connecticut, 2009 Advances in SNP genotyping technologies have played of cases and controls at up to millions of single nucleotide polymorphism (SNP) loci, generating very large
Mandoiu, Ion
Haplotype inference from unphased SNP data in heterozygous polyploids based on SAT
Background Haplotype inference based on unphased SNP markers is an important task in population genetics. Although there are different approaches to the inference of haplotypes in diploid species, the existing software is not suitable for inferring haplotypes from unphased SNP data in polyploid species, such as the cultivated potato (Solanum tuberosum). Potato species are tetraploid and highly heterozygous. Results Here we present the software SATlotyper which is able to handle polyploid and polyallelic data. SATlo-typer uses the Boolean satisfiability problem to formulate Haplotype Inference by Pure Parsimony. The software excludes existing haplotype inferences, thus allowing for calculation of alternative inferences. As it is not known which of the multiple haplotype inferences are best supported by the given unphased data set, we use a bootstrapping procedure that allows for scoring of alternative inferences. Finally, by means of the bootstrapping scores, it is possible to optimise the phased genotypes belonging to a given haplotype inference. The program is evaluated with simulated and experimental SNP data generated for heterozygous tetraploid populations of potato. We show that, instead of taking the first haplotype inference reported by the program, we can significantly improve the quality of the final result by applying additional methods that include scoring of the alternative haplotype inferences and genotype optimisation. For a sub-population of nineteen individuals, the predicted results computed by SATlotyper were directly compared with results obtained by experimental haplotype inference via sequencing of cloned amplicons. Prediction and experiment gave similar results regarding the inferred haplotypes and phased genotypes. Conclusion Our results suggest that Haplotype Inference by Pure Parsimony can be solved efficiently by the SAT approach, even for data sets of unphased SNP from heterozygous polyploids. SATlotyper is freeware and is distributed as a Java JAR file. The software can be downloaded from the webpage of the GABI Primary Database at . The application of SATlotyper will provide haplotype information, which can be used in haplotype association mapping studies of polyploid plants. PMID:18667059
Neigenfind, Jost; Gyetvai, Gabor; Basekow, Rico; Diehl, Svenja; Achenbach, Ute; Gebhardt, Christiane; Selbig, Joachim; Kersten, Birgit
A sequential Monte Carlo framework for haplotype inference in CNV/SNP genotype data
Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme 'Tree-Based Deterministic Sampling CNV' (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv. PMID:24868199
Due to the large size (150 kb) of the ataxia-telangiectasia mutated (ATM) gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia (A-T) is labor intensive. We compared the SNP and STR haplotypes of A-T patients from varying ethnicities who were carrying common ATM mutations. We used SSCP to determine SNP haplotypes. To our surprise, all of the most common ATM mutations in our large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predated STR haplotypes but not SNP haplotypes. We conclude that these frequently observed ATM mutations are not hot spots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. We estimate this approach will identify approximately 30% of mutations in A-T patients across all ethnic groups. PMID:12497634
Campbell, Catarina; Mitui, Midori; Eng, Laura; Coutinho, Gabriela; Thorstenson, Yvonne; Gatti, Richard A
Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ?50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ?83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder. PMID:22387017
Lee, Jong-Min; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Ramos, Eliana Marisa; Myers, Richard H.; Hayden, Michael R.; Morrison, Patrick J.; Nance, Martha; Ross, Christopher A.; Margolis, Russell L.; Squitieri, Ferdinando; Griguoli, Annamaria; Di Donato, Stefano; Gomez-Tortosa, Estrella; Ayuso, Carmen; Suchowersky, Oksana; Trent, Ronald J.; McCusker, Elizabeth; Novelletto, Andrea; Frontali, Marina; Jones, Randi; Ashizawa, Tetsuo; Frank, Samuel; Saint-Hilaire, Marie-Helene; Hersch, Steven M.; Rosas, Herminia D.; Lucente, Diane; Harrison, Madaline B.; Zanko, Andrea; Abramson, Ruth K.; Marder, Karen; Sequeiros, Jorge; MacDonald, Marcy E.; Gusella, James F.
Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software. PMID:19918759
Stone, J; Gurrin, L C; Hayes, V M; Southey, M C; Hopper, J L; Byrnes, G B
The creation of single-nucleotide polymorphism (SNP) databases (such as NCBI dbSNP) has facilitated scientific research in many fields. SNP discovery and detection has improved to the extent that there are over 17 million human reference (rs) SNPs reported to date (Build 129 of dbSNP). SNP databases are unfortunately not always complete and/or accurate. In fact, half of the reported SNPs are still only candidate SNPs and are not validated in a population. We describe the identification of SNDs (Single Nucleotide Differences) in humans, that may contaminate the dbSNP database. These SNDs, reported as real SNPs in the database, do not exist as such, but are merely artifacts due to the presence of a paralogue (highly similar duplicated) sequence in the genome. Using sequencing we showed how SNDs could originate in two paralogous genes and evaluated samples from a population of 100 individuals for the presence/absence of SNPs. Moreover using bioinformatics, we predicted as many as 8.32% of the biallelic, coding SNPs in the dbSNP database to be SNDs. Our identification of SNDs in the database will allow researchers to not only select truly informative SNPs for association studies, but also aid in determining accurate SNP genotypes and haplotypes. PMID:19877174
Musumeci, Lucia; Arthur, Jonathan W; Cheung, Florence SG; Hoque, Ashraful; Lippman, Scott; Reichardt, Juergen KV
Fast and accurate haplotype frequency estimation for large haplotype vectors from pooled DNA data
Background Typically, the first phase of a genome wide association study (GWAS) includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. Results We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals) and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool) package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. Conclusions Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets. PMID:23110720
Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed
T Li; D Ball; J Zhao; R M Murray; X Liu; P C Sham; D A Collier
Site frequency spectra from genomic SNP surveys.
Genomic survey data now permit an unprecedented level of sensitivity in the detection of departures from canonical evolutionary models, including expansions in population size and selective sweeps. Here, we examine the effects of seemingly subtle differences among sampling distributions on goodness of fit analyses of site frequency spectra constructed from single nucleotide polymorphisms. Conditioning on the observation of exactly two alleles in a random sample results in a site frequency spectrum that is independent of the scaled rate of neutral substitution (theta). Other sampling distributions, including conditioning on a single mutational event in the sample genealogy or randomly selecting a single mutation from a genealogy with multiple mutations, have distinct site frequency spectra that show highly significant departures from the predictions of the biallelic model. Some aspects of data filtering may contribute to significant departures of site frequency spectra from expectation, apart from any violation of the standard neutral model. PMID:19371756
Ganapathy, Ganeshkumar; Uyenoyama, Marcy K
Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed by regions of low LD. A small fraction of SNPs (tag SNPs) is sufficient to capture most of the haplotype structure of the human genome. In this paper, we develop a method to partition haplotypes into blocks and to
Kui Zhang; Zhaohui S. Qin; Jun S. Liu; Ting Chen; Michael S. Waterman; Fengzhu Sun
Rapid gene-based SNP and haplotype marker development in non-model eukaryotes using 3'UTR sequencing
Background Sweet cherry (Prunus avium L.), a non-model crop with narrow genetic diversity, is an important member of sub-family Amygdoloideae within Rosaceae. Compared to other important members like peach and apple, sweet cherry lacks in genetic and genomic information, impeding understanding of important biological processes and development of efficient breeding approaches. Availability of single nucleotide polymorphism (SNP)-based molecular markers can greatly benefit breeding efforts in such non-model species. RNA-seq approaches employing second generation sequencing platforms offer a unique avenue to rapidly identify gene-based SNPs. Additionally, haplotype markers can be rapidly generated from transcript-based SNPs since they have been found to be extremely utile in identification of genetic variants related to health, disease and response to environment as highlighted by the human HapMap project. Results RNA-seq was performed on two sweet cherry cultivars, Bing and Rainier using a 3' untranslated region (UTR) sequencing method yielding 43,396 assembled contigs. In order to test our approach of rapid identification of SNPs without any reference genome information, over 25% (10,100) of the contigs were screened for the SNPs. A total of 207 contigs from this set were identified to contain high quality SNPs. A set of 223 primer pairs were designed to amplify SNP containing regions from these contigs and high resolution melting (HRM) analysis was performed with eight important parental sweet cherry cultivars. Six of the parent cultivars were distantly related to Bing and Rainier, the cultivars used for initial SNP discovery. Further, HRM analysis was also performed on 13 seedlings derived from a cross between two of the parents. Our analysis resulted in the identification of 84 (38.7%) primer sets that demonstrated variation among the tested germplasm. Reassembly of the raw 3'UTR sequences using upgraded transcriptome assembly software yielded 34,620 contigs containing 2243 putative SNPs in 887 contigs after stringent filtering. Contigs with multiple SNPs were visually parsed to identify 685 putative haplotypes at 335 loci in 301 contigs. Conclusions This approach, which leverages the advantages of RNA-seq approaches, enabled rapid generation of gene-linked SNP and haplotype markers. The general approach presented in this study can be easily applied to other non-model eukaryotes irrespective of the ploidy level to identify gene-linked polymorphisms that are expected to facilitate efficient Gene Assisted Breeding (GAB), genotyping and population genetics studies. The identified SNP haplotypes reveal some of the allelic differences in the two sweet cherry cultivars analyzed. The identification of these SNP and haplotype markers is expected to significantly improve the genomic resources for sweet cherry and facilitate efficient GAB in this non-model crop. PMID:22239826
Inferring the Joint Demographic History of Multiple Populations from Multidimensional SNP Frequency Demographic History of Multiple Populations from Multidimensional SNP Frequency Data. PLoS Genet 5(10): e
Sorenson, Michael
Human haplotypes include essential information about SNPs, which in turn provide valuable information for such studies as finding relationships between some diseases and their potential genetic causes, e.g., for Genome Wide Association Studies. Due to expensiveness of directly determining haplotypes and recent progress in high throughput sequencing, there has been an increasing motivation for haplotype assembly, which is the problem of finding a pair of haplotypes from a set of aligned fragments. Although the problem has been extensively studied and a number of algorithms have already been proposed for the problem, more accurate methods are still beneficial because of high importance of the haplotypes information. In this paper, first, we develop a probabilistic model, that incorporates the Minor Allele Frequency (MAF) of SNP sites, which is missed in the existing maximum likelihood models. Then, we show that the probabilistic model will reduce to the Minimum Error Correction (MEC) model when the information of MAF is omitted and some approximations are made. This result provides a novel theoretical support for the MEC, despite some criticisms against it in the recent literature. Next, under the same approximations, we simplify the model to an extension of the MEC in which the information of MAF is used. Finally, we extend the haplotype assembly algorithm HapSAT by developing a weighted Max-SAT formulation for the simplified model, which is evaluated empirically with positive results. PMID:24491253
Mousavi, Sayyed R; Khodadadi, Ilnaz; Falsafain, Hossein; Nadimi, Reza; Ghadiri, Nasser
SNP and haplotype mapping for genetic analysis in The STAR Consortium*
of cases breeding stocks were distributed before the line became inbred, with varying physiological. The presence of a number of recombinant inbred lines (RI)--in particular the HXB-BXH sets, derived from the BN commonly used rat inbred lines, and we developed a comprehensive open resource of validated SNP markers
Cai, Long
Cytochrome P450 2E1, gene symbol CYP2E1, is one of a family of enzymes with a central role in activating and detoxifying xenobiotics and endogenous compounds. Genetic variation at this gene has been reported in different human populations, and some association studies have reported increased risk for cancers and other diseases. To the best of our knowledge, multi-SNP haplotypes and linkage disequilibrium (LD) have not been systematically studied for CYP2E1 in multiple populations. Haplotypes can greatly increase the power both to identify patterns of genetic variation relevant for gene expression as well as to detect disease-related susceptibility mutations. We present frequency and LD data and analyses for 11 polymorphisms and their haplotypes that we have studied on over 2,600 individuals from 50 human population samples representing the major geographical regions of the world. The diverse patterns of haplotype variation found in the different populations we have studied show that ethnicity may be an important variable helping to explain inconsistencies that have been reported by association studies. More studies clearly are needed of the variants we have studied, especially those in the 5? region, such as the VNTR, as well as studies of additional polymorphisms known for this gene to establish evidence relating any systematic differences in gene expression that exist to the haplotypes at this gene. PMID:18663376
Lee, Mi-Young; Mukherjee, Namita; Pakstis, Andrew J.; Khaliq, Shagufta; Mohyuddin, Aisha; Mehdi, S. Qasim; Speed, William C.; Kidd, Judith R.; Kidd, Kenneth K.
The Structure of Haplotype Blocks in the Human Genome
Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the
Stacey B. Gabriel; Stephen F. Schaffner; Huy Nguyen; Jamie M. Moore; Jessica Roy; Brendan Blumenstiel; John Higgins; Matthew DeFelice; Amy Lochner; Maura Faggart; Shau Neen Liu-Cordero; Charles Rotimi; Adebowale Adeyemo; Richard Cooper; Ryk Ward; Eric S. Lander; Mark J. Daly; David Altshuler
SNP Calling, Genotype Calling, and Sample Allele Frequency Estimation from New-Generation Sequencing
SNP Calling, Genotype Calling, and Sample Allele Frequency Estimation from New, and show how the method can be used for genotype calling and SNP calling. We also show how the method can. Citation: Nielsen R, Korneliussen T, Albrechtsen A, Li Y, Wang J (2012) SNP Calling, Genotype Calling
Nielsen, Rasmus
Soybean rust (SBR), caused by Phakopsora pachyrhizi Sydow, is one of the most economically important and destructive diseases of soybean [Glycine max (L.) Merr.] and the discovery of novel SBR resistance genes is needed because of virulence diversity in the pathogen. The objectives of this research were to map SBR resistance in plant introduction (PI) 561356 and to identify single nucleotide polymorphism (SNP) haplotypes within the region on soybean chromosome 18 where the SBR resistance gene Rpp1 maps. One-hundred F(2:3) lines derived from a cross between PI 561356 and the susceptible experimental line LD02-4485 were genotyped with genetic markers and phenotyped for resistance to P. pachyrhizi isolate ZM01-1. The segregation ratio of reddish brown versus tan lesion type in the population supported that resistance was controlled by a single dominant gene. The gene was mapped to a 1-cM region on soybean chromosome 18 corresponding to the same interval as Rpp1. A haplotype analysis of diverse germplasm across a 213-kb interval that included Rpp1 revealed 21 distinct haplotypes of which 4 were present among 5 SBR resistance sources that have a resistance gene in the Rpp1 region. Four major North American soybean ancestors belong to the same SNP haplotype as PI 561356 and seven belong to the same haplotype as PI 594538A, the Rpp1-b source. There were no North American soybean ancestors belonging to the SNP haplotypes found in PI 200492, the source of Rpp1, or PI 587886 and PI 587880A, additional sources with SBR resistance mapping to the Rpp1 region. PMID:22837016
Kim, Ki-Seung; Unfried, Jair R; Hyten, David L; Frederick, Reid D; Hartman, Glen L; Nelson, Randall L; Song, Qijian; Diers, Brian W
Development of accurate high-throughput molecular marker systems such as SNPs permits evaluation and selection of favourable gene variants to accelerate elite varietal production. SNP discovery in perennial ryegrass has been based on PCR amplification and sequencing of multiple amplicons designed to scan all components of the transcriptional unit. Full-length genes (with complete intron-exon structure and promoter information) corresponding to well-defined biochemical functions such as lignin biosynthesis and oligosaccharide metabolism are ideal for complete SNP haplotype determination. Multiple SNPs at regular intervals across the transcriptional unit were detected within and between the heterozygous parents and validated in the progeny of the F (1)(NA(6) x AU(6)) genetic mapping family. Haplotype structures in the parental genotypes were defined and haplotypic abundance, structure and variation were assessed in diverse germplasm sources. Decay of LD to r (2) values of c. 0.2 typically occurs over 500-3,000 bp, comparable with gene length and with little apparent variation between diverse, ecotypic and varietal population sub-groups. Similar patterns were revealed as limited blocks of intragenic LD. The results are compatible with the reproductive biology of perennial ryegrass and the effects of large ancestral population size. This analysis provides crucial information to validate strategies for correlation of haplotypic diversity and phenotypic variation through association mapping. PMID:17647019
Ponting, Rebecca C; Drayton, Michelle C; Cogan, Noel O I; Dobrowolski, Mark P; Spangenberg, Germán C; Smith, Kevin F; Forster, John W
SNP discovery and allele frequency estimation by deep sequencing of reduced representation libraries
High-density single-nucleotide polymorphism (SNP) arrays have revolutionized the ability of genome-wide association studies to detect genomic regions harboring sequence variants that affect complex traits. Extensive numbers of validated SNPs with known allele frequencies are essential to construct genotyping assays with broad utility. We describe an economical, efficient, single-step method for SNP discovery, validation and characterization that uses deep sequencing of
Timothy P L Smith; Lakshmi K Matukumalli; Jeremy F Taylor; Robert D Schnabel; Cynthia Taylor Lawley; Christian D Haudenschild; Stephen S Moore; Wesley C Warren; Tad S Sonstegard; Curtis P Van Tassell
NASA Astrophysics Data System (ADS)
The distribution pattern of mtDNA haplotypes in distinct populations of the glacial relict crustacean Saduria entomon was examined to assess phylogeographic relationships among them. Populations from the Baltic, the White Sea and the Barents Sea were screened for mtDNA variation using PCR-based RFLP analysis of a 1150 bp fragment containing part of the CO I and CO II genes. Five mtDNA haplotypes were recorded. An analysis of geographical heterogeneity in haplotype frequency distributions revealed significant differences among populations. The isolated populations of S. entomon have diverged since the retreat of the last glaciation. The geographical pattern of variation is most likely the result of stochastic (founder effect, genetic drift) mechanisms and suggests that the haplotype differentiation observed is probably older than the isolation of the Baltic and Arctic seas.
Sell, Jerzy
Estimating haplotype frequencies by combining data from large DNA pools with database information.
We assume that allele frequency data have been extracted from several large DNA pools, each containing genetic material of up to hundreds of sampled individuals. Our goal is to estimate the haplotype frequencies among the sampled individuals by combining the pooled allele frequency data with prior knowledge about the set of possible haplotypes. Such prior information can be obtained, for example, from a database such as HapMap. We present a Bayesian haplotyping method for pooled DNA based on a continuous approximation of the multinomial distribution. The proposed method is applicable when the sizes of the DNA pools and/or the number of considered loci exceed the limits of several earlier methods. In the example analyses, the proposed model clearly outperforms a deterministic greedy algorithm on real data from the HapMap database. With a small number of loci, the performance of the proposed method is similar to that of an EM-algorithm, which uses a multinormal approximation for the pooled allele frequencies, but which does not utilize prior information about the haplotypes. The method has been implemented using Matlab and the code is available upon request from the authors. PMID:21071795
Gasbarra, Dario; Kulathinal, Sangita; Pirinen, Matti; Sillanpää, Mikko J
Background DNA extracted from historical samples is an important resource for understanding genetic consequences of anthropogenic influences and long-term environmental change. However, such samples generally yield DNA of a lower amount and quality, and the extent to which DNA degradation affects SNP genotyping success and allele frequency estimation is not well understood. We conducted high density SNP genotyping and allele frequency estimation in both individual DNA samples and pooled DNA samples extracted from dried Atlantic salmon (Salmo salar) scales stored at room temperature for up to 35 years, and assessed genotyping success, repeatability and accuracy of allele frequency estimation using a high density SNP genotyping array. Results In individual DNA samples, genotyping success and repeatability was very high (> 0.973 and?>?0.998, respectively) in samples stored for up to 35 years; both increased with the proportion of DNA of fragment size?>?1000 bp. In pooled DNA samples, allele frequency estimation was highly repeatable (Repeatability?=?0.986) and highly correlated with empirical allele frequency measures (Mean Adjusted R2?=?0.991); allele frequency could be accurately estimated in?>?95% of pooled DNA samples with a reference group of at least 30 individuals. SNPs located in polyploid regions of the genome were more sensitive to DNA degradation: older samples had lower genotyping success at these loci, and a larger reference panel of individuals was required to accurately estimate allele frequencies. Conclusions SNP genotyping was highly successful in degraded DNA samples, paving the way for the use of degraded samples in SNP genotyping projects. DNA pooling provides the potential for large scale population genetic studies with fewer assays, provided enough reference individuals are also genotyped and DNA quality is properly assessed beforehand. We provide recommendations for future studies intending to conduct high-throughput SNP genotyping and allele frequency estimation in historical samples. PMID:23819691
Background: The frequency of a haplotype comprising one allele at each of two loci can be expressed as a cubic equation (the 'Hill equation'), the solution of which gives that frequency. Most haplotype and linkage disequilibrium analysis programs use iteration-based algorithms which substitute an estimate of haplotype frequency into the equation, producing a new estimate which is repeatedly fed back
Tom R. Gaunt; Santiago Rodríguez; Ian N. M. Day
SNP frequency, haplotype structure and linkage disequilibrium in elite maize inbred lines
BACKGROUND: Recent studies of ancestral maize populations indicate that linkage disequilibrium tends to dissipate rapidly, sometimes within 100 bp. We set out to examine the linkage disequilibrium and diversity in maize elite inbred lines, which have been subject to population bottlenecks and intense selection by breeders. Such population events are expected to increase the amount of linkage disequilibrium, but reduce
Ada Ching; Katherine S Caldwell; Mark Jung; Maurine Dolan; Scott Tingey; Michele Morgante; Antoni J Rafalski
Rh phenotype, allele and haplotype frequencies among 51,857 blood donors in North India
Background This study was performed to provide information on the frequencies of Rh antigens, alleles, phenotypes, and haplotypes from our region in India and to compare them with those from other races. Materials and methods This observational study was conducted on blood donors from March 2009 to August 2011 using a fully automated system for Rh typing of blood cells. The data were collected and calculations done to determine the antigen, phenotypes, allele and haplotype frequencies. The chi square test was used for comparisons between the results of our study and those of other studies. Results A total of 51,857 donors were included in this study. The most common Rh antigen found was "e". DCCee was the most prevalent phenotype in our study with the phenotype distribution being significantly different between our study and other studies from different regions of the world. Discussion We have determined the prevalence of Rh antigens and Rh phenotypes in the North Indian blood donor population and derived the allele and haplotype frequencies in the same population. The Rh blood group distribution in this population was different from that in other populations. PMID:24120600
Makroo, Raj; Gupta, Richa; Bhatia, Aakanksha; Rosamma, Nakamatathil L.
Publicly available single nucleotide polymorphism (SNP) allele frequencies are an important resource for the selection of genetic markers that may be most useful for gene mapping and association studies. Data mining these allele frequencies through disparate public databases and Websites is time consuming and can result in inconsistent findings. We have developed a web-based software tool, Frequency Finder, to acquire SNP allele frequencies from multiple public data sources and return a summarized result to the user. Our software optimizes and automates the search of candidate markers, decreasing the amount of time it would take to extract pertinent data manually. We have included several methods to output the data, including on-screen and as a compressed text file. We show that Frequency Finder accurately retrieves available frequency data from the available sources. Using this tool, we detect significant differences between Asian, African and Caucasian populations in the allele frequency spectra of 246 097 SNPs. While limited to public databases that provide web-based access to allele frequencies, Frequency Finder provides a single, user-friendly interface for retrieving allele frequencies for large batches of SNPs from multiple data sources. PMID:14960477
Nguyen, Tu H; Liu, Chunyu; Gershon, Elliot S; McMahon, Francis J
Haplotype frequency estimation error analysis in the presence of missing genotype data
Background Increasingly researchers are turning to the use of haplotype analysis as a tool in population studies, the investigation of linkage disequilibrium, and candidate gene analysis. When the phase of the data is unknown, computational methods, in particular those employing the Expectation-Maximisation (EM) algorithm, are frequently used for estimating the phase and frequency of the underlying haplotypes. These methods have proved very successful, predicting the phase-known frequencies from data for which the phase is unknown with a high degree of accuracy. Recently there has been much speculation as to the effect of unknown, or missing allelic data – a common phenomenon even with modern automated DNA analysis techniques – on the performance of EM-based methods. To this end an EM-based program, modified to accommodate missing data, has been developed, incorporating non-parametric bootstrapping for the calculation of accurate confidence intervals. Results Here we present the results of the analyses of various data sets in which randomly selected known alleles have been relabelled as missing. Remarkably, we find that the absence of up to 30% of the data in both biallelic and multiallelic data sets with moderate to strong levels of linkage disequilibrium can be tolerated. Additionally, the frequencies of haplotypes which predominate in the complete data analysis remain essentially the same after the addition of the random noise caused by missing data. Conclusions These findings have important implications for the area of data gathering. It may be concluded that small levels of drop out in the data do not affect the overall accuracy of haplotype analysis perceptibly, and that, given recent findings on the effect of inaccurate data, ambiguous data points are best treated as unknown. PMID:15574202
Kelly, Enda D; Sievers, Fabian; McManus, Ross
The discrete Laplace exponential family and estimation of Y-STR haplotype frequencies.
Estimating haplotype frequencies is important in e.g. forensic genetics, where the frequencies are needed to calculate the likelihood ratio for the evidential weight of a DNA profile found at a crime scene. Estimation is naturally based on a population model, motivating the investigation of the Fisher-Wright model of evolution for haploid lineage DNA markers. An exponential family (a class of probability distributions that is well understood in probability theory such that inference is easily made by using existing software) called the 'discrete Laplace distribution' is described. We illustrate how well the discrete Laplace distribution approximates a more complicated distribution that arises by investigating the well-known population genetic Fisher-Wright model of evolution by a single-step mutation process. It was shown how the discrete Laplace distribution can be used to estimate haplotype frequencies for haploid lineage DNA markers (such as Y-chromosomal short tandem repeats), which in turn can be used to assess the evidential weight of a DNA profile found at a crime scene. This was done by making inference in a mixture of multivariate, marginally independent, discrete Laplace distributions using the EM algorithm to estimate the probabilities of membership of a set of unobserved subpopulations. The discrete Laplace distribution can be used to estimate haplotype frequencies with lower prediction error than other existing estimators. Furthermore, the calculations could be performed on a normal computer. This method was implemented in the freely available open source software R that is supported on Linux, MacOS and MS Windows. PMID:23524164
Andersen, Mikkel Meyer; Eriksen, Poul Svante; Morling, Niels
Haplotypic Background of a Private Allele at High Frequency in the Americas
Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 single nucleotide polymorphisms across ?500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared with other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared with that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population that may have been isolated from other Asian populations prior to expanding into the Americas. PMID:19221006
Schroeder, Kari B.; Jakobsson, Mattias; Crawford, Michael H.; Schurr, Theodore G.; Boca, Simina M.; Conrad, Donald F.; Tito, Raul Y.; Osipova, Ludmilla P.; Tarskaia, Larissa A.; Zhadanov, Sergey I.; Wall, Jeffrey D.; Pritchard, Jonathan K.; Malhi, Ripan S.; Smith, David G.; Rosenberg, Noah A.
The analysis of human short tandem repeats of the Y-chromosome (Y-STRs) provides a powerful tool in forensic cases for male sex identification, male lineage identification and identification of the geographical origin of male lineages. As the commonly used 12 and 17 Y-STR multiplexes do not discriminate between some unrelated males, additional Y-STRs were implemented in the PowerPlex(®) Y23 System to supplement the existing commercial Y-STR kits. Until today, the forensic value of a (near) 23 versus 17 Y-STR haplotype match between an unknown DNA donor and a certain biological sample in a database is not yet well studied. This will be of huge interest for cases where an autosomal DNA profile yields no match to a DNA database and the database is used for familial searching (male relative(s) of the offender) or for the estimation of the geographical origin of the offender. In order to value (near) 23 Y-STR haplotype matches in a local sample from Western Europe, we selected the region of Flanders (Belgium) due to the already present knowledge on its Y-chromosomal variants. Many Y-chromosomes of this region were previously genotyped with Y-SNPs at a high resolution of the most recently updated Y-chromosomal tree and the deep-rooted genealogy of each DNA donor was already established. By comparing (near) matches of 23 versus 17 Y-STR haplotypes between patrilineal-unrelated males, a substantial lower number of uninformative (near) 23 Y-STR haplotype matches has been observed compared to 17 Y-STR haplotypes. Furthermore, the use of SNP data was informative to discriminate >60% of unrelated males with an (near) identical 17 Y-STR match while SNP data was only necessary to discriminate about 10% of unrelated males with a 23 Y-STR haplotype that differed at only two Y-STRs. This shows the higher value of the Y23 haplotype within familial DNA searching and the estimation of the geographical origin of a DNA donor. Therefore, the use of the PowerPlex(®) Y23 System instead of the commonly used 12 and 17 Y-STRs by the forensic community is recommended as it will increase the efficiency of Y-STRs in forensic casework. PMID:24815371
Larmuseau, Maarten H D; Vanderheyden, Nancy; Van Geystelen, Anneleen; Decorte, Ronny
We present a statistical framework for estimation and application of sample allele frequency spectra from New-Generation Sequencing (NGS) data. In this method, we first estimate the allele frequency spectrum using maximum likelihood. In contrast to previous methods, the likelihood function is calculated using a dynamic programming algorithm and numerically optimized using analytical derivatives. We then use a bayesian method for estimating the sample allele frequency in a single site, and show how the method can be used for genotype calling and SNP calling. We also show how the method can be extended to various other cases including cases with deviations from Hardy-Weinberg equilibrium. We evaluate the statistical properties of the methods using simulations and by application to a real data set. PMID:22911679
Nielsen, Rasmus; Korneliussen, Thorfinn; Albrechtsen, Anders; Li, Yingrui; Wang, Jun
Heuristics for haplotype frequency estimation with a large number of analyzed loci
NASA Astrophysics Data System (ADS)
Determining haplotypes with laboratory methods is an expensive and time-consuming activity therefore unsuit- able for the analysis of genetic data coming from a large number of tested individuals. Many existing algorithms for phasing genotypes operate on very impractical runtime and take into account only certain types of polymor- phisms, often without providing graphical user interface. The heuristic algorithm for estimating haplotype frequency developed in this work was examined in terms of time complexity, the speed of execution and the accuracy of results. Consequently, a Rich Internet Application that implements described algorithm has been created and its performance and accuracy to a known set of test data is analyzed. Eventually, a discussion on the architecture and the applications usability in bioinformatics applications is presented. Proposed algorithm can be used to improve the complexity of any algorithm that solves the problem of genotype phasing, which has a worse time complexity and is convergent. The algorithm is easy to scale and can achieve the desired ratio of calculations accuracy to execution time. Implemented application meets all requirements for the programs to solve problems in biology i.e. high performance, accessibility, scalability and usability.
Nowotka, Micha?; Nowak, Robert
Aim To type a set of 194 US African American, Caucasian, and Hispanic samples (self-declared ancestry) for 40 autosomal single nucleotide polymorphism (SNP) markers intended for human identification purposes. Methods Genotyping was performed on an automated commercial electrospray ionization time-of-flight mass spectrometer, the PLEX-ID. The 40 SNP markers were amplified in eight unique 5plex PCRs, desalted, and resolved based on amplicon mass. For each of the three US sample groups statistical analyses were performed on the resulting genotypes. Results The assay was found to be robust and capable of genotyping the 40 SNP markers consuming approximately 4 nanograms of template per sample. The combined random match probabilities for the 40 SNP assay ranged from 10?16 to 10?21. Conclusion The multiplex PLEX-ID SNP-40 assay is the first fully automated genotyping method capable of typing a panel of 40 forensically relevant autosomal SNP markers on a mass spectrometry platform. The data produced provided the first allele frequencies estimates for these 40 SNPs in a National Institute of Standards and Technology US population sample set. No population bias was detected although one locus deviated from its expected level of heterozygosity. PMID:23771752
Kiesler, Kevin M.; Vallone, Peter M.
Background: HLA allele identification is used in bone marrow transplant programs as HLA compatibility between the donor and recipient may prevent graft rejection. Objective: This study aimed to estimate the frequency of alleles and haplotypes of the HLA system in the region of Bauru and compare these with the frequencies found in other regions of the country. Methods: HLA-A*, HLA-B*, and HLA-DRB1* allele frequencies and haplotypes were analyzed in a sample of 3542 volunteer donors at the National Registry of Voluntary Bone Marrow Donors (REDOME) in Bauru. HLA low resolution typing was performed using reverse line blot with the Dynal Reli(tm) SSO-HLA Typing Kit and automated Dynal AutoReli(tm)48 device (Invitrogen, USA). Results: Twenty, 36, and 13 HLA-A*, HLA-B*, and HLA-DRB1* allele groups, respectively, were identified. The most common alleles for each locus were HLA-A*02, HLA-B*35, and HLA-DRB1*07. The most frequent haplotype was A*01-B*08-DRB1*03. Allele and haplotype frequencies were compared to other regions in Brazil and the similarities and differences among populations are shown. Conclusion: The knowledge of the immunogenic profile of a population contributes to the comprehension of the historical and anthropological aspects of different regions. Moreover, this helps to find suitable donors quickly, thereby shortening waiting lists for transplants and thus increasing survival rates among recipients. PMID:24790535
Salvadori, Luana de Cassia; Santana, Fabiana Covolo de Souza; Marcos, Elaine Valim Camarinha
Detecting Local Haplotype Sharing and Haplotype Association
A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org. PMID:24812308
Xu, Hanli; Guan, Yongtao
Allele frequencies for a SNP (rs17822931) and a 27-bp deletion that are the determinant of earwax type in the ABCC11 gene were investigated in seven Japanese, one Korean, and one German populations. The SNP will be useful as one of ancestry information markers, because it showed marked difference in frequencies between Asian and European populations.
Takashi Kitano; Isao Yuasa; Kentaro Yamazaki; Nori Nakayashiki; Aya Miyoshi; Kyung Sook Park; Kazuo Umetsu
BACKGROUND: Human leukocyte antigen (HLA) is comprised of a highly polymorphic set of genes which determines the histocompatibility of organ transplantation. The present study was undertaken to identify HLA class I and class II allele, genotype and haplotype frequencies in renal transplant recipients and donors from West Central India. MATERIALS AND METHODS: HLA typing was carried out using Polymerase Chain Reaction-Sequence Specific Primer in 552 live related and unrelated renal transplant recipients and donors. RESULTS: The most frequent HLA class I and class II alleles and their frequencies in recipients were HLA-AFNx0101 (0.1685) and AFNx0102 (0.1649), HLA-BFNx0135 (0.1322), and HLA-DR beta 1 (DRB 1)FNx0115 (0.2192), whereas in donors, these were HLA-AFNx0102 (0.1848) and AFNx0101 (0.1667), HLA-BFNx0135 (0.1359), and HLA-DRB1FNx0115 (0.2409). The two-locus haplotype statistical analysis revealed HLA-AFNx0102-B61 as the most common haplotype with the frequency of 0.0487 and 0.0510 in recipients and donors, respectively. Further, among the three locus haplotypes HLA-AFNx0133-BFNx0144-DRB1FNx0107 and HLA-AFNx0102-BFNx0161-DRB1FNx0115 were the most common haplotypes with frequencies 0.0362 and 0.0326, respectively in recipients and 0.0236 and 0.0323, respectively in donors. Genotype frequency revealed a high prevalence of genotype HLA-AFNx0102/AFNx0124 in recipients (0.058) compared to donors (0.0109) whereas low prevalence of HLA-AFNx0101/AFNx0102 in recipients (0.0435) than in donors (0.0797). The phylogenetic and principal component analysis of HLA allele and haplotype frequency distribution revealed genetic similarities of various ethnic groups. Further, case control analysis provides preliminary evidence of association of HLA-A genotype (P < 0.05) with renal failure. CONCLUSION: This study will be helpful in suitable donor search besides providing valuable information for population genetics and HLA disease association analysis. PMID:24019626
Patel, Jaina S.; Patel, Manisha M.; Koringa, Prakash G.; Shah, Tejas M.; Patel, Amrutlal K.; Tripathi, Ajai K.; Mathew, Anila; Rajapurkar, Mohan M.; Joshi, Chaitanya G.
ATM haplotypes and breast cancer risk in Jewish high-risk women.
While genetic factors clearly play a role in conferring breast cancer risk, the contribution of ATM gene mutations to breast cancer is still unsettled. To shed light on this issue, ATM haplotypes were constructed using eight SNPs spanning the ATM gene region (142 kb) in ethnically diverse non-Ashkenazi Jewish controls (n=118) and high-risk (n=142) women. Of the 28 haplotypes noted, four were encountered in frequencies of 5% or more and accounted for 85% of all haplotypes. Subsequently, ATM haplotyping of high-risk, non-Ashkenazi Jews was performed on 66 women with breast cancer and 76 asymptomatic. One SNP (rs228589) was significantly more prevalent among breast cancer cases compared with controls (P=4 x 10(-9)), and one discriminative ATM haplotype was significantly more prevalent among breast cancer cases (33.3%) compared with controls (3.8%), (P< or =10(-10)). There was no significant difference in the SNP and haplotype distribution between asymptomatic high-risk and symptomatic women as a function of disease status. We conclude that a specific ATM SNP and a specific haplotype are associated with increased breast cancer risk in high-risk non-Ashkenazi Jews. PMID:16622469
Koren, M; Kimmel, G; Ben-Asher, E; Gal, I; Papa, M Z; Beckmann, J S; Lancet, D; Shamir, R; Friedman, E
A genome-wide approach found significant association of two at-risk haplotypes (HapA, HapB) in the ALOX5AP gene with myocardial infarction and stroke. To date, it is still controversial whether ALOX5AP gene polymorphisms are risk factors for stroke. The aim of the present study is to investigate the association between the\\u000a ALOX5AP gene polymorphism and the risk for stroke in Eastern Chinese
Hao Sun; Hao Wu; Jing Zhang; Jun Wang; Ying Lu; Haixia Ding; Hang Xiao; Jinsong Zhang
Genetic marker effects and interactions are estimated with poor precision when minor marker allele frequencies are low. An Angus population was subjected to marker assisted selection for multiple years to increase divergent haplotype and minor marker allele frequencies to 1) estimate effect size and mode of inheritance for previously reported SNP on targeted beef carcass quality traits; 2) estimate effects of previously reported SNP on nontarget performance traits; and 3) evaluate tenderness SNP specific residual variance models compared to a single residual variance model for tenderness. Divergent haplotypes within µ-calpain (CAPN1), and SNP within calpastatin (CAST) and growth hormone receptor (GHR) were successfully selected to increase their frequencies. Traits evaluated were birth BW, weaning BW, final BW, fat thickness, LM area, USDA marbling score, yield grade, slice shear force (SSF), and visible and near infrared predicted slice shear force. Both CAPN1 and CAST exhibited additive (P < 0.001) modes of inheritance for SSF and neither exhibited dominance (P ? 0.19). Furthermore, the interaction between CAPN1 and CAST for SSF was not significant (P = 0.55). Estimated additive effects of CAPN1 (1.049 kg) and CAST (1.257 kg) on SSF were large in this study. Animals homozygous for tender alleles at both CAPN1 and CAST would have 4.61 kg lower SSF (38.6% of the mean) than animals homozygous tough for both markers. There was also an effect of CAST on yield grade (P < 0.02). The tender CAST allele was associated with more red meat yield and less trimmable fat. There were no significant effects (P ? 0.23) for GHR on any of the traits evaluated in this study. Furthermore, CAST specific residual variance models were found to fit significantly better (P < 0.001) than single residual variance models for SSF, with the tougher genotypes having larger residual variance. Thus, the risk of a tough steak from the undesired CAST genotype is increased through both an increase in mean and an increase in variation. This work confirms the importance of CAPN1 and CAST for tenderness in beef, provides a new effect of CAST on beef tenderness, and questions the utility of GHR as a selection marker for beef quality. PMID:24398843
Tait, R G; Shackelford, S D; Wheeler, T L; King, D A; Casas, E; Thallman, R M; Smith, T P L; Bennett, G L
SNP discovery and allele frequency estimation by deep sequencing of reduced representation libraries
Schnabel4, Cynthia Taylor Lawley5, Christian D Haudenschild5, Stephen S Moore6, Wesley C Warren7 & Tad S Sonstegard1 High-density single-nucleotide polymorphism (SNP) arrays have revolutionized the ability of genome-wide association studies to detect genomic regions harboring sequence variants that affect complex
Cai, Long
It has been estimated that there are more than 60 million Hepatitis C virus (HCV) carriers in the World Health Organisation's Western Pacific region (WHO-WPR), where liver cancer is among the top three causes of cancer death. WHO and the US Centres for Disease Control and Prevention report the prevalence of HCV in the South Pacific islands (countries within the WHO-WPR) to be high (5–10% and >2% respectively). However, since HCV is not tested for in many of these countries, there is sparse data available to support this assertion. We screened ?2000 apparently healthy individuals from Papua New Guinea, Fiji and Kiribati and found a sero-prevalence of 2.0%, 0.1% and 0%, respectively. All sero-positive samples tested negative for HCV RNA. Curious as to why all the sero-positive individuals were negative for HCV-RNA, we also screened them for the HCV protective IL28B SNP markers rs12979860 and rs8099917. All antibody-positive participants bar one had HCV protective haplotypes. Our results suggest that HCV is present in these Pacific island countries, albeit at a prevalence lower than previous estimates. As none of our participants had undergone antiviral treatment, and therefore must have cleared infection naturally, we hypothesise that genotypes 1 and/or 4 are circulating in South Pacific Island people and that these peoples are genetically predisposed to be more likely to spontaneous resolve HCV infection than to become chronic carriers. PMID:23976941
Harrison, G. L. Abby; Pryor, Jan; Malani, Joji; Supuri, Mathias; Masta, Andrew; Teriboriki, Burentau; Toatu, Tebuka; Penny, David; Allain, Jean-Pierre; Barnes, Eleanor; Pybus, Oliver G.; Klenerman, Paul
HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics. PMID:24691290
Li, Xiao-Feng; Zhang, Xu; Chen, Yang; Zhang, Kun-Lian; Liu, Xiang-Jun; Li, Jian-Ping
HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics. PMID:24691290
Li, Xiao-Feng; Zhang, Xu; Chen, Yang; Zhang, Kun-Lian; Liu, Xiang-Jun; Li, Jian-Ping
Genome-Wide SNP Detection, Validation, and Development of an 8K SNP Array for Apple
As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide evaluation of allelic variation in apple (Malus×domestica) breeding germplasm. For genome-wide SNP discovery, 27 apple cultivars were chosen to represent worldwide breeding germplasm and re-sequenced at low coverage with the Illumina Genome Analyzer II. Following alignment of these sequences to the whole genome sequence of 'Golden Delicious', SNPs were identified using SoapSNP. A total of 2,113,120 SNPs were detected, corresponding to one SNP to every 288 bp of the genome. The Illumina GoldenGate® assay was then used to validate a subset of 144 SNPs with a range of characteristics, using a set of 160 apple accessions. This validation assay enabled fine-tuning of the final subset of SNPs for the Illumina Infinium® II system. The set of stringent filtering criteria developed allowed choice of a set of SNPs that not only exhibited an even distribution across the apple genome and a range of minor allele frequencies to ensure utility across germplasm, but also were located in putative exonic regions to maximize genotyping success rate. A total of 7867 apple SNPs was established for the IRSC apple 8K SNP array v1, of which 5554 were polymorphic after evaluation in segregating families and a germplasm collection. This publicly available genomics resource will provide an unprecedented resolution of SNP haplotypes, which will enable marker-locus-trait association discovery, description of the genetic architecture of quantitative traits, investigation of genetic variation (neutral and functional), and genomic selection in apple. PMID:22363718
Chagne, David; Crowhurst, Ross N.; Troggio, Michela; Davey, Mark W.; Gilmore, Barbara; Lawley, Cindy; Vanderzande, Stijn; Hellens, Roger P.; Kumar, Satish; Cestaro, Alessandro; Velasco, Riccardo; Main, Dorrie; Rees, Jasper D.; Iezzoni, Amy; Mockler, Todd; Wilhelm, Larry; Van de Weg, Eric; Gardiner, Susan E.; Bassil, Nahla; Peace, Cameron
A consistent finding in major depressive disorder (MDD) research is dysfunction of the immune system. One of the relevant metabolic pathways in this regard is the kynurenine pathway. In patients with major depression, an imbalance between neuroprotective and neurotoxic arms of the pathway with lower plasma kynurenic acid concentration was demonstrated. Therefore, we investigated Single Nucleotide Polymorphism (SNP) and haplotype association of three candidate genes of the three enzymes involved in this metabolism. The three genes, namely, tryptophan hydroxylase 2 (TPH2), kynurenine 3 monooxygenase (KMO) and kynurenine amino transferase 3 (KAT III) SNPs and haplotype association analysis was performed in 338 (266 major depression and 72 bipolar depression) unrelated Caucasian patients with major depressive episodes and 310 age, gender and ethnicity matched controls. In sliding window analyses using PLINK of the haplotypes of KAT III, all windows which include the first SNP (rs12729558), the overall haplotype distribution (OMNIBUS) was significantly different between patients with a major depressive episode and control for all windows, with p-values ranging between 1.75 × 10=5 and 0.006. This is due to the haplotype CGCTCT (referring to 6 SNP window analysis), which is found in about 5.7% of patients and 1.9% of healthy controls. It was due to CGCTCT haplotype and the frequencies of this haplotype in both bipolar patients and patients with major depression showed significantly higher than the control population (p<0.001). This haplotype of KAT III gene CGCTCT may have effect on the function of this enzyme in formation of kynurenic acid in some patients with major depressive episodes. PMID:21492941
Claes, Stephan; Myint, Aye-Mu; Domschke, Katharina; Del-Favero, Jurgen; Entrich, Kathrin; Engelborghs, Sebastiaan; De Deyn, Peter; Mueller, Norbert; Baune, Bernhard; Rothermundt, Matthias
The rs2476601-T allele at the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene has been consistently associated with several autoimmune diseases in European-derived populations. However, little is known about the allele and haplotype frequency distributions in PTPN22 among populations derived from other ethnic groups. In the present study, the allele and haplotype frequency distributions of six single nucleotide polymorphisms (SNPs) in the PTPN22 gene were compared among Brazilian populations and HapMap phase 3 dataset. A total of 10 different population samples were evaluated. Additionally, in admixed populations, individual genetic ancestries were estimated for Native American, African, and European contributions. Estimated individual ancestries were used as quantitative traits in a conditional approach for single-marker and haplotype-specific regression analyses. It was shown that several SNPs and haplotypes have different frequencies among different ethnic populations. Individual genetic ancestries were not associated with the rs2476601-T allele, but were associated with PTPN22 haplotypes in Brazilian, Mexican, and African-American admixed populations. Our results suggest caution in the interpretation of results found in association studies involving PTPN22 polymorphisms in admixed populations. Correction for stratification generated by admixture should be mandatory to minimize or avoid chances of spurious association. PMID:20166877
Lins, Tulio C; Vieira, Rodrigo G; Grattapaglia, Dario; Pereira, Rinaldo W
Theoretically, a haplotype has a higher level of heterozygosity than individual single nucleotide polymorphism (SNP) and the association study based on the haplotype may have an increased power for detecting disease associations compared with SNP-based analysis. In this study, we investigated the effects of four haplotype-tagging SNPs (htSNP) and the inferred haplotype pairs of the X-ray cross-complementing group 1 (XRCC1) gene on chromosome damage detected by the cytokinesis-block micronucleus assay. The study included 141 coke-oven workers with exposure to a high level of polycyclic aromatic hydrocarbons and 66 nonexposed controls. The frequencies of total MN and MNed cells were borderline associated with the Arg{sup 194}Trp polymorphism (P = 0.053 and P = 0.050, respectively) but not associated with the Arg{sup 280}His, Arg{sup 399}Gln and Gln{sup 632}Gln polymorphisms among coke-oven workers. Five haplotypes, including CGGG, TGGG, CAGG, CGAG, and CGGA, were inferred based on the four htSNPs of XRCC1 gene. The haplotype CGGG was associated with the decreased frequencies of total MN and MNed cells, and the haplotypes TGGG and CGAG were associated with the increased frequencies of total MN and MNed cells with adjustment for covariates among coke-oven workers. This study showed that the haplotypes derived from htSNPs in the XRCC1 gene were more likely than single SNPs to correlate with the polycyclic aromatic hydrocarbon-induced chromosome damage among coke-oven workers.
Shuguang Leng; Juan Cheng; Linyuan Zhang; Yong Niu; Yufei Dai; Zufei Pan; Bin Li; Fengsheng He; Yuxin Zheng [Chinese Center for Disease Control and Prevention, Beijing (China). National Institute of Occupational Health and Poison Control
[Genetic variation of SNP loci based on candidate gene for resistance to soybean cyst nematode].
For clarifying the difference of genetic diversity and linkage disequilibrium (LD) level between cultivated (Glycine max (L.) Merr.) and annual wild soybean (Glycine soja Sieb. & Zucc.), genetic variation pattern of 8 SNP loci developed from soybean cyst nematode resistance candidate genes rhg1 and Rhg4 in soybean germplasm were analyzed. The results indicated that G. max population, consisted of cultivated soybean mini-core collection and modern cultivars, had a higher LD levels (R2 value is 0.216) than G. soja population. Since 100% of pairwise loci within a gene and 16.6% of pairwise loci between genes were significant in G. max population, two specific LD regions were formed for each gene. A total of 46 haplotypes were detected in 363 soybean germplasm. The population of G. soja had less number of haplotypes and higher haplotype diversity than the population of G. max. Among the 31 population-specific haplotypes, 15 haplotypes were specific for G. soja population. In addition, the frequency of two major predominant haplotypes (Hap_10 and Hap_11) in G. soja population was obviously decreased in G. max population, which might indicate that some new haplotypes were formed and some old haplotypes were lost during the G. max domesticated from G. soja. PMID:20042394
Li, Ying-Hui; Yuan, Cui-Ping; Zhang, Chen; Li, Wei; Nan, Hai-Yang; Chang, Ru-Zhen; Qiu, Li-Juan
Haplotype uncertainty in association studies.
Inferring haplotypes from genotype data is commonly undertaken in population genetic association studies. Within such studies the importance of accounting for uncertainty in the inference of haplotypes is well recognised. We investigate the effectiveness of correcting for uncertainty using simple methods based on the output provided by the PHASE haplotype inference methodology. In case-control analyses investigating non-Hodgkin lymphoma and haplotypes associated with immune regulation we find little effect of making adjustment for uncertainty in inferred haplotypes. Using simulation we introduce a higher degree of haplotype uncertainty than was present in our study data. The simulation represents two genetic loci, physically close on a chromosome, forming haplotypes. Considering a range of allele frequencies, degrees of linkage between the loci, and frequency of missing genotype data, we detail the characteristics of genetic regions which may be susceptible to the influence of haplotype uncertainty. Within our evaluation we find that bias is avoided by considering haplotype probabilities or using multiple imputation, provided that for each of these methods haplotypes are inferred separately for case and control populations; furthermore using multiple imputation provides the facility to incorporate haplotype uncertainty in the estimation of confidence intervals. We discuss the implications of our findings within the context of the complexity of haplotype inference for larger marker rich regions as would typically be encountered in genetic analyses. PMID:17323369
Mensah, F K; Gilthorpe, M S; Davies, C F; Keen, L J; Adamson, P J; Roman, E; Morgan, G J; Bidwell, J L; Law, G R
Coding region SNP analysis to enhance dog mtDNA discrimination power in forensic casework.
The high population frequencies of three control region haplotypes contribute to the low discrimination power of the dog mtDNA control region. It also diminishes the evidential power of a match with one of these haplotypes in forensic casework. A mitochondrial genome study of 214 Belgian dogs suggested 26 polymorphic coding region sites that successfully resolved dogs with the three most frequent control region haplotypes. In this study, three SNP assays were developed to determine the identity of the 26 informative sites. The control region of 132 newly sampled dogs was sequenced and added to the study of 214 dogs. The assays were applied to 58 dogs of the haplotypes of interest, which confirmed their suitability for enhancing dog mtDNA discrimination power. In the Belgian population study of 346 dogs, the set of 26 sites divided the dogs into 25 clusters of mtGenome sequences with substantially lower population frequency estimates than their control region sequences. In case of a match with one of the three control region haplotypes, using these three SNP assays in conjunction with control region sequencing would augment the exclusion probability of dog mtDNA analysis from 92.9% to 97.0%. PMID:25299153
Verscheure, Sophie; Backeljau, Thierry; Desmyter, Stijn
Background The Y-chromosomal diversity in the African buffalo (Syncerus caffer) population of Kruger National Park (KNP) is characterized by rainfall-driven haplotype frequency shifts between year cohorts. Stable Y-chromosomal polymorphism is difficult to reconcile with haplotype frequency variations without assuming frequency-dependent selection or specific interactions in the population dynamics of X- and Y-chromosomal genes, since otherwise the fittest haplotype would inevitably sweep to fixation. Stable Y-chromosomal polymorphism due one of these factors only seems possible when there are Y-chromosomal distorters of an equal sex ratio, which act by negatively affecting X-gametes, or Y-chromosomal suppressors of a female-biased sex ratio. These sex-ratio (SR) genes modify (suppress) gamete transmission in their own favour at a fitness cost, allowing for stable polymorphism. Results Here we show temporal correlations between Y-chromosomal haplotype frequencies and foetal sex ratios in the KNP buffalo population, suggesting SR genes. Frequencies varied by a factor of five; too high to be alternatively explained by Y-chromosomal effects on pregnancy loss. Sex ratios were male-biased during wet and female-biased during dry periods (male proportion: 0.47-0.53), seasonally and annually. Both wet and dry periods were associated with a specific haplotype indicating a SR distorter and SR suppressor, respectively. Conclusions The distinctive properties suggested for explaining Y-chromosomal polymorphism in African buffalo may not be restricted to this species alone. SR genes may play a broader and largely overlooked role in mammalian sex-ratio variation. PMID:20416038
Genetic variation and haplotype structures of innate immunity genes in eastern India
This study reports results of an extensive and comprehensive study of genetic diversity in 12 genes of the innate immune system in a population of eastern India. Genomic variation was assayed in 171 individuals by resequencing ~75 kb of DNA comprising these genes in each individual. Almost half of the 548 DNA variants discovered was novel. DNA sequence comparisons with human and chimpanzee reference sequences revealed evolutionary features indicative of natural selection operating among individuals, who are residents of an area with a high load of microbial and other pathogens. Significant differences in allele and haplotype frequencies of the study population were observed with the HapMap populations. Gene and haplotype diversities were observed to be high. The genetic positioning of the study population among the HapMap populations based on data of the innate immunity genes substantially differed from what has been observed for Indian populations based on data of other genes. The reported range of variation in SNP density in the human genome is one SNP per 1.19 kb (chromosome 22) to one SNP per 2.18 kb (chromosome 19). The SNP density in innate immunity genes observed in this study (>3 SNPs kb?1) exceeds the highest density observed for any autosomal chromosome in the human genome. The extensive genomic variation and the distinct haplotype structure of innate immunity genes observed among individuals have possibly resulted from the impact of natural selection. PMID:18396467
Bairagya, Bijan B.; Bhattacharya, Paramita; Bhattacharya, Sujit K.; Dey, Biplab; Dey, Uposoma; Ghosh, Trina; Maiti, Sujit; Majumder, Partha P.; Mishra, Kankadeb; Mukherjee, Sinchita; Mukherjee, Souvik; Narayanasamy, K.; Poddar, Sonia; Roy, Neeta Sarkar; Sengupta, Priya; Sharma, Sangeeta; Sur, Dipika; Sutradhar, Debabrata; Wagener, Diane K.
MalHaploFreq: A computer programme for estimating malaria haplotype frequencies from blood samples
BACKGROUND: Molecular markers, particularly those associated with drug resistance, are important surveillance tools that can inform policy choice. People infected with falciparum malaria often contain several genetically-distinct clones of the parasite; genotyping the patients' blood reveals whether or not the marker is present (i.e. its prevalence), but does not reveal its frequency. For example a person with four malaria clones
Ian M Hastings; Thomas A Smith
Introduction: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. Methods: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. Results: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. Conclusion: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians. PMID:25035853
Umamaheswaran, Gurusamy; Dkhar, Steven Aibor; Kumar, Annan Sudarsan Arun; Srinivasa, Rao Katiboina; Kadambari, Dharanipragada; Adithan, Chandrasekaran
Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease. PMID:11078475
Bonnen, P E; Story, M D; Ashorn, C L; Buchholz, T A; Weil, M M; Nelson, D L
Copy number variation (CNV) has been reported to be associated with disease and various cancers. Hence, identifying the accurate position and the type of CNV is currently a critical issue. There are many tools targeting on detecting CNV regions, constructing haplotype phases on CNV regions, or estimating the numerical copy numbers. However, none of them can do all of the three tasks at the same time. This paper presents a method based on Hidden Markov Model to detect parent specific copy number change on both chromosomes with signals from SNP arrays. A haplotype tree is constructed with dynamic branch merging to model the transition of the copy number status of the two alleles assessed at each SNP locus. The emission models are constructed for the genotypes formed with the two haplotypes. The proposed method can provide the segmentation points of the CNV regions as well as the haplotype phasing for the allelic status on each chromosome. The estimated copy numbers are provided as fractional numbers, which can accommodate the somatic mutation in cancer specimens that usually consist of heterogeneous cell populations. The algorithm is evaluated on simulated data and the previously published regions of CNV of the 270 HapMap individuals. The results were compared with five popular methods: PennCNV, genoCN, COKGEN, QuantiSNP and cnvHap. The application on oral cancer samples demonstrates how the proposed method can facilitate clinical association studies. The proposed algorithm exhibits comparable sensitivity of the CNV regions to the best algorithm in our genome-wide study and demonstrates the highest detection rate in SNP dense regions. In addition, we provide better haplotype phasing accuracy than similar approaches. The clinical association carried out with our fractional estimate of copy numbers in the cancer samples provides better detection power than that with integer copy number states. PMID:24849202
Lin, Yen-Jen; Chen, Yu-Tin; Hsu, Shu-Ni; Peng, Chien-Hua; Tang, Chuan-Yi; Yen, Tzu-Chen; Hsieh, Wen-Ping
Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes
To dissect the haplotype structure of candidate genes for disease association studies, it is important to understand the nature of genetic variation at these loci in different populations. We present a survey of haplotype structure and linkage disequilibrium of chemokine and chemokine receptor genes in 11 geographically-distinct population samples (n = 728). Chemokine proteins are involved in intercellular signalling and the immune response. These molecules are important modulators of human immunodeficiency virus (HIV)-1 infection and the progression of the acquired immune deficiency syndrome, tumour development and the metastatic process of cancer. To study the extent of genetic variation in this gene family, single nucleotide polymorphisms (SNPs) from 13 chemokine and chemokine receptor genes were genotyped using the 5' nuclease assay (TaqMan). SNP haplotypes, estimated from unphased genotypes using the Expectation-Maximization-algorithm, are described in a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21, and a cluster of three CC-chemokine genes [MPIF-1 (CCL23) PARC (CCL18) and MIP- 1? (CCL3)] on chromosome 17q11-12. The 32 base pair (bp) deletion in exon 4 of CCR5 was also included in the haplotype analysis of 3p21. A total of 87.5 per cent of the variation of 14 biallelic loci scattered over 150 kilobases of 3p21 is explained by 11 haplotypes which have a frequency of at least 1 per cent in the total sample. An analysis of haplotype blocks in this region indicates recombination between CCR2 and CCR5, although long-range pairwise linkage disequilibrium across the region appears to remain intact on two common haplotypes. A reduced-median network demonstrates a clear relationship between 3p21 haplotypes, rooted by the putative ancestral haplotype determined by direct sequencing of four primate species. Analysis of six SNPs on 17q11-12 indicates that 97.5 per cent of the variation is explained by 15 haplotypes, representing at least 1 per cent of the total sample. Additionally, a possible signature of selection at a non-synonymous coding SNP (M106V) in the MPIF-1 (CCL23) gene warrants further study. We anticipate that the results of this study of chemokine and chemokine receptor variation will be applicable to more extensive surveys of long-range haplotype structure in these gene regions and to association studies of HIV-1 disease and cancer. PMID:15588486
Sickle cell anemia is a genetic disease with high prevalence in people of African descent. There are five typical haplotypes associated with this disease and the haplotypes associated with the beta-globin gene cluster have been used to establish the origin of African-descendant people in America. In this work, we determined the frequency and the origin of haplotypes associated with hemoglobin S in a sample of individuals with sickle cell anemia (HbSS) and sickle cell hemoglobin trait (HbAS) in coastal regions of Colombia. Blood samples from 71 HbAS and 79 HbSS individuals were obtained. Haplotypes were determined based on the presence of variable restriction sites within the ?-globin gene cluster. On the Pacific coast of Colombia the most frequent haplotype was Benin, while on the Atlantic coast Bantu was marginally higher than Benin. Eight atypical haplotypes were observed on both coasts, being more diverse in the Atlantic than in the Pacific region. These results suggest a differential settlement of the coasts, dependent on where slaves were brought from, either from the Gulf of Guinea or from Angola, where the haplotype distributions are similar. Atypical haplotypes probably originated from point mutations that lost or gained a restriction site and/or by recombination events. PMID:24385850
Fong, Cristian; Lizarralde-Iragorri, María Alejandra; Rojas-Gallardo, Diana; Barreto, Guillermo
Single Nucleotide Polymorphisms and Haplotypes in Native American Populations
Single Nucleotide Polymorphisms and Haplotypes in Native American Populations Judith R. Kidd,1 of California, San Diego, CA 92093 KEY WORDS Native Americans; SNP; haplotype; structure; PCA ABSTRACT Autosomal of and relationships among modern Native American populations. At the same time that autosomal markers can be highly
Kidd, Kenneth
Identifying haplotype block structure using an ancestor-derived model
Recently, haplotype-based association studies have become popular for detecting disease-related or drug-response-associated\\u000a genes. In these studies, it has been gradually recognized that a haplotype block structure is important. A rational and automatic\\u000a method for identifying the haplotype block structure from SNP data has been desired. We have developed a new method using\\u000a an ancestor-derived model and the minimum description length
Hironori Fujisawa; Minoru Isomura; Shinto Eguchi; Masaru Ushijima; Satoshi Miyata; Yoshio Miki; Masaaki Matsuura
The receptor for the homeostatic T cell cytokine interleukin-7 (IL-7R?) has recently shown genetic association to multiple sclerosis (MS). To investigate the functional contribution of IL-7R? polymorphisms to the pathogenesis of MS, we correlated the IL-7R? haplotypes with different T cell parameters in a group of MS patients and healthy controls. We show that carriers of one of the four
Bieke Broux; Niels Hellings; Koen Venken; Jean-Luc Rummens; Karen Hensen; Bart Van Wijmeersch; Piet Stinissen
Fast accurate missing SNP genotype local imputation
Background Single nucleotide polymorphism (SNP) genotyping assays normally give rise to certain percents of no-calls; the problem becomes severe when the target organisms, such as cattle, do not have a high resolution genomic sequence. Missing SNP genotypes, when related to target traits, would confound downstream data analyses such as genome-wide association studies (GWAS). Existing methods for recovering the missing values are successful to some extent – either accurate but not fast enough or fast but not accurate enough. Results To a target missing genotype, we take only the SNP loci within a genetic distance vicinity and only the samples within a similarity vicinity into our local imputation process. For missing genotype imputation, the comparative performance evaluations through extensive simulation studies using real human and cattle genotype datasets demonstrated that our nearest neighbor based local imputation method was one of the most efficient methods, and outperformed existing methods except the time-consuming fastPHASE; for missing haplotype allele imputation, the comparative performance evaluations using real mouse haplotype datasets demonstrated that our method was not only one of the most efficient methods, but also one of the most accurate methods. Conclusions Given that fastPHASE requires a long imputation time on medium to high density datasets, and that our nearest neighbor based local imputation method only performed slightly worse, yet better than all other methods, one might want to adopt our method as an alternative missing SNP genotype or missing haplotype allele imputation method. PMID:22863359
Private haplotypes can reveal local adaptation
Background Genome-wide scans for regions that demonstrate deviating patterns of genetic variation have become common approaches for finding genes targeted by selection. Several genomic patterns have been utilized for this purpose, including deviations in haplotype homozygosity, frequency spectra and genetic differentiation between populations. Results We describe a novel approach based on the Maximum Frequency of Private Haplotypes – MFPH – to search for signals of recent population-specific selection. The MFPH statistic is straightforward to compute for phased SNP- and sequence-data. Using both simulated and empirical data, we show that MFPH can be a powerful statistic to detect recent population-specific selection, that it performs at the same level as other commonly used summary statistics (e.g. FST, iHS and XP-EHH), and that MFPH in some cases capture signals of selection that are missed by other statistics. For instance, in the Maasai, MFPH reveals a strong signal of selection in a region where other investigated statistics fail to pick up a clear signal that contains the genes DOCK3, MAPKAPK3 and CISH. This region has been suggested to affect height in many populations based on phenotype-genotype association studies. It has specifically been suggested to be targeted by selection in Pygmy groups, which are on the opposite end of the human height spectrum compared to the Maasai. Conclusions From the analysis of both simulated and publicly available empirical data, we show that MFPH represents a summary statistic that can provide further insight concerning population-specific adaptation. PMID:24885734
Efficient haplotyping for families
Hapi is a novel dynamic programming algorithm for haplotyping nuclear families that outperforms contemporary family-based haplotyping algorithms. Haplotypes are useful for mapping and identifying genes which cause and ...
Williams, Amy Lynne, Ph.D. Massachusetts Institute of Technology
A haplotype inference method based on sparsely connected multi-body ising model
NASA Astrophysics Data System (ADS)
Statistical haplotype inference is an indispensable technique in the field of medical science. The method usually has two steps: inference of haplotype frequencies and inference of diplotype for each subject. The first step can be done by using the expectation-maximization (EM) algorithm, but it incurs an unreasonably large calculation cost when the number of single-nucleotide polymorphism (SNP) loci of concern is large. In this article, we describe an approximate probabilistic model of haplotype frequencies. The model is constructed by using several distributions of nearby local SNPs. This approximation seems good because SNPs are generally more strongly correlated when they are close to one another on a chromosome. To implement this approach, we use a log linear model, the Walsh-Hadamard transform, and a combinatorial optimization method. Artificial data suggested that the overall haplotype inference of our method is good if there are nine or more local consecutive SNPs. Some minor problems should be dealt with before this method can be applied to real data.
Kato, Masashi; Gao, Qian Ji; Chigira, Hiroshi; Shindo, Hiroyuki; Inoue, Masato
Understanding Y haplotype matching probability.
The Y haplotype population-genetic terrain is better explored from a fresh perspective rather than by analogy with the more familiar autosomal ideas. For haplotype matching probabilities, versus for autosomal matching probabilities, explicit attention to modelling - such as how evolution got us where we are - is much more important while consideration of population frequency is much less so. This paper explores, extends, and explains some of the concepts of "Fundamental problem of forensic mathematics - the evidential strength of a rare haplotype match". That earlier paper presented and validated a "kappa method" formula for the evidential strength when a suspect matches a previously unseen haplotype (such as a Y-haplotype) at the crime scene. Mathematical implications of the kappa method are intuitive and reasonable. Suspicions to the contrary raised in rest on elementary errors. Critical to deriving the kappa method or any sensible evidential calculation is understanding that thinking about haplotype population frequency is a red herring; the pivotal question is one of matching probability. But confusion between the two is unfortunately institutionalized in much of the forensic world. Examples make clear why (matching) probability is not (population) frequency and why uncertainty intervals on matching probabilities are merely confused thinking. Forensic matching calculations should be based on a model, on stipulated premises. The model inevitably only approximates reality, and any error in the results comes only from error in the model, the inexactness of the approximation. Sampling variation does not measure that inexactness and hence is not helpful in explaining evidence and is in fact an impediment. Alternative haplotype matching probability approaches that various authors have considered are reviewed. Some are based on no model and cannot be taken seriously. For the others, some evaluation of the models is discussed. Recent evidence supports the adequacy of the simple exchangability model on which the kappa method rests. However, to make progress toward forensic calculation of Y haplotype mixture evidence a different tack is needed. The "Laplace distribution" model of Andersen et al. [3] which estimates haplotype frequencies by identifying haplotype clusters in population data looks useful. PMID:24315614
Brenner, Charles H
The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3(+) NK cells. Further analysis showed that KIR2DL1(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3(+) NK cells. KIR2DL1-3(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-? and TNF-? production. These results identify a novel relationship between HLA-C and KIR2DL(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection. PMID:25043727
Körner, Christian; Granoff, Mitchell E; Amero, Molly A; Sirignano, Michael N; Vaidya, Sagar A; Jost, Stephanie; Allen, Todd M; Rosenberg, Eric S; Altfeld, Marcus
Variant alleles of the butyrylcholinesterase gene, BCHE, have often been used to trace the genetic histories of populations. The D70G substitution in BCHE causes prolonged postanesthesia apnea ({open_quotes}atypical{close_quotes} phenotype); H322N substitution in the closely related acetylcholinesterase gene, ACHE, is the basis of the mutually incompatible YT blood groups. In both genes, additional point mutations were reported to be linked to these phenotypically evident ones. To examine whether the intragenic linkage reported for the ACHE and BCHE mutations in Americans is universal, the authors studied frequencies of these mutations in trans-Caucasian Georgian Jews, a population that has remained relatively isolated for 1500 years. To this end they employed PCR amplification followed by DNA sequencing and enzymatic restriction and compared the frequencies found to corresponding reported phenotype data. Georgian Jews` N322 ACHE was a rather low 7.0% and was totally linked to a P446 mutation, in agreement with a recent report. In BCHE, however, G70 was a relatively high 5.8%, and the V497 and T539 mutations were not found, either in Georgian or in Ashkenazi Jews, in contrast to reported findings in Americans. The findings reveal distinct displays of ACHE and BCHE haplotypes in Georgian Jews and suggest different founder effects, genetic drifts, and/or selection pressures in the evolution of each of these genes. 29 refs., 3 figs., 2 tabs.
Ehrlich, G.; Ginzberg, D.; Loewenstein, Y. [Hebrew Univ., Jerusalem (Israel)] [and others] [Hebrew Univ., Jerusalem (Israel); and others
Association of CAPN10 SNPs and Haplotypes with Polycystic Ovary Syndrome among South Indian Women
Polycystic Ovary Syndrome (PCOS) is known to be characterized by metabolic disorder in which hyperinsulinemia and peripheral insulin resistance are central features. Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results. Our study is first of its kind to investigate the association pattern of CAPN10 polymorphisms (UCSNP-44, 43, 56, 19 and 63) with PCOS among Indian women. 250 PCOS cases and 299 controls from Southern India were recruited for this study. Allele and genotype frequencies of the SNPs were determined and compared between the cases and controls. Results show significant association of UCSNP-44 genotype CC with PCOS (p?=?0.007) with highly significant odds ratio when compared to TC (OR?=?2.51, p?=?0.003, 95% CI?=?1.37–4.61) as well as TT (OR?=?1.94, p?=?0.016, 95% CI?=?1.13–3.34). While the haplotype carrying the SNP-44 and SNP-19 variants (21121) exhibited a 2 fold increase in the risk for PCOS (OR?=?2.37, p?=?0.03), the haplotype containing SNP-56 and SNP-19 variants (11221) seems to have a protective role against PCOS (OR?=?0.20, p?=?0.004). Our results support the earlier evidence for a possible role of UCSNP-44 of the CAPN10 gene in the manifestation of PCOS. PMID:22384174
Dasgupta, Shilpi; Sirisha, Pisapati V. S.; Neelaveni, Kudugunti; Anuradha, Katragadda; Reddy, B. Mohan
We have previously demonstrated that haplotypes of three single nucleotide polymorphisms (SNPs) within the first intron of the OCA2 gene are extremely strongly associated with variation in human eye color. In the present work, we describe additional fine association mapping of eye color SNPs in the intergenic region upstream of OCA2 and within the neighboring HERC2 (hect domain and RLD2) gene. We screened an additional 92 SNPs in 300–3000 European individuals and found that a single SNP in intron 86 of HERC2, rs12913832, predicted eye color significantly better (ordinal logistic regression R2 = 0.68, association LOD = 444) than our previous best OCA2 haplotype. Comparison of sequence alignments of multiple species showed that this SNP lies in the center of a short highly conserved sequence and that the blue-eye-associated allele (frequency 78%) breaks up this conserved sequence, part of which forms a consensus binding site for the helicase-like transcription factor (HLTF). We were also able to demonstrate the OCA2 R419Q, rs1800407, coding SNP acts as a penetrance modifier of this new HERC2 SNP for eye color, and somewhat independently, of melanoma risk. We conclude that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, which we postulate to be the ultimate cause of blue eye color. PMID:18252222
Sturm, Richard A.; Duffy, David L.; Zhao, Zhen Zhen; Leite, Fabio P.N.; Stark, Mitchell S.; Hayward, Nicholas K.; Martin, Nicholas G.; Montgomery, Grant W.
We have previously demonstrated that haplotypes of three single nucleotide polymorphisms (SNPs) within the first intron of the OCA2 gene are extremely strongly associated with variation in human eye color. In the present work, we describe additional fine association mapping of eye color SNPs in the intergenic region upstream of OCA2 and within the neighboring HERC2 (hect domain and RLD2) gene. We screened an additional 92 SNPs in 300-3000 European individuals and found that a single SNP in intron 86 of HERC2, rs12913832, predicted eye color significantly better (ordinal logistic regression R(2) = 0.68, association LOD = 444) than our previous best OCA2 haplotype. Comparison of sequence alignments of multiple species showed that this SNP lies in the center of a short highly conserved sequence and that the blue-eye-associated allele (frequency 78%) breaks up this conserved sequence, part of which forms a consensus binding site for the helicase-like transcription factor (HLTF). We were also able to demonstrate the OCA2 R419Q, rs1800407, coding SNP acts as a penetrance modifier of this new HERC2 SNP for eye color, and somewhat independently, of melanoma risk. We conclude that the conserved region around rs12913832 represents a regulatory region controlling constitutive expression of OCA2 and that the C allele at rs12913832 leads to decreased expression of OCA2, particularly within iris melanocytes, which we postulate to be the ultimate cause of blue eye color. PMID:18252222
Sturm, Richard A; Duffy, David L; Zhao, Zhen Zhen; Leite, Fabio P N; Stark, Mitchell S; Hayward, Nicholas K; Martin, Nicholas G; Montgomery, Grant W
Because Korean society is fast becoming multi-ethnic, the determination of ambiguous human leukocyte antigen (HLA) types using HLA allele frequencies is becoming less applicable. In this study, we focused on the development of new technical methods to directly resolve the ambiguities arising from HLA genotyping. One hundred and fifty unrelated healthy Korean adults were included in this study. All alleles from each HLA locus were first divided into 2-4 groups, with each group amplified in a single PCR tube (multi-group-specific amplification, MGSA). To resolve phase ambiguities, some allele groups were also amplified separately in small group-specific amplification (SGSA) tubes. In order to then resolve incomplete sequence ambiguities, primers for MGSA and SGSA were initially designed to cover additional exons. If needed, a heterozygous ambiguity resolving primer (HARP) or sequence specific primer (SSP) was also used. When MGSA and SGSA methods were applied, the rate of phase ambiguity was greatly reduced to an average of 6% (1.3% in HLA-A, 15.7% in -B, and 2.0% in -C). Additional HARP and SSP methods could resolve all the phase ambiguities. Using our proposed method, we also detected three alleles that have not been previously reported in Korea, C*04:82, C*07:18, and C*08:22, and report 6-digit level HLA allele and haplotype frequencies among Koreans. In conclusion, the use of MGSA/SGSA for the initial amplification step is a cost-effective method facilitating timely and accurate reporting, given the continuing increase in the ethnic diversity of the Korean population. The MGSA described here can be applicable to various populations and thus could be shared by the majority of HLA typing laboratories. However, efforts to solve HLA ambiguity should continue, because SGSA, HARPs and SSPs would be specific to a particular population. PMID:24851935
Jun, J-H; Hwang, K; Kim, S-K; Oh, H-B; Cho, M-C; Lee, K-J
Missing SNP Genotype Imputation.
??High-throughput single nucleotide polymorphism (SNP) genotyping technologies conveniently produce large SNP genotype datasets for genome-wide linkage and association studies. Various factors, from array design and… (more)
Wang, Yining
HLA class-I and class-II allele frequencies and two-locus haplotypes were examined in 367 unrelated Melanesians living on the islands of Vanuatu and New Caledonia. Diversity at all HLA class-I and class-II loci was relatively limited. In class-I loci, three HLA-A allelic groups (HLA-A*24, HLA-A*34 and HLA-A*11), seven HLA-B alleles or allelic groups (HLA-B*1506, HLA-B*5602, HLA-B*13, HLA-B*5601, HLA-B*4001, HLA-B*4002 and HLA-B*2704) and four HLA-C alleles or allelic groups (HLA-Cw*04, HLA-Cw*01, HLA-Cw*0702 and HLA-Cw*15) constituted more than 90% of the alleles observed. In the class-II loci, four HLA-DRB1 alleles (HLA-DRB1*15, HLA-DRB1*11, HLA-DRB1*04 and HLA-DRB1*16), three HLA-DRB3-5 alleles (HLA-DRB3*02, HLA-DRB4*01 and HLA-DRB5*01/02) and five HLA-DQB1 alleles (HLA-DQB1*0301, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*0601 and HLA-DQB1*0602) constituted over 93, 97 and 98% of the alleles observed, respectively. Homozygosity showed significant departures from expected levels for neutrality based on allele frequency (i.e. excess diversity) at the HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB3/5 loci on some islands. The locus with the strongest departure from neutrality was HLA-DQB1, homozygosity being significantly lower than expected on all islands except New Caledonia. No consistent pattern was demonstrated for any HLA locus in relation to malaria endemicity. PMID:15546341
Maitland, K; Bunce, M; Harding, R M; Barnardo, M C N M; Clegg, J B; Welsh, K; Bowden, D K; Williams, T N
Order of precedence and age of Y-DNA haplotypes
A simple method, inspired by procedures used in physics of nuclear multifragmentation, allows to establish order of precedence and age of pairs of haplotypes separated by one mutation. For both haplotypes of the pair, searches for existing haplotypes, differing by increasing number of mutations, are carried out using a database. The resulting ratios of frequences of haplotypes, found at given mutation distances, are compared to calculated probability ratios. The order of precedence and age of the pair of haplotypes can be deduced when the resulting ratios follow hyperbolic dependence. Method can be used with relatively small and not necessarily complete samples, using publicly accessible databases.
Martin Veselsky
Bovine mastitis is a very complex and common disease of dairy cattle and a major source of economic losses to the dairy industry worldwide. In this study, the bovine TLR4 was taken as a candidate gene for mastitis resistance. This study aimed to analyze the associations of single nucleotide polymorphisms (SNP) or haplotype and somatic cell score (SCS) in 404 Chinese commercial dairy cattle including Chinese Holstein, Sanhe cattle and Chinese Simmental breeds. The polymerase chain reaction and sequencing methods were used for detecting genotype and allele frequency distribution of the two SNPs (rs8193062, rs8193064), statistical results showed that T allele at rs8193062 and C allele at rs8193064 were the predominate alleles. Moreover, six SNPs, including two SNPs (rs8193062, rs8193064) and four SNPs (rs8193060, rs8193069, rs29017188, rs8193046) which were chosen according the polymorphism level for the same cattle populations in previous studies, were used for haplotype analysis, the results revealed that twenty-one haplotypes were found in the mentioned animals, of which, Hap1 (30.5 %) and Hap2 (30.4 %) were the most common haplotypes. Hap2, Hap4 and Hap12 might negatively effect on milk SCS, whereas Hap13 might positively effect on milk SCS. The results in this study might assist in marker assisted selection and provided some reference to be implemented in breeding programs to improve the mastitis resistance of dairy cattle. PMID:24415303
Wang, Xing Ping; Luoreng, Zhuo Ma; Gao, Shu Xin; Guo, Dong Sheng; Li, Jun Ya; Gao, Xue; Xu, Shang Zhong; Li, Feng; Chen, Gang; Wang, Jin Ren
To assist cattle producers transition from microsatellite (MS) to single nucleotide polymorphism (SNP) genotyping for parental verification we previously devised an effective and inexpensive method to impute MS alleles from SNP haplotypes. While the reported method was verified with only a limited data set (N = 479) from Brown Swiss, Guernsey, Holstein, and Jersey cattle, some of the MS-SNP haplotype associations were concordant across these phylogenetically diverse breeds. This implied that some haplotypes predate modern breed formation and remain in strong linkage disequilibrium. To expand the utility of MS allele imputation across breeds, MS and SNP data from more than 8000 animals representing 39 breeds (Bos taurus and B. indicus) were used to predict 9410 SNP haplotypes, incorporating an average of 73 SNPs per haplotype, for which alleles from 12 MS markers could be accurately be imputed. Approximately 25% of the MS-SNP haplotypes were present in multiple breeds (N = 2 to 36 breeds). These shared haplotypes allowed for MS imputation in breeds that were not represented in the reference population with only a small increase in Mendelian inheritance inconsistancies. Our reported reference haplotypes can be used for any cattle breed and the reported methods can be applied to any species to aid the transition from MS to SNP genetic markers. While ~91% of the animals with imputed alleles for 12 MS markers had ?1 Mendelian inheritance conflicts with their parents' reported MS genotypes, this figure was 96% for our reference animals, indicating potential errors in the reported MS genotypes. The workflow we suggest autocorrects for genotyping errors and rare haplotypes, by MS genotyping animals whose imputed MS alleles fail parentage verification, and then incorporating those animals into the reference dataset. PMID:24065982
McClure, Matthew C.; Sonstegard, Tad S.; Wiggans, George R.; Van Eenennaam, Alison L.; Weber, Kristina L.; Penedo, Cecilia T.; Berry, Donagh P.; Flynn, John; Garcia, Jose F.; Carmo, Adriana S.; Regitano, Luciana C. A.; Albuquerque, Milla; Silva, Marcos V. G. B.; Machado, Marco A.; Coffey, Mike; Moore, Kirsty; Boscher, Marie-Yvonne; Genestout, Lucie; Mazza, Raffaele; Taylor, Jeremy F.; Schnabel, Robert D.; Simpson, Barry; Marques, Elisa; McEwan, John C.; Cromie, Andrew; Coutinho, Luiz L.; Kuehn, Larry A.; Keele, John W.; Piper, Emily K.; Cook, Jim; Williams, Robert; Van Tassell, Curtis P.
For most complex diseases, the fraction of heritability that can be explained by the variants discovered from genome-wide association studies is minor. Although the so-called 'rare variants' (minor allele frequency [MAF] < 1%) have attracted increasing attention, they are unlikely to account for much of the 'missing heritability' because very few people may carry these rare variants. The genetic variants that are likely to fill in the 'missing heritability' include uncommon causal variants (MAF < 5%), which are generally untyped in association studies using tagging single-nucleotide polymorphisms (SNPs) or commercial SNP arrays. Developing powerful statistical methods can help to identify chromosomal regions harboring uncommon causal variants, while bypassing the genome-wide or exome-wide next-generation sequencing. In this work, we propose a haplotype kernel association test (HKAT) that is equivalent to testing the variance component of random effects for distinct haplotypes. With an appropriate weighting scheme given to haplotypes, we can further enhance the ability of HKAT to detect uncommon causal variants. With scenarios simulated according to the population genetics theory, HKAT is shown to be a powerful method for detecting chromosomal regions harboring uncommon causal variants. PMID:23740760
Lin, Wan-Yu; Yi, Nengjun; Lou, Xiang-Yang; Zhi, Degui; Zhang, Kui; Gao, Guimin; Tiwari, Hemant K.; Liu, Nianjun
Model, properties and imputation method of missing SNP genotype data utilizing mutual information
NASA Astrophysics Data System (ADS)
Mutual information can be used as a measure for the association of a genetic marker or a combination of markers with the phenotype. In this paper, we study the imputation of missing genotype data. We first utilize joint mutual information to compute the dependence between SNP sites, then construct a mathematical model in order to find the two SNP sites having maximal dependence with missing SNP sites, and further study the properties of this model. Finally, an extension method to haplotype-based imputation is proposed to impute the missing values in genotype data. To verify our method, extensive experiments have been performed, and numerical results show that our method is superior to haplotype-based imputation methods. At the same time, numerical results also prove joint mutual information can better measure the dependence between SNP sites. According to experimental results, we also conclude that the dependence between the adjacent SNP sites is not necessarily strongest.
Wang, Ying; Wan, Weiming; Wang, Rui-Sheng; Feng, Enmin
SKM-SNP: SNP markers detection method , Mark Li a
SKM-SNP: SNP markers detection method Yang Liu a , Mark Li a , Yiu M. Cheung b , Pak C. Sham c online 17 November 2009 Keywords: Single nucleotide polymorphism Subspace clustering SKM-SNP K-mode a b s t r a c t SKM-SNP, SNP markers detection program, is proposed to identify a set of relevant SNPs
Cheung, Yiu-ming
General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have a natural origin. PMID:22956910
Staubach, Fabian; Lorenc, Anna; Messer, Philipp W.; Tang, Kun; Petrov, Dmitri A.; Tautz, Diethard
We analyzed mitochondrial DNA haplotypes from 144 samples of islanders of the Taquile and Amantani (Quechua speakers) and Los Uros and Anapia (Aymara speakers) of the Lake Titicaca, Peru. We have found the highest frequency of B1 mtDNA haplotype ever reported: 100% in Taquile (n= 57); 88,6% in Amantani (n= 35); 87,5% in Anapia (n= 24) and 75% in Los
José Sandoval; Bedsabé Delgado; Luis Rivas; Bertha Bonilla; Daniel Nugent; Ricardo Fujita
There have been increasing efforts to relate drug efficacy and disease predisposition with genetic polymorphisms. We present statistical tests for association of haplotype frequencies with discrete and continuous traits in samples of unrelated individuals. Haplotype frequencies are estimated through the expectation-maximization algorithm, and each individual in the sample is expanded into all possible haplotype configurations with corresponding probabilities, conditional on
Dmitri V. Zaykin; Peter H. Westfall; S. Stanley Young; Maha A. Karnoub; Michael J. Wagner; Margaret G. Ehm
The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters. PMID:16702730
Maekawa, Keiko; Itoda, Masaya; Sai, Kimie; Saito, Yoshiro; Kaniwa, Nahoko; Shirao, Kuniaki; Hamaguchi, Tetsuya; Kunitoh, Hideo; Yamamoto, Noboru; Tamura, Tomohide; Minami, Hironobu; Kubota, Kaoru; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Kamatani, Naoyuki; Ozawa, Shogo; Sawada, Jun-ichi
The effect of using genealogy-based haplotypes for genomic prediction
Background Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (?) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. Results About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter ? when fitting haplotypes compared to fitting markers. Conclusions Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy. PMID:23496971
RFLP haplotypes at the {alpha}-globin gene complex have been examined in 190 individuals from the Niokolo Mandenka population of Senegal: haplotypes were assigned unambiguously for 210 chromosomes. The Mandenka share with other African populations a sample size-independent haplotype diversity that is much greater than that in any non-African population: the number of haplotypes observed in the Mandenka is typically twice that seen in the non-African populations sampled to date. Of these haplotypes, 17.3% had not been observed in any previous surveys, and a further 19.1% have previously been reported only in African populations. The haplotype distribution shows clear differences between African and non-African peoples, but this is on the basis of population-specific haplotypes combined with haplotypes common to all. The relationship of the newly reported haplotypes to those previously recorded suggests that several mutation processes, particularly recombination as homologous exchange or gene conversion, have been involved in their production. A computer program based on the expectation-maximization (EM) algorithm was used to obtain maximum-likelihood estimates of haplotype frequencies for the entire data set: good concordance between the unambiguous and EM-derived sets was seen for the overall haplotype frequencies. Some of the low-frequency haplotypes reported by the estimation algorithm differ greatly, in structure, from those haplotypes known to be present in human populations, and they may not represent haplotypes actually present in the sample. 43 refs., 4 figs., 4 tabs.
Martinson, J.J.; Swinburn, C.; Clegg, J.B. [and others
Haplotype and allele frequencies for eight Y-STRs were determined in a population sample of Old Believers residing in the Northeastern Poland. A total of 127 unrelated males produced 100 different haplotypes. The most common haplotype was shared by 3.97% of the sample, while 85 haplotypes were unique. The gene diversity was 0.99. PMID:15177632
Pepinski, Witold; Niemcunowicz-Janica, Anna; Skawronska, Malgorzata; Koc-Zorawska, Ewa; Janica, Jerzy; Soltyszewski, Ireneusz
Haplotype and allele frequencies for eight Y-STRs were determined in a population sample of Old Believers residing in the Northeastern Poland. A total of 127 unrelated males produced 100 different haplotypes. The most common haplotype was shared by 3.97% of the sample, while 85 haplotypes were unique. The gene diversity was 0.99.
Witold Pepinski; Anna Niemcunowicz-Janica; Malgorzata Skawronska; Ewa Koc-Zorawska; Jerzy Janica; Ireneusz Soltyszewski
Tumor necrosis factor haplotype diversity in Mestizo and native populations of Mexico.
The so-called tumor necrosis factor (TNF) block includes the TNFA, lymphotoxin alpha and beta (LTA and LTB) genes with single-nucleotide polymorphisms (SNP) and microsatellites with an allele frequency that exhibits interpopulation variability. To date, no reports have included both SNPs and microsatellites at the TNF block to study Mestizo or Amerindian populations from Mexico. In this study, samples of five Mexican Mestizo populations (Durango, Guadalajara, Monterrey, Puebla, and Tierra Blanca) and four native-Mexican populations (North Lacandonians, South Lacandonians, Tepehuanos, and Yaquis) were genotyped for two SNPs (LTA+252A>G and TNFA-308G>A) and four microsatellites (TNFa, d, e, and f), to analyze the genetic substructure of the Mexican population. Allele and haplotype frequencies, linkage disequilibrium (LD), and interpopulation genetic relationships were calculated. There was significant LD along almost all of the TNF block but the lowest D' values were observed for the TNFf-TNFd pair. Mestizos showed higher allele and haplotype diversity than did natives. The genetic differentiation level was reduced among Mestizos; however, a slightly, but significant genetic substructure was observed between northern and southern Mexican Mestizos. Among the Amerindian populations, the genetic differentiation level was significantly elevated, particularly in both North and South Lacandonians. Furthermore, among Southern Lacandonians, inhabitants of Lacanja town were the most differentiated from all the Mexicans analyzed. The data presented here will serve as a reference for further population and epidemiological studies including these TNF polymorphisms in the Mexican population. PMID:24517517
Castro-Martínez, X H; Leal-Cortés, C; Flores-Martínez, S E; García-Zapién, A G; Sánchez-Corona, J; Portilla-de Buen, E; Gómez-Espinel, I; Zamora-Ginez, I; Pérez-Fuentes, R; Islas-Andrade, S; Revilla-Monsalve, C; Guerrero-Romero, F; Rodríguez-Morán, M; Mendoza-Carrera, F
iHAP - integrated haplotype analysis pipeline for characterizing the haplotype structure of genes
Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at , provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies. PMID:17137522
Song, Chun Meng; Yeo, Boon Huat; Tantoso, Erwin; Yang, Yuchen; Lim, Yun Ping; Li, Kuo-Bin; Rajagopal, Gunaretnam
Motivated by the increasing availability of high-density single nucleotide polymorphism (SNP) markers across the genome, various haplotype-based methods have been developed for candidate gene association studies, and even for genome-wide association studies. Although haplotype approaches dramatically reduce the multiple comparisons problem (as compared to single SNP analysis), even the number of existing haplotypes is relatively large, which increases the degrees of freedom and decreases the power for the corresponding test statistic. Grouping haplotypes is a way to reduce the degrees of freedom. We propose a procedure that uses a tree-based recursive partitioning algorithm to group haplotypes into a small number of clusters, and conducts the association test based on groups of haplotypes instead of individual haplotypes. The method can be used for both population-based and family-based association studies, with known or ambiguous phase information. Simulation studies suggest that the proposed method has the right type I error rate, and is more powerful than some existing haplotype-based tests. PMID:16138916
Yu, Kai; Xu, Jun; Rao, D C; Province, Michael
Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA-SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T), two missense mutations K80R (ADA c239A>G) and R142Q (ADA c425G>A), and a TAAA repeat located at the 3' end of an Alu element (AluVpA) positioned 1.1 kb upstream of the ADA transcription start site. All patients were homozygous for the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7. Among 207 Somali immigrants to Denmark, the frequency of ADA c7C>T and the maximum likelihood estimate of the frequency of the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7 were both 0.012 (carrier frequency 2.4%). Based on the analysis of AluVpA alleles, the ADA c7C/T mutation was estimated to be approximately 7,100 years old. Approximately 1 out of 5 - 10000 Somali children will be born with ADA deficiency due to an ADA c7C/T mutation, although within certain clans the frequency may be significantly higher. ADA-SCID may be a frequent immunodeficiency disorder in Somalia, but will be underdiagnosed due to the prevailing socioeconomic and nutritional deprivation. PMID:17181544
Sanchez, Juan J; Monaghan, Gemma; Břrsting, Claus; Norbury, Gail; Morling, Niels; Gaspar, H Bobby
Two variants in the equine myostatin gene (MSTN), including a T/C SNP in the first intron and a 227-bp SINE insertion in the promoter, are associated with muscle fiber type proportions in the Quarter Horse (QH) and with the prediction of race distance propensity in the Thoroughbred (TB). Genotypes from these loci, along with 18 additional variants surrounding MSTN, were examined in 301 horses of 14 breeds to evaluate haplotype relationships and diversity. The C allele of intron 1 was found in 12 of 14 breeds at a frequency of 0.27; the SINE was observed in five breeds, but common in only the TB and QH (0.73 and 0.48 respectively). Haplotype data suggest the SINE insertion is contemporary to and arose upon a haplotype containing the intron 1 C allele. Gluteal muscle biopsies of TBs showed a significant association of the intron 1 C allele and SINE with a higher proportion of Type 2B and lower proportion of Type 1 fibers. However, in the Belgian horse, in which the SINE is not present, the intron 1 SNP was not associated with fiber type proportions, and evaluation of fiber type proportions across the Belgian, TB and QH breeds shows the significant effect of breed on fiber type proportions is negated when evaluating horses without the SINE variant. These data suggest the SINE, rather than the intron 1 SNP, is driving the observed muscle fiber type characteristics and is the variant targeted by selection for short-distance racing. PMID:25160752
Petersen, Jessica L; Valberg, Stephanie J; Mickelson, James R; McCue, Molly E
The class III complement components, C4, C2 and factor B (BF), are encoded in the human major histocompatibility complex (MHC). The two genes determining C4 (C4A and C4B) display considerable polymorphism and, thus, are important markers for HLA. In combination with alleles of C2 and BF they can be grouped into unique complotypes. We have analyzed the C4 alleles in a panel of 204 unrelated German Caucasians and studied their segregation with HLA haplotypes in 24 normal families. Inclusion of the class III markers with the class I and II alleles provides a more refined picture of the genetic structure of the MHC in these families. When charted according to the HLA-B locus specificities the MHCs can be clustered into groups showing distinctly homogenous or heterogenous complotypes. The identification of such groups is valuable for the selection of genetic material to analyze the molecular genetics of the human MHC. PMID:6589207
Schendel, D J; O'Neill, G J; Wank, R
RET Variants and Haplotype Analysis in a Cohort of Czech Patients with Hirschsprung Disease
Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of RET proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic RET variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire RET proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR. PMID:24897126
Vaclavikova, Eliska; Dvorakova, Sarka; Skaba, Richard; Pos, Lucie; Sykorova, Vlasta; Halkova, Tereza; Vcelak, Josef; Bendlova, Bela
RET variants and haplotype analysis in a cohort of Czech patients with Hirschsprung disease.
Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses in variable length of the intestine. This study investigated the influence and a possible modifying function of RET proto-oncogene's single nucleotide polymorphisms (SNPs) and haplotypes in the development and phenotype of the disease in Czech patients. Genotyping of 14 SNPs was performed using TaqMan Genotyping Assays and direct sequencing. The frequencies of SNPs and generated haplotypes were statistically evaluated using chi-square test and the association with the risk of HSCR was estimated by odds ratio. SNP analysis revealed significant differences in frequencies of 11 polymorphic RET variants between 162 HSCR patients and 205 unaffected controls. Particularly variant alleles of rs1864410, rs2435357, rs2506004 (intron 1), rs1800858 (exon 2), rs1800861 (exon 13), and rs2565200 (intron 19) were strongly associated with increased risk of HSCR (p<0.00000) and were over-represented in males vs. females. Conversely, variant alleles of rs1800860, rs1799939 and rs1800863 (exons 7, 11, 15) had a protective role. The haploblock comprising variants in intron 1 and exon 2 was constructed. It represented a high risk of HSCR, however, the influence of other variants was also found after pruning from effect of this haploblock. Clustering patients according to genotype status in haploblock revealed a strong co-segregation with several SNPs and pointed out the differences between long and short form of HSCR. This study involved a large number of SNPs along the entire RET proto-oncogene with demonstration of their risk/protective role also in haplotype and diplotype analysis in the Czech population. The influence of some variant alleles on the aggressiveness of the disease and their role in gender manifestation differences was found. These data contribute to worldwide knowledge of the genetics of HSCR. PMID:24897126
Vaclavikova, Eliska; Dvorakova, Sarka; Skaba, Richard; Pos, Lucie; Sykorova, Vlasta; Halkova, Tereza; Vcelak, Josef; Bendlova, Bela
Analysis of DAZL SNP260 and SNP386 in infertile Chinese males using multi-analyte suspension array.
The aim of the present study was to investigate the association between two single nucleotide polymorphisms (SNPs) and infertility in Chinese males using multi-analyte suspension array (MASA). A total of 196 male patients with azoospermia or severe oligospermia (sperm density <5x106/ml, non?obstructed) who had a normal karyotype and no azoospermia factor microdeletions were recruited, along with 40 healthy, fertile males as controls. Two SNPs of the deleted in azoospermia-like (DAZL) gene, SNP260 and SNP386, were genotyped by allele?specific primer extension (ASPE) combined with MASA technology. The SNP260A>G and SNP386A>G mutations were found in the males with infertility. The SNP260, but not the SNP386, mutation was detectable in the control group. The mutation rates in the controls and patients were 2.5 and 3.06% for SNP260, and 0 and 2.04% for SNP386, respectively. A ?2 analysis did not identify any significant differences in the frequency of either mutation between the fertile and infertile males. In conclusion, the combination of ASPE and MASA methods for SNP genotyping was high?throughput, accurate and cost?efficient. The method was applied to detect SNP polymorphisms in the DAZL gene; and neither the A260G nor the A386G polymorphism of DAZL appeared to be involved in male infertility in the Chinese population. PMID:25323654
Zhu, Yijian; Ma, Mingfu; Wan, Ling; Zhang, Danyan; Zhao, Letian; Wei, Li; Li, Lianbing
Bicuspid Aortic Valve (BAV) is a highly heritable congenital heart defect. The low frequency of BAV (1% of general population) limits our ability to perform genome-wide association studies. We present the application of four a priori SNP selection techniques, reducing the multiple-testing penalty by restricting analysis to SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV probands and 830 control subjects. Two knowledge-based approaches, CANDID and STRING, were used to systematically identify BAV genes, and their SNPs, from the published literature, microarray expression studies and a genome scan. We additionally tested Functionally Interpolating SNPs (fitSNPs) present on the array; the fourth consisted of SNPs selected by Random Forests, a machine learning approach. These approaches reduced the multiple testing penalty by lowering the fraction of the genome probed to 0.19% of the total, while increasing the likelihood of studying SNPs within relevant BAV genes and pathways. Three loci were identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926×10?06) and a haplotype within the Endoglin gene (p-value of 5.881×10?04) were found to be strongly associated with BAV. The Random Forests approach identified a SNP on chromosome 3 in association with BAV (p-value 5.061×10?06). The results presented here support an important role for genetic variants in BAV and provide support for additional studies in well-powered cohorts. Further, these studies demonstrate that leveraging existing expression and genomic data in the context of GWAS studies can identify biologically relevant genes and pathways associated with a congenital heart defect. PMID:20098615
Wooten, Eric C.; Iyer, Lakshmanan K.; Montefusco, Maria Claudia; Hedgepeth, Alyson Kelley; Payne, Douglas D.; Kapur, Navin K.; Housman, David E.; Mendelsohn, Michael E.; Huggins, Gordon S.
Haplotype of single nucleotide polymorphisms in exon 6 of the MZF-1 gene and Alzheimer's disease.
Our previous works showed that single nucleotide polymorphisms (SNPs) in genes with regulatory function upon inflammatory response and cholesterol metabolism were associated with Alzheimer's disease (AD) risk. The list comprises SNPs located on the promoters of alpha 1 antichymotrypsin (rs1884082), hydroxy methyl glutaryl coenzime A reductase (rs376140), tumor necrosis factor alpha (rs1800629), and interleukin 10 (rs1800869). Here we investigated the effect of these SNPs on the binding for transcription factors. We computationally detected putative binding sites for transcription factors located in the SNP regions. To this aim, the TESS program for scanning the promoter sequences against the binding-site models available at TRANSFACT and JASPAR databases was adopted. All the analyzed SNPs appeared to affect the binding of myeloid zinc finger protein 1 (MZF-1) to the promoter sequence of the above reported genes. Therefore 16 SNPs in MZF-1 gene were tested in 120 AD cases and 88 controls to asses a possible association between MZF-1 and AD. 14 SNPs showed no variability in AD and control populations, while two SNPs rs4756 and rs2228162 showed the three genotypes. Genotype distributions and allele frequencies of these two SNPs were comparable between AD and controls. On the other hand, the haplotype distribution of rs4756 and rs2228162 was different between AD and controls; being the AG haplotype associated with a decreased AD risk. In conclusion, selected SNPs in MZF-1 gene exert a minor effect on AD risk. PMID:23241556
Porcellini, Elisa; Carbone, Ilaria; Martelli, Pier Luigi; Ianni, Manuela; Casadio, Rita; Pession, Annalisa; Licastro, Federico
Identification and genetic effect of haplotype in the bovine BMP7 gene.
Bone morphogenetic proteins (BMPs) are peptide growth factors belonging to the transforming growth factor-beta (TGF-?) superfamily, and some members of the BMP family support white adipocyte differentiation. In this study, we focused on the BMP7 which singularly promotes the differentiation of brown preadipocytes. Haplotypes involving 5 single nucleotide polymorphism (SNP) sites in the bovine BMP7 gene were identified and their effect on body weight was analyzed. 16 haplotypes and 18 combined haplotypes were revealed and the linkage disequilibrium was assessed in the cattle population with 602 individuals representing three main cattle breeds from China. The results showed that haplotypes 3, 10 and 14 were predominant and accounted for 75.64%, 69.85%, and 83.36% in Nanyang, Qinchuan and Jiaxian cattle breeds, respectively. The statistical analyses indicated that the SNP 1, 4, and 5 are associated with the body weight, body length, and heart girth at 12 and 24 months in Nanyang cattle population (P<0.05), whereas there is no significant association between their 16 haplotypes and 18 combined haplotypes. Our results provide evidence that some SNPs and haplotypes in BMP7 are associated with growth traits, and may be utilized as a genetic marker in marker-assisted selection for beef cattle breeding programs. PMID:23500594
Huang, Yong-Zhen; Wang, Xin-Lei; He, Hua; Lan, Xian-Yong; Lei, Chu-Zhao; Zhang, Chun-Lei; Chen, Hong
SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients.
Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4- (AQP4-) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4+ against AQP4- patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4- MS, which excluded DRB1*15:01. This study is the largest study of the HLA's contribution to MS in Japanese individuals. PMID:21654846
McElroy, J P; Isobe, N; Gourraud, P A; Caillier, S J; Matsushita, T; Kohriyama, T; Miyamoto, K; Nakatsuji, Y; Miki, T; Hauser, S L; Oksenberg, J R; Kira, J
Combinatorial Analysis of Disease Association and Susceptibility for Rheumatoid Arthritis SNP Data
Combinatorial Analysis of Disease Association and Susceptibility for Rheumatoid Arthritis SNP Data, GA 30303 E-mail: {dima, firstname.lastname@example.com 1 Introduction In this paper we analyze the SNP data (GAW, 4]. Disease association analysis searches for a SNP with frequency among diseased individuals (cases
Zelikovsky, Alexander
Socioaffective Neuroscience & Psychology (SNP)
Socioaffective Neuroscience & Psychology (SNP) I t is an exciting challenge for us to launch a new interdisciplinary journal, Socioaffective Neuroscience & Psychology. We believe the journal will appeal to a wide advances have shed new light on psychological and neural processes. For example, in the area
Paris-Sud XI, Université de
Haplotypes are an important concept for genetic association studies, but involve uncertainty due to statistical reconstruction from single nucleotide polymorphism (SNP) genotypes and genotype error. We developed a re-sampling approach to quantify haplotype misclassification probabilities and implemented the MC-SIMEX approach to tackle this as a 3 x 3 misclassification problem. Using a previously published approach as a benchmark for comparison, we evaluated the performance of our approach by simulations and exemplified it on real data from 15 SNPs of the APM1 gene. Misclassification due to reconstruction error was small for most, but notable for some, especially rarer haplotypes. Genotype error added misclassification to all haplotypes resulting in a non-negligible drop in sensitivity. In our real data example, the bias of association estimates due to reconstruction error alone reached -48.2% for a 1% genotype error, indicating that haplotype misclassification should not be ignored if high genotype error can be expected. Our 3 x 3 misclassification view of haplotype error adds a novel perspective to currently used methods based on genotype intensities and expected number of haplotype copies. Our findings give a sense of the impact of haplotype error under realistic scenarios and underscore the importance of high-quality genotyping, in which case the bias in haplotype association estimates is negligible. PMID:20649529
Lamina, Claudia; Küchenhoff, Helmut; Chang-Claude, Jenny; Paulweber, Bernhard; Wichmann, H-Erich; Illig, Thomas; Hoehe, Margret R; Kronenberg, Florian; Heid, Iris M
Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype-phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17-60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333, MAF 13-42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%) was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947 and rs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re-evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. PMID:23985325
Wang, Danxin; Poi, Ming J; Sun, Xiaochun; Gaedigk, Andrea; Leeder, J Steven; Sadee, Wolfgang
Robust estimation of allele frequencies in pools of DNA has the potential to reduce genotyping costs and\\/or increase the number of individuals contribut- ing to a study where hundreds of thousands of genetic markers need to be genotyped in very large popula- tions sample sets, such as genome wide association studies. In order to make accurate allele frequency estimations from
Jesper Brohede; Rob Dunne; James D. McKay; Garry N. Hannan
HLA Type Inference via Haplotypes Identical by Descent
NASA Astrophysics Data System (ADS)
The Human Leukocyte Antigen (HLA) genes play a major role in adaptive immune response and are used to differentiate self antigens from non self ones. HLA genes are hyper variable with nearly every locus harboring over a dozen alleles. This variation plays an important role in susceptibility to multiple autoimmune diseases and needs to be matched on for organ transplantation. Unfortunately, HLA typing by serological methods is time consuming and expensive compared to high throughput Single Nucleotide Polymorphism (SNP) data. We present a new computational method to infer per-locus HLA types using shared segments Identical By Descent (IBD), inferred from SNP genotype data. IBD information is modeled as graph where shared haplotypes are explored among clusters of individuals with known and unknown HLA types to identify the latter. We analyze performance of the method in a previously typed subset of the HapMap population, achieving accuracy of 96% in HLA-A, 94% in HLA-B, 95% in HLA-C, 77% in HLA-DR1, 93% in HLA-DQA1 and 90% in HLA-DQB1 genes. We compare our method to a tag SNP based approach and demonstrate higher sensitivity and specificity. Our method demonstrates the power of using shared haplotype segments for large-scale imputation at the HLA locus.
Setty, Manu N.; Gusev, Alexander; Pe'Er, Itsik
SNP characteristics predict replication success in association studies.
Successful independent replication is the most direct approach for distinguishing real genotype-disease associations from false discoveries in genome-wide association studies (GWAS). Selecting SNPs for replication has been primarily based on P values from the discovery stage, although additional characteristics of SNPs may be used to improve replication success. We used disease-associated SNPs from more than 2,000 published GWASs to identify predictors of SNP reproducibility. SNP reproducibility was defined as a proportion of successful replications among all replication attempts. The study reporting association for the first time was considered to be discovery and all consequent studies targeting the same phenotype replications. We found that -Log(P), where P is a P value from the discovery study, is the strongest predictor of the SNP reproducibility. Other significant predictors include type of the SNP (e.g., missense vs intronic SNPs) and minor allele frequency. Features of the genes linked to the disease-associated SNP also predict SNP reproducibility. Based on empirically defined rules, we developed a reproducibility score (RS) to predict SNP reproducibility independently of -Log(P). We used data from two lung cancer GWAS studies as well as recently reported disease-associated SNPs to validate RS. Minus Log(P) outperforms RS when the very top SNPs are selected, while RS works better with relaxed selection criteria. In conclusion, we propose an empirical model to predict SNP reproducibility, which can be used to select SNPs for validation and prioritization. PMID:25273843
Gorlov, Ivan P; Moore, Jason H; Peng, Bo; Jin, Jennifer L; Gorlova, Olga Y; Amos, Christopher I
Imputation of Microsatellite Alleles from Dense SNP Genotypes for Parental Verification
Microsatellite (MS) markers have recently been used for parental verification and are still the international standard despite higher cost, error rate, and turnaround time compared with Single Nucleotide Polymorphisms (SNP)-based assays. Despite domestic and international interest from producers and research communities, no viable means currently exist to verify parentage for an individual unless all familial connections were analyzed using the same DNA marker type (MS or SNP). A simple and cost-effective method was devised to impute MS alleles from SNP haplotypes within breeds. For some MS, imputation results may allow inference across breeds. A total of 347 dairy cattle representing four dairy breeds (Brown Swiss, Guernsey, Holstein, and Jersey) were used to generate reference haplotypes. This approach has been verified (>98% accurate) for imputing the International Society of Animal Genetics recommended panel of 12 MS for cattle parentage verification across a validation set of 1,307 dairy animals. Implementation of this method will allow producers and breed associations to transition to SNP-based parentage verification utilizing MS genotypes from historical data on parents where SNP genotypes are missing. This approach may be applicable to additional cattle breeds and other species that wish to migrate from MS- to SNP-based parental verification. PMID:22912645
McClure, Matthew; Sonstegard, Tad; Wiggans, George; Van Tassell, Curtis P
A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees
Motivation: The use of dense single nucleotide polymorphism (SNP) data in genetic linkage analysis of large pedigrees is impeded by significant technical, methodological and computational challenges. Here we describe Superlink-Online SNP, a new powerful online system that streamlines the linkage analysis of SNP data. It features a fully integrated flexible processing workflow comprising both well-known and novel data analysis tools, including SNP clustering, erroneous data filtering, exact and approximate LOD calculations and maximum-likelihood haplotyping. The system draws its power from thousands of CPUs, performing data analysis tasks orders of magnitude faster than a single computer. By providing an intuitive interface to sophisticated state-of-the-art analysis tools coupled with high computing capacity, Superlink-Online SNP helps geneticists unleash the potential of SNP data for detecting disease genes. Results: Computations performed by Superlink-Online SNP are automatically parallelized using novel paradigms, and executed on unlimited number of private or public CPUs. One novel service is large-scale approximate Markov Chain–Monte Carlo (MCMC) analysis. The accuracy of the results is reliably estimated by running the same computation on multiple CPUs and evaluating the Gelman–Rubin Score to set aside unreliable results. Another service within the workflow is a novel parallelized exact algorithm for inferring maximum-likelihood haplotyping. The reported system enables genetic analyses that were previously infeasible. We demonstrate the system capabilities through a study of a large complex pedigree affected with metabolic syndrome. Availability: Superlink-Online SNP is freely available for researchers at http://cbl-hap.cs.technion.ac.il/superlink-snp. The system source code can also be downloaded from the system website. Contact: email@example.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23162081
Silberstein, Mark; Weissbrod, Omer; Otten, Lars; Tzemach, Anna; Anisenia, Andrei; Shtark, Oren; Tuberg, Dvir; Galfrin, Eddie; Gannon, Irena; Shalata, Adel; Borochowitz, Zvi U.; Dechter, Rina; Thompson, Elizabeth; Geiger, Dan
Distribution of Y-chromosome STR defined haplotypes in Iberia
Seven Y-specific STR loci (DYS19, DYS389I, DY5389II, DYS390, DYS391, DYS392 and DYS393) were studied in five populations from the Iberian Peninsula: Andalusia, Valencia, Basque Country, Galicia and Northern Portugal. Haplotype and allele frequencies of these seven Y-chromosome STRs were estimated. Observed haplotype diversities are in a range between 0.96 (Basque Country) and 0.99 (Valencia and Andalusia). Significant population differentiation was
Annabel González-Neira; Leonor Gusmăo; Mar??a Brión; Mar??a Victoria Lareu; António Amorim; Angel Carracedo
Background Pesticide resistance monitoring is a crucial part to achieving sustainable integrated pest management (IPM) in agricultural production systems. Monitoring of resistance in arthropod populations is initially performed by bioassay, a method that detects a phenotypic response to pesticides. Molecular diagnostic assays, offering speed and cost improvements, can be developed when the causative mutation for resistance has been identified. However, improvements to throughput are limited as genotyping methods cannot be accurately applied to pooled DNA. Quantifying an allele frequency from pooled DNA would allow faster and cheaper monitoring of pesticide resistance. Methodology/Principal Findings We demonstrate a new method to quantify a resistance allele frequency (RAF) from pooled insects via TaqMan assay by using raw fluorescence data to calculate the transformed fluorescence ratio k' at the inflexion point based on a four parameter sigmoid curve. Our results show that k' is reproducible and highly correlated with RAF (r >0.99). We also demonstrate that k' has a non-linear relationship with RAF and that five standard points are sufficient to build a prediction model. Additionally, we identified a non-linear relationship between runs for k', allowing the combination of samples across multiple runs in a single analysis. Conclusions/Significance The transformed fluorescence ratio (k') method can be used to monitor pesticide resistance in IPM and to accurately quantify allele frequency from pooled samples. We have determined that five standards (0.0, 0.2, 0.5, 0.8, and 1.0) are sufficient for accurate prediction and are statistically-equivalent to the 13 standard points used experimentally PMID:24614533
Chen, Yizhou; Bogema, Daniel R.; Barchia, Idris M.; Herron, Grant A.
Online resources for SNP analysis
The major online single nucleotide polymorphism (SNP) databases freely available as research tools for genetic analysis are\\u000a explained, reviewed, and compared. An outline is given of the search strategies that can be used with the most extensive current\\u000a SNP databases: National Centre for Biotechnology Information (NCBI) dbSNP and HapMap to help the use secure the most appropriate\\u000a data for the
Christopher Phillips
Mannose-binding lectin (MBL) is a protein critical in activating complement. Patients with wild-type and variant mbl2 genotypes have high or low concentrations of MBL protein, which is known to increase susceptibility to transplant rejection or infection, respectively. Our objective was to determine mbl2 genotype frequencies in future solid organ transplant recipients in order to optimize their induction and maintenance immunosuppressive therapies, and to provide MBL reference data for this unique population. We genotyped 1687 patients, and concurrently measured protein in 807 of them, during 2010-2011. Frequencies of the structural allele SNPs in our population were similar to those of other studied populations; however, Black patients with the same intermediate and deficient mbl2 genotypes as Caucasians produced significantly lower levels of MBL protein; therefore, within this population more genotypes should be considered MBL-deficient. Overall, the most critical parameter in determining serum MBL protein concentration was genotype, which was independent of other factors including ethnicity, gender, or diseased native organ type. PMID:23439277
Stevenson, Heather L; Amador, Alexandra; McCue, Jennifer; Weppler, Deborah; Tryphonopoulos, Panagiotis; Roth, David; Ciancio, Gaetano; Burke, George; Chaparro, Sandra; Pham, Si; Tzakis, Andreas; Ruiz, Phillip
Haplotype estimation from fuzzy genotypes using penalized likelihood.
The Composite Link Model is a generalization of the generalized linear model in which expected values of observed counts are constructed as a sum of generalized linear components. When combined with penalized likelihood, it provides a powerful and elegant way to estimate haplotype probabilities from observed genotypes. Uncertain ("fuzzy") genotypes, like those resulting from AFLP scores, can be handled by adding an extra layer to the model. We describe the model and the estimation algorithm. We apply it to a data set of accurate human single nucleotide polymorphism (SNP) and to a data set of fuzzy tomato AFLP scores. PMID:21931662
Uh, Hae-Won; Eilers, Paul H C
Haplotype Estimation from Fuzzy Genotypes Using Penalized Likelihood
The Composite Link Model is a generalization of the generalized linear model in which expected values of observed counts are constructed as a sum of generalized linear components. When combined with penalized likelihood, it provides a powerful and elegant way to estimate haplotype probabilities from observed genotypes. Uncertain ("fuzzy") genotypes, like those resulting from AFLP scores, can be handled by adding an extra layer to the model. We describe the model and the estimation algorithm. We apply it to a data set of accurate human single nucleotide polymorphism (SNP) and to a data set of fuzzy tomato AFLP scores. PMID:21931662
Uh, Hae-Won; Eilers, Paul H. C.
The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P ?=?1.34×10?8, OR ?=?1.22, CI 95% ?=?1.14–1.30; rs2004640: P ?=?4.60×10?7, OR ?=?0.84, CI 95% ?=?0.78–0.90; rs10488631: P ?=?7.53×10?20, OR ?=?1.63, CI 95% ?=?1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P ?=?0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P ?=?9.04×10?22, OR ?=?1.75, CI 95% ?=?1.56–1.97) better explained the observed association (likelihood P-value ?=?1.48×10?4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific. PMID:23372721
Beretta, Lorenzo; Simeon, Carmen P.; Carreira, Patricia E.; Callejas, Jose Luis; Fernandez-Castro, Monica; Saez-Comet, Luis; Beltran, Emma; Camps, Maria Teresa; Egurbide, Maria Victoria; Airo, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Riemekasten, Gabriela; Witte, Torsten; Kreuter, Alexander; Distler, Jorg H. W.; Madhok, Rajan; Shiels, Paul; van Laar, Jacob M.; Fonseca, Carmen; Denton, Christopher; Herrick, Ariane; Worthington, Jane; Schuerwegh, Annemie J.; Vonk, Madelon C.; Voskuyl, Alexandre E.; Radstake, Timothy R. D. J.; Martin, Javier
Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S)
The advent of complete-genome genotyping across phenotype cohorts has provided a rich source of information for bioinformaticians. However the search for SNPs from this data is generally performed on a study-by-study case without any specific hypothesis of the location for SNPs that are predictive for the phenotype. We have designed a method whereby very large SNP lists (several gigabytes in size), combining several genotyping studies at once, can be sorted and traced back to their ultimate consequence in protein structure. Given a working hypothesis, researchers are able to easily search whole genome genotyping data for SNPs that link genetic locations to phenotypes. This allows a targeted search for correlations between phenotypes and potentially relevant systems, rather than utilizing statistical methods only. HyDn-SNP-S returns results that are less data dense, allowing more thorough analysis, including haplotype analysis. We have applied our method to correlate DNA polymerases to cancer phenotypes using four of the available cancer databases in dbGaP. Logistic regression and derived haplotype analysis indicates that ~80 SNPs, previously overlooked, are statistically significant. Derived haplotypes from this work link POLL to breast cancer and POLG to prostate cancer with an increase in incidence of 3.01- and 9.6-fold, respectively. Molecular dynamics simulations on wild-type and one of the SNP mutants from the haplotype of POLL provide insights at the atomic level on the functional impact of this cancer related SNP. Furthermore, HyDn-SNP-S has been designed to allow application to any system. The program is available upon request from the authors. PMID:23830898
Swett, Rebecca J.; Elias, Angela; Miller, Jeffrey A.; Dyson, Gregory E.; Cisneros, G. Andres
Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S).
The advent of complete-genome genotyping across phenotype cohorts has provided a rich source of information for bioinformaticians. However the search for SNPs from this data is generally performed on a study-by-study case without any specific hypothesis of the location for SNPs that are predictive for the phenotype. We have designed a method whereby very large SNP lists (several gigabytes in size), combining several genotyping studies at once, can be sorted and traced back to their ultimate consequence in protein structure. Given a working hypothesis, researchers are able to easily search whole genome genotyping data for SNPs that link genetic locations to phenotypes. This allows a targeted search for correlations between phenotypes and potentially relevant systems, rather than utilizing statistical methods only. HyDn-SNP-S returns results that are less data dense, allowing more thorough analysis, including haplotype analysis. We have applied our method to correlate DNA polymerases to cancer phenotypes using four of the available cancer databases in dbGaP. Logistic regression and derived haplotype analysis indicates that ~80SNPs, previously overlooked, are statistically significant. Derived haplotypes from this work link POLL to breast cancer and POLG to prostate cancer with an increase in incidence of 3.01- and 9.6-fold, respectively. Molecular dynamics simulations on wild-type and one of the SNP mutants from the haplotype of POLL provide insights at the atomic level on the functional impact of this cancer related SNP. Furthermore, HyDn-SNP-S has been designed to allow application to any system. The program is available upon request from the authors. PMID:23830898
Swett, Rebecca J; Elias, Angela; Miller, Jeffrey A; Dyson, Gregory E; Andrés Cisneros, G
Molecular haplotyping at high throughput
Reconstruction of haplotypes, or the allelic phase, of single nucleotide polymorphisms (SNPs) is a key component of studies aimed at the identification and dissection of genetic factors involved in com- plex genetic traits. In humans, this often involves investigation of SNPs in case\\/control or other cohorts in which the haplotypes can only be partially inferred from genotypes by statistical approaches
Jorg Tost; Ole Brandt; Francis Boussicault; David Derbala; Christophe Caloustian; Doris Lechner; Ivo Glynne Gut
SNP deserts of Asian cultivated rice: genomic regions under domestication.
When performing a genome-wide comparison between indica (93-11) and japonica (Nipponbare), we find 8% of the genome, which have an extremely low SNP rate (< 1 SNP/kb). Inside these 'SNP deserts', experimentally confirmed genes show increased K(a)/K(s) that indicate adaptive selection. To further elucidate this connection, we survey the level and pattern of genetic variation in both cultivated and wild rice groups, using 155 noncoding regions located within SNP deserts. The results suggest that cultivated rice has greatly reduced genetic variation within SNP deserts as compared to either the nondesert or corresponding genomic regions in wild rice. Consistent with this reduction in genetic variation, we find a biased distribution of derived allele frequency in the cultivated group, indicative of positive selection. Furthermore, over half of the confirmed, domestication-related genes are found within SNP deserts, also suggesting that SNP deserts are strongly related to domestication, and might be the key sites in the process of domestication. PMID:19243488
Wang, L; Hao, L; Li, X; Hu, S; Ge, S; Yu, J
dbSNP VCF Submission Format Guidelines Contact: email@example.com
dbSNP VCF Submission Format Guidelines Contact: email@example.com Last update: June 05, 2014 Introduction Submission Overview Required Metadata Files dbSNP VCF Submission Format Submission Tags Appendix: Example of a VCF Formatted dbSNP Submission Introduction dbSNP Submissions dbSNP
Levin, Judith G.
MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS R. SHARAN International Computer Scienceďż˝ mally multiplexing SNP genotyping using generic assays. We devise a graph theoretic formulation need to be inferred. The development of efficient SNP detection, genotyping and measurement techniques
Sharan, Roded
SNP-array reveals genome-wide patterns of geographical and potential adaptive divergence across the development of a medium-density Atlantic salmon single nucleotide poly- morphism (SNP) array based of SNP allele frequencies across populations and among regional groups. In Europe, secondary contact
Bernatchez, Louis
SNP screening via best subsets regression Address reprint requests to Marc A. Suchard, Department find 694 SNP loci with minimum allele frequencies of at least 0.01. We assume an additive casual model subsets of SNP loci, using a generalization of Mallows' Cp as our optimality criterion. The simple
Suchard, Marc A.
A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women
Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. PMID:23468962
Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Le Marchand, Loic; Kolonel, Laurence N.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.
Chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) were studied in 24 populations of Prunus spinosa sampled across Europe. The cpDNA and mtDNA fragments were amplified using universal primers and subsequently digested with restriction enzymes to obtain the polymorphisms. Combinations of all the polymorphisms resulted in 33 cpDNA haplotypes and two mtDNA haplotypes. Strict association between the cpDNA haplotypes and the mtDNA haplotypes was detected in most cases, indicating conjoint inheritance of the two genomes. The most frequent and abundant cpDNA haplotype (C20; frequency, 51 %) is always associated with the more frequent and abundant mtDNA haplotype (M1; frequency, 84 %). All but two of the cpDNA haplotypes associated with the less frequent mtDNA haplotype (M2) are private haplotypes. These private haplotypes are phylogenetically related but geographically unrelated. They form a separate cluster on the minimum?length spanning tree. PMID:14534199
Genome-Wide Haplotype Changes Produced by Artificial Selection during Modern Rice Breeding in Japan
During the last 90 years, the breeding of rice has delivered cultivars with improved agronomic and economic characteristics. Crossing of different lines and successive artificial selection of progeny based on their phenotypes have changed the chromosomal constitution of the ancestors of modern rice; however, the nature of these changes is unclear. The recent accumulation of data for genome-wide single-nucleotide polymorphisms (SNPs) in rice has allowed us to investigate the change in haplotype structure and composition. To assess the impact of these changes during modern breeding, we studied 177 Japanese rice accessions, which were categorized into three groups: landraces, improved cultivars developed from 1931 to 1974 (the early breeding phase), and improved cultivars developed from 1975 to 2005 (the late breeding phase). Phylogenetic tree and structure analysis indicated genetic differentiation between non-irrigated (upland) and irrigated (lowland) rice groups as well as genetic structuring within the irrigated rice group that corresponded to the existence of three subgroups. Pedigree analysis revealed that a limited number of landraces and cultivars was used for breeding at the beginning of the period of systematic breeding and that 11 landraces accounted for 70% of the ancestors of the modern improved cultivars. The values for linkage disequilibrium estimated from SNP alleles and the haplotype diversity determined from consecutive alleles in five-SNP windows indicated that haplotype blocks became less diverse over time as a result of the breeding process. A decrease in haplotype diversity, caused by a reduced number of polymorphisms in the haplotype blocks, was observed in several chromosomal regions. However, our results also indicate that new haplotype polymorphisms have been generated across the genome during the breeding process. These findings will facilitate our understanding of the association between particular haplotypes and desirable phenotypes in modern Japanese rice cultivars. PMID:22427922
Yamamoto, Eiji; Nagasaki, Hideki; Shibaya, Taeko; Yano, Masahiro
Polymorphisms and haplotypes of the UDP-glucuronosyltransferase 2B7 gene promoter.
Identification of functional polymorphisms in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene predicting interpatient variability in the glucuronidation of drugs that are primarily metabolized by UGT2B7 has been the subject of many studies. These studies have shown linkage disequilibrium (LD) covering the region from -2 kb to 16 kb of the UGT2B7 gene. We identified three novel single-nucleotide polymorphisms (SNPs) and extended this LD in the 5'-upstream direction to cover an additional nine prevalent polymorphisms in the distal -2600- to -4000-base pair (bp) promoter. We further showed complete LD between these distal promoter SNPs and the SNP (802C>T) in exon 2 in a panel of 26 livers. Because of this LD, we showed that all of the 23 prevalent polymorphisms in the 4-kb UGT2B7 promoter are linked together, defining two major haplotypes (i.e., I and II). The addition of the minor allele of a rare polymorphism and allele exchanges between haplotypes I and II generated subhaplotypes of I and II. We demonstrated a higher promoter activity of haplotype II over haplotype I, and this higher activity was abolished by an A-to-G change at a single SNP (-900A>G). This mutation changed a consensus activating protein-1 (AP-1) site (TGAGTCA) as occurred in haplotype II to a mutated AP-1 site (TGAGTCG) as occurred in haplotype I. Finally, we showed that the previously reported Alu element resides exclusively in haplotype I and is a highly conserved CG-rich Alu Y element. PMID:24561451
Hu, Dong Gui; Meech, Robyn; Lu, Lu; McKinnon, Ross A; Mackenzie, Peter I
[Analysis of mitochondrial DNA haplotypes in yakut population].
To study the mitochondrial gene pool structure in Yakuts, polymorphism of mtDNA hypervariable segment I (16,024-16,390) was analyzed in 191 people sampled from the indigenous population of the Sakha Republic. In total, 67 haplotypes of 14 haplogroups were detected. Most (91.6%) haplotypes belonged to haplogroups A, B, C, D, F, G, M*, and Y, which are specific for East Eurasian ethnic groups; 8.4% haplotypes represented Caucasian haplogroups H, HV1, J, T, U, and W. A high frequency of mtDNA types belonging to Asian supercluster M was peculiar for Yakuts: mtDNA types belonging to haplogroup C, D, or G and undifferentiated mtDNA types of haplogroup M (M*) accounted for 81% of all haplotypes. The highest diversity was observed for haplogroups C and D, which comprised respectively 22 (44%) and 18 (30%) haplotypes. Yakuts showed the lowest genetic diversity (H = 0.964) among all Turkic ethnic groups. Phylogenetic analysis testified to a common genetic substrate of Yakuts, Mongols, and Central Asian (Kazakh, Kyrgyz, Uigur) populations. Yakuts proved to share 21 (55.5%) mtDNA haplogroups with the Central Asian ethnic groups and Mongols. Comparisons with modern paleo-Asian populations (Chukcha, Itelmen, Koryaks) revealed three (8.9%) haplotypes common for Yakuts and Koryaks. The results of mtDNA analysis disagree with the hypothesis of an appreciable paleo-Asian contribution to the modern Yakut gene pool. PMID:12942638
Fedorova, S A; Bermisheva, M A; Villems, R; Maksimova, N R; Khusnutdinova, E K
Catechol-O-methyltransferase (COMT) is an enzyme that plays a key role in the modulation of catechol-dependent functions such as cognition, cardiovascular function, and pain processing. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous (val158met) position, designated as low (LPS), average (APS), and high pain sensitive (HPS), are associated with experimental pain sensitivity and risk of developing chronic musculoskeletal pain conditions. APS and HPS haplotypes produce significant functional effects, coding for 3- and 20-fold reductions in COMT enzymatic activity, respectively. In the present study, we investigated whether additional minor single nucleotide polymorphisms (SNPs), accruing in 1 to 5% of the population, situated in the COMT transcript region contribute to haplotype-dependent enzymatic activity. Computer analysis of COMT ESTs showed that one synonymous minor SNP (rs769224) is linked to the APS haplotype and three minor SNPs (two synonymous: rs6267, rs740602 and one nonsynonymous: rs8192488) are linked to the HPS haplotype. Results from in silico and in vitro experiments revealed that inclusion of allelic variants of these minor SNPs in APS or HPS haplotypes did not modify COMT function at the level of mRNA folding, RNA transcription, protein translation, or enzymatic activity. These data suggest that neutral variants are carried with APS and HPS haplotypes, while the high activity LPS haplotype displays less linked variation. Thus, both minor synonymous and nonsynonymous SNPs in the coding region are markers of functional APS and HPS haplotypes rather than independent contributors to COMT activity. PMID:19365560
Nackley, Andrea G.; Shabalina, Svetlana A.; Lambert, Jason E.; Conrad, Mathew S.; Gibson, Dustin G.; Spiridonov, Alexey N.; Satterfield, Sarah K.; Diatchenko, Luda
Single nucleotide polymorphisms and haplotypes associated with feed efficiency in beef cattle
Background General, breed- and diet-dependent associations between feed efficiency in beef cattle and single nucleotide polymorphisms (SNPs) or haplotypes were identified on a population of 1321 steers using a 50 K SNP panel. Genomic associations with traditional two-step indicators of feed efficiency – residual feed intake (RFI), residual average daily gain (RADG), and residual intake gain (RIG) – were compared to associations with two complementary one-step indicators of feed efficiency: efficiency of intake (EI) and efficiency of gain (EG). Associations uncovered in a training data set were evaluated on independent validation data set. A multi-SNP model was developed to predict feed efficiency. Functional analysis of genes harboring SNPs significantly associated with feed efficiency and network visualization aided in the interpretation of the results. Results For the five feed efficiency indicators, the numbers of general, breed-dependent, and diet-dependent associations with SNPs (P-value?0.0001) were 31, 40, and 25, and with haplotypes were six, ten, and nine, respectively. Of these, 20 SNP and six haplotype associations overlapped between RFI and EI, and five SNP and one haplotype associations overlapped between RADG and EG. This result confirms the complementary value of the one and two-step indicators. The multi-SNP models included 89 SNPs and offered a precise prediction of the five feed efficiency indicators. The associations of 17 SNPs and 7 haplotypes with feed efficiency were confirmed on the validation data set. Nine clusters of Gene Ontology and KEGG pathway categories (mean P-value?0.001) including, 9nucleotide binding; ion transport, phosphorous metabolic process, and the MAPK signaling pathway were overrepresented among the genes harboring the SNPs associated with feed efficiency. Conclusions The general SNP associations suggest that a single panel of genomic variants can be used regardless of breed and diet. The breed- and diet-dependent associations between SNPs and feed efficiency suggest that further refinement of variant panels require the consideration of the breed and management practices. The unique genomic variants associated with the one- and two-step indicators suggest that both types of indicators offer complementary description of feed efficiency that can be exploited for genome-enabled selection purposes. PMID:24066663
Y-STR haplotypes of Native American populations from the Brazilian Amazon region.
The allele and haplotype frequencies of nine Y-STRs (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS393, DYS385 I/II) were determined in a sample of six native tribes from the Brazilian Amazon (Tiriyó, Awa-Guajá, Waiăpi, Urubu-Kaapor, Zoé and Parakană). Forty-eight different haplotypes were identified, 28 of which unique. Five haplotypes are very frequent and were shared by over 10 individuals. The estimated haplotype diversity (0.9114) was very low compared to other geographic groups, including Africans, Europeans and Asians. PMID:20457062
Palha, Teresinha Jesus Brabo Ferreira; Rodrigues, Elzemar Martins Ribeiro; dos Santos, Sidney Emanuel Batista
PanSNPdb: the Pan-Asian SNP genotyping database.
The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP. PMID:21731755
Ngamphiw, Chumpol; Assawamakin, Anunchai; Xu, Shuhua; Shaw, Philip J; Yang, Jin Ok; Ghang, Ho; Bhak, Jong; Liu, Edison; Tongsima, Sissades
RESEARCH ARTICLE Open Access A genome-wide search for common SNP x SNP
RESEARCH ARTICLE Open Access A genome-wide search for common SNP x SNP interactions on the risk and modulate the risk of VT. Methods: A genome-wide SNP x SNP interaction analysis on VT risk was conducted patients. Conclusion: This study, the first genome-wide SNP interaction analysis conducted so far on VT
Paris-Sud XI, Université de
Am. J. Hum. Genet. 66:1882Â1899, 2000 1882 Haplotypes and Linkage Disequilibrium phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene that haplotype-frequency variation exists between some regions of the world. In European populations, linkage
Kidd, Kenneth
Geographical distribution gradients of the major PKU mutations and the linked haplotypes
Analysis of 81 phenylketonuria families from Bulgaria, Lithuania and eastern Germany demonstrated a high frequency of haplotype 2 and the associated Arg408 ? Trp408 substitution. Haplotype 3 and the splicing mutation in intron 12 are rare or absent in the groups studies. Pooling the data on European populations suggests a Balto-Slavic origin of the defect in codon 408 of the
L. Kalaydjieva; B. Dworniczak; V. Kucinskas; V. Yurgeliavicius; E. Kunert; J. Horst
Linkage disequilibrium and haplotype block structure in a composite beef cattle breed
Background The development of linkage disequilibrium (LD) maps and the characterization of haplotype block structure at the population level are useful parameters for guiding genome wide association (GWA) studies, and for understanding the nature of non-linear association between phenotypes and genes. The elucidation of haplotype block structure can reduce the information of several single nucleotide polymorphisms (SNP) into the information of a haplotype block, reducing the number of SNPs in a coherent way for consideration in GWA and genomic selection studies. Results The maximum average LD, measured by r2 varied between 0.33 to 0.40 at a distance of < 2.5 kb, and the minimum average values of r2 varied between 0.05 to 0.07 at distances ranging from 400 to 500 kb, clearly showing that the average r2 reduced with the increase in SNP pair distances. The persistence of LD phase showed higher values at shorter genomic distances, decreasing with the increase in physical distance, varying from 0.96 at a distance of < 2.5 kb to 0.66 at a distance from 400 to 500 kb. A total of 78% of all SNPs were clustered into haplotype blocks, covering 1,57 Mb of the total autosomal genome size. Conclusions This study presented the first high density linkage disequilibrium map and haplotype block structure for a composite beef cattle population, and indicates that the high density SNP panel over 700 k can be used for genomic selection implementation and GWA studies for Canchim beef cattle.
[The origin of Yakuts: analysis of Y-chromosome haplotypes].
Gene pool structure of Sakha Republic (Yakutia) native population has been studied: we defined composition and frequencies of Y-chromosome haplogroups for Yakuts. Six haplogroups: C3 x M77, C3c, N*, N2, N3a and R1a1 have been revealed in Yakut gene pool. A greater part of Y-chromosome in Yakut population belongs to N3a haplogroup (89%). All investigated Yakut population samples have low values of gene diversity, calculated based on haplogroup frequencies. Gene differentiation of the investigated samples estimated using the analysis of molecular variance (AMOVA) by two marker systems (haplogroup frequencies and microsatellite haplotypes of Y-chromosome) revealed a portion of interpopulation differences amounting to 0.24 and 2.85%, respectively. Frequencies and molecular phylogeny of YSTR-haplotypes were revealed for N3a haplogroup of Y-chromosome. Altogether forty haplotypes were found in Yakuts. Evenks and Yakuts are characterized by overlapping and very specific spectrum of N3a haplotypes, which is not typical for other Siberian ethnic groups. Cluster analysis of populations by N3a YSTR-haplotypes shows Yakut isolation from Turkic-speaking populations in the South Siberia. Genetic diversity generation time for a specific spectrum of Yakut haplotypes was estimated as 4.45 +/- 1.96 thousand years. As opposed to the data on mtDNA, the obtained results give an evidence for significant contribution of a local palaeolithic component into Y-chromosomal Yakut gene pool. Ethnogenetic reconstruction of the present picture of genetic diversity in N3a haplogroup in the territory of Siberia is under consideration. PMID:18610830
Khar'kov, V N; Stepanov, V A; Medvedev, O F; Spiridonova, M G; Maksimova, N R; Nogovitsyna, A N; Puzyrev, V P
Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T). Many different mutations have been identified using various techniques, with detection efficiencies ranging from 57 to 85%. In this study, we employed short tandem repeat (STR) haplotypes to enhance mutation identification in 55 unrelated A-T families of Iberian origin (20 Spanish, 17 Brazilian, and 18 Hispanic-American); we were able to identify 95% of the expected mutations. Allelic sizes were standardized based on a reference sample (CEPH 1347-2). Subsequent mutation screening was performed by PTT, SSCP, and DHPLC, and abnormal regions were sequenced. Many STR haplotypes were found within each population and six haplotypes were observed across several of these populations. Single nucleotide polymorphism (SNP) haplotypes further suggested that most of these common mutations are ancestrally related, and not hot spots. However, two mutations (8977C>T and 8264_8268delATAAG) may indeed be recurring mutational events. Common haplotypes were present in 13 of 20 Spanish A-T families (65%), in 11 of 17 Brazilian A-T families (65%), and, in contrast, in only eight of 18 Hispanic-American families (44%). Three mutations were identified that would be missed by conventional screening strategies. In all, 62 different mutations (28 not previously reported) were identified and their associated haplotypes defined, thereby establishing a new database for Iberian A-T families, and extending the spectrum of worldwide ATM mutations. PMID:12815592
Mitui, Midori; Campbell, Catarina; Coutinho, Gabriela; Sun, Xia; Lai, Chih-Hung; Thorstenson, Yvonne; Castellvi-Bel, Sergi; Fernandez, Luis; Monros, Eugenia; Carvalho, Beatriz Tavares Costa; Porras, Oscar; Fontan, Gumersindo; Gatti, Richard A
Hap-seq: an optimal algorithm for haplotype phasing with imputation using sequencing data.
Inference of haplotypes, or the sequence of alleles along each chromosome, is a fundamental problem in genetics and is important for many analyses, including admixture mapping, identifying regions of identity by descent, and imputation. Traditionally, haplotypes are inferred from genotype data obtained from microarrays using information on population haplotype frequencies inferred from either a large sample of genotyped individuals or a reference dataset such as the HapMap. Since the availability of large reference datasets, modern approaches for haplotype phasing along these lines are closely related to imputation methods. When applied to data obtained from sequencing studies, a straightforward way to obtain haplotypes is to first infer genotypes from the sequence data and then apply an imputation method. However, this approach does not take into account that alleles on the same sequence read originate from the same chromosome. Haplotype assembly approaches take advantage of this insight and predict haplotypes by assigning the reads to chromosomes in such a way that minimizes the number of conflicts between the reads and the predicted haplotypes. Unfortunately, assembly approaches require very high sequencing coverage and are usually not able to fully reconstruct the haplotypes. In this work, we present a novel approach, Hap-seq, which is simultaneously an imputation and assembly method that combines information from a reference dataset with the information from the reads using a likelihood framework. Our method applies a dynamic programming algorithm to identify the predicted haplotype, which maximizes the joint likelihood of the haplotype with respect to the reference dataset and the haplotype with respect to the observed reads. We show that our method requires only low sequencing coverage and can reconstruct haplotypes containing both common and rare alleles with higher accuracy compared to the state-of-the-art imputation methods. PMID:23383995
He, Dan; Han, Buhm; Eskin, Eleazar
In the 100-year period 1880-1980 the Hutterite population increased from about 442 to 23,000 individuals in North America. There are three endogamous subdivisions in this Caucasian genetic isolate. A total of 11 cystic fibrosis (CF) families from Canada and the United States were investigated, including at least two families from each of the three subdivisions, the Dariusleut, Lehrerleut, and Schmiedeleut. A study of RFLPs for the loci D7S8, D7S23, MET, and D7S18 (also called D7S16) in the region of the CF gene in 10 families shows considerable genetic variability. There were three different extended CF gene-region haplotypes on CF chromosomes (CF haplotypes), and there were 13 different extended CF gene-region haplotypes on normal chromosomes (normal haplotypes). The three CF haplotypes have different D7S23 and MET haplotypes. Parents who have the same CF haplotype are, on the average, more closely related than parents who have different haplotypes, but only within the same subdivision. A marriage node graph of 11 families illustrates the complexity of Hutterite genealogies. The frequency distribution of CF haplotypes in the Hutterite sample differs notably from those of larger agglomerates of family data from collaborative studies, with respect to D7S8, MET haplotypes, and D7S23 haplotypes. We propose that there were at least three CF carriers among the founders of the Hutterite population and that copies of a particular CF haplotype in current individuals are identical by descent. The alternative that one or more genetically distinguishable CF haplotypes resulted from recombination since the founding of the population is considered to be less likely. PMID:2563632
Fujiwara, T M; Morgan, K; Schwartz, R H; Doherty, R A; Miller, S R; Klinger, K; Stanislovitis, P; Stuart, N; Watkins, P C
High-resolution haplotype structure in the human genome
Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non- monotonic picture, because the power to detect allelic associa- tions depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has
John D. Rioux; Stephen F. Schaffner; Thomas J. Hudson; Mark J. Daly; Eric S. Lander
Combining data when data are collected under different study designs, such as family trios and unrelated case-control samples, gains more power and is cost-effective than analyzing each data separately. However, a potential concern is population stratification (PS) among unrelated case-control samples and analyses integrating data should address this confounding effect. In this paper, we develop a simpler method, haplotype generalized linear model (HGLM), that tests and estimates haplotype effects on disease risk and allows for modification against PS for combining data. We proposed to combine information across aggregations of haplotype weighted-counts estimated from population case-control data and trio data separately, and to perform subsequent GLM analysis. Furthermore, we present a framework of analysis of variance based on haplotype weighted-counts for detecting whether it is appropriate to combine two data sources, as well as the modified HGLM with clustering methods for addressing PS. We evaluate the statistical properties in terms of the accuracy, false positive rate (FPR) and empirical power using simulated data with regard to various disease risks, sample sizes, multi-SNP haplotypes and the presence of PS. Our simulation results indicate that HGLM performs comparably well with the likelihood-based haplotype association analysis, particularly when the haplotype effects are moderate, but may not perform well when dealing with lengthy haplotypes for small sample sizes. In the presence of PS, the modified HGLM remains valid and has satisfactory nominal level and small bias. Overall, HGLM appears to be successful in combining data and is simple to implement in standard statistical software. PMID:24860592
Wen, Shu-Hui; Tsai, Miao-Yu
Background: Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African–Americans compared with European–Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African–Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. Methods: To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African–Americans and 302 European–Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. Results: VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European–Americans and 5% (8% with CYP2C9) among African–Americans. Four common haplotypes in European–Americans and twelve in African–Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group B). African–Americans had a lower frequency of Group A haplotype (10.6%) compared with European–Americans (35%, p < 0.0001).The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. Conclusions: Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African– and European–Americans. A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population. PMID:18855533
Limdi, Nita A; Beasley, T Mark; Crowley, Michael R; Goldstein, Joyce A; Rieder, Mark J; Flockhart, David A; Arnett, Donna K; Acton, Ronald T; Liu, Nianjun
Prenatal diagnosis of congenital adrenal hyperplasia (CAH) is of clinical significance because in utero treatment is available to prevent virilization of an affected female fetus. However, traditional prenatal diagnosis of CAH relies on genetic testing of fetal genomic DNA obtained using amniocentesis or chorionic villus sampling, which is associated with an increased risk of miscarriage. The aim of this study was to demonstrate the feasibility of a new haplotype-based approach for the noninvasive prenatal testing of CAH due to 21-hydroxylase deficiency. Parental haplotypes were constructed using target-region sequencing data of the parents and the proband. With the assistance of the parental haplotypes, we recovered fetal haplotypes using a hidden Markov model (HMM) through maternal plasma DNA sequencing. In the genomic region around the CYP21A2 gene, the fetus inherited the paternal haplotype '0' alleles linked to the mutant CYP21A2 gene, but the maternal haplotype '1' alleles linked to the wild-type gene. The fetus was predicted to be an unaffected carrier of CAH, which was confirmed by genetic analysis of fetal genomic DNA from amniotic fluid cells. This method was further validated by comparing the inferred SNP genotypes with the direct sequencing data of fetal genomic DNA. The result showed an accuracy of 96.41% for the inferred maternal alleles and an accuracy of 97.81% for the inferred paternal alleles. The haplotype-based approach is feasible for noninvasive prenatal testing of CAH. PMID:24768736
Ma, Dingyuan; Ge, Huijuan; Li, Xuchao; Jiang, Tao; Chen, Fang; Zhang, Yanyan; Hu, Ping; Chen, Shengpei; Zhang, Jingjing; Ji, Xiuqing; Xu, Xun; Jiang, Hui; Chen, Minfeng; Wang, Wei; Xu, Zhengfeng
WHAP: haplotype-based association analysis
Summary: We describe a software tool to perform haplotype-based associationanalysis,forquantitativeandqualitativetraits,inpopulation and family samples, using single nucleotide polymorphism or multi- allelic marker data. A range of tests is offered: omnibus and haplotype- specifictests;prospectiveandretrospectivelikelihoods;covariatesand moderators; sliding window analyses; permutation P-values. We focus on the ability to flexibly impose constraints on haplotype effects, which allows for a range of conditional haplotype-based likelihood ratio
Shaun Purcell; Mark J. Daly; Pak Chung Sham
Probabilistic Logic Learning from Haplotype Data
The analysis of haplotype data of human populations has received much attention recently. For instance, problems such as Haplo- type Reconstruction are important intermediate steps in gene association studies, which seek to uncover the genetic basis of complex diseases. In this chapter, we explore the application of probabilistic logic learning techniques to haplotype data. More specifically, a new haplotype recon-
Niels Landwehr; Taneli Mielikäinen
Homozygosity haplotype allows a genomewide search for the autosomal segments shared among patients.
A promising strategy for identifying disease susceptibility genes for both single- and multiple-gene diseases is to search patients' autosomes for shared chromosomal segments derived from a common ancestor. Such segments are characterized by the distinct identity of their haplotype. The methods and algorithms currently available have only a limited capability for determining a high-resolution haplotype genomewide. We herein introduce the homozygosity haplotype (HH), a haplotype described by the homozygous SNPs that are easily obtained from high-density SNP genotyping data. The HH represents haplotypes of both copies of homologous autosomes, allowing for direct comparisons of the autosomes among multiple patients and enabling the identification of the shared segments. The HH successfully detected the shared segments from members of a large family with Marfan syndrome, which is an autosomal dominant, single-gene disease. It also detected the shared segments from patients with model multigene diseases originating with common ancestors who lived 10-25 generations ago. The HH is therefore considered to be useful for the identification of disease susceptibility genes in both single- and multiple-gene diseases. PMID:17503327
Miyazawa, Hitoshi; Kato, Masaaki; Awata, Takuya; Kohda, Masakazu; Iwasa, Hiroyasu; Koyama, Nobuyuki; Tanaka, Tomoaki; Huqun; Kyo, Shunei; Okazaki, Yasushi; Hagiwara, Koichi
SNP-VISTA: An Interactive SNP Visualization Tool Nameeta Shah1,2
SNP-VISTA: An Interactive SNP Visualization Tool Nameeta Shah1,2 , Michael V. Teplitsky2 , Simon, and the recent application of random shotgun sequencing to environmental samples enables more extensive SNP, SNP-VISTA, to aid in the analyses of the following types of data: A. Large-scale re-sequence data
Hamann, Bernd
Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working/T nicotinic receptor SNP affected visuospatial attention, but not working memory, and the DBH rs#1108580 G/A noradrenergic enzyme SNP affected working memory, but not attention, we predicted that both SNPs would modulate
Parasuraman, Raja
Pyrobayes: an improved base caller for SNP
Pyrobayes: an improved base caller for SNP discovery in pyrosequences Aaron R Quinlan, Donald, for pyrosequencing reads. Pyrobayes permits accurate single-nucleotide polymorphism (SNP) calling in resequencing be distinguished from sequencing error. Reliable SNP calls can only be made if the base error rate for the called
Cai, Long
MULTIPLEXING SCHEMES FOR GENERIC SNP GENOTYPING ASSAYS R. SHARAN International Computer Science- mally multiplexing SNP genotyping using generic assays. We devise a graph theoretic formulation. The development of e cient SNP detection, genotyping and measurement techniques is an active research area
Shamir, Ron
Whole genome SNP discovery and analysis of genetic diversity in Turkey (Meleagris gallopavo)
Background The turkey (Meleagris gallopavo) is an important agricultural species and the second largest contributor to the world's poultry meat production. Genetic improvement is attributed largely to selective breeding programs that rely on highly heritable phenotypic traits, such as body size and breast muscle development. Commercial breeding with small effective population sizes and epistasis can result in loss of genetic diversity, which in turn can lead to reduced individual fitness and reduced response to selection. The presence of genomic diversity in domestic livestock species therefore, is of great importance and a prerequisite for rapid and accurate genetic improvement of selected breeds in various environments, as well as to facilitate rapid adaptation to potential changes in breeding goals. Genomic selection requires a large number of genetic markers such as e.g. single nucleotide polymorphisms (SNPs) the most abundant source of genetic variation within the genome. Results Alignment of next generation sequencing data of 32 individual turkeys from different populations was used for the discovery of 5.49 million SNPs, which subsequently were used for the analysis of genetic diversity among the different populations. All of the commercial lines branched from a single node relative to the heritage varieties and the South Mexican turkey population. Heterozygosity of all individuals from the different turkey populations ranged from 0.17-2.73 SNPs/Kb, while heterozygosity of populations ranged from 0.73-1.64 SNPs/Kb. The average frequency of heterozygous SNPs in individual turkeys was 1.07 SNPs/Kb. Five genomic regions with very low nucleotide variation were identified in domestic turkeys that showed state of fixation towards alleles different than wild alleles. Conclusion The turkey genome is much less diverse with a relatively low frequency of heterozygous SNPs as compared to other livestock species like chicken and pig. The whole genome SNP discovery study in turkey resulted in the detection of 5.49 million putative SNPs compared to the reference genome. All commercial lines appear to share a common origin. Presence of different alleles/haplotypes in the SM population highlights that specific haplotypes have been selected in the modern domesticated turkey. PMID:22891612
FasL expression on human immune cells and cancer cells plays important roles in immune homeostasis and in cancer development. Our previous study suggests that polymorphisms in the FasL promoter can significantly affect the gene expression in human cells. In addition to the functional FasL SNP -844C>T (rs763110), three other SNPs (SNP -756A>G or rs2021837, SNP -478A>T or rs41309790, and SNP -205 C>G or rs74124371) exist in the proximal FasL promoter. In the current study, we established three major FasL hyplotypes in humans. Interestingly, a transcription motif search revealed that the FasL promoter possessed two consensus T-cell factor (TCF/LEF1) binding elements (TBEs), which is either polymorphic (SNP -205C>G) or close to the functional SNP -844C>T. Subsequently, we demonstrate that both FasL TBEs formed complexes with the TCF-4 and ?-catenin transcription factors in vitro and in vivo. Co-transfection of LEF-1 and ?-catenin transcription factors significantly increased FasL promoter activities, suggesting that FasL is a target gene of the ?-catenin/T-cell factor pathway. More importantly, we found that the rare allele (-205G) of the polymorphic FasL TBE (SNP -205C>G) failed to bind the TCF-4 transcription factor and that SNP -205 C>G significantly affected the promoter activity. Furthermore, promoter reporter assays revealed that FasL SNP haplotypes influenced promoter activities in human colon cancer cells and in human T cells. Finally, ?-catenin knockdown significantly decreased the FasL expression in human SW480 colon cancer cells. Collectively, our data suggest that ?-catenin may be involved in FasL gene regulation and that FasL expression is influenced by FasL SNP haplotypes, which may have significant implications in immune response and tumorigenesis. PMID:22022540
Wu, Jianming; Richards, Maureen H.; Huang, Jinhai; Al-Harthi, Lena; Xu, Xiulong; Lin, Rui; Xie, Fenglong; Gibson, Andrew W.; Edberg, Jeffrey C.; Kimberly, Robert P.
Background Hirschsprung's disease (HSCR) is a congenital disorder associated with the lack of intramural ganglion cells in the myenteric and sub-mucosal plexuses along varying segments of the gastrointestinal tract. The RET gene is the major gene implicated in this gastrointestinal disease. A highly recurrent mutation in RET (RETR114H) has recently been identified in ?6–7% of the Chinese HSCR patients which, to date, has not been found in Caucasian patients or controls nor in Chinese controls. Due to the high frequency of RETR114H in this population, we sought to investigate whether this mutation may be a founder HSCR mutation in the Chinese population. Methodology and Principal Findings To test whether all RETR114 were originated from a single mutational event, we predicted the approximate age of RETR114H by applying a Bayesian method to RET SNPs genotyped in 430 Chinese HSCR patients (of whom 25 individuals had the mutation) to be between 4–23 generations old depending on growth rate. We reasoned that if RETR114H was a founder mutation then those with the mutation would share a haplotype on which the mutation resides. Including SNPs spanning 509.31 kb across RET from a recently obtained 500 K genome-wide dataset for a subset of 181 patients (14 RETR114H patients), we applied haplotype estimation methods to determine whether there were any segments shared between patients with RETR114H that are not present in those without the mutation or controls. Analysis yielded a 250.2 kb (51 SNP) shared segment over the RET gene (and downstream) in only those patients with the mutation with no similar segments found among other patients. Conclusions This suggests that RETR114H is a founder mutation for HSCR in the Chinese population. PMID:20532249
Cornes, Belinda K.; Tang, Clara S.; Leon, Thomas Y. Y.; Hui, Kenneth J. W. S.; So, Man-Ting; Miao, Xiaoping; Cherny, Stacey S.; Sham, Pak C.; Tam, Paul K. H.; Garcia-Barcelo, Maria-Merce
Weighted SNP set analysis in genome-wide association study.
Genome-wide association studies (GWAS) are popular for identifying genetic variants which are associated with disease risk. Many approaches have been proposed to test multiple single nucleotide polymorphisms (SNPs) in a region simultaneously which considering disadvantages of methods in single locus association analysis. Kernel machine based SNP set analysis is more powerful than single locus analysis, which borrows information from SNPs correlated with causal or tag SNPs. Four types of kernel machine functions and principal component based approach (PCA) were also compared. However, given the loss of power caused by low minor allele frequencies (MAF), we conducted an extension work on PCA and used a new method called weighted PCA (wPCA). Comparative analysis was performed for weighted principal component analysis (wPCA), logistic kernel machine based test (LKM) and principal component analysis (PCA) based on SNP set in the case of different minor allele frequencies (MAF) and linkage disequilibrium (LD) structures. We also applied the three methods to analyze two SNP sets extracted from a real GWAS dataset of non-small cell lung cancer in Han Chinese population. Simulation results show that when the MAF of the causal SNP is low, weighted principal component and weighted IBS are more powerful than PCA and other kernel machine functions at different LD structures and different numbers of causal SNPs. Application of the three methods to a real GWAS dataset indicates that wPCA and wIBS have better performance than the linear kernel, IBS kernel and PCA. PMID:24098741
Dai, Hui; Zhao, Yang; Qian, Cheng; Cai, Min; Zhang, Ruyang; Chu, Minjie; Dai, Juncheng; Hu, Zhibin; Shen, Hongbing; Chen, Feng
OBJECTIVE Vitamin A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A (RARA, RARB and RARG) and vitamin D receptor (VDR)/RXRA genes and inter-individual variations in immune responses after two doses of measles vaccine in 745 subjects. METHODS Using a tagSNP approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A and D receptor genes. RESULTS The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global p=0.013) and cytokine secretion levels, such as IL-10 (global p=0.006), IFN-? (global p=0.008), and TNF-? (global p=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype AAC was associated with higher (t-statistic 3.27, p=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic ?2.32, p=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype CTGGGCAA remained marginally significant (p<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-? Elispot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444 (global p=0.004) and rs6537944/rs3118571 (global p<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-?, IFN-?, IFN?-1, and TNF-? cytokine secretion. CONCLUSION Our results suggest that specific allelic variations and haplotypes in the vitamin A and D receptor genes may influence adaptive immune responses to measles vaccine. PMID:22082653
Ovsyannikova, Inna G.; Haralambieva, Iana H.; Vierkant, Robert A.; O'Byrne, Megan M.; Jacobson, Robert M.; Poland, Gregory A.
NSDL National Science Digital Library
This site from the Sudbury Neutrino Observatory provides an explanation of neutrinos and of the former discrepancy between theoretical models and solar neutrino data known as the Solar Neutrino Problem (SNP). The site contains a brief history of the study of neutrinos, a graph of the solar neutrinos spectrum, and a discussion of their flux. The role of the Sudbury Neutrino Observatory in collecting neutrinos data is also presented.
SNP ascertainment bias in population genetic analyses: Why it is important, and how to correct it
Summary Whole genome sequencing and SNP genotyping arrays can paint strikingly different pictures of demographic history and natural selection. This is because genotyping arrays contain biased sets of pre-ascertained SNPs. In this short review, we use comparisons between high-coverage whole genome sequences of African hunter-gatherers and data from genotyping arrays to highlight how SNP ascertainment bias distorts population genetic inferences. Sample sizes and the populations in which SNPs are discovered affect the characteristics of observed variants. We find that SNPs on genotyping arrays tend to be older and present in multiple populations. In addition, genotyping arrays cause allele frequency distributions to be shifted towards intermediate frequency alleles, and estimates of linkage disequilibrium are modified. Since population genetic analyses depend on allele frequencies it is imperative that researchers are aware of the effects of SNP ascertainment bias. With this in mind we describe multiple ways to correct for SNP ascertainment bias. PMID:23836388
Lachance, Joseph; Tishkoff, Sarah A.
Results of a haplotype-based GWAS for recurrent laryngeal neuropathy in the horse.
Recurrent laryngeal neuropathy (RLN) is a major upper-airway disease of horses that causes abnormal respiratory noise during exercise and can impair performance. Etiopathogenesis remains unclear but genetic factors have been suspected for many decades. The objective of this study was to identify risk loci associated with RLN. To that end we genotyped 234 cases (196 Warmbloods, 20 Trotters, 14 Thoroughbreds, and 4 Draft horses), 228 breed-matched controls, and 69 parents with the Illumina Equine SNP50 BeadChip. Using these data, we quantified population structure and performed single-marker and haplotype-based association studies, as well as family-based linkage analyses. We accounted for population stratification by modeling a random polygenic background effect with covariance structure estimated from genome-wide SNP data. Using the haplotype-based approach, we identified two genome-wide suggestive loci in Warmbloods, respectively on chromosomes 21 (p = 1.62 × 10(-6)) and 31 (p = 1.69 × 10(-5)). The two signals were driven by the enrichment of a "protective" haplotype in controls compared to cases. PMID:21698472
Dupuis, Marie-Capucine; Zhang, Zhiyan; Druet, Tom; Denoix, Jean-Marie; Charlier, Carole; Lekeux, Pierre; Georges, Michel
Association of prolactin haplotypes with reproductive traits in Tsaiya ducks.
A previous cDNA microarray study showed that the prolactin (PRL) gene may be involved in the duck ovarian follicle development and egg formation process. The purpose of this study was to investigate the relationship between PRL genotypes of single nucleotide polymorphism (SNP) and reproductive traits of Tsaiya ducks. Primer pairs for the coding regions in the PRL were designed based on the duck genomic sequence database. Polymorphisms were detected by polymerase chain reaction (PCR)-single strand polymorphism (SSCP) and were verified by DNA sequencing. Six novel SNPs (T233C, T295C, G309T, C381A, G3941T and A3975C) were identified in the 1972 bp region of duck PRL gene, and all of them were located in non-coding regions. Single SNP-trait association analysis showed that each SNP was associated with at least one duck reproductive trait (P<0.05). Haplotype combinations constructed on these SNPs were associated with egg weight at 40 weeks of age (EW40), fertility rate (FR) and maximum duration of fertility (MDF) (P<0.0001). In particular, diplotype H1H2 had positive effect on EW40, whereas it had negative effect on FR and MDF (P<0.05). Positive effects of the diplotype H1H5 were observed for FR and MDF, but a negative effect was observed for EW40 (P<0.05). This suggested that the PRL gene plays an important role in the regulation of egg weight and fertility-related traits and could be a potential marker in a marker assisted selection program during duck balancing selection. Further investigations on more duck populations with large sample sizes are needed to confirm this finding. PMID:22959514
Chang, Mu-Tzu; Cheng, Yu-Shin; Huang, Mu-Chiou
IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1? and C-reactive protein
Interleukin-1? (IL-1?) activates inflammatory mediator cascades and has been implicated in the pathogenesis of several diseases.\\u000a Single nucleotide polymorphisms (SNPs) of the IL1B promoter have been associated with various inflammatory diseases. We recently\\u000a reported that IL1B gene transcription was influenced by four promoter SNPs, and that individual SNP function in vitro was\\u000a governed by haplotype context. In the present study
John Rogus; James D. Beck; Steven Offenbacher; Kenneth Huttner; Licia Iacoviello; Maria Carmela Latella; Monica de Gaetano; Hwa-Ying Wang; Kenneth S. Kornman; Gordon W. Duff
Inferring selection intensity and allele age from multilocus haplotype structure.
It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144-0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories. PMID:23797107
Chen, Hua; Slatkin, Montgomery
Background E-selectin is implicated in various inflammatory processes and related disorders. We aimed to investigate the role of SELE-gene genotypes/haplotypes on plasma levels of MMP9 and sE-selectin in Taiwanese individuals. Methods Five hundred twenty individuals were enrolled. Seven tagging SELE single nucleotide polymorphisms were analyzed. Results SELE genotypes were found associated with MMP9 and sE-selectin levels. Multivariate analysis identified that the most significant genetic polymorphism (rs5368 genotype) was independently associated with MMP9 levels (P?0.001). One haplotype (GGAGAGT) was marginally associated with MMP9 levels (P?=?0.0490). One SELE SNP, (rs3917406, P?=?0.031) was associated with sE-selectin levels after adjusting for MMP9 and sICAM1 levels. Subgroup and interaction analysis revealed association of SELE SNP rs10800469 with sE-selectin levels only in the highest quartile of MMP9 level (P?=?0.002, interaction P?=?0.023). Haplotype analysis showed one haplotype (AAAAAGC) borderline associated with sE-selectin level (P?=?0.0511). Conclusion SELE genotypes/haplotypes are independently associated with MMP9 and E-selectin levels in Taiwanese individuals. The associations of SELE genotypes/haplotypes with sE-selectin levels are affected by MMP9 levels. PMID:23190470
SNP-SNP interactions in breast cancer susceptibility
Background Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. Methods In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. Results None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. Conclusion The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management. PMID:16672066
Onay, Venus Ummiye; Briollais, Laurent; Knight, Julia A; Shi, Ellen; Wang, Yuanyuan; Wells, Sean; Li, Hong; Rajendram, Isaac; Andrulis, Irene L; Ozcelik, Hilmi
[Haplotype analysis of serotonin 2A receptor gene polymorphisms and smoking behavior].
In this study, the relationship between the haplotypes consisting of single nucleotide polymorphisms (SNPs) of serotonin 2A receptor (5HT2AR) gene (HTR2A) 102T/C (rs6313) and -1438A/G (rs6311) and smoking behavior was studied among 101 smokers and 99 non-smokers. It was shown that the genotypic and allelic frequencies of these polymorphisms were not associated with the smoking behavior. However, according to haplotype analysis, higher haplotype 1 ((-1438G) G-(102)T) frequency was observed in smokers than in non-smokers (P < 0.05). Pairwise D' and gamma2 values between the two SNPs in this study were 0.916 and 0.805, respectively. The two SNPs thus showed strong linkage disequilibrium with each other. This study suggests that 5-HT2AR gene haplotype (G-T) may be related to smoking behavior. PMID:25069264
Narita, Shin; Nagahori, Kenta; Iwahashi, Kazuhiko; Numajiri, Maki; Yoshihara, Eiji; Nishizawa, Daisuke; Ikeda, Kazutaka; Ishigooka, Jun
Abstract Objective Significant evidence supports a genetic contribution to the development of posttraumatic stress disorder (PTSD). Three previous studies have demonstrated an association between PTSD and the nine repeat allele of the 3? untranslated region (3?UTR) variable number tandem repeat (VNTR) in the dopamine transporter (DAT, rs28363170). Recently a novel, functionally significant C/T single-nucleotide polymorphism (SNP) in the 3?UTR (rs27072) with putative interactions with the 3?VNTR, has been identified. To provide enhanced support for the role of DAT and striatal dopamine regulation in the development of PTSD, this study examined the impact of a haplotype defined by the C allele of rs27072 and the nine repeat allele of the 3?VNTR on PTSD diagnosis in young trauma-exposed children. Methods DAT haplotypes were determined in 150 trauma-exposed 3–6 year-old children. PTSD was assessed with a semistructured interview. After excluding double heterozygotes, analysis was performed on 143 total subjects. Haplotype was examined in relation to categorical and continuous measures of PTSD, controlling for trauma type and race. Additional analysis within the two largest race categories was performed, as other means of controlling for ethnic stratification were not available. Results The number of haplotypes (0, 1, or 2) defined by the presence of the nine repeat allele of rs28363170 (VNTR in the 3?UTR) and the C allele of rs27072 (SNP in the 3?UTR) was significantly associated with both the diagnosis of PTSD and total PTSD symptoms. Specifically, children with one or two copies of the haplotype had significantly more PTSD symptoms and were more likely to be diagnosed with PTSD than were children without this haplotype. Conclusions These findings extend previous findings associating genetic variation in the DAT with PTSD. The association of a haplotype in DAT with PTSD provides incremental traction for a model of genetic vulnerability to PTSD, a specific underlying mechanism implicating striatal dopamine regulation, and insight into potential future personalized interventions. PMID:23647133
Brett, Zoe H.; Henry, Caitlin; Scheeringa, Michael
SNP and haplotype identification of the wheat monomeric ?-amylase inhibitor genes
Seventy-three gene sequences encoding monomeric ?-amylase inhibitors were characterized from cultivated wheat "Chinese Spring",\\u000a group 6 nullisomic-tetrasomic lines of "Chinese Spring" and diploid putative progenitors of common wheat. The monomeric ?-amylase\\u000a inhibitors from the different sources shared very high homology (99.54%). The different ?-amylase inhibitors, which were determined\\u000a by the 24 single nucleotide polymorphisms (SNPs) of their gene sequences, were
Ji-Rui Wang; Yu-Ming Wei; Ze-Hong Yan; You-Liang Zheng
Genome-Wide Association Studies Using Haplotypes and Individual SNPs in Simmental Cattle
Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID:25330174
Wu, Yang; Fan, Huizhong; Wang, Yanhui; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Ren, HongYan; Gao, Huijiang
Genome-Wide Association Studies Using Haplotypes and Individual SNPs in Simmental Cattle.
Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID:25330174
Wu, Yang; Fan, Huizhong; Wang, Yanhui; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Ren, HongYan; Gao, Huijiang
A Powerful Test of Parent-of-Origin Effects for Quantitative Traits Using Haplotypes
Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing parent-of-origin effects have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this study, we develop a powerful maximum likelihood test to evaluate the parent-of-origin effects of SNPs on quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate parent-of-origin effects is to recruit one parent and as many offspring as possible under practical constraints. As a demonstration, we applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to test the parent-of-origin effects of the SNPs within the PPARGC1A, MTP and FABP2 genes on diabetes-related phenotypes, and found that several SNPs in the MTP gene show parent-of-origin effects on insulin and glucose levels. PMID:22174922
Feng, Rui; Wu, Yinghua; Jang, Gun Ho; Ordovas, Jose M.; Arnett, Donna
Design and Characterization of a 52K SNP Chip for Goats
The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50–60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID:24465974
Tosser-Klopp, Gwenola; Bardou, Philippe; Bouchez, Olivier; Cabau, Cedric; Crooijmans, Richard; Dong, Yang; Donnadieu-Tonon, Cecile; Eggen, Andre; Heuven, Henri C. M.; Jamli, Saadiah; Jiken, Abdullah Johari; Klopp, Christophe; Lawley, Cynthia T.; McEwan, John; Martin, Patrice; Moreno, Carole R.; Mulsant, Philippe; Nabihoudine, Ibouniyamine; Pailhoux, Eric; Palhiere, Isabelle; Rupp, Rachel; Sarry, Julien; Sayre, Brian L.; Tircazes, Aurelie; Jun Wang; Wang, Wen; Zhang, Wenguang
Design and characterization of a 52K SNP chip for goats.
The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50-60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo-chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID:24465974
Tosser-Klopp, Gwenola; Bardou, Philippe; Bouchez, Olivier; Cabau, Cédric; Crooijmans, Richard; Dong, Yang; Donnadieu-Tonon, Cécile; Eggen, André; Heuven, Henri C M; Jamli, Saadiah; Jiken, Abdullah Johari; Klopp, Christophe; Lawley, Cynthia T; McEwan, John; Martin, Patrice; Moreno, Carole R; Mulsant, Philippe; Nabihoudine, Ibouniyamine; Pailhoux, Eric; Palhičre, Isabelle; Rupp, Rachel; Sarry, Julien; Sayre, Brian L; Tircazes, Aurélie; Jun Wang; Wang, Wen; Zhang, Wenguang
A haplotype similarity based transmission/disequilibrium test under founder heterogeneity.
Taking advantage of increasingly available high-density single nucleotide polymorphisms (SNP) markers across the genome, various types of transmission/disequilibrium tests (TDT) using haplotype information have been developed. A practical challenge arising in such studies is the possibility that transmitted haplotypes have inherited disease-causing mutations from different ancestral chromosomes, or do not bear any disease-causing mutations (founder heterogeneity). To reduce the loss of signal strength due to founder heterogeneity, we propose an SP-TDT test that combines a sequential peeling procedure with the haplotype similarity based TDT method. The proposed SP-TDT method is applicable to any size of nuclear family with or without ambiguous phase information. Simulation studies suggest that the SP-TDT method has the correct type I error rate in stratified populations, and enhanced power compared with some existing haplotype similarity based TDT methods. Finally, we apply the proposed method to study the association of the leptin gene with obesity from the National Heart, Lung, and Blood Institute Family Heart Study. PMID:15996173
Yu, Kai; Zhang, Shuanglin; Borecki, Ingrid; Kraja, Aldi; Xiong, Chengjie; Myers, Richard; Province, Michael
Development of the catfish 250K SNP array for genome-wide association studies
Background Quantitative traits, such as disease resistance, are most often controlled by a set of genes involving a complex array of regulation. The dissection of genetic basis of quantitative traits requires large numbers of genetic markers with good genome coverage. The application of next-generation sequencing technologies has allowed discovery of over eight million SNPs in catfish, but the challenge remains as to how to efficiently and economically use such SNP resources for genetic analysis. Results In this work, we developed a catfish 250K SNP array using Affymetrix Axiom genotyping technology. The SNPs were obtained from multiple sources including gene-associated SNPs, anonymous genomic SNPs, and inter-specific SNPs. A set of 640K high-quality SNPs obtained following specific requirements of array design were submitted. A panel of 250,113 SNPs was finalized for inclusion on the array. The performance evaluated by genotyping individuals from wild populations and backcross families suggested the good utility of the catfish 250K SNP array. Conclusions This is the first high-density SNP array for catfish. The array should be a valuable resource for genome-wide association studies (GWAS), fine QTL mapping, high-density linkage map construction, haplotype analysis, and whole genome-based selection. PMID:24618043
Major Soybean Maturity Gene Haplotypes Revealed by SNPViz Analysis of 72 Sequenced Soybean Genomes
In this Genomics Era, vast amounts of next-generation sequencing data have become publicly available for multiple genomes across hundreds of species. Analyses of these large-scale datasets can become cumbersome, especially when comparing nucleotide polymorphisms across many samples within a dataset and among different datasets or organisms. To facilitate the exploration of allelic variation and diversity, we have developed and deployed an in-house computer software to categorize and visualize these haplotypes. The SNPViz software enables users to analyze region-specific haplotypes from single nucleotide polymorphism (SNP) datasets for different sequenced genomes. The examination of allelic variation and diversity of important soybean [Glycine max (L.) Merr.] flowering time and maturity genes may provide additional insight into flowering time regulation and enhance researchers' ability to target soybean breeding for particular environments. For this study, we utilized two available soybean genomic datasets for a total of 72 soybean genotypes encompassing cultivars, landraces, and the wild species Glycine soja. The major soybean maturity genes E1, E2, E3, and E4 along with the Dt1 gene for plant growth architecture were analyzed in an effort to determine the number of major haplotypes for each gene, to evaluate the consistency of the haplotypes with characterized variant alleles, and to identify evidence of artificial selection. The results indicated classification of a small number of predominant haplogroups for each gene and important insights into possible allelic diversity for each gene within the context of known causative mutations. The software has both a stand-alone and web-based version and can be used to analyze other genes, examine additional soybean datasets, and view similar genome sequence and SNP datasets from other species. PMID:24727730
Langewisch, Tiffany; Zhang, Hongxin; Vincent, Ryan; Joshi, Trupti; Xu, Dong; Bilyeu, Kristin
Ancient mitochondrial haplotypes and evidence for intragenic recombination in a gynodioecious plant.
Because of their extremely low nucleotide mutation rates, plant mitochondrial genes are generally not expected to show variation within species. Remarkably, we found nine distinct cytochrome b sequence haplotypes in the gynodioecious alpine plant Silene acaulis, with two or more haplotypes coexisting locally in each of three sampled regions. Moreover, there is evidence for intragenic recombination in the history of the haplotype sample, implying at least transient heteroplasmy of mitochondrial DNA (mtDNA). Heteroplasmy might be achieved by one of two potential mechanisms, either continuous coexistence of subgenomic fragments in low stoichiometry, or occasional paternal leakage of mtDNA. On the basis of levels of synonymous nucleotide substitutions, the average divergence time between haplotypes is estimated to be at least 15 million years. Ancient coalescence of extant haplotypes is further indicated by the paucity of fixed differences in haplotypes obtained from related species, a pattern expected under trans-specific evolution. Our data are consistent with models of frequency-dependent selection on linked cytoplasmic male-sterility factors, the putative molecular basis of females in gynodioecious populations. However, associations between marker loci and the inferred male-sterility genes can be maintained only with very low rates of recombination. Heteroplasmy and recombination between divergent haplotypes imply unexplored consequences for the evolutionary dynamics of gynodioecy, a widespread plant breeding system. PMID:12192087
Städler, Thomas; Delph, Lynda F
Ancient mitochondrial haplotypes and evidence for intragenic recombination in a gynodioecious plant
Because of their extremely low nucleotide mutation rates, plant mitochondrial genes are generally not expected to show variation within species. Remarkably, we found nine distinct cytochrome b sequence haplotypes in the gynodioecious alpine plant Silene acaulis, with two or more haplotypes coexisting locally in each of three sampled regions. Moreover, there is evidence for intragenic recombination in the history of the haplotype sample, implying at least transient heteroplasmy of mitochondrial DNA (mtDNA). Heteroplasmy might be achieved by one of two potential mechanisms, either continuous coexistence of subgenomic fragments in low stoichiometry, or occasional paternal leakage of mtDNA. On the basis of levels of synonymous nucleotide substitutions, the average divergence time between haplotypes is estimated to be at least 15 million years. Ancient coalescence of extant haplotypes is further indicated by the paucity of fixed differences in haplotypes obtained from related species, a pattern expected under trans-specific evolution. Our data are consistent with models of frequency-dependent selection on linked cytoplasmic male-sterility factors, the putative molecular basis of females in gynodioecious populations. However, associations between marker loci and the inferred male-sterility genes can be maintained only with very low rates of recombination. Heteroplasmy and recombination between divergent haplotypes imply unexplored consequences for the evolutionary dynamics of gynodioecy, a widespread plant breeding system. PMID:12192087
Stadler, Thomas; Delph, Lynda F.
The recent discovery of bovine haplotypes with negative effects on fertility in the Brown Swiss, Holstein, and Jersey breeds has allowed producers to identify carrier animals using commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the causative mutations underlying defective bovine embryo development contained within three of these haplotypes (Brown Swiss haplotype 1 and Holstein haplotypes 2 and 3) by combining exome capture with next generation sequencing. Of the 68,476,640 sequence variations (SV) identified, only 1,311 genome-wide SNP were concordant with the haplotype status of 21 sequenced carriers. Validation genotyping of 36 candidate SNP identified only 1 variant that was concordant to Holstein haplotype 3 (HH3), while no variants located within the refined intervals for HH2 or BH1 were concordant. The variant strictly associated with HH3 is a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. Because only exome capture sequencing was used, we could not rule out the possibility that the true causative mutation for HH3 might lie in a non-exonic genomic location. Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation. The absence of concordant variations for HH2 or BH1 suggests either the underlying causative mutations lie within a non-exomic region or in exome regions not covered by the capture array. PMID:24667746
McClure, Matthew C; Bickhart, Derek; Null, Dan; Vanraden, Paul; Xu, Lingyang; Wiggans, George; Liu, George; Schroeder, Steve; Glasscock, Jarret; Armstrong, Jon; Cole, John B; Van Tassell, Curtis P; Sonstegard, Tad S
A posteriori and modified granddaughter designs were applied to determine haplotype effects for Holstein bulls and cows with BovineSNP50 [~50,000 single nucleotide polymorphisms (SNP); Illumina Inc., San Diego, CA] genotypes. The a posteriori granddaughter design was applied to 52 sire families, each with ?100 genotyped sons with genetic evaluations based on progeny tests. For 33 traits (milk, fat, and protein yields; fat and protein percentages; somatic cell score; productive life; daughter pregnancy rate; heifer and cow conception rates; service-sire and daughter calving ease; service-sire and daughter stillbirth; 18 conformation traits; and net merit), the analysis was applied to the autosomal segment with the SNP with the greatest effect in the genomic evaluation of each trait. All traits except 2 had a within-family haplotype effect. The same design was applied with the genetic evaluations of sons corrected for SNP effects associated with chromosomes besides the one under analysis. The number of within-family contrasts was 166 without adjustment and 211 with adjustment. Of the 52 bulls analyzed, 36 had BovineHD (high density; Illumina Inc.) genotypes that were used to test for concordance between sire quantitative trait loci and SNP genotypes; complete concordance was not obtained for any effects. Of the 31 traits with effects from the a posteriori granddaughter design, 21 were analyzed with the modified granddaughter design. Only sires with a contrast for the a posteriori granddaughter design and ?200 granddaughters with a record usable for genetic evaluation were included. Calving traits could not be analyzed because individual cow evaluations were not computed. Eight traits had within-family haplotype effects. With respect to milk and fat yields and fat percentage, the results on Bos taurus autosome (BTA) 14 corresponded to the hypothesis that a missense mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is the main causative mutation, although other polymorphisms in that gene also modify fat yield and percentage. The positive allele for protein concentration was less frequent, which indicated that selection on that locus could be effective. Although the results can be used to determine causative polymorphisms for most of the analyzed traits, complete DNA sequencing of most of the analyzed sires probably will be required. PMID:23746582
Weller, J I; VanRaden, P M; Wiggans, G R
SNPsyn: detection and exploration of SNP-SNP interactions.
SNPsyn (http://snpsyn.biolab.si) is an interactive software tool for the discovery of synergistic pairs of single nucleotide polymorphisms (SNPs) from large genome-wide case-control association studies (GWAS) data on complex diseases. Synergy among SNPs is estimated using an information-theoretic approach called interaction analysis. SNPsyn is both a stand-alone C++/Flash application and a web server. The computationally intensive part is implemented in C++ and can run in parallel on a dedicated cluster or grid. The graphical user interface is written in Adobe Flash Builder 4 and can run in most web browsers or as a stand-alone application. The SNPsyn web server hosts the Flash application, receives GWAS data submissions, invokes the interaction analysis and serves result files. The user can explore details on identified synergistic pairs of SNPs, perform gene set enrichment analysis and interact with the constructed SNP synergy network. PMID:21576219
Curk, Tomaz; Rot, Gregor; Zupan, Blaz
Bovine leukocyte antigen (BoLA), the major histocompatibility complex of cattle, is one of the most polymorphic gene clusters. We genotyped a population of 109 Japanese Black and 39 Holstein cattle to analyze their BoLA class II haplotypes, BoLA-DRB3 locus, 5 BoLA-DQA loci, and 5 BoLA-DQB loci. We identified 26 previously reported DRB3 alleles, 22 previously reported and 3 new DQA alleles, and 24 previously reported and 6 new DQB alleles. A dendrogram was constructed based on the predicted amino acid sequences of the ?1 or ?1 domains encoded by BoLA-DQA or -DQB alleles, which revealed that DQA alleles were clustered into 5 loci, whereas DQB alleles could not be clearly assigned to specific DQB loci. The BoLA-DRB3-DQA-DQB haplotypes were sorted by sequential analytical processes, and 42 distinct haplotypes, including 11 previously published haplotypes and 31 novel haplotypes, were defined. Strong linkage disequilibrium was present in the BoLA genes. We also compared DRB3-DQA1 haplotype frequencies between 507 Japanese Black and 143 Holstein cattle. Thirty-nine DRB3-DQA1 haplotypes were identified, including 29 haplotypes from Japanese Black and 22 haplotypes from Holstein cattle. The majority of the haplotypes could be identified in both breeds, although several haplotypes were identified in only a single breed. This is the first report presenting a detailed study of the BoLA class II haplotype in Japanese Black and Holstein cattle in Japan. PMID:22192221
Miyasaka, T; Takeshima, S-N; Sentsui, H; Aida, Y
CaSNP: a database for interrogating copy number alterations of cancer genome from SNP array data
CaSNP: a database for interrogating copy number alterations of cancer genome from SNP array data genes and infer cancer mechanisms. Although single-nucleotide polymorphism (SNP) arrays have infor- mation from SNP array data is still lacking. We developed a web-based CaSNP (http
Liu, Xiaole Shirley
Network analysis of human Y microsatellite haplotypes
To investigate the utility of Y chromosome micro- satellites for studying human male-lineage evolution, we typed samples from three populations for five tetranucleotide repeats and an Alu insertion poly- morphism. We found very high levels of haplotype diversity and evidence that most mutations involve the gain or loss of only one repeat unit, implying that any given microsatellite haplotype may
Gillian Cooper; William Amos; Dorota Hoffman; David C. Rubinsztein
Most parsimonious haplotype allele sharing determination
Background The "common disease – common variant" hypothesis and genome-wide association studies have achieved numerous successes in the last three years, particularly in genetic mapping in human diseases. Nevertheless, the power of the association study methods are still low, in particular on quantitative traits, and the description of the full allelic spectrum is deemed still far from reach. Given increasing density of single nucleotide polymorphisms available and suggested by the block-like structure of the human genome, a popular and prosperous strategy is to use haplotypes to try to capture the correlation structure of SNPs in regions of little recombination. The key to the success of this strategy is thus the ability to unambiguously determine the haplotype allele sharing status among the members. The association studies based on haplotype sharing status would have significantly reduced degrees of freedom and be able to capture the combined effects of tightly linked causal variants. Results For pedigree genotype datasets of medium density of SNPs, we present two methods for haplotype allele sharing status determination among the pedigree members. Extensive simulation study showed that both methods performed nearly perfectly on breakpoint discovery, mutation haplotype allele discovery, and shared chromosomal region discovery. Conclusion For pedigree genotype datasets, the haplotype allele sharing status among the members can be deterministically, efficiently, and accurately determined, even for very small pedigrees. Given their excellent performance, the presented haplotype allele sharing status determination programs can be useful in many downstream applications including haplotype based association studies. PMID:19379528
Cai, Zhipeng; Sabaa, Hadi; Wang, Yining; Goebel, Randy; Wang, Zhiquan; Xu, Jiaofen; Stothard, Paul; Lin, Guohui
Myelodysplastic syndromes have increased in frequency and incidence in the American population, but patient prognosis has not significantly improved over the last decade. Such improvements could be realized if biomarkers for accurate diagnosis and prognostic stratification were successfully identified. In this study, we propose a method that associates two state-of-the-art array technologies—single nucleotide polymorphism (SNP) array and gene expression array—with gene motifs considered transcription factor-binding sites (TFBS). We are particularly interested in SNP-containing motifs introduced by genetic variation and mutation as TFBS. The potential regulation of SNP-containing motifs affects only when certain mutations occur. These motifs can be identified from a group of co-expressed genes with copy number variation. Then, we used a sliding window to identify motif candidates near SNPs on gene sequences. The candidates were filtered by coarse thresholding and fine statistical testing. Using the regression-based LARS-EN algorithm and a level-wise sequence combination procedure, we identified 28 SNP-containing motifs as candidate TFBS. We confirmed 21 of the 28 motifs with ChIP-chip fragments in the TRANSFAC database. Another six motifs were validated by TRANSFAC via searching binding fragments on co-regulated genes. The identified motifs and their location genes can be considered potential biomarkers for myelodysplastic syndromes. Thus, our proposed method, a novel strategy for associating two data categories, is capable of integrating information from different sources to identify reliable candidate regulatory SNP-containing motifs introduced by genetic variation and mutation. PMID:23327800
Fan, Jing; Dy, Jennifer G.; Chang, Chung-Che; Zhou, Xiaobo
The goal of the SNP500Cancer project is to resequence 102 reference samples to find known or newly discovered single nucleotide polymorphisms (SNPs) which are of immediate importance to molecular epidemiology studies in cancer. SNP500Cancer provides a central resource for sequence verification of SNPs.
Haplotype analysis in Huntington desease provides insights into mechanisms of CAG repeat expansion
Huntington disease (HD) is one of 7 disorders now known to be caused by expansion of a trinucleotide repeat. The HD mutation is a polymorphic trinucleotide (CAG) repeat in the 5{prime} region of a novel gene that expands beyond the normal range of 10-35 repeats in persons destined to develop the disease. Haplotype analysis of other dynamic mutation disorders such as myotonic dystrophy and Fragil X have suggested that a rare ancestral expansion event on a normal chromosome is followed by subsequent expansion events, resulting in a pool of chromosomes in the premutation range, which is inherently unstable and prone to further multiple expansion events leading to disease range chromosomes. Haplotype analysis of 67 HD and 84 control chromosomes using 5 polymorphic markers, both intragenic and 5{prime} to the disease mutation, demonstrate that multiple haplotypes underlie HD. However, 94% of the chromosomes can be grouped under two major haplotypes. These two haplotypes are also present in the normal population. A third major haplotype is seen on 38% of normal chromosomes but rarely on HD chromosomes (6%). CAG lengths on the normal chromosomes with the two haplotypes seen in the HD population are higher than those seen on the normal chromosomes with the haplotype rarely seen on HD chromosomes. Furthermore, in populations with a diminished frequency of HD, CAG length on normal chromosomes is significantly less than other populations with higher prevalence rates for HD. These data suggest that CAG length on normal chromosomes may be a significant factor contributing to repeat instability that eventually leads to chromosomes with CAG repeat lengths in the HD range. Haplotypes on the HD chromosomes are identical to those normal chromosomes which have CAG lengths in the high range of normal, suggesting that further expansions of this pool of chromosomes leads to chromosomes with CAG repeat sizes within the disease range, consistent with a multistep model.
Andrew, S.E.; Goldberg, Y.P.; Squitieri, F. [Univ. of British Columbia, Vancouver (Canada)] [and others
The objectives of this study were to make subsets of high-density (HD) loci based on localized haplotype clusters, without loss of genomic information, to reduce computing time compared with the use of all HD loci and to investigate the effect on the reliability of the direct genomic value (DGV) when using this HD subset based on localized haplotype clusters in the genomic evaluation for Holstein-Friesians. The DNA was isolated from semen samples of 548 bulls (key ancestors) of the EuroGenomics Consortium, a collaboration between 4 European dairy cattle breeding organizations and scientific partners. These bulls were genotyped with the BovineHD BeadChip [~777,000 (777K) single nucleotide polymorphisms (SNP); Illumina Inc., San Diego, CA] and used to impute all 30,483 Holstein-Friesians from the BovineSNP50 BeadChip [~50,000 (50K) SNP; Illumina Inc.] to HD, using the BEAGLE software package. The final data set consisted of 30,483 animals and 603,145 SNP. For each locus, localized haplotype clusters (i.e., edges of the fitted graph model) identifications were obtained from BEAGLE. Three subsets [38,000 (38K), 116,000 (116K), and 322,000 (322K) loci] were made based on deleting obsolete loci (i.e., loci that do not give extra information compared with the neighboring loci). A fourth data set was based on 38K SNP, which is currently used for routine genomic evaluation at the Cattle Improvement Cooperative (CRV, Arnhem, the Netherlands). A validation study using the HD loci subsets based on localized haplotype clusters was performed for 9 traits (production, conformation, and functional traits). Error of imputation from 50K to HD averaged 0.78%. Three thresholds (0.17, 0.05, and 0.008%) were used for the identification of obsolete HD loci based on localized haplotype clusters to obtain a desired number of HD loci (38K, 116K, and 322K). On average, 46% (using threshold 0.008%) to 93% (using threshold 0.17%) of HD loci were eliminated. The computing time was about 9 d for 38K loci, 15.5d for 116K loci, 21d for 322K loci, and 7.5 d for 38K SNP. The increase in reliability of DGV compared with pedigree-based estimated breeding values for kilograms of protein was similar for 322K and 116K loci (30.7%), but was 1.5 to 2% higher compared with 38K loci and 38K SNP. Averaged over 9 traits, subset 116K loci resulted in a higher increase in reliability compared with 38K loci and 38K SNP. Eliminating obsolete loci enormously decreased the amount of data to be analyzed for genomic evaluations. The more HD loci used in a genomic evaluation, the higher the increase in reliability of DGV. It is possible to increase the reliability of DGV by 1 to 2% compared with the SNP currently used for routine genomic evaluation. PMID:24140319
Schopen, G C B; Schrooten, C
Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis has been associated with the etiology of major depression. One of the factors underlying altered glucocorticoid signaling might be variability of the glucocorticoid receptor gene (GR, NR3C1). GR polymorphisms have been associated with variability in glucocorticoid sensitivity and endocrine responses to psychosocial stress. Furthermore, a common GR SNP (rs10482605), located in the promoter region, has been associated with major depression. We performed functional characterization of this SNP in vitro using a reporter gene assay under different stimulation conditions. Furthermore, we genotyped 219 subjects previously genotyped for four common GR SNPs to further characterize GR haplotype structure. The minor C allele of the rs10482605 SNP showed reduced transcriptional activity under unstimulated conditions and under different stimulation conditions in two brain derived cell lines. Linkage analyses revealed that the rs10482605 SNP is in high linkage disequilibrium with a A/G SNP in exon 9beta (rs6198), associated with relative glucocorticoid resistance and increased GRbeta mRNA stability. We provide evidence that two functional GR SNPs in linkage disequilibrium are responsible for both regulation of GR expression and mRNA stability. This newly characterized haplotype could increase the risk for the development of stress related disorders, including major depression. PMID:18663733
Kumsta, Robert; Moser, Dirk; Streit, Fabian; Koper, Jan Willem; Meyer, Jobst; Wüst, Stefan
Haplotype Analyses of DNA Repair Gene Polymorphisms and Their Role in Ulcerative Colitis
Ulcerative colitis (UC) is a major clinical form of inflammatory bowel disease. UC is characterized by mucosal inflammation limited to the colon, always involving the rectum and a variable extent of the more proximal colon in a continuous manner. Genetic variations in DNA repair genes may influence the extent of repair functions, DNA damage, and thus the manifestations of UC. This study thus evaluated the role of polymorphisms of the genes involved in DNA repair mechanisms. A total of 171 patients and 213 controls were included. Genotyping was carried out by ARMS PCR and PCR-RFLP analyses for RAD51, XRCC3 and hMSH2 gene polymorphisms. Allelic and genotypic frequencies were computed in both control & patient groups and data was analyzed using appropriate statistical tests. The frequency of 'A' allele of hMSH2 in the UC group caused statistically significant increased risk for UC compared to controls (OR 1.64, 95% CI 1.16–2.31, p?=?0.004). Similarly, the CT genotype of XRCC3 gene was predominant in the UC group and increased the risk for UC by 1.75 fold compared to controls (OR 1.75, 95% CI 1.15–2.67, p?=?0.03), further confirming the risk of 'T' allele in UC. The GC genotype frequency of RAD51 gene was significantly increased (p?=?0.02) in the UC group (50.3%) compared to controls (38%). The GC genotype significantly increased the risk for UC compared to GG genotype by 1.73 fold (OR 1.73, 95% CI 1.14–2.62, p?=?0.02) confirming the strong association of 'C' allele with UC. Among the controls, the SNP loci combination of hMSH2:XRCC3 were in perfect linkage. The GTC and ACC haplotypes were found to be predominant in UC than controls with a 2.28 and 2.93 fold significant increase risk of UC. PMID:25247297
Bardia, Avinash; Tiwari, Santosh K.; Vishwakarma, Sandeep K.; Habeeb, Md. Aejaz; Nallari, Pratibha; Sultana, Shaik A.; Pasha, Shaik A.; Reddy, Yugandhar P.; Khan, Aleem A.
Background Following transmission, HIV-1 evolves into a diverse population, and next generation sequencing enables us to detect variants occurring at low frequencies. Studying viral evolution at the level of whole genomes was hitherto not possible because next generation sequencing delivers relatively short reads. Results We here provide a proof of principle that whole HIV-1 genomes can be reliably reconstructed from short reads, and use this to study the selection of immune escape mutations at the level of whole genome haplotypes. Using realistically simulated HIV-1 populations, we demonstrate that reconstruction of complete genome haplotypes is feasible with high fidelity. We do not reconstruct all genetically distinct genomes, but each reconstructed haplotype represents one or more of the quasispecies in the HIV-1 population. We then reconstruct 30 whole genome haplotypes from published short sequence reads sampled longitudinally from a single HIV-1 infected patient. We confirm the reliability of the reconstruction by validating our predicted haplotype genes with single genome amplification sequences, and by comparing haplotype frequencies with observed epitope escape frequencies. Conclusions Phylogenetic analysis shows that the HIV-1 population undergoes selection driven evolution, with successive replacement of the viral population by novel dominant strains. We demonstrate that immune escape mutants evolve in a dependent manner with various mutations hitchhiking along with others. As a consequence of this clonal interference, selection coefficients have to be estimated for complete haplotypes and not for individual immune escapes. PMID:24996694
Haplotype approach for association analysis on hypertension
We applied a gene-based haplotype approach for the genome-wide association analysis on hypertension using Genetic Analysis Workshop 18 data for unrelated individuals. Association of single-nucleotide polymorphisms and clinical outcome were first assessed and haplotypes were then constructed based on the gene information and the linkage disequilibrium plot. Extensive haplotype analysis was also conducted for the whole chromosome 3. We found 1 block from the ULK4 gene and 2 blocks from the LOC64690 gene that were significantly associated with hypertension.
Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus. PMID:22690378
Johnson, Nicole V.; Ahn, Sun Hee; Deshmukh, Hitesh; Levin, Mikhail K.; Nelson, Charlotte L.; Scott, William K.; Allen, Andrew; Fowler, Vance G.; Cowell, Lindsay G.
Suicide is a significant public health issue and a major cause of death throughout the world. According to WHO it accounts for almost 2% of deaths worldwide. The etiology of suicidal behavior is complex but the results of many studies suggest that genetic determinants are of significant importance. In our study,- we have analyzed selected SNPs polymorphisms in the DRD2 and ANKK1 genes in patients with alcohol dependence syndrome (169 Caucasian subjects) including a subgroup of individuals (n?=?61) who have experienced at least one suicide attempt. The aim of the study was to verify if various haplotypes of selected genes, comprising Taq1A, Taq1B, and Taq1D single nucleotide polymorphisms (SNP), play any role in the development of alcohol dependence and suicidal behavior. The control group comprised 157 unrelated individuals matched for ethnicity, gender,- and age and included no individuals with mental disorders. All subjects were recruited in the North West region of Poland. The study showed that alcohol dependent subjects with a history of at least one suicidal attempt were characterized by a significantly higher frequency of the T-G-A2 haplotype when compared to individuals in whom alcohol dependence was not associated with suicidal behavior (p?=?0.006). It appears that studies based on identifying correlation between SNPs is the future for research on genetic risk factors that contribute to the development of alcohol addiction and other associated disorders. To sum up, there is a necessity to perform further research to explain dependencies between the dopaminergic system, alcohol use disorders and suicidal behavior. PMID:25415204
Jasiewicz, Andrzej; Samochowiec, Agnieszka; Samochowiec, Jerzy; Ma?ecka, Iwona; Suchanecka, Aleksandra; Grzywacz, Anna
HLA B-C haplotypes exhibit common disequilibria in populations drawn from four continents, indicating that they are subject to broadly active selective forces. However, the A-B and A-C associations we have examined show no consistent disequilibrium pattern, leaving open the possibility that these disequilibria are due to descent from common progenitors. By examining HLA haplotype distributions, I have explored the implications that would follow from the hypothesis that biological selection played no role in determining A-C disequilibria in 10 diverse tribes of the lower Amazon Basin. Certain haplotypes are in strong positive disequilibria across a broad geographic area, suggesting that members of diverse tribes descend from common ancestors. On the basis of the extent of diffusion of the components of these haplotypes, one can estimate that the progenitors lived less than 6,000 years ago. One widely encountered lineage entered the area within the last 1,200 years. When haplotype frequencies are used in genetic distance measurements, they give a pattern of relationships very similar to that obtained by conventional chord measurements based on several genetic markers; but more than that, when individual haplotype disequilibria in the several tribes are compared, multiple origins of a single tribe are discernible and relationships are revealed that correlate more closely to geographic and linguistic patterns than do the genetic distance measurements. PMID:6595946
Black, F L
Rapid haplotype inference for nuclear families
Hapi is a new dynamic programming algorithm that ignores uninformative states and state transitions in order to efficiently compute minimum-recombinant and maximum likelihood haplotypes. When applied to a dataset containing ...
Williams, Amy L.
SNP genotyping by DNA photoligation: application to SNP detection of genes from food crops
NASA Astrophysics Data System (ADS)
We describe a simple and inexpensive single-nucleotide polymorphism (SNP) typing method, using DNA photoligation with 5-carboxyvinyl-2'-deoxyuridine and two fluorophores. This SNP-typing method facilitates qualitative determination of genes from indica and japonica rice, and showed a high degree of single nucleotide specificity up to 10 000. This method can be used in the SNP typing of actual genomic DNA samples from food crops.
Yoshimura, Yoshinaga; Ohtake, Tomoko; Okada, Hajime; Ami, Takehiro; Tsukaguchi, Tadashi; Fujimoto, Kenzo
Background Bcl-3 as an oncoprotein is overexpressed in nasopharyngeal carcinoma (NPC). Nedd4 binding protein 2 (N4BP2), which is located in the NPC susceptibility locus, is a Bcl-3 binding protein. This study is aimed to explore the association between N4BP2 genetic polymorphism and the risk of NPC. Methods We performed a hospital-based case-control study, including 531 sporadic NPC and 480 cancer-free control subjects from southern China. PCR-sequencing was carried out on Exons, promoter region and nearby introns of the N4BP2 gene. The expression pattern of N4BP2 and Bcl-3 was also analyzed. Results We observed a statistically significant difference in haplotype blocks ATTA and GTTG between cases and controls. In addition, three novel SNPs were identified, two of which were in exons (loc123-e3l-snp2, position 39868005, A/G, Met171Val; RS17511668-SNP2, position 39926432, G/A, Glu118Lys), and one was in the intron6 (RS794001-SNP1, position 39944127, T/G). Moreover, N4BP2 was at higher levels in a majority of tumor tissues examined, relative to paired normal tissues. Conclusion These data suggest that haplotype blocks ATTA and GTTG of N4BP2 is correlation with the risk of sporadic nasopharyngeal carcinoma in the Southern Chinese population and N4BP2 has a potential role in the development of NPC. PMID:17626640
Zheng, Mei-Zhen; Qin, Hai-De; Yu, Xing-Juan; Zhang, Ru-Hua; Chen, Li-Zhen; Feng, Qi-Sheng; Zeng, Yi-Xin
SNP: An Interface for Secure Network Programming
SNP provides a high-level abstraction for secure end-to- end network communications. It supports both stream and datagram semantics with security guarantees (e.g., data origin authenticity, data integrity and data confidentiality). It is designed to resemble the Berkeley sockets interface so that security can be easily retrofitted into existing socket programs with only minor modifications. SNP is built on top of
Thomas Y. C. Woo; Raghuram Bindignavle; Shaowen Su; Simon S. Lam
Managing large SNP datasets with SNPpy.
Using relational databases to manage SNP datasets is a very useful technique that has significant advantages over alternative methods, including the ability to leverage the power of relational databases to perform data validation, and the use of the powerful SQL query language to export data. SNPpy is a Python program which uses the PostgreSQL database and the SQLAlchemy Python library to automate SNP data management. This chapter shows how to use SNPpy to store and manage large datasets. PMID:23756888
Mitha, Faheem
The Invader ® assay for SNP genotyping
The Invader® assay uses a structure-specific flap endonuclease (FEN) to cleave a three-dimensional complex formed by hybridization of allele-specific overlapping oligonucleotides to target DNA containing a single nucleotide polymorphism (SNP) site. Annealing of the oligonucleotide complementary to the SNP allele in the target molecule triggers the cleavage of the oligonucleotide by cleavase, a thermostable FEN. Cleavage can be detected by
Michael Olivier
Background Next-generation sequencing technologies are widely used for detection of millions of Single Nucleotide Polymorphisms (SNPs) and also provide a means of assessing their variation. This information is useful for composing subsets of highly informative SNPs for region-specific or genome-wide analysis and to identify mutations regulating phenotypic differences within or between populations. In this study, we investigated the sensitivity of SNP detection and introduced the flanking SNPs value (FSV) as a novel measure for predicting SNP-variability using ~5X genome resequencing with ABI SOLID and DNA pools from two chicken lines divergently selected for juvenile bodyweight. Results Genotyping with a 60 K SNP chip revealed polymorphisms within or between two divergently selected chicken lines for 31 363 SNPs, 48% of which were also detected using resequencing of DNA pools. SNP detection using resequencing was more powerful for positions with larger differences in allele frequency between the lines. About 50% of the SNPs with non-reference allele frequencies in the range 0.5-0.6 and 67% of those with frequencies > 0.9 could be detected. On average, ~3.7 SNPs/kb were detected by resequencing, with about 5% lower density on microchromosomes than on macrochromosomes. There was a positive correlation between the observed between-line SNP variation from the 60 K chip analysis and our proposed FSV score computed from the genome resequencing data. The strongest correlations on macrochromosomes and microchromosomes were observed when the FSV was calculated with total flanking regions of 62 kb (correlation 0.55) and 38 kb (correlation 0.45), respectively. Conclusions Genome resequencing with limited coverage (~5X) using pooled DNA samples and three non-reference reads as a threshold for SNP detection, identified 50 - 67% of the 60 K SNPs with a non-reference allele frequency larger than 0.5. The SNP density was around 5% lower on the microchromosomes, most likely because of their higher gene content. Our proposed method to estimate the SNP variation (FSV) uses additional sequence information to better predict SNP informativity. The FSV scores showed higher correlations for SNPs with a larger difference in allele frequency between the populations. The correlation was strongest on macrochromosomes, probably due to a lower recombination rate. PMID:21108801
Ascertainment Biases in SNP Chips Affect Measures of Population Divergence
Ascertainment Biases in SNP Chips Affect Measures of Population Divergence Anders Albrechtsen,*,1 polymorphism (SNP) chip data suffer from ascertainment biases caused by the SNP discovery process in which in one of the common genome-wide genotyping platforms. We generate SNP genotyping data for individuals
Nielsen, Rasmus
Accelerating Disease Gene Identification Through Integrated SNP Data Analysis
Accelerating Disease Gene Identification Through Integrated SNP Data Analysis P. Missier , S-standing research goal in biology. While a number of established public SNP databases are available, the specifica- tion of effective techniques for SNP analysis remains an open issue. We describe a secondary SNP
Sattler, Ulrike
Linear Reduction Method for Predictive and Informative Tag SNP Selection
Linear Reduction Method for Predictive and Informative Tag SNP Selection Jingwu He, Kelly measure the quality of our tag SNP selection algorithm by com- paring actual SNPs with SNPs predicted from: Single nucleotide polymorphism, tag SNP, linear independence. 1 Introduction Genome-wide SNP scans
Zelikovsky, Alexander
Simultaneous SNP Identification in Association Studies with Missing Data
Simultaneous SNP Identification in Association Studies with Missing Data Zhen Li Vikneswaran Gopal that updating one SNP at each iteration preserves the ergodic property of the Markov chain, and at the same time detection of SNP interactions. Simulations show that unbiased estimates of SNP effects are recovered
Casella, George
Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels
Introduction MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer's disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this. Methods We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases?=?9,814, n-controls?=?11,550) from Mayo Clinic (n-cases?=?2,052, n-controls?=?3,406) and the Alzheimer's Disease Genetics Consortium (ADGC, n-cases?=?7,762, n-controls?=?8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n?=?197) and temporal cortex (n?=?202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated. Results H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (? = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03). Conclusions These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression. PMID:25324900
WinHAP2: an extremely fast haplotype phasing program for long genotype sequences
Background The haplotype phasing problem tries to screen for phenotype associated genomic variations from millions of candidate data. Most of the current computer programs handle this problem with high requirements of computing power and memory. By replacing the computation-intensive step of constructing the maximum spanning tree with a heuristics of estimated initial haplotype, we released the WinHAP algorithm version 1.0, which outperforms the other algorithms in terms of both running speed and overall accuracy. Results This work further speeds up the WinHAP algorithm to version 2.0 (WinHAP2) by utilizing the divide-and-conquer strategy and the OpenMP parallel computing mode. WinHAP2 can phase 500 genotypes with 1,000,000 SNPs using just 12.8?MB in memory and 2.5?hours on a personal computer, whereas the other programs require unacceptable memory or running times. The parallel running mode further improves WinHAP2's running speed with several orders of magnitudes, compared with the other programs, including Beagle, SHAPEIT2 and 2SNP. Conclusions WinHAP2 is an extremely fast haplotype phasing program which can handle a large-scale genotyping study with any number of SNPs in the current literature and at least in the near future. PMID:24884701
Taking advantage of increasingly available high-density single nucleotide polymorphism (SNP) markers within genes and across genomes, more and more genetic association studies began to use multiple closely linked markers in candidate genes. A practical analytical challenge arising in such studies is the possibility that not all case chromosomes have inherited disease-causing mutations from a common ancestral chromosome (founder heterogeneity). To alleviate the problem, we propose a method that applies a clustering algorithm to haplotype similarity analysis. The method identifies a sequence of nested subsets of case chromosomes by a peeling procedure, where each subset is relatively homogeneous. The average similarity score estimated from each subset in the sequence is compared to that estimated in controls, and a raw (unadjusted for multiple comparisons) P value is obtained. The test for the association between the trait and the candidate gene is based on the minimum raw P value observed in the comparison sequence, with its significance level estimated by a permutation procedure. The method can be applied to both haplotype and genotype data. Simulation studies suggest that our method has the correct type I error rate, and is generally more powerful than existing methods of haplotype similarity analysis. PMID:15389925
Yu, K; Gu, C Charles; Province, M; Xiong, C J; Rao, D C
SNP and mRNA expression for glutathione peroxidase 4 in Kashin-Beck disease.
Kashin-Beck disease (KBD) is a chronic endemic osteoarthropathy, which mainly occurs in West and Northeast China. Epidemiological studies suggest that Se deficiency is an important environmental factor for the incidence of KBD. Glutathione peroxidase 4 (GPx4) belongs to the glutathione peroxidase family, which is crucial for optimal antioxidant defences. Our purpose is to investigate the putative association between GPx4 polymorphisms and the risk of KBD. Restriction fragment length polymorphism-PCR was used to detect two SNP (rs713041, rs4807542) in 219 cases and 194 controls in Han Chinese subjects, and quantitative analysis for the GPx4 mRNA level was performed by the real-time PCR method. The results revealed that linkage disequilibrium existed in the two SNP. A significant difference was observed in the haplotype A-T (P = 0·0066) of GPx4, which was obviously lower in the KBD cases (0·006 v. 0·032 %). Correlation analysis based on a single locus showed no association between each SNP and KBD risk. Furthermore, the GPx4 mRNA level was dramatically lower in the blood of KBD patients. Overall, our finding indicated GPx4 polymorphisms and decreased mRNA level may be related to the development of KBD in the Chinese population, suggesting GPx4 as a possible candidate susceptibility gene for KBD. PMID:21733339
Du, Xiao Hong; Dai, Xiao Xia; Xia Song, Rui; Zou, Xiu Zhen; Yan Sun, Wen; Mo, Xiao Yan; Lu Bai, Guang; Xiong, Yong Min
The number of units and especially the number of different HLA haplotypes present in a cord blood (CB) bank is a crucial determinant of its usefulness. We generated data relevant to the development of our national CB in Finland. The HLA haplotype distribution was examined between specific populations. We developed graphical ways of data presentation that enable easy visualization of differences. First, we estimated the optimal size of a CB bank for Finland and found that approximately 1700 units are needed to provide a 5/6 HLA-matched donor for 80% of Finnish patients. Secondly, we evaluated HLA haplotype distributions between four locations, Finland, Japan, Sweden and Belgium. Our results showed that the Japanese Tokyo Cord Blood Bank differs in both the frequency and distribution of haplotypes from the European banks. The European banks (Finnish Cord Blood Registry, The Swedish National Cord Blood Bank, and Marrow Donor Program-Belgium) have similar frequencies of common haplotypes, but 26% of the haplotypes in the Finnish CB bank are unique, which justifies the existence of a national bank. The tendency to a homogenous HLA haplotype distribution in banks underlines the need for targeting recruitment at the poorly represented minority populations. PMID:23137880
Haimila, Katri; Penttilä, Antti; Arvola, Anne; Auvinen, Marja-Kaisa; Korhonen, Matti
Bayesian spatial modeling of haplotype associations.
We review methods for relating the risk of disease to a collection of single nucleotide polymorphisms (SNPs) within a small region. Association studies using case-control designs with unrelated individuals could be used either to test for a direct effect of a candidate gene and characterize the responsible variant(s), or to fine map an unknown gene by exploiting the pattern of linkage disequilibrium (LD). We consider a flexible class of logistic penetrance models based on haplotypes and compare them with an alternative formulation based on unphased multilocus genotypes. The likelihood for haplotype-based models requires summation over all possible haplotype assignments consistent with the observed genotype data, and can be fitted using either Expectation-Maximization (E-M) or Markov chain Monte Carlo (MCMC) methods. Subtleties involving ascertainment correction for case-control studies are discussed. There has been great interest in methods for LD mapping based on the coalescent or ancestral recombination graphs as well as methods based on haplotype sharing, both of which we review briefly. Because of their computational complexity, we propose some alternative empirical modeling approaches using techniques borrowed from the Bayesian spatial statistics literature. Here, space is interpreted in terms of a distance metric describing the similarity of any pair of haplotypes to each other, and hence their presumed common ancestry. Specifically, we discuss the conditional autoregressive model and two spatial clustering models: Potts and Voronoi. We conclude with a discussion of the implications of these methods for modeling cryptic relatedness, haplotype blocks, and haplotype tagging SNPs, and suggest a Bayesian framework for the HapMap project. PMID:14614236
Thomas, Duncan C; Stram, Daniel O; Conti, David; Molitor, John; Marjoram, Paul
Allergic rhinitis is a chronic inflammatory disease that is assumed to be due to an interaction between different genetic and/or environmental factors. A disintegrin and metalloprotease domain 33 (ADAM33) has been extensively studied as a susceptibility gene in asthma and has been linked to bronchial hyper-responsiveness. In this study, we investigated the association between ADAM33 single nucleotide polymorphisms and the incidence of allergic rhinitis among the Jordanian population. We conducted a case-control association study on 120 adult individuals diagnosed with allergic rhinitis and 128 normal healthy controls. 8 single-nucleotide polymorphisms in ADAM33 were genotyped using PCR-RFLP method. No significant differences in the allelic frequencies of all SNPs tested between AR patients and the control volunteers were found, although S2 C/G SNP showed a tendency toward significance with P=0.06. On the genotype level significant association were found in the following genotypes: T1 AA, T1 AG, T2 GG, T2 AG, T+1 GG, T+1 AG, V4 CG, S2 CC, S2 CG, Q-1AA. Seven haplotypes were present only within AR patients and eight haplotypes were completely absent from the AR patients. Three haplotypes exhibited significant association with AR P ? 0.05, two of them were present only in AR patients. In conclusion, the polymorphisms in the ADAM33 gene are associated with susceptibility to AR in the Jordanian population. Furthermore, the haplotype of the tested SNPs were also associated with the risk of AR. PMID:24035932
Zihlif, Malek; Mahafza, Tareq; Obeidat, Nathir M; Froukh, Tawfiq; Shaban, Mazen; Al-Akhras, Fatima M; Zihlif, Nadwa; Naffa, Randa
Twenty-six Y-chromosomal short tandem repeat (STR) loci were amplified in a sample of 769 unrelated males from Nepal, using two multiplex polymerase chain reaction (PCR) assays. The 26 loci gave a discriminating power of 0.997, with 59% unique haplotypes, and the highest frequency haplotype occurring 12 times. We identified novel alleles at four loci, microvariants at a further two, and
Emma J. Parkin; Thirsa Kraayenbrink; Jean Robert M. L. Opgenort; George L. van Driem; Nirmal Man Tuladhar; Peter de Knijff; Mark A. Jobling
Sockeye salmon samples from five largest lacustrine-riverine systems of Kamchatka Peninsula were tested for polymorphism at six microsatellite (STR) and five single nucleotide polymorphism (SNP) loci. Statistically significant genetic differentiation among local populations from this part of the species range examined was demonstrated. The data presented point to pronounced genetic divergence of the populations from two geographical regions, Eastern and Western Kamchatka. For sockeye salmon, the individual identification test accuracy was higher for microsatellites compared to similar number of SNP markers. Pooling of the STR and SNP allele frequency data sets provided the highest accuracy of the individual fish population assignment. PMID:21261065
Khrustaleva, A M; Volkov, A A; Stoklitskaia, D S; Miuge, N S; Zelenina, D A
Aim To find an association between Y chromosome polymorphisms and some ethnic groups. Methods Short tandem repeats (STR) and single-nucleotide polymorphisms (SNP) on the Y chromosome were typed in 311 unrelated men from four different ethnic groups – Italians from northern Italy, Albanians, Africans from the Maghreb region, and Indo-Pakistanis, using the AmpFlSTR® Yfiler PCR Amplification Kit and the SNaPshot Multiplex Kit. Results STRs analysis found 299 different haplotypes and SNPs analysis 11 different haplogroups. Haplotypes and haplogroups were analyzed and compared between different ethnic groups. Significant differences were found among all the population groups, except between Italians and Indo-Pakistanis and between Albanians and Indo-Pakistanis. Conclusions Typing both STRs and SNPs on the Y chromosome could become useful in determining ethnic origin of a potential suspect. PMID:23771759
Cortellini, Venusia; Verzeletti, Andrea; Cerri, Nicoletta; Marino, Alberto; De Ferrari, Francesco
SNP-based association mapping of the polled gene in divergent cattle breeds.
Naturally, hornless cattle are called polled. Although the POLL locus could be assigned to a c. 1.36-Mb interval in the centromeric region of BTA1, the underlying genetic basis for the polled trait is still unknown. Here, an association mapping design was set up to refine the candidate region of the polled trait for subsequent high-throughput sequencing. The case group comprised 101 homozygous polled animals from nine divergent cattle breeds, the majority represented by Galloway, Angus, Fleckvieh and Holstein Friesian. Additionally, this group included some polled individuals of Blonde d'Aquitaine, Charolais, Hereford, Jersey and Limousin breeds. The control group comprised horned Belgian Blue, Fleckvieh, Holstein Friesian and Illyrian Buša cattle. A genome-wide scan using 49,163 SNPs was performed, which revealed one shared homozygous haplotype block consisting of nine neighbouring SNPs in all polled animals. This segment defines a 381-kb interval on BTA1 that we consider to be the most likely location of the POLL mutation. Our results further demonstrate that the polled-associated haplotype is also frequent in horned animals included in this study, and thus the haplotype as such cannot be used for population-wide genetic testing. The actual trait-associated haplotype may be revealed by using higher-density SNP arrays. For the final identification of the causal mutation, we suggest high-throughput sequencing of the entire candidate region, because the identification of functional candidate genes is difficult owing to the lack of a comparable model. PMID:22497248
Seichter, D; Russ, I; Rothammer, S; Eder, J; Förster, M; Medugorac, I
Leukotriene A4 Hydrolase Haplotype, Diet and Atherosclerosis: A Twin Study
Objective Atherosclerosis is an inflammatory process resulting from the interaction between genetic and environmental factors. Leukotrienes are inflammatory mediators generated from arachidonic acid, and genetic polymorphisms involved in leukotriene metabolism are implicated in atherosclerosis. The objectives of this study are to examine whether genetic variants in key leukotriene enzymes are associated with atherosclerosis, and whether dietary intake of competing leukotriene substrates modifies the effect of leukotriene variants on atherosclerosis. Methods Atherosclerosis was assessed by common carotid intima-media thickness (IMT) using ultrasound. Sequence variants within arachidonate 5-lipoxygenase activating protein (ALOX5AP) and leukotriene A4 hydrolase (LTA4H) genes were analyzed with 32 single nucleotide polymorphisms (SNPs) in 169 Caucasian twin pairs from the Vietnam Era Twin Registry. The associations between genetic polymorphisms and carotid atherosclerosis, and gene × diet interactions were examined by generalized estimating equation controlling for potential confounders. Results A six-SNP haplotype in LTA4H, designated HapE, was significantly associated with carotid IMT after adjusting for known coronary risk factors. Twins carrying HapE had a much lower IMT compared to twins not carrying (695 ?m vs. 750 ?m, p=0.0007). Moreover, dietary intake of polyunsaturated fatty acids strongly augmented the cardioprotective effect of HapE among those with this haplotype but not those without, suggesting a haplotype × diet interaction (Interaction PHapE × n-3 = 0.03, PHapE × n-6 = 0.015). Conclusion We identified a novel leukotriene haplotype that appears to be protective towards subclinical atherosclerosis. This association is modified by dietary intake of polyunsaturated fatty acids. PMID:23153620
Zhao, Jinying; Goldberg, Jack; Vaccarino, Viola
Cluster analysis of European Y-chromosomal STR haplotypes using the discrete Laplace method.
The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous studies. We also compared pairwise distances (between geographically separated samples) with those obtained using the AMOVA method and found good agreement. Further analyses that are impossible with AMOVA were made using the discrete Laplace method: analysis of the homogeneity in two different ways and calculating marginal STR distributions. We found that the Y-STR haplotypes from e.g. Finland were relatively homogeneous as opposed to the relatively heterogeneous Y-STR haplotypes from e.g. Lublin, Eastern Poland and Berlin, Germany. We demonstrated that the observed distributions of alleles at each locus were similar to the expected ones. We also compared pairwise distances between geographically separated samples from Africa with those obtained using the AMOVA method and found good agreement. PMID:24793845
Andersen, Mikkel Meyer; Eriksen, Poul Svante; Morling, Niels
Single nucleotide polymorphisms (SNPs) with large allele frequency differences between human populations are relatively rare. The longest run of SNPs with an allele frequency difference of one between the Yoruba of Nigeria and the Han Chinese is found on the long arm of the X chromosome in the intergenic region separating the EDA2R and AR genes. It has been proposed that the unusual allele frequency distributions of these SNPs are the result of a selective sweep affecting African populations that occurred after the out-of-Africa migration. To investigate the evolutionary history of the EDA2R/AR intergenic region, we characterized the haplotype structure of 52 of its highly differentiated SNPs. Using a publicly available data set of 3,000 X chromosomes from 65 human populations, we found that nearly all human X chromosomes carry one of two modal haplotypes for these 52 SNPs. The predominance of two highly divergent haplotypes at this locus was confirmed by use of a subset of individuals sequenced to high coverage. The first of these haplotypes, the ?-haplotype is at high frequencies in most of the African populations surveyed and likely arose before the separation of African populations into distinct genetic entities. The second, the ?-haplotype, is frequent or fixed in all non-African populations and likely arose in East Africa before the out-of-Africa migration. We also observed a small group or rare haplotypes with no clear relationship to the ?- and ?-haplotypes. These haplotypes occur at relatively high frequencies in African hunter-gatherer populations, such as the San and Mbuti Pygmies. Our analysis indicates that these haplotypes are part of a pool of diverse, ancestral haplotypes that have now been almost entirely replaced by the ?- and ?-haplotypes. We suggest that the rise of the ?- and ?-haplotypes was the result of the demographic forces that human populations experienced during the formation of modern African populations and the out-of-Africa migration. However, we also present evidence that this region is the target of selection in the form of positive selection on the ?- and ?-haplotypes and of purifying the selection against ?/? recombinants. PMID:23959643
Casto, Amanda M; Henn, Brenna M; Kidd, Jeffery M; Bustamante, Carlos D; Feldman, Marcus W
The haplotype analysis of seven Y-chromosome microsatellites in three regional populations of Tuvinians revealed high intrapopulation variation in the male gene pool of the modern population of the Tuva Republic. In total, 49 haplotypes were found in 111 individuals; only four haplotypes occurred at a frequency higher than 5%. High genetic diversity (H = 0.935) suggested a high power of discrimination for the Y-chromosome haplotypes. The analysis of molecular variance (AMOVA) and other data did not reveal subdivision of the Tuvinian population with respect to Y-chromosome haplotypes. Most haplotypes found in Tuvinians formed two lines. Line A included approximately 64% of the haplotypes found, line B, approximately 24%. A putative ancestral haplotype of line B was similar to a haplotype most common in modern Caucasoids (Md = 3), whereas a putative ancestral haplotype of line A proved to be distant from the ancestral haplotype of line A and haplotypes common for Caucasoids and Mongoloids. Estimates of the age of the Y-chromosome lines showed that the male gene pool of modern Tuvinians originated in the late Paleolithic or Neolithic period. With two methods, the age of line A was estimated at 3500 or 18,000 years and the age of line B was approximately at 5500 or 15,000 years. Considering the less conservative estimates to be more reliable, line B was assumed to originate from the ancient Caucasoid population of the Tuva region. The more widespread and evolutionarily younger line A was associated with the peopling region by ancient Mongoloid tribes of the Turkic language group in the Hun-Sarmatian period. PMID:10779914
Stepanov, V A; Puzyrev, V P
Haplotypes of alpha-globin gene regulatory element in two Brazilian native populations.
The alpha-major regulatory element (alpha-MRE), located 40 Kb far upstream of the alpha-globin gene cluster on chromosome 16, is involved in the regulation of human alpha-globin genes expression. The activity of this element is restricted to a 350-bp fragment in which several nuclear protein binding sites have been identified. This element is genetically polymorphic and different haplotypes, named A-F, have been determined in seven populations of Europe, Africa, Asia, and Oceania. We describe here the alpha-MRE haplotypes found in native Indians from two nonmiscegenated tribes of the north region of Brazil, in Amazonia, the Parakană and the Xikrin. The A haplotype was predominant in both (70% and 87%, respectively), followed by the B haplotype (30% and 13%, respectively). The haplotype frequency distribution among the Parakană was similar to that reported for Indonesians and Southeast Asian populations, while the distribution among the Xikrin showed higher similarity to that observed in Indonesians. These results corroborate the existence of genetic affinities between Brazilian Indians and Southeast Asian and Oceanic populations. This was the first investigative work on the alpha-MRE polymorphism in South American native populations in general or Brazilian native populations in particular. PMID:12687583
Ribeiro, Daniela M; Figueiredo, Maria S; Costa, Fernando F; Sonati, Maria F
Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.
We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena. PMID:3793924
Alper, C A; Fleischnick, E; Awdeh, Z; Katz, A J; Yunis, E J
PADI4 Haplotypes in Association with RA Mexican Patients, a New Prospect for Antigen Modulation
Peptidyl arginine deiminase IV (PAD 4) is the responsible enzyme for a posttranslational modification called citrullination, originating the antigenic determinant recognized by anti-cyclic citrullinated peptide antibodies (ACPA). Four SNPs (single nucleotide polymorphisms) have been described in PADI4 gene to form a susceptibility haplotype for rheumatoid arthritis (RA); nevertheless, results in association studies appear contradictory in different populations. The aim of the study was to analyze if the presence of three SNPs in PADI4 gene susceptibility haplotype (GTG) is associated with ACPA positivity in patients with RA. This was a cross-sectional study that included 86 RA patients and 98 healthy controls. Polymorphisms PADI4_89, PADI4_90, and PADI4_92 in the PADI4 gene were genotyped. The susceptibility haplotype (GTG) was more frequent in RA patients; interestingly, we found a new haplotype associated with RA with a higher frequency (GTC). There were no associations between polymorphisms and high scores in Spanish HAQ-DI and DAS-28, but we did find an association between RARBIS index and PADI4_89, PADI4_90 polymorphisms. We could not confirm an association between susceptibility haplotype presence and ACPA positivity. Further evidence about proteomic expression of this gene will determine its participation in antigenic generation and autoimmunity. PMID:24454473
Gonzalez-Montoya, Norma Guadalupe; Gamez-Nava, Jorge I.; Moran-Moguel, Maria Cristina; Rosales-Gomez, Roberto Carlos; Gutierrez-Rubio, Susan Andrea; Sanchez-Corona, Jose; Davalos-Rodriguez, Ingrid Patricia; Salazar-Paramo, Mario
Evolution of the mouse t haplotype: recent and worldwide introgression to Mus musculus.
Mouse t haplotypes are variants of chromosome 17, consisting of four inversions. Despite the homozygous lethality and pleiotropic effect on embryonic development, sperm production, and recombination, they have widely spread in natural populations of the house mouse (10-40% in frequency) because of the meiotic drive advantage. We sequenced 14 Tcp-1 (t-complex polypeptide 1) genes from four t haplotypes, nine wild mice, and a rat as a reference. From a comparison of intron sequences of 610 base pairs, we dated the origin of t haplotypes to 2.9 +/- 0.7 million years ago, which predates the splitting of Mus musculus subspecies (approximately 1 million years ago). However, the Tcp-1 intron sequences of t haplotypes from different M. musculus subspecies from various parts of the world show no divergence, indicating the recent introgression (no earlier than 0.8 million years ago) of a single ancestral type. Nucleotide changes in coding regions are also consistent with this conclusion. Hence, polymorphisms among t haplotypes including lethality factors have accumulated during this short time period independently in each M. musculus subspecies. PMID:1495973
Morita, T; Kubota, H; Murata, K; Nozaki, M; Delarbre, C; Willison, K; Satta, Y; Sakaizumi, M; Takahata, N; Gachelin, G
Eight polymorphic restriction enzyme sites at the phenylalanine hydroxylase (PAH) locus were analyzed from the parental chromosomes in 33 Danish nuclear families with at least one phenylketonuric (PKU) child. Determination of haplotypes of 66 normal chromosomes and 66 chromosomes bearing mutant allele(s) demonstrated that there are at least two haplotypes which occur predominantly on PKU chromosomes and rarely otherwise. Overall, the relative frequencies of the various haplotypes are significantly different on PKU- and normal-allele bearing chromosomes, even though there is no predominantly occurring unique haplotype which can characterize the PKU chromosomes. In addition, no significant association (linkage disequilibrium) between any single polymorphic site and the mutant allele(s) was observed. The results suggest that either the phenylketonuric mutation was very ancient so that the polymorphic sites and the mutation have reached linkage equilibrium or the mutant allele(s) are the results of multiple mutations in the phenylalanine hydroxylase gene in man. Furthermore, a crude relationship between standardized linkage disequilibria and physical map distances of the polymorphic sites indicates that there is no apparent recombination hot-spot in the human phenylalanine hydroxylase gene, since the recombination rate within the locus appears to be uniform and likely to be occurring at a rate similar to that within the HLA gene cluster. The limitations of this later analysis are discussed in view of the sampling errors of disequilibrium measure used, and the potential utility of the PAH haplotypes for prenatal diagnosis and detection of PKU carriers is established. PMID:2883110
Chakraborty, R; Lidsky, A S; Daiger, S P; Güttler, F; Sullivan, S; Dilella, A G; Woo, S L
SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Aggressiveness
Angiogenesis has been shown to be associated with prostate cancer development. The majority of prostate cancer studies focused on individual single nucleotide polymorphisms (SNPs) while SNP-SNP interactions are suggested having a great impact on unveiling the underlying mechanism of complex disease. Using 1,151 prostate cancer patients in the Cancer Genetic Markers of Susceptibility (CGEMS) dataset, 2,651 SNPs in the angiogenesis genes associated with prostate cancer aggressiveness were evaluated. SNP-SNP interactions were primarily assessed using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach in the CGEMS group, and were then re-evaluated in the Moffitt group with 1,040 patients. For the identified gene pairs, cross-evaluation was applied to evaluate SNP interactions in both study groups. Five SNP-SNP interactions in three gene pairs (MMP16+ ROBO1, MMP16+ CSF1, and MMP16+ EGFR) were identified to be associated with aggressive prostate cancer in both groups. Three pairs of SNPs (rs1477908+ rs1387665, rs1467251+ rs7625555, and rs1824717+ rs7625555) were in MMP16 and ROBO1, one pair (rs2176771+ rs333970) in MMP16 and CSF1, and one pair (rs1401862+ rs6964705) in MMP16 and EGFR. The results suggest that MMP16 may play an important role in prostate cancer aggressiveness. By integrating our novel findings and available biomedical literature, a hypothetical gene interaction network was proposed. This network demonstrates that our identified SNP-SNP interactions are biologically relevant and shows that EGFR may be the hub for the interactions. The findings provide valuable information to identify genotype combinations at risk of developing aggressive prostate cancer and improve understanding on the genetic etiology of angiogenesis associated with prostate cancer aggressiveness. PMID:23593148
Lin, Hui-Yi; Amankwah, Ernest K.; Tseng, Tung-Sung; Qu, Xiaotao; Chen, Dung-Tsa; Park, Jong Y.
Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips
Background Illumina's Infinium SNP BeadChips are extensively used in both small and large-scale genetic studies. A fundamental step in any analysis is the processing of raw allele A and allele B intensities from each SNP into genotype calls (AA, AB, BB). Various algorithms which make use of different statistical models are available for this task. We compare four methods (GenCall, Illuminus, GenoSNP and CRLMM) on data where the true genotypes are known in advance and data from a recently published genome-wide association study. Results In general, differences in accuracy are relatively small between the methods evaluated, although CRLMM and GenoSNP were found to consistently outperform GenCall. The performance of Illuminus is heavily dependent on sample size, with lower no call rates and improved accuracy as the number of samples available increases. For X chromosome SNPs, methods with sex-dependent models (Illuminus, CRLMM) perform better than methods which ignore gender information (GenCall, GenoSNP). We observe that CRLMM and GenoSNP are more accurate at calling SNPs with low minor allele frequency than GenCall or Illuminus. The sample quality metrics from each of the four methods were found to have a high level of agreement at flagging samples with unusual signal characteristics. Conclusions CRLMM, GenoSNP and GenCall can be applied with confidence in studies of any size, as their performance was shown to be invariant to the number of samples available. Illuminus on the other hand requires a larger number of samples to achieve comparable levels of accuracy and its use in smaller studies (50 or fewer individuals) is not recommended. PMID:21385424
Rampant gene rearrangement and haplotype hypervariation among nematode mitochondrial genomes.
Rare syntenic conservation, sequence duplication, and the use of both DNA strands to encode genes are signature architectural features defining mitochondrial genomes of enoplean nematodes. These characteristics stand in contrast to the more conserved mitochondrial genome sizes and transcriptional organizations of mitochondrial DNAs (mtDNAs) derived from chromadorean nematodes. To address the frequency of gene rearrangement within nematode mitochondrial DNA (mtDNA), mitochondrial genome variation has been characterized within a more confined enoplean taxonomic unit, the family Mermithidae. The complete nucleotide sequences of the mosquito parasitic nematodes Romanomermis culicivorax, R. nielseni, and R. iyengari mtDNA have been determined. Duplicated expanses encompassing different regions of the mitochondrial genomes were found in each of these congeners. These mtDNA shared few rRNA and protein gene junctions, indicating extensive gene rearrangement within the Romanomermis lineage. Rapid structural changes are also observed at the conspecific level where no two individual nematodes carry the same haplotype. Rolling circle amplification was used to isolate complete mitochondrial genomes from individuals in local populations of Thaumamermis cosgrovei, a parasite of terrestrial isopods. Mitochondrial DNA length variants ranging from 19 to 34 kb are observed, but haplotypes are not shared between any two individuals. The complete nucleotide sequences of three haplotypes have been determined, revealing a constant region encoding most mitochondrial genes and a hypervariable segment that contains intact and pseudogene copies of several mitochondrial genes, duplicated to different copy numbers, resulting in mtDNA size variation. Constant rearrangement generates new T. cosgrovei mtDNA forms. PMID:21136141
Hyman, Bradley C; Lewis, Samantha C; Tang, Sha; Wu, Zhen
The Norwegian dairy goat population has a high frequency of a CSN1S1 (alphaS1-casein) haplotype with negative effects on protein and fat content. It is characterized by a single point deletion in exon 12 of CSN1S1, leading to a truncated protein and hence a low content of alphaS1-casein in the milk. This haplotype together with another haplotype with a deletion in exon 9 are called "weak" haplotypes. "Strong" haplotypes, on the other hand, have positive effects on important milk production traits. We show that expression of CSN1S1 in the mammary gland of lactating goats is significantly lower in animals with 2 weak haplotypes. Moreover, the effects of defective alleles were not detected in animals having 1 strong and 1 weak haplotype. Expression levels of other genes in the casein cluster were not affected by the CSN1S1 haplotypes investigated. Milk samples from goats with 2 weak haplotypes could be distinguished from the other milk samples using Fourier transform infrared (FTIR) spectroscopy and partial least squares discriminant analysis (PLS-DA). The PLS-DA components were related to spectra of pure caseins and whey proteins, hence FTIR has a potential for identifying milk samples with low alphaS1-casein content and different protein composition. The results indicate that FTIR-based measurements can be incorporated into breeding plans, or for selection of milk samples with high casein content, which in turn may improve cheese-making properties of the milk. PMID:20723707
Berget, I; Martens, H; Kohler, A; Sjurseth, S K; Afseth, N K; Narum, B; Adnřy, T; Lien, S
A Class Representative Model for Pure Parsimony Haplotyping
Keywords: haplotype inference, computational biology, integer programming. ... In human pharmacogenetics, haplotypes explain why people react differently .... homozygous sites of type 0 (1), and entries equal to 2 indicate heterozygous sites
Forensic application of SNP-based resequencing array for individual identification.
In forensic field investigations using single nucleotide polymorphism (SNP) have been performed for various purposes. Based on the characteristics of SNP, it is essential to have a multi-amplification technology and a platform to analyze the amplified SNP markers accurately. Here, we have developed a platform based on the resequencing array of Affymetrix analyzing 169 SNP markers amplified via multiplex PCR and verified its forensic application. From the 1000 genomes database, the SNP markers were selected under the condition of less than 0.04 fixation index (Fst) and 0.3 linkage disequilibrium (LD) R(2) value, and 0.4-0.5 minor allele frequency (MAF). It was identified that more than 120 out of 169 SNPs were able to be typed with approximately 10pg of DNA and artificially degraded samples in various tests. The DNA extracted from bones also showed a similar rate of success. The results indicated that our platform has a potential role to assist the current short tandem repeat (STR) method in analyzing harsh samples, such as bone or degraded DNA. With a possibility to expand the platform, it was expected to apply to various uses in different areas in the future. PMID:25082136
Cho, Sohee; Yu, Hyung Jin; Han, Jisung; Kim, Yoonsoo; Lee, Jihyun; Lee, Soong Deok
Digital genotyping and haplotyping with polymerase colonies
by cloning or somatic cell fusion. The results indicate that polony genotyping and haplotyping may play in the human population has the potential to greatly improve human health, both by predict- ing susceptibility to disease and guiding choice of therapy. The most common genetic variations in the human population
Church, George M.
ORIGINAL ARTICLE Conserved extended haplotypes discriminate
with type 1 diabetes mellitus and celiac disease JR Bilbao1,2,9 , B Calvo1,9 , AM Aransay3 , A Martin and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD 2006 Keywords: conserved extended haplotypes; type 1 diabetes mellitus; celiac disease; HLA-DR3; single
Alper, Chester A.
Original article Prion gene (PRNP) haplotype variation
Original article Prion gene (PRNP) haplotype variation in United States goat breeds (Open Access not examined before at PRNP. scrapie / goat / polymorphism / resistance / prion 1. INTRODUCTION Scrapie that encodes prion protein have been associated with differential resistance and susceptibility to scrapie
Boyer, Edmond
An SNP map of human chromosome 22
The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1SNP
J. C. Mullikin; S. E. Hunt; C. G. Cole; B. J. Mortimore; C. M. Rice; J. Burton; L. H. Matthews; R. Pavitt; R. W. Plumb; S. K. Sims; R. M. R. Ainscough; J. Attwood; J. M. Bailey; K. Barlow; R. M. M. Bruskiewich; P. N. Butcher; N. P. Carter; Y. Chen; C. M. Clee; P. C. Coggill; J. Davies; R. M. Davies; E. Dawson; M. D. Francis; A. A. Joy; R. G. Lamble; C. F. Langford; J. Macarthy; V. Mall; A. Moreland; E. K. Overton-Larty; M. T. Ross; L. C. Smith; C. A. Steward; J. E. Sulston; E. J. Tinsley; K. J. Turney; D. L. Willey; G. D. Wilson; A. A. McMurray; I. Dunham; J. Rogers; D. R. Bentley
Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes.
To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from ?0.30 to 0.41; however, the CYP2C8 frequencies were much lower (?0.04-0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1-2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications. PMID:22491019
Martis, S; Peter, I; Hulot, J-S; Kornreich, R; Desnick, R J; Scott, S A
Background Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. Results Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. Conclusions Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2. PMID:24405739
In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ?4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOE?4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOE?4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOE?4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920
Liang, Winnie S.; Chen, Kewei; Lee, Wendy; Sidhar, Kunal; Corneveaux, Jason J.; Allen, April N.; Myers, Amanda; Villa, Stephen; Meechoovet, Bessie; Pruzin, Jeremy; Bandy, Daniel; Fleisher, Adam S.; Langbaum, Jessica B.S.; Huentelman, Matthew J.; Jensen, Kendall; Dunckley, Travis; Caselli, Richard J.; Kaib, Susan; Reiman, Eric M.
The Computational Structure of Monotone Monadic SNP and Constraint Satisfaction
The Computational Structure of Monotone Monadic SNP and Constraint Satisfaction: A Study through does not achieve this goal, it does isolate a class (of problems specified by) ``Monotone Monadic SNP of syntactic restrictions. The logic class SNP is contained in NP, and can be restricted with three further
Vardi, Moshe Y.
Research article Report on ISFG SNP Panel Discussion
Research article Report on ISFG SNP Panel Discussion J.M. Butler a,*, B. Budowle b , P. Gill c , K nucleotide polymorphism (SNP) markers, multiplexes, and methods regarding their potential application different SNP marker categories and assays available. # 2008 Elsevier Ireland Ltd. All rights reserved
Kidd, Kenneth
Visualisation of Associations Between Nucleotides in SNP Neighbourhoods
Visualisation of Associations Between Nucleotides in SNP Neighbourhoods Kimmo Kulovesi, , Juho A single nucleotide polymorphism (SNP) is a site in DNA where at least two different nucleotides occurMap Consortium, 2005]. The data is publicly available in the dbSNP database [Wheeler et al., 2005]. New mutations
Toivonen, Hannu
Statistical methods of SNP data analysis with applications
Statistical methods of SNP data analysis with applications A.V.Bulinski1,2 , O.A.Butkovsky1 , A's DNA variations are typically described in terms of single nucleotide polymorphisms (SNP), i the paradigm that the increasing risks of complex diseases can be explained by combinations of certain SNP
SNP genotyping: six technologies that keyed a Jeffrey Perkel
SNP genotyping: six technologies that keyed a revolution Jeffrey Perkel With abundant sequencing process that contin- ues on." What is in a SNP? The most common form of genetic varia- tion between in the National Center for Biotechnology Information's dbSNP database, covering organisms from Anopheles gambiae
Cai, Long
INVESTIGATION An SNP-Based Linkage Map for Zebrafish Reveals
INVESTIGATION An SNP-Based Linkage Map for Zebrafish Reveals Sex Determination Loci Kevin M-wide linkage study of sex determination in zebrafish using a novel SNP genetic map. We identified loci doublesex CYP21A2 21-hydroxylase sex determination teleost fish SNP genetic map recombination rate genetic
Broman, Karl W.
In case-control studies, the assessment of the association between a binary disease outcome and a single nucleotide polymorphism (SNP) is often based on comparing the observed genotype distribution for the cases against that for the controls. In this article, we investigate an alternative analytic strategy in which the observed genotype frequencies of cases are compared against the expected genotype frequencies
Jinbo Chen; Nilanjan Chatterjee
Correcting Coalescent Analyses for Panel-Based SNP Ascertainment
Single-nucleotide polymorphism (SNP) data are routinely obtained by sequencing a region of interest in a small panel, constructing a chip with probes specific to sites found to vary in the panel, and using the chip to assay subsequent samples. The size of the chip is often reduced by removing low-frequency alleles from the set of SNPs. Using coalescent estimation of the scaled population size parameter, ?, as a test case, we demonstrate the loss of information inherent in this procedure and develop corrections for coalescent analysis of SNPs obtained via a panel. We show that more accurate ?-estimates can be recovered if the panel size is known, but at considerable computational cost as the panel individuals must be explicitly modeled in the analysis. We extend this technique to apply to the case where rare alleles have been omitted from the SNP panel. We find that when appropriate corrections for panel ascertainment and rare-allele omission are used, the biases introduced by ascertainment are largely correctable, but recovered estimates are less accurate than would be obtained with fully sequenced data. This method is then applied to recombinant multiple population data to investigate the effects of recombination and migration on the estimate of ?. PMID:23335334
McGill, James R.; Walkup, Elizabeth A.; Kuhner, Mary K.
Adiponectin modulates lipid and glucose metabolism in adipose tissues and is also related to bone metabolism. Polymorphisms in the ADIPOQ gene likely have an impact on growth traits in cattle. In this study, we examined the relationship between ADIPOQ polymorphisms and body measurement parameters in Chinese beef cattle. First, we sequenced ADIPOQ and 1.2 kb of DNA upstream of its promoter, and we found 14 polymorphisms. With the luciferase reporter assay, we showed that the two polymorphisms SNP PR_-135 A>G and PR_-68 G>C, which are located in the core region of promoter, influence promoter activity of ADIPOQ. Second, we identified three haplotypes involved in these two polymorphic sites: A (A-135/C-68), B (A-135/G-68), and C (G-135/G-68). Haplotypes B and C are major haplotypes in five Chinese populations of cattle (Qinchuan, Nanyang, Jiaxian, Hazakh, and Chinese Holstein). We studied the effects of these three haplotypes on body measurements, gene expression, and promoter activity, and we found that the genotypes are associated with body measurement parameters in Qinchuan cattle. Individuals with genotype BC (AG/GG) had significantly higher body height and heart girth than others, and this result may be interpreted by the following two observations. The promoter activity with haplotype B (A/G) is significantly higher than those with A (A/C) and C (G/G) in driving reporter gene transcription; the ADIPOQ mRNA level in cattle with genotype BC (AG/GG) is relatively lower than that in cattle with genotype BB (AA/GG). PMID:24099391
Zhang, Liangzhi; Li, Mijie; Lai, Xinsheng; Yang, Mingjuan; Xu, Yao; Hua, Liushuai; Lan, Xianyong; Zhang, Chunlei; Chen, Hong
Dynorphin peptides and the kappa opioid receptor play important roles in the rewarding properties of cocaine, heroin and alcohol. We tested polymorphisms of the prodynorphin gene (PDYN) for association with cocaine dependence and cocaine/alcohol codependence. We genotyped six SNPs, located in the promoter region, exon 4 coding and 3? untranslated region (UTR), in 106 Caucasians and 204 African Americans who were cocaine dependent, cocaine/alcohol codependent or controls. In Caucasians, we found point-wise significant associations of 3?UTR SNPs (rs910080, rs910079, and rs2235749) with cocaine dependence and cocaine/alcohol codependence. These SNPs are in high linkage disequilibrium, comprising a haplotype block. The haplotype CCT was significantly experiment-wise associated with cocaine dependence and with combined cocaine dependence and cocaine/alcohol codependence (FDR, q=0.04 and 0.03, respectively). We investigated allele-specific gene expression of PDYN, using SNP rs910079 as a reporter, in postmortem human brains from eight heterozygous subjects, using SNaPshot assay. There was significantly lower expression for C allele (rs910079), with ratios ranging from 0.48 to 0.78, indicating lower expression of the CCT haplotype of PDYN in both the caudate and nucleus accumbens. Analysis of total PDYN expression in 43 postmortem brains also showed significantly lower levels of preprodynorphin mRNA in subjects having the risk CCT haplotype. This study provides evidence that a 3?UTR PDYN haplotype, implicated in vulnerability to develop cocaine addiction and/or cocaine/alcohol codependence, is related to lower mRNA expression of the PDYN gene in human dorsal and ventral striatum. PMID:18923396
Yuferov, Vadim; Ji, Fei; Nielsen, David A.; Levran, Orna; Ho, Ann; Morgello, Susan; Shi, Ruijin; Ott, Jurg; Kreek, Mary Jeanne
Fast and efficient high-throughput techniques are essential for the molecular diagnosis of highly heterogeneous hereditary diseases, such as retinitis pigmentosa (RP). We had previously approached RP genetic testing by devising a chip based on co-segregation analysis for the autosomal recessive forms. In this study, we aimed to design a diagnostic tool for all the known genes (40 up to now) responsible for the autosomal dominant and recessive RP and Leber congenital amaurosis (LCA). This new chip analyzes 240 single nucleotide polymorphisms (SNPs) (6 per gene) on a high-throughput genotyping platform (SNPlex, Applied Biosystems), and genetic diagnosis is based on the co-segregation analysis of SNP haplotypes in independent families. In a single genotyping step, the number of RP candidates to be screened for mutations is considerably reduced, and in the most informative families, all the candidates are ruled out at once. In a panel of RP Spanish pedigrees, the disease chip became a crucial tool for selecting those suitable for genome-wide RP gene search, and saved the burdensome direct mutational screening of every known RP gene. In a large adRP family, the chip allowed ruling out of all but the causative gene, and identification of an unreported null mutation (E181X) in PRPF31. Finally, on the basis of the conservation of the SNP haplotype linked to this pathogenic variant, we propose that the E181X mutation spread through a cohort of geographically isolated families by a founder effect. PMID:19584904
Pomares, Esther; Riera, Marina; Permanyer, Jon; Méndez, Pilar; Castro-Navarro, Joaquín; Andrés-Gutiérrez, Angeles; Marfany, Gemma; Gonzŕlez-Duarte, Roser
Beta-globin gene linked DNA haplotypes and frameworks in three South-East Asian populations.
DNA haplotypes and frameworks (numbers in parenthesis) linked to the beta-globin gene were determined by restriction fragment analysis using eight restriction endonucleases on 86 (97) chromosomes bearing the normal beta-globin gene (HBB*A) and 108 (118) chromosomes bearing HBB*E in subjects homozygous for HBB*A or HBB*E from three South-East Asian populations with high HBB*E frequencies (northern Thailand, north-eastern Thailand and Cambodia). A systematic nomenclature for beta-globin gene-linked haplotype characterized by six polymorphic sites is introduced. In all populations, HBB*A occurred preferentially (greater than 80%) in linkage with the haplotype 41 (+----+) and all three frameworks described by Antonarakis et al. (1982). In contrast, almost 80% of the HBB*E genes occurred with the haplotype 27 (-+- ). In northern and north-eastern Thailand, HBB*E was present almost exclusively in frame-work 2; HBB*E in framework 3 (Asian) was limited to the Khmer population of Cambodia, and the frequency of HBB*E-linked framework 3 increased from the west to the east in this country. PMID:3417310
Hundrieser, J; Sanguansermsri, T; Papp, T; Laig, M; Flatz, G
We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5?Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P?=?4.69?×?10(-4)). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P?=?1.42?×?10(-5)). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P?=?8.89?×?10(-6)). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P?=?3.43?×?10(-4)). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P?=?1.76?×?10(-6)). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region. PMID:23038240
Nissen, Stephanie; Liang, Sherri; Shehktman, Tatyana; Kelsoe, John R; Greenwood, Tiffany A; Nievergelt, Caroline M; McKinney, Rebecca; Shilling, Paul D; Smith, Erin N; Schork, Nicholas J; Bloss, Cinnamon S; Nurnberger, John I; Edenberg, Howard J; Foroud, Tatiana; Koller, Daniel L; Gershon, Elliot S; Liu, Chunyu; Badner, Judith A; Scheftner, William A; Lawson, William B; Nwulia, Evaristus A; Hipolito, Maria; Coryell, William; Rice, John; Byerley, William; McMahon, Francis J; Berrettini, Wade H; Potash, James B; Zandi, Peter P; Mahon, Pamela B; McInnis, Melvin G; Zöllner, Sebastian; Zhang, Peng; Craig, David W; Szelinger, Szabolics; Barrett, Thomas B; Schulze, Thomas G
Title: Powerful SNP Set Analysis for Case-Control Genome Wide Association Studies Running Title: Powerful SNP Set Analysis Michael C. Wu , Peter Kraft , Michael P. Epstein , Deanne M. Taylor , Stephen J-control GWAS involves assessing the association between each individual geno- typed SNP and disease risk
Lin, Xihong
Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese. PMID:17329911
Fukushima-Uesaka, Hiromi; Saito, Yoshiro; Tohkin, Masahiro; Maekawa, Keiko; Hasegawa, Ryuichi; Kawamoto, Manabu; Kamatani, Naoyuki; Suzuki, Kazuko; Yanagawa, Tatsuo; Kajio, Hiroshi; Kuzuya, Nobuaki; Yasuda, Kazuki; Sawada, Jun-ichi
QualitySNPng: a user-friendly SNP detection and visualization tool
QualitySNPng is a new software tool for the detection and interactive visualization of single-nucleotide polymorphisms (SNPs). It uses a haplotype-based strategy to identify reliable SNPs; it is optimized for the analysis of current RNA-seq data; but it can also be used on genomic DNA sequences derived from next-generation sequencing experiments. QualitySNPng does not require a sequenced reference genome and delivers reliable SNPs for di- as well as polyploid species. The tool features a user-friendly interface, multiple filtering options to handle typical sequencing errors, support for SAM and ACE files and interactive visualization. QualitySNPng produces high-quality SNP information that can be used directly in genotyping by sequencing approaches for application in QTL and genome-wide association mapping as well as to populate SNP arrays. The software can be used as a stand-alone application with a graphical user interface or as part of a pipeline system like Galaxy. Versions for Windows, Mac OS X and Linux, as well as the source code, are available from http://www.bioinformatics.nl/QualitySNPng. PMID:23632165
Nijveen, Harm; van Kaauwen, Martijn; Esselink, Danny G.; Hoegen, Brechtje; Vosman, Ben
Thrombotic Antiphospholipid Syndrome Shows Strong Haplotypic Association with SH2B3-ATXN2 Locus
Background Thrombotic antiphospholipid syndrome is defined as a complex form of thrombophilia that is developed by a fraction of antiphospholipid antibody (aPLA) carriers. Little is known about the genetic risk factors involved in thrombosis development among aPLA carriers. Methods To identify new loci conferring susceptibility to thrombotic antiphospholipid syndrome, a two-stage genotyping strategy was performed. In stage one, 19,000 CNV loci were genotyped in 14 thrombotic aPLA+ patients and 14 healthy controls by array-CGH. In stage two, significant CNV loci were fine-mapped in a larger cohort (85 thrombotic aPLA+, 100 non-thrombotic aPLA+ and 569 healthy controls). Results Array-CGH and fine-mapping analysis led to the identification of 12q24.12 locus as a new susceptibility locus for thrombotic APS. Within this region, a TAC risk haplotype comprising one SNP in SH2B3 gene (rs3184504) and two SNPs in ATXN2 gene (rs10774625 and rs653178) exhibited the strongest association with thrombotic antiphospholipid syndrome (p-value?=?5,9 × 10?4 OR 95% CI 1.84 (1.32–2.55)). Conclusion The presence of a TAC risk haplotype in ATXN2-SH2B3 locus may contribute to increased thrombotic risk in aPLA carriers. PMID:23844121
Ochoa, Eguzkine; Iriondo, Mikel; Bielsa, Ana; Ruiz-Irastorza, Guillermo; Estonba, Andone; Zubiaga, Ana M.
We analyzed for association between the Family with sequence similarity 46, member A (FAM46A) gene (located on chromosome 6q14.1), BCL2-Associated Athanogene 6 (BAG6) gene (located on chromosome 6p21.3) and tuberculosis in Croatian Caucasian. We genotyped the FAM46A rs11040 SNP, FAM46A VNTR and BAG6 rs3117582 polymorphisms in a case-control study with 257 tuberculosis patients and 493 healthy individuals in a Croatian Caucasian population. We found that genotype FAM46A 3/3 (three VNTR repeats homozygote) was associated with susceptibility to tuberculosis (p<0.0015, Pcorr.<0.029, Odds ratio?=?2.42, 95% Confidence Interval?=?1.34–4.3). This association suggests that the protein domain encoded by the VNTR might be important for the function of the FAM46A protein, which, in turn, could be relevant in developing tuberculosis. In addition, we found that FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotype 132 (G-3-C) is associated with susceptibility to tuberculosis (p<0.012, pcorr.<0.024, Odds ratio 3.45, 95% Confidence Interval?=?1.26–9.74). This may suggests that the interaction between the FAM46A and BAG6 proteins may be involved in tuberculosis etiology. We found also that infection of human macrophages with heat-killed M. tuberculosis (H37Rv) led to over-expression of FAM46A (VNTR 3/4) transcript. This is the first study to show associations between the FAM46A gene VNTR polymorphisms, FAM46A rs11040 SNP:FAM46A VNTR:BAG6 haplotypes and any disease. PMID:24625963
Etokebe, Godfrey Essien; Bulat-Kardum, Ljiljana; Munthe, Ludvig Andre; Balen, Sanja; Dembic, Zlatko
Snap: an integrated SNP annotation platform.
Snap (Single Nucleotide Polymorphism Annotation Platform) is a server designed to comprehensively analyze single genes and relationships between genes basing on SNPs in the human genome. The aim of the platform is to facilitate the study of SNP finding and analysis within the framework of medical research. Using a user-friendly web interface, genes can be searched by name, description, position, SNP ID or clone name. Several public databases are integrated, including gene information from Ensembl, protein features from Uniprot/SWISS-PROT, Pfam and DAS-CBS. Gene relationships are fetched from BIND, MINT, KEGG and are integrated with ortholog data from TreeFam to extend the current interaction networks. Integrated tools for primer-design and mis-splicing analysis have been developed to facilitate experimental analysis of individual genes with focus on their variation. Snap is available at http://snap.humgen.au.dk/ and at http://snap.genomics.org.cn/. PMID:17135198
Li, Shengting; Ma, Lijia; Li, Heng; Vang, Sřren; Hu, Yafeng; Bolund, Lars; Wang, Jun
A Bayesian Framework for SNP Identification
Current proteomics techniques, such as mass spectrometry, focus on protein identification, usually ignoring most types of modifications beyond post-translational modifications, with the assumption that only a small number of peptides have to be matched to a protein for a positive identification. However, not all proteins are being identified with current techniques and improved methods to locate points of mutation are becoming a necessity. In the case when single-nucleotide polymorphisms (SNPs) are observed, brute force is the most common method to locate them, quickly becoming computationally unattractive as the size of the database associated with the model organism grows. We have developed a Bayesian model for SNPs, BSNP, incorporating evolutionary information at both the nucleotide and amino acid levels. Formulating SNPs as a Bayesian inference problem allows probabilities of interest to be easily obtained, for example the probability of a specific SNP or specific type of mutation over a gene or entire genome. Three SNP databases were observed in the evaluation of the BSNP model; the first SNP database is a disease specific gene in human, hemoglobin, the second is also a disease specific gene in human, p53, and the third is a more general SNP database for multiple genes in mouse. We validate that the BSNP model assigns higher posterior probabilities to the SNPs defined in all three separate databases than can be attributed to chance under specific evolutionary information, for example the amino acid model described by Majewski and Ott in conjunction with either the four-parameter nucleotide model by Bulmer or seven-parameter nucleotide model by Majewski and Ott.
Webb-Robertson, Bobbie-Jo M.; Havre, Susan L.; Payne, Deborah A.
Analyzing cancer samples with SNP arrays.
Single nucleotide polymorphism (SNP) arrays are powerful tools to delineate genomic aberrations in cancer genomes. However, the analysis of these SNP array data of cancer samples is complicated by three phenomena: (a) aneuploidy: due to massive aberrations, the total DNA content of a cancer cell can differ significantly from its normal two copies; (b) nonaberrant cell admixture: samples from solid tumors do not exclusively contain aberrant tumor cells, but always contain some portion of nonaberrant cells; (c) intratumor heterogeneity: different cells in the tumor sample may have different aberrations. We describe here how these phenomena impact the SNP array profile, and how these can be accounted for in the analysis. In an extended practical example, we apply our recently developed and further improved ASCAT (allele-specific copy number analysis of tumors) suite of tools to analyze SNP array data using data from a series of breast carcinomas as an example. We first describe the structure of the data, how it can be plotted and interpreted, and how it can be segmented. The core ASCAT algorithm next determines the fraction of nonaberrant cells and the tumor ploidy (the average number of DNA copies), and calculates an ASCAT profile. We describe how these ASCAT profiles visualize both copy number aberrations as well as copy-number-neutral events. Finally, we touch upon regions showing intratumor heterogeneity, and how they can be detected in ASCAT profiles. All source code and data described here can be found at our ASCAT Web site ( http://www.ifi.uio.no/forskning/grupper/bioinf/Projects/ASCAT/). PMID:22130873
Van Loo, Peter; Nilsen, Gro; Nordgard, Silje H; Vollan, Hans Kristian Moen; Břrresen-Dale, Anne-Lise; Kristensen, Vessela N; Lingjćrde, Ole Christian
Haplotypes of NOS3 Gene Polymorphisms in Dilated Cardiomyopathy
Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 5? flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p?=?0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34–3.27, p?=?0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p?=?0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM phenotype. PMID:23923002
Matsa, Lova Satyanarayana; Rangaraju, Advithi; Vengaldas, Viswamitra; Latifi, Mona; Jahromi, Hossein Mehraban; Ananthapur, Venkateshwari; Nallari, Pratibha
Haplotypes of NOS3 gene polymorphisms in dilated cardiomyopathy.
Dilated Cardiomyopathy (DCM) is characterized by systolic dysfunction, followed by heart failure necessitating cardiac transplantation. The genetic basis is well established by the identification of mutations in sarcomere and cytoskeleton gene/s. Modifier genes and environmental factors are also considered to play a significant role in the variable expression of the disease, hence various mechanisms are implicated and one such mechanism is oxidative stress. Nitric Oxide (NO), a primary physiological transmitter derived from endothelium seems to play a composite role with diverse anti-atherogenic effects as vasodilator. Three functional polymorphisms of endothelial nitric oxide synthase (NOS3) gene viz., T-786C of the 5' flanking region, 27bp VNTR in intron4 and G894T of exon 7 were genotyped to identify their role in DCM. A total of 115 DCM samples and 454 controls were included. Genotyping was carried out by PCR -RFLP method. Allelic and genotypic frequencies were computed in both control & patient groups and appropriate statistical tests were employed. A significant association of TC genotype (T-786C) with an odds ratio of 1.74, (95% CI 1.14 - 2.67, p?=?0.01) was observed in DCM. Likewise the GT genotypic frequency of G894T polymorphism was found to be statistically significant (OR 2.10, 95% CI 1.34-3.27, p?=?0.0011), with the recessive allele T being significantly associated with DCM (OR 1.64, 95% CI 1.18 - 2.30, p?=?0.003). The haplotype carrying the recessive alleles of G894T and T-786C, C4bT was found to exhibit 7 folds increased risk for DCM compared to the controls. Hence C4bT haplotype could be the risk haplotype for DCM. Our findings suggest the possible implication of NOS3 gene in the disease phenotype, wherein NOS3 may be synergistically functioning in DCM associated heart failure via the excessive production of NO in cardiomyocytes resulting in decreased myocardial contractility and systolic dysfunction, a common feature of DCM phenotype. PMID:23923002
Matsa, Lova Satyanarayana; Rangaraju, Advithi; Vengaldas, Viswamitra; Latifi, Mona; Jahromi, Hossein Mehraban; Ananthapur, Venkateshwari; Nallari, Pratibha
Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis
Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ. PMID:16322765
Development and evaluation of the first high-throughput SNP array for common carp (Cyprinus carpio)
Background A large number of single nucleotide polymorphisms (SNPs) have been identified in common carp (Cyprinus carpio) but, as yet, no high-throughput genotyping platform is available for this species. C. carpio is an important aquaculture species that accounts for nearly 14% of freshwater aquaculture production worldwide. We have developed an array for C. carpio with 250,000 SNPs and evaluated its performance using samples from various strains of C. carpio. Results The SNPs used on the array were selected from two resources: the transcribed sequences from RNA-seq data of four strains of C. carpio, and the genome re-sequencing data of five strains of C. carpio. The 250,000 SNPs on the resulting array are distributed evenly across the reference C.carpio genome with an average spacing of 6.6 kb. To evaluate the SNP array, 1,072 C. carpio samples were collected and tested. Of the 250,000 SNPs on the array, 185,150 (74.06%) were found to be polymorphic sites. Genotyping accuracy was checked using genotyping data from a group of full-siblings and their parents, and over 99.8% of the qualified SNPs were found to be reliable. Analysis of the linkage disequilibrium on all samples and on three domestic C.carpio strains revealed that the latter had the longer haplotype blocks. We also evaluated our SNP array on 80 samples from eight species related to C. carpio, with from 53,526 to 71,984 polymorphic SNPs. An identity by state analysis divided all the samples into three clusters; most of the C. carpio strains formed the largest cluster. Conclusions The Carp SNP array described here is the first high-throughput genotyping platform for C. carpio. Our evaluation of this array indicates that it will be valuable for farmed carp and for genetic and population biology studies in C. carpio and related species. PMID:24762296
The HLA haplotype B18-DR3 has a widespread geographical distribution, but has its greatest frequencies in Southern Europe, probably vestigial of the earliest populations of this region, particularly in the Pays Basque and Sardinia. This haplotype is of medical significance, being that most implicated as a factor of risk in insulin-dependent diabetes mellitus. In this study, the closely linked microsatellite markers (TNFa,b,c) in the region of the tumor necrosis factor (TNF) genes have been used in an attempt to subtype this haplotype in the two populations and/or in healthy and diabetic populations. A total of 79 HLA-B18-DR3 haplotypes were analyzed: 54 in Basques (12 from healthy individuals and 42 from diabetics or their first-degree relatives) and 25 in Sardinians (13 from healthy and 13 from diabetic individuals). The TNF haplotype a1-b5-c2 is completely associated with B18-DR3 in both populations. The homogeneity of the B18-DR3 haplotype in two ethnically pure populations implies stability in evolution, which suggest that the mutation rate of these microsatellite markers must be less than is usually assumed (i.e., {approximately} 5x10{sup {minus}6} per site per generation). Such markers should be powerful tools for studying genetic drift and admixture of populations, but it remains to be established whether this stability is a rule for all microsatellites in HLA haplotypes or whether or whether it is restricted to some microsatellites and/or some HLA haplotypes. The population genetics of those microsatellites associated with HLA B18-DR3 was also studied in a random sample of the Basque population. 44 refs., 3 tabs.
Crouau-Roy, B.; Bouzekri, N.; Clayton, J. [CNRS, Toulouse (France)] [and others] [CNRS, Toulouse (France); and others
High-resolution SNP mapping by denaturing HPLC
With the availability of complete genome sequences, new rapid and reliable strategies for positional cloning become possible. Single-nucleotide polymorphisms (SNPs) permit the mapping of mutations at a resolution not amenable to classical genetics. Here we describe a SNP mapping procedure that relies on resolving polymorphisms by denaturing HPLC without the necessity of determining the nature of the SNPs. With the example of mapping mutations to the Drosophila nicastrin locus, we discuss the benefits of this method, evaluate the frequency of closely linked and potentially misleading second site mutations, and demonstrate the use of denaturing high-performance liquid chromatography to identify mutations in the candidate genes and to fine-map chromosomal breakpoints. Furthermore, we show that recombination events are not uniformly dispersed over the investigated region but rather occur at hot spots. PMID:12149455
Nairz, Knud; Stocker, Hugo; Schindelholz, Benno; Hafen, Ernst
Background High-throughput sequencing has opened up exciting possibilities in population and conservation genetics by enabling the assessment of genetic variation at genome-wide scales. One approach to reduce genome complexity, i.e. investigating only parts of the genome, is reduced-representation library (RRL) sequencing. Like similar approaches, RRL sequencing reduces ascertainment bias due to simultaneous discovery and genotyping of single-nucleotide polymorphisms (SNPs) and does not require reference genomes. Yet, generating such datasets remains challenging due to laboratory and bioinformatical issues. In the laboratory, current protocols require improvements with regards to sequencing homologous fragments to reduce the number of missing genotypes. From the bioinformatical perspective, the reliance of most studies on a single SNP caller disregards the possibility that different algorithms may produce disparate SNP datasets. Results We present an improved RRL (iRRL) protocol that maximizes the generation of homologous DNA sequences, thus achieving improved genotyping-by-sequencing efficiency. Our modifications facilitate generation of single-sample libraries, enabling individual genotype assignments instead of pooled-sample analysis. We sequenced ~1% of the orangutan genome with 41-fold median coverage in 31 wild-born individuals from two populations. SNPs and genotypes were called using three different algorithms. We obtained substantially different SNP datasets depending on the SNP caller. Genotype validations revealed that the Unified Genotyper of the Genome Analysis Toolkit and SAMtools performed significantly better than a caller from CLC Genomics Workbench (CLC). Of all conflicting genotype calls, CLC was only correct in 17% of the cases. Furthermore, conflicting genotypes between two algorithms showed a systematic bias in that one caller almost exclusively assigned heterozygotes, while the other one almost exclusively assigned homozygotes. Conclusions Our enhanced iRRL approach greatly facilitates genotyping-by-sequencing and thus direct estimates of allele frequencies. Our direct comparison of three commonly used SNP callers emphasizes the need to question the accuracy of SNP and genotype calling, as we obtained considerably different SNP datasets depending on caller algorithms, sequencing depths and filtering criteria. These differences affected scans for signatures of natural selection, but will also exert undue influences on demographic inferences. This study presents the first effort to generate a population genomic dataset for wild-born orangutans with known population provenance. PMID:24405840
mrSNP: Software to detect SNP effects on microRNA binding
Background MicroRNAs (miRNAs) are short (19-23 nucleotides) non-coding RNAs that bind to sites in the 3'untranslated regions (3'UTR) of a targeted messenger RNA (mRNA). Binding leads to degradation of the transcript or blocked translation resulting in decreased expression of the targeted gene. Single nucleotide polymorphisms (SNPs) have been found in 3'UTRs that disrupt normal miRNA binding or introduce new binding sites and some of these have been associated with disease pathogenesis. This raises the importance of detecting miRNA targets and predicting the possible effects of SNPs on binding sites. In the last decade a number of studies have been conducted to predict the location of miRNA binding sites. However, there have been fewer algorithms published to analyze the effects of SNPs on miRNA binding. Moreover, the existing software has some shortcomings including the requirement for significant manual labor when working with huge lists of SNPs and that algorithms work only for SNPs present in databases such as dbSNP. These limitations become problematic as next-generation sequencing is leading to large numbers of novel variants in 3'UTRs. Result In order to overcome these issues, we developed a web-server named mrSNP which predicts the impact of a SNP in a 3'UTR on miRNA binding. The proposed tool reduces the manual labor requirements and allows users to input any SNP that has been identified by any SNP-calling program. In testing the performance of mrSNP on SNPs experimentally validated to affect miRNA binding, mrSNP correctly identified 69% (11/16) of the SNPs disrupting binding. Conclusions mrSNP is a highly adaptable and performing tool for predicting the effect a 3'UTR SNP will have on miRNA binding. This tool has advantages over existing algorithms because it can assess the effect of novel SNPs on miRNA binding without requiring significant hands on time. PMID:24629096
Molecular haplotyping by linking emulsion PCR: analysis of paraoxonase 1 haplotypes and phenotypes
Linking emulsion PCR (LE-PCR) enables formation of minichromosomes preserving phase information of two polymorphic loci, hence the haplotype. Emulsion PCR confines two amplicons of two linked polymorphic sites on a single template molecule to one aqueous-phase droplet. Linking PCR uses biotinylated, overlapping linking primers to connect these amplicons in the droplet. After LE-PCR, unlinked amplicons are removed on streptavidin-coated magnetic beads and single-stranded runoff products are capped by primer extension. Quantitative ASPCR can then be used to ascertain the haplotypes of the two polymorphic loci on the minichromosomes. Using LE-PCR, we determined the human paraoxonase-1 [PON1] molecular haplotypes at three loci (?909g>c, L55M, Q192R) in women who were compound heterozygotes for ?909g>c/L55M (n = 89), ?909g>c/Q192R (n = 77) and L55M/Q192R (n = 68). We observed a strong association between PON1 substrate specificity (paraoxon/phenylacetate substrate activity ratios) and ?909g>c/Q192R haplotype. We have demonstrated here a powerful molecular haplotyping technology that can be applied in population studies. PMID:15886392
Wetmur, James G.; Kumar, Madhu; Zhang, Li; Palomeque, Caroline; Wallenstein, Sylvan; Chen, Jia
In a large variety of genetic studies, probabilistic inferences are made based on information available in population databases. The accuracy of the estimates based on population samples are highly dependent on the number of chromosomes being analyzed as well as the correct representation of the reference population. For frequency calculations the size of a database is especially critical for haploid markers, and for countries with complex admixture histories it is important to assess possible substructure effects that can influence the coverage of the database. Aiming to establish a representative Brazilian population database for haplotypes based on 23 Y chromosome STRs, more than 2,500 Y chromosomes belonging to Brazilian, European and African populations were analyzed. No matter the differences in the colonization history of the five geopolitical regions that currently exist in Brazil, for the Y chromosome haplotypes of the 23 studied Y-STRs, a lack of genetic heterogeneity was found, together with a predominance of European male lineages in all regions of the country. Therefore, if we do not consider the diverse Native American or Afro-descendent isolates, which are spread through the country, a single Y chromosome haplotype frequency database will adequately represent the urban populations in Brazil. In comparison to the most commonly studied group of 17 Y-STRs, the 23 markers included in this work allowed a high discrimination capacity between haplotypes from non-related individuals within a population and also increased the capacity to discriminate between paternal relatives. Nevertheless, the expected haplotype mutation rate is still not enough to distinguish the Y chromosome profiles of paternally related individuals. Indeed, even for rapidly mutating Y-STRs, a very large number of markers will be necessary to differentiate male lineages from paternal relatives. PMID:22808085
Palha, Teresinha; Gusmăo, Leonor; Ribeiro-Rodrigues, Elzemar; Guerreiro, Joăo Farias; Ribeiro-dos-Santos, Ândrea; Santos, Sidney
Background The increasingly narrow genetic background characteristic of modern crop germplasm presents a challenge for the breeding of cultivars that require adaptation to the anticipated change in climate. Thus, high priority research aims at the identification of relevant allelic variation present both in the crop itself as well as in its progenitors. This study is based on the characterization of genetic variation in barley, with a view to enhancing its response to terminal drought stress. Results The expression patterns of drought regulated genes were monitored during plant ontogeny, mapped and the location of these genes was incorporated into a comprehensive barley SNP linkage map. Haplotypes within a set of 17 starch biosynthesis/degradation genes were defined, and a particularly high level of haplotype variation was uncovered in the genes encoding sucrose synthase (types I and II) and starch synthase. The ability of a panel of 50 barley accessions to maintain grain starch content under terminal drought conditions was explored. Conclusion The linkage/expression map is an informative resource in the context of characterizing the response of barley to drought stress. The high level of haplotype variation among starch biosynthesis/degradation genes in the progenitors of cultivated barley shows that domestication and breeding have greatly eroded their allelic diversity in current elite cultivars. Prospective association analysis based on core drought-regulated genes may simplify the process of identifying favourable alleles, and help to understand the genetic basis of the response to terminal drought. PMID:21205309
SERPINE2 haplotype as a risk factor for panlobular type of emphysema
Background SERPINE2 (serpin peptidase inhibitor, clade E, member 2) has previously been identified as a positional candidate gene for chronic obstructive pulmonary disease (COPD) and has subsequently been associated to COPD and emphysema in several populations. We aimed to further examine the role of SERPINE2 polymorphisms in the development of pulmonary emphysema and different emphysema subtypes. Methods Four single nucleotide polymorphisms (SNPs) in SERPINE2 were analyzed from 951 clinically and radiologically examined Finnish construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high-resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), diffusing capacity (DLCO), and specific diffusing capacity (DLCO/VA). Results Three of the studied SERPINE2 SNPs (rs729631, rs975278, and rs6748795) were found to be in tight linkage disequilibrium. Therefore, only one of these SNPs (rs729631) was included in the subsequent analyses, in addition to the rs840088 SNP which was in moderate linkage with the other three studied SNPs. The rs729631 SNP showed a significant association with panlobular emphysema (p = 0.003). In further analysis, the variant allele of the rs729631 SNP was found to pose over two-fold risk (OR 2.22, 95% CI 1.05-4.72) for overall panlobular changes and over four-fold risk (OR 4.37, 95% CI 1.61-11.86) for pathological panlobular changes. A haplotype consisting of variant alleles of both rs729631 and rs840088 SNPs was found to pose an almost four-fold risk for overall panlobular (OR 3.72, 95% CI 1.56-8.90) and subnormal (OR 3.98, 95% CI 1.55-10.20) emphysema. Conclusions Our results support the previously found association between SERPINE2 polymorphisms and pulmonary emphysema. As a novel finding, our study suggests that the SERPINE2 gene may in particular be involved in the development of panlobular changes, i.e., the same type of changes that are involved in alpha-1-antitrypsin (AAT) -deficiency. PMID:22145704
Expression of prolactin hormone is a crucial event in regulating egg production in chickens for which promoter plays the vital role in expressing the prolactin gene. The objective of the present study was to identify haplotypes in the prolactin promoter and their effects on egg production and egg quality traits in White Leghorn chicken. Single stranded conformation polymorphism followed by sequencing was conducted to explore polymorphism at 561 bp promoter of prolactin gene. The effect of haplotype combinations on egg production and quality traits were estimated following general linear model technique. The expression of prolactin by different haplogroups was quantified by qPCR. Total 28 haplotypes were found in White Leghorn chicken of which h1 haplotype possessed the highest frequency of 0.46 and h8, h14, h16, h25, h26, and h28 haplotypes had the lowest frequency (0.1%). The egg production up to 52 and 64 weeks of age were found to be significantly (p < 0.05) associated with haplotype combinations where the highest 52-w (52 weeks) egg production was found in animals with h1/h22 combination and the lowest production was observed in the birds with h1/h2 haplogroup. The haplotype combinations had the significant effect (p < 0.05) on Haugh Unit, yolk index and albumen weight at 40 weeks of age; Haugh Unit and albumen weight at 52 weeks of age and Haugh unit, yolk weight and yolk percentage at 64 weeks of age. The prolactin expression in h1/h22 birds was found to be the lowest and in h1/h5 birds to be the highest. The prolactin expression showed significant effect on 52-w egg production and albumin weight at 52 weeks age. In conclusion, it may be stated that the prolactin promoter was highly polymorphic and had the significant association with egg production and quality traits in White Leghorn chicken. PMID:21500109
Bhattacharya, T K; Chatterjee, R N; Sharma, R P; Niranjan, M; Rajkumar, U; Reddy, B L N
Casein SNP in Norwegian goats: additive and dominance effects on milk composition and quality
Background The four casein proteins in goat milk are encoded by four closely linked casein loci (CSN1S1, CSN2, CSN1S2 and CSN3) within 250 kb on caprine chromosome 6. A deletion in exon 12 of CSN1S1, so far reported only in Norwegian goats, has been found at high frequency (0.73). Such a high frequency is difficult to explain because the national breeding goal selects against the variant's effect. Methods In this study, 575 goats were genotyped for 38 Single Nucleotide Polymorphisms (SNP) located within the four casein genes. Milk production records of these goats were obtained from the Norwegian Dairy Goat Control. Test-day mixed models with additive and dominance fixed effects of single SNP were fitted in a model including polygenic effects. Results Significant additive effects of single SNP within CSN1S1 and CSN3 were found for fat % and protein %, milk yield and milk taste. The allele with the deletion showed additive and dominance effects on protein % and fat %, and overdominance effects on milk quantity (kg) and lactose %. At its current frequency, the observed dominance (overdominance) effects of the deletion allele reduced its substitution effect (and additive genetic variance available for selection) in the population substantially. Conclusions The selection pressure of conventional breeding on the allele with the deletion is limited due to the observed dominance (overdominance) effects. Inclusion of molecular information in the national breeding scheme will reduce the frequency of this deletion in the population. PMID:21864407
The gene frequencies of HLA class II alleles were studied in 95 healthy Lebanese Arab and 72 healthy Bahraini Arab subjects. Our aim was to establish the genetic relationship between Bahraini and Lebanese Arabs in terms of HLA class II gene and haplotype frequencies and to compare these results with frequencies for other countries with populations of Caucasian and non-Caucasian
Wassim Y. Almawi; Marc Busson; Hala Tamim; Einas M. Al-Harbi; Ramzi R. Finan; Saria F. Wakim-Ghorayeb; Ayesha A. Motala
The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB haplotype is likely to be applicable to many other genes.
Rapacz, J.; Hasler-Rapacz, J.O. (Univ. of Wisconsin, Madison (United States)); Chen, L.; Wu, Mingjiuan; Schumaker, V.N. (Univ. of California, Los Angeles (United States)); Butler-Brunner, E.; Butler, R. (Swiss Red Cross Blood Transfusion Service, Bern (Switzerland))
Restriction map studies previously revealed extensive linkage disequilibria in the transcriptional unit of the white locus in natural Drosophila melanogaster populations. To understand the causes of these disequilibria, we sequenced a 4722-bp region of the white gene from 15 lines of D. melanogaster and 1 line of Drosophila simulans. Statistical tests applied to the entire 4722-bp region do not reject neutrality. In contrast, a test for high-frequency haplotypes ({open_quotes}Haplotype test{close_quotes}) revealed an 834-bp segment, encompassing the 3{prime} end of intron 1 to the 3{prime} end of intron 2, in which the structure of variation deviates significantly from the predictions of a neutral equilibrium model. The variants in this 834-bp segment segregate as single haplotype blocks. We propose that these unusually large haplotype blocks are due to positive selection on polymorphisms within the white gene, including a replacement polymorphism, Arg{yields}Leu, within this segment. 45 refs., 4 figs., 1 tab.
Kirby, D.A.; Stephan, W. [Univ. of Maryland, College Park, MD (United States)
Patterns of haplotypes for 92 cystic fibrosis mutations: Variability, association and recurrence
Most CFTR mutations are very uncommon among the cystic fibrosis population, with frequencies of less than 1%, and many are found only in specific areas. We have analyzed 92 CF mutations for several markers (4 microsatellites and 3 other polymorphisms) scattered in the CFTR gene. Haplotypes associated with these mutations can be used as a framework in the screening of chromosomes carrying unknown mutations. The association between mutation and haplotype reduces the number of mutations it is necessary to search for to a maximum of 16 for the same haplotype. Only mutations {triangle}F508, G542X and N1303K are associated with more than one haplotype as a result of slippage at more than one microsatellite loci, suggesting that these three are the most ancient CF mutations. Recurrence has been found for at least 7 mutations: H199Y, R347P, L558S, R553X, 2184insA, 3272-26A{r_arrow}G, 3849+10kbC{r_arrow}T and R1162X. Also microsatellite analysis of chromosomes of several ethnic origins (Czech, Italian, Russian, Slovac and Spanish) suggested that possibility of three or more independent origins for mutations R334W, R347P, R1162X, and 3849+10kbC{r_arrow}T, which was confirmed by analysis of markers flanking these mutations.
Morral, N.; Llevadot, R.; Estivill, X. [I.R.O., Barcelona (Spain)] [and others
Possible Positive Selection for an Arsenic-Protective Haplotype in Humans
Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis. PMID:23070617
Schlebusch, Carina M.; Lewis, Cecil M.; Vahter, Marie; Engstrom, Karin; Tito, Raul Y.; Obregon-Tito, Alexandra J.; Huerta, Doris; Polo, Susan I.; Medina, Angel C.; Brutsaert, Tom D.; Concha, Gabriela; Jakobsson, Mattias
?-Globin gene linked DNA haplotypes and frameworks in three South-East Asian populations
DNA haplotypes and frameworks (numbers in parenthesis) linked to the ß-globin gene were determined by restriction fragment analysis using eight restriction endonucleases on 86 (97) chromosomes bearing the normal ß-globin gene (HBB*A) and 108 (118) chromosomes bearing HBB*E in subjects homozygous for HBB*A or HBB*E from three South-East Asian populations with high HBB*E frequencies (northern Thailand, north-eastern Thailand and Cambodia).
J. Hundrieser; T. Sanguansermsri; T. Papp; Marion Laig; G. Flatz
Molecular cloning and SNP association analysis of chicken PMCH gene.
The pre-melanin-concentrating hormone (PMCH) gene is an important gene functionally concerning the regulations of body fat content, feeding behavior and energy balance. In this study, the full-length cDNA of chicken PMCH gene was amplified by SMART RACE method. The single nucleotide polymorphisms (SNPs) in the PMCH gene were screened by comparative sequence analysis. The obtained non-synonymous coding SNPs (ncSNPs) were designed for genotyping firstly. Its effects on growth, carcass characteristics and meat quality traits were investigated employing the F2 resource population of Gushi chicken crossed with Anak broiler by AluI CRS-PCR-RFLP. Our results indicated that the cDNA of chicken PMCH shared 67.25 and 66.47% homology with that of human and bovine PMCH, respectively. The deduced amino acid sequence of chicken PMCH (163 amino acids) were 52.07 and 50.89% identical to those of human and bovine PMCH, respectively. The PMCH protein sequence is predicted to have several functional domains, including pro-MCH, CSP, IL7, XPGI and some low complexity sequence. It has 8 phosphorylation sites and no signal peptide sequence. gga-miR-18a, gga-miR-18b, gga-miR-499 microRNA targeting site was predicted in the 3' untranslated region of chicken PMCH mRNA. In addition, a total of seven SNPs including an ncSNP and a synonymous coding SNP, were identified in the PMCH gene. The ncSNP c.81 A>T was found to be in moderate polymorphic state (polymorphic index=0.365), and the frequencies for genotype AA, AB and BB were 0.3648, 0.4682 and 0.1670, respectively. Significant associations between the locus and shear force of breast and leg were observed. This polymorphic site may serve as a useful target for the marker assisted selection of the growth and meat quality traits in chicken. PMID:23670042
Sun, Guirong; Li, Ming; Li, Hong; Tian, Yadong; Chen, Qixin; Bai, Yichun; Kang, Xiangtao
Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human
P Zill; T C Baghai; P Zwanzger; C Schüle; D Eser; R Rupprecht; H-J Möller; B Bondy; M Ackenheil
Bayesian Modeling of Haplotype Effects in Multiparent Populations
A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley–Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus. PMID:25236455
Zhang, Zhaojun; Wang, Wei; Valdar, William
Bayesian modeling of haplotype effects in multiparent populations.
A general Bayesian model, Diploffect, is described for estimating the effects of founder haplotypes at quantitative trait loci (QTL) detected in multiparental genetic populations; such populations include the Collaborative Cross (CC), Heterogeneous Socks (HS), and many others for which local genetic variation is well described by an underlying, usually probabilistically inferred, haplotype mosaic. Our aim is to provide a framework for coherent estimation of haplotype and diplotype (haplotype pair) effects that takes into account the following: uncertainty in haplotype composition for each individual; uncertainty arising from small sample sizes and infrequently observed haplotype combinations; possible effects of dominance (for noninbred subjects); genetic background; and that provides a means to incorporate data that may be incomplete or has a hierarchical structure. Using the results of a probabilistic haplotype reconstruction as prior information, we obtain posterior distributions at the QTL for both haplotype effects and haplotype composition. Two alternative computational approaches are supplied: a Markov chain Monte Carlo sampler and a procedure based on importance sampling of integrated nested Laplace approximations. Using simulations of QTL in the incipient CC (pre-CC) and Northport HS populations, we compare the accuracy of Diploffect, approximations to it, and more commonly used approaches based on Haley-Knott regression, describing trade-offs between these methods. We also estimate effects for three QTL previously identified in those populations, obtaining posterior intervals that describe how the phenotype might be affected by diplotype substitutions at the modeled locus. PMID:25236455
Zhang, Zhaojun; Wang, Wei; Valdar, William
Genomic evolution in domestic cattle: ancestral haplotypes and healthy beef.
We have identified numerous Ancestral Haplotypes encoding a 14-Mb region of Bota C19. Three are frequent in Simmental, Angus and Wagyu and have been conserved since common progenitor populations. Others are more relevant to the differences between these 3 breeds including fat content and distribution in muscle. SREBF1 and Growth Hormone, which have been implicated in the production of healthy beef, are included within these haplotypes. However, we conclude that alleles at these 2 loci are less important than other sequences within the haplotypes. Identification of breeds and hybrids is improved by using haplotypes rather than individual alleles. PMID:21338665
Williamson, Joseph F; Steele, Edward J; Lester, Susan; Kalai, Oscar; Millman, John A; Wolrige, Lindsay; Bayard, Dominic; McLure, Craig; Dawkins, Roger L
A genotype calling algorithm for affymetrix SNP arrays
Motivation: A classification algorithm, based on a multi-chip, multi- SNP approach is proposed for Affymetrix SNP arrays. Current proceduresforcallinggenotypesonSNParraysprocessallthefeatures associated with one chip and one SNP at a time. Using a large training samplewherethegenotypelabelsareknown,wedevelopasupervised learningalgorithmtoobtainmoreaccurateclassificationresultsonnew data. The method we propose, RLMM, is based on a robustly fitted, linear model and uses the Mahalanobis distance for classification. The chip-to-chip non-biological variance
Nusrat Rabbee; Terence P. Speed
A method for inferring evolutionary relationships among haplotypes, exemplified by haplotypes at the
at the monoamine oxidase locus Hoa Nguyen1 , Kathryn Roeder1 , B. Devlin1-4 , Brion S. Maher4,5 , Ling-Mei Yu3 decisions for data analysis. We evaluate these methods using data on monoamine oxidase (MAO) haplotypes from
significant one at position ~4,863 kb. These results are supported by a single marker chi-square test chi-square test or the TDT-test [5]. The advantage of single locus tests is that haplotypes testing André R. de Vriesa , Ilja M. Nolteb , Geert T. Spijkerc , Dumitru Brinzad , Alexander Zelikovskyd
Zelikovsky, Alexander
TRM: a powerful two-stage machine learning approach for identifying SNP-SNP interactions.
Studies have shown that interactions of single nucleotide polymorphisms (SNPs) may play an important role in understanding the causes of complex disease. We have proposed an integrated machine learning method that combines two machine-learning methods-Random Forests (RF) and Multivariate Adaptive Regression Splines (MARS)-to identify a subset of important SNPs and detect interaction patterns more effectively and efficiently. In this two-stage RF-MARS (TRM) approach, RF is first applied to detect a predictive subset of SNPs, and then MARS is used to identify the interaction patterns. We evaluated the TRM performances in four models. RF variable selection was based on out-of-bag classification error rate (OOB) and variable important spectrum (IS). Our results support that RF(OOB) had better performance than MARS and RF(IS) in detecting important variables. This study demonstrates that TRM(OOB) , which is RF(OOB) plus MARS, has combined the strengths of RF and MARS in identifying SNP-SNP interactions in a scenario of 100 candidate SNPs. TRM(OOB) had greater true positive rate and lower false positive rate compared with MARS, particularly for searching interactions with a strong association with the outcome. Therefore, the use of TRM(OOB) is favored for exploring SNP-SNP interactions in a large-scale genetic variation study. PMID:22150548
Lin, Hui-Yi; Chen, Y Ann; Tsai, Ya-Yu; Qu, Xiaotao; Tseng, Tung-Sung; Park, Jong Y
Background Numerous quantitative trait loci (QTL) have been detected in pigs over the past 20 years using microsatellite markers. However, due to the low density of these markers, the accuracy of QTL location has generally been poor. Since 2009, the dense genome coverage provided by the Illumina PorcineSNP60 BeadChip has made it possible to more accurately map QTL using genome-wide association studies (GWAS). Our objective was to perform high-density GWAS in order to identify genomic regions and corresponding haplotypes associated with production traits in a French Large White population of pigs. Methods Animals (385 Large White pigs from 106 sires) were genotyped using the PorcineSNP60 BeadChip and evaluated for 19 traits related to feed intake, growth, carcass composition and meat quality. Of the 64 432 SNPs on the chip, 44 412 were used for GWAS with an animal mixed model that included a regression coefficient for the tested SNPs and a genomic kinship matrix. SNP haplotype effects in QTL regions were then tested for association with phenotypes following phase reconstruction based on the Sscrofa10.2 pig genome assembly. Results Twenty-three QTL regions were identified on autosomes and their effects ranged from 0.25 to 0.75 phenotypic standard deviation units for feed intake and feed efficiency (four QTL), carcass (12 QTL) and meat quality traits (seven QTL). The 10 most significant QTL regions had effects on carcass (chromosomes 7, 10, 16, 17 and 18) and meat quality traits (two regions on chromosome 1 and one region on chromosomes 8, 9 and 13). Thirteen of the 23 QTL regions had not been previously described. A haplotype block of 183 kb on chromosome 1 (six SNPs) was identified and displayed three distinct haplotypes with significant (0.0001?SNP60 BeadChip enabled the detection of 23 QTL regions that affect feed consumption, carcass and meat quality traits in a LW population, of which 13 were novel QTL. The proportionally larger number of QTL found for meat quality traits suggests a specific opportunity for improving these traits in the pig by genomic selection. PMID:24528607
TRM: A Powerful Two-stage Machine Learning Approach for Identifying SNP-SNP Interactions
SUMMARY Studies have shown that interactions of single nucleotide polymorphism (SNP) may play an important role for understanding causes of complex disease. Machine learning approaches provide useful features to explore interactions more effectively and efficiently. We have proposed an integrated method that combines two machine learning methods - Random Forests (RF) and Multivariate Adaptive Regression Splines (MARS) - to identify a subset of important SNPs and detect interaction patterns. In this two-stage RF-MARS (TRM) approach, RF is first applied to detect a predictive subset of SNPs, and then MARS is used to identify the interaction patterns among the selected SNPs. We evaluated the TRM performances in four models: three causal models with one two-way interaction and one null model. RF variable selection was based on out-of-bag classification error rate (OOB) and variable important spectrum (IS). First, we compared the selection of important variable of RF and MARS. Our results support that RFOOB had better performance than MARS and RFIS in detecting important variables. We also evaluated the true positive rate and false positive rate of identifying interaction patterns in TRM and MARS. This study demonstrates that TRMOOB, which is RFOOB plus MARS, has combined the strengths of RF and MARS in identifying SNP-SNP interaction patterns in a scenario of 100 candidate SNPs. TRMOOB had greater true positive rate and lower false positive rate compared with MARS, particularly for searching interactions with a strong association with the outcome. Therefore the use of TRMOOB is favored for exploring SNP-SNP interactions in a large-scale genetic variation study. PMID:22150548
Lin, Hui-Yi; Chen, Y. Ann; Tsai, Ya-Yu; Qu, Xiaotao; Tseng, Tung-Sung; Park, Jong Y.
Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction.
Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); P<0.001), and g.5612A>G (OR, 0.21 (0.08-0.55); P < 0.001) in FGR. There were no differences in maternal haplotype frequencies between normal pregnancy and FGR for AGTR1 or AGTR2 (P > 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor. PMID:16395664
Tower, Clare; Chappell, Sally; Acharya, Meera; Crane, Richard; Szolin, Stephanie; Symonds, Lyneth; Chevins, Helen; Kalsheker, Noor; Baker, Philip; Morgan, Linda
Severe malarial anemia (SMA) is a leading cause of morbidity and mortality in children residing in regions where Plasmodium falciparum transmission is holoendemic. Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (?137G?C [rs187238] and ?607C?A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes/haplotypes, SMA (hemoglobin [Hb], <5.0 g/dl], and longitudinal clinical outcomes were then investigated in Kenyan children (n = 719). Multivariate logistic regression analyses controlling for age, gender, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the ?607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90], P = 0.031) in children with acute infection. In contrast, carriers of the ?137G/?607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05], P = 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (? = ?0.293, P = 0.010) and that carriers of the "susceptible" GC haplotype had elevated IL-18 transcripts (P = 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (?1% frequency) had 5.76 times higher mortality than noncarriers (P = 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality. PMID:21969001
Anyona, Samuel B.; Kempaiah, Prakasha; Raballah, Evans; Ouma, Collins; Were, Tom; Davenport, Gregory C.; Konah, Stephen N.; Vulule, John M.; Hittner, James B.; Gichuki, Charity W.; Ong'echa, John M.; Perkins, Douglas J.
Cytochrome P450 oxidoreductase (POR) transfers electrons from NADPH to all microsomal cytochrome P450 (CYP) enzymes and is necessary for microsomal CYP activities. In this study, to find genetic variations and to elucidate the haplotype structures of POR, we comprehensively screened the genetic variations in the 5'-flanking region, all the exons and their flanking introns of POR for 235 Japanese subjects. Seventy-five genetic variations including 26 novel ones were found: 7 were in the 5'-flanking region, 2 in the 5'-untranslated region (5'-UTR, non-coding exon 1), 16 in the coding exons (10 nonsynonymous and 6 synonymous), 45 in the introns, 4 in the 3'-UTR and 1 in the 3'-flanking region. Of these, 4 novel nonsynonymous variations, 86C>T (T29M), 1648C>T (R550W), 1708C>T (R570C) and 1975G>A (A659T), were detected with allele frequencies of 0.002. We also detected known nonsynonymous SNPs 683C>T (P228L), 1237G>A (G413S), 1453G>A (A485T), 1508C>T (A503V), 1510G>A (G504R) and 1738G>C (E580Q) with frequencies of 0.002, 0.009, 0.002, 0.434, 0.002 and 0.002, respectively. Based on the linkage disequilibrium (LD) profiles, the analyzed region could be divided into two LD blocks. For Blocks 1 and 2, 14 and 46 haplotypes were inferred, respectively, and 2 and 6 common haplotypes found in more than 0.03 frequencies accounted for more than 81% of the inferred haplotypes. This study provides fundamental and useful information for the pharmacogenetic studies of drugs metabolized by CYPs in the Japanese population. PMID:21084761
Saito, Yoshiro; Yamamoto, Noboru; Katori, Noriko; Maekawa, Keiko; Fukushima-Uesaka, Hiromi; Sugimoto, Daisuke; Kurose, Kouichi; Sai, Kimie; Kaniwa, Nahoko; Sawada, Jun-Ichi; Kunitoh, Hideo; Ohe, Yuichiro; Yoshida, Teruhiko; Matsumura, Yasuhiro; Saijo, Nagahiro; Okuda, Haruhiro; Tamura, Tomohide
The mutated S1-haplotype in sour cherry has an altered S-haplotype-specific F-box protein gene.
Gametophytic self-incompatibility (GSI) is an outcrossing mechanism in flowering plants that is genetically controlled by 2 separate genes located at the highly polymorphic S-locus, termed S-haplotype. This study characterizes a pollen part mutant of the S(1)-haplotype present in sour cherry (Rosaceae, Prunus cerasus L.) that contributes to the loss of GSI. Inheritance of S-haplotypes from reciprocal interspecific crosses between the self-compatible sour cherry cultivar Ujfehértói Fürtös carrying the mutated S(1)-haplotype (S(1)'S(4)S(d)S(null)) and the self-incompatible sweet cherry (Prunus avium L.) cultivars carrying the wild-type S(1)-haplotype revealed that the mutated S(1)-haplotype confers unilateral incompatibility with a functional pistil component and a nonfunctional pollen component. The altered sour cherry S(1)-haplotype pollen part mutant, termed S(1)', contains a 615-bp Ds-like element within the S(1)-haplotype-specific F-box protein gene (SFB(1)'). This insertion generates a premature in-frame stop codon that would result in a putative truncated SFB(1) containing only 75 of the 375 amino acids present in the wild-type SFB(1). S(1)' along with 2 other previously characterized Prunus S-haplotype mutants, S(f) and S(6m), illustrate that mobile element insertion is an evolutionary force contributing to the breakdown of GSI. PMID:16985081
Hauck, Nathanael R; Ikeda, Kazuo; Tao, Ryutaro; Iezzoni, Amy F
The origins of the inhabitants of Madagascar have not been fully resolved. Anthropological studies and preliminary genetic data point to two main sources of ancestry of the Malagasy, namely, Indonesian and African, with additional contributions from India and Arabia. The sickle-cell (beta s) mutation is found in populations of African and Indian origin. The frequency of the beta s-globin gene, derived from 1,425 Malagasy individuals, varies from 0 in some highland populations to .25 in some coastal populations. The beta s mutation is thought to have arisen at least five times, on the basis of the presence of five distinct beta s-associated haplotypes, each found in a separate geographic area. Twenty-five of the 35 Malagasy beta s haplotypes were of the typical "Bantu" type, 1 "Senegal" haplotype was found, and 2 rare or atypical haplotypes were observed; the remaining 7 haplotypes were consistent with the Bantu haplotype. The Bantu beta s mutation is thought to have been introduced into Madagascar by Bantu-speaking immigrants (colonists or slaves) from central or east Africa. The Senegal beta s mutation may have been introduced to the island via Portuguese naval explorers. This study provides the first definitive biological evidence that a major component of Malagasy ancestry is derived from African populations, in particular, Bantu-speaking Negroids. beta A haplotypes are also consistent with the claim for a significant African contribution to Malagasy ancestry but are also suggestive of Asian/Oceanic and Caucasoid admixture within the Malagasy population. PMID:8651308
Hewitt, R.; Krause, A.; Goldman, A.; Campbell, G.; Jenkins, T.
The human angiotensinogen (hAGT) gene contains an A/G polymorphism at -217, and frequency of -217A allele is increased in African-American hypertensive patients. The hAGT gene has seven polymorphic sites in the 1.2-kb region of its promoter, and variant -217A almost always occurs with -532T, -793A, and -1074T, whereas variant -217G almost always occurs with -532C, -793G, and -1074G. Since allele -6A is the predominant allele in African-Americans, the AGT gene can be subdivided into two main haplotypes, -6A:-217A (AA) and -6A:-217G (AG). To understand the role of these haplotypes on hAGT gene expression and on blood pressure regulation in an in vivo situation, we have generated double transgenic mice containing human renin gene and either AA or AG haplotype of the hAGT gene using knock-in strategy at the hypoxanthine phosphoribosyltransferase locus. We show here that 1) hAGT mRNA level is increased in the liver by 60% and in the kidney by 40%; and 2) plasma AGT level is increased by approximately 40%, and plasma angiotensin II level is increased by approximately 50% in male double transgenic mice containing AA haplotype of the hAGT gene compared with the AG haplotype. In addition, systolic blood pressure is increased by 8 mmHg in transgenic mice containing the AA haplotype compared with the AG haplotype. This is the first report to show the effect of polymorphisms in the promoter of a human gene on its transcription in an in vivo situation that ultimately leads to an increase in blood pressure. PMID:18945948
Jain, Sudhir; Vinukonda, Govindaiah; Fiering, Steven N; Kumar, Ashok
Tetraploid sour cherry (Prunus cerasus) has an S-RNase-based gametophytic self-incompatibility (GSI) system; however, individuals can be either self-incompatible (SI) or self-compatible (SC). Unlike the situation in the Solanaceae, where self-compatibility accompanying polyploidization is often due to the compatibility of heteroallelic pollen, the genotype-dependent loss of SI in sour cherry is due to the compatibility of pollen containing two nonfunctional S haplotypes. Sour cherry individuals with the S(4)S(6)S(36a)S(36b) genotype are predicted to be SC, as only pollen containing both nonfunctional S(36a) and S(36b) haplotypes would be SC. However, we previously found that individuals of this genotype were SI. Here we describe four nonfunctional S(36) variants. Our molecular analyses identified a mutation that would confer loss of stylar S function for one of the variants, and two alterations that might cause loss of pollen S function for all four variants. Genetic crosses showed that individuals possessing two nonfunctional S(36) haplotypes and two functional S haplotypes have reduced self-fertilization due to a very low frequency of transmission of the one pollen type that would be SC. Our finding that the underlying mechanism limiting successful transmission of genetically compatible gametes does not involve GSI is consistent with our previous genetic model for Prunus in which heteroallelic pollen is incompatible. This provides a unique case in which breakdown of SI does not occur despite the potential to generate SC pollen genotypes. PMID:19917768
Tsukamoto, Tatsuya; Hauck, Nathanael R; Tao, Ryutaro; Jiang, Ning; Iezzoni, Amy F
Tetraploid sour cherry (Prunus cerasus) has an S-RNase-based gametophytic self-incompatibility (GSI) system; however, individuals can be either self-incompatible (SI) or self-compatible (SC). Unlike the situation in the Solanaceae, where self-compatibility accompanying polyploidization is often due to the compatibility of heteroallelic pollen, the genotype-dependent loss of SI in sour cherry is due to the compatibility of pollen containing two nonfunctional S haplotypes. Sour cherry individuals with the S4S6S36aS36b genotype are predicted to be SC, as only pollen containing both nonfunctional S36a and S36b haplotypes would be SC. However, we previously found that individuals of this genotype were SI. Here we describe four nonfunctional S36 variants. Our molecular analyses identified a mutation that would confer loss of stylar S function for one of the variants, and two alterations that might cause loss of pollen S function for all four variants. Genetic crosses showed that individuals possessing two nonfunctional S36 haplotypes and two functional S haplotypes have reduced self-fertilization due to a very low frequency of transmission of the one pollen type that would be SC. Our finding that the underlying mechanism limiting successful transmission of genetically compatible gametes does not involve GSI is consistent with our previous genetic model for Prunus in which heteroallelic pollen is incompatible. This provides a unique case in which breakdown of SI does not occur despite the potential to generate SC pollen genotypes. PMID:19917768
Tsukamoto, Tatsuya; Hauck, Nathanael R.; Tao, Ryutaro; Jiang, Ning; Iezzoni, Amy F.
The application of next generation sequencing technology has greatly facilitated high throughput single nucleotide polymorphism (SNP) discovery and genotyping in genetic research. In the present study, SNPs were discovered based on two transcriptomes of Litopenaeus vannamei (L. vannamei) generated from Illumina sequencing platform HiSeq 2000. One transcriptome of L. vannamei was obtained through sequencing on the RNA from larvae at mysis stage and its reference sequence was de novo assembled. The data from another transcriptome were downloaded from NCBI and the reads of the two transcriptomes were mapped separately to the assembled reference by BWA. SNP calling was performed using SAMtools. A total of 58,717 and 36,277 SNPs with high quality were predicted from the two transcriptomes, respectively. SNP calling was also performed using the reads of two transcriptomes together, and a total of 96,040 SNPs with high quality were predicted. Among these 96,040 SNPs, 5,242 and 29,129 were predicted as non-synonymous and synonymous SNPs respectively. Characterization analysis of the predicted SNPs in L. vannamei showed that the estimated SNP frequency was 0.21% (one SNP per 476 bp) and the estimated ratio for transition to transversion was 2.0. Fifty SNPs were randomly selected for validation by Sanger sequencing after PCR amplification and 76% of SNPs were confirmed, which indicated that the SNPs predicted in this study were reliable. These SNPs will be very useful for genetic study in L. vannamei, especially for the high density linkage map construction and genome-wide association studies. PMID:24498047
Yu, Yang; Wei, Jiankai; Zhang, Xiaojun; Liu, Jingwen; Liu, Chengzhang; Li, Fuhua; Xiang, Jianhai
The application of next generation sequencing technology has greatly facilitated high throughput single nucleotide polymorphism (SNP) discovery and genotyping in genetic research. In the present study, SNPs were discovered based on two transcriptomes of Litopenaeus vannamei (L. vannamei) generated from Illumina sequencing platform HiSeq 2000. One transcriptome of L. vannamei was obtained through sequencing on the RNA from larvae at mysis stage and its reference sequence was de novo assembled. The data from another transcriptome were downloaded from NCBI and the reads of the two transcriptomes were mapped separately to the assembled reference by BWA. SNP calling was performed using SAMtools. A total of 58,717 and 36,277 SNPs with high quality were predicted from the two transcriptomes, respectively. SNP calling was also performed using the reads of two transcriptomes together, and a total of 96,040 SNPs with high quality were predicted. Among these 96,040 SNPs, 5,242 and 29,129 were predicted as non-synonymous and synonymous SNPs respectively. Characterization analysis of the predicted SNPs in L. vannamei showed that the estimated SNP frequency was 0.21% (one SNP per 476 bp) and the estimated ratio for transition to transversion was 2.0. Fifty SNPs were randomly selected for validation by Sanger sequencing after PCR amplification and 76% of SNPs were confirmed, which indicated that the SNPs predicted in this study were reliable. These SNPs will be very useful for genetic study in L. vannamei, especially for the high density linkage map construction and genome-wide association studies. PMID:24498047
Yu, Yang; Wei, Jiankai; Zhang, Xiaojun; Liu, Jingwen; Liu, Chengzhang; Li, Fuhua; Xiang, Jianhai
NCBI Handout Series | SNP | Last Update January 8, 2014 Contact: email@example.com dbSNP http://www.ncbi.nlm.nih.gov/snp/ National Center for Biotechnology Information · National Library The NCBI Short Genetic Variations (SNV) database, also known as dbSNP, catalogs short variations
Levin, Judith G.
NANOBIOSCIENCE" 1 Informative SNP Selection Methods Based on SNP Prediction Jingwu He, Member, IEEE of the SNPs. Tag SNP selection can achieve (i) considerable budget savings by genotyping only a limited number of SNPs and computationally inferring all other SNPs or (ii)necessary reduction of the huge SNP sets
Zelikovsky, Alexander
Identification of RNA editing sites in the SNP database
The relationship between human inherited genomic variations and phenotypic differences has been the focus of much research effort in recent years. These studies benefit from millions of single-nucleotide polymorphism (SNP) records available in public databases, such as dbSNP. The importance of identifying false dbSNP records increases with the growing role played by SNPs in linkage analysis for disease traits. In particular, the emerging understanding of the abundance of DNA and RNA editing calls for a careful distinction between inherited SNPs and somatic DNA and RNA modifications. In order to demonstrate that some of the SNP database records are actually somatic modification, we focus on one type of these modifications, namely A-to-I RNA editing, and present evidence for hundreds of dbSNP records that are actually editing sites. We provide a list of 102 RNA editing sites previously annotated in dbSNP database as SNPs, and experimentally validate seven of these. Interestingly, we show how dbSNP can serve as a starting point to look for new editing sites. Our results, for this particular type of RNA editing, demonstrate the need for a careful analysis of SNP databases in light of the increasing recognition of the significance of somatic sequence modifications. PMID:16100382
Eisenberg, Eli; Adamsky, Konstantin; Cohen, Lital; Amariglio, Ninette; Hirshberg, Abraham; Rechavi, Gideon; Levanon, Erez Y.
B. Comp Dissertation SNP Data Integration and Analysis for Drug-
B. Comp Dissertation SNP Data Integration and Analysis for Drug- Response Biomarker Discovery 2008/2009 #12;i B. Comp Dissertation SNP Data Integration and Analysis for Drug- Response methods to develop drugs targeted at various diseases. To maximize drug viability and profit, one
Wong, Limsoon
High-throughput SNP genotyping on universal bead arrays
We have developed a flexible, accurate and highly multiplexed SNP genotyping assay for high-throughput genetic analysis of large populations on a bead array platform. The novel genotyping system combines high assay conversion rate and data quality with >1500 multiplexing, and Array of Arrays™ formats. Genotyping assay oligos corresponding to specific SNP sequences are each linked to a unique sequence (address)
Richard Shen; Jian-Bing Fan; Derek Campbell; Weihua Chang; Jing Chen; Dennis Doucet; Jo Yeakley; Marina Bibikova; Eliza Wickham Garcia; Celeste McBride; Frank Steemers; Francisco Garcia; Bahram G. Kermani; Kevin Gunderson; Arnold Oliphant
Chromosomal Haplotypes by Genetic Phasing of Human Families
Assignment of alleles to haplotypes for nearly all the variants on all chromosomes can be performed by genetic analysis of a nuclear family with three or more children. Whole-genome sequence data enable deterministic phasing of nearly all sequenced alleles by permitting assignment of recombinations to precise chromosomal positions and specific meioses. We demonstrate this process of genetic phasing on two families each with four children. We generate haplotypes for all of the children and their parents; these haplotypes span all genotyped positions, including rare variants. Misassignments of phase between variants (switch errors) are nearly absent. Our algorithm can also produce multimegabase haplotypes for nuclear families with just two children and can handle families with missing individuals. We implement our algorithm in a suite of software scripts (Haploscribe). Haplotypes and family genome sequences will become increasingly important for personalized medicine and for fundamental biology. PMID:21855840
Roach, Jared C.; Glusman, Gustavo; Hubley, Robert; Montsaroff, Stephen Z.; Holloway, Alisha K.; Mauldin, Denise E.; Srivastava, Deepak; Garg, Vidu; Pollard, Katherine S.; Galas, David J.; Hood, Leroy; Smit, Arian F.A.
Evaluation of computational methods for the reconstruction of HLA haplotypes.
Human leukocyte antigen (HLA) haplotypes are frequently evaluated for population history inferences and association studies. However, the available typing techniques for the main HLA loci usually do not allow the determination of the allele phase and the constitution of a haplotype, which may be obtained by a very time-consuming and expensive family-based segregation study. Without the family-based study, computational inference by probabilistic models is necessary to obtain haplotypes. Several authors have used the expectation-maximization (EM) algorithm to determine HLA haplotypes, but high levels of erroneous inferences are expected because of the genetic distance among the main HLA loci and the presence of several recombination hotspots. In order to evaluate the efficiency of computational inference methods, 763 unrelated individuals stratified into three different datasets had their haplotypes manually defined in a family-based study of HLA-A, -B, -DRB1 and -DQB1 segregation, and these haplotypes were compared with the data obtained by the following three methods: the Expectation-Maximization (EM) and Excoffier-Laval-Balding (ELB) algorithms using the arlequin 3.11 software, and the PHASE method. When comparing the methods, we observed that all algorithms showed a poor performance for haplotype reconstruction with distant loci, estimating incorrect haplotypes for 38%-57% of the samples considering all algorithms and datasets. We suggest that computational haplotype inferences involving low-resolution HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 haplotypes should be considered with caution. PMID:20670352
Castelli, E C; Mendes-Junior, C T; Veiga-Castelli, L C; Pereira, N F; Petzl-Erler, M L; Donadi, E A
Atomic Force Microscopy for DNA SNP Identification
NASA Astrophysics Data System (ADS)
The knowledge of the effects of single-nucleotide polymorphisms (SNPs) in the human genome greatly contributes to better comprehension of the relation between genetic factors and diseases. Sequence analysis of genomic DNA in different individuals reveals positions where variations that involve individual base substitutions can occur. Single-nucleotide polymorphisms are highly abundant and can have different consequences at phenotypic level. Several attempts were made to apply atomic force microscopy (AFM) to detect and map SNP sites in DNA strands. The most promising approach is the study of DNA mutations producing heteroduplex DNA strands and identifying the mismatches by means of a protein that labels the mismatches. MutS is a protein that is part of a well-known complex of mismatch repair, which initiates the process of repairing when the MutS binds to the mismatched DNA filament. The position of MutS on the DNA filament can be easily recorded by means of AFM imaging.
Valbusa, Ugo; Ierardi, Vincenzo
SNPWave: a flexible multiplexed SNP genotyping technology.
Scalable multiplexed amplification technologies are needed for cost-effective large-scale genotyping of genetic markers such as single nucleotide polymorphisms (SNPs). We present SNPWave, a novel SNP genotyping technology to detect various subsets of sequences in a flexible fashion in a fixed detection format. SNPWave is based on highly multiplexed ligation, followed by amplification of up to 20 ligated probes in a single PCR. Depending on the multiplexing level of the ligation reaction, the latter employs selective amplification using the amplified fragment length polymorphism (AFLP) technology. Detection of SNPWave reaction products is based on size separation on a sequencing instrument with multiple fluorescence labels and short run times. The SNPWave technique is illustrated by a 100-plex genotyping assay for Arabidopsis, a 40-plex assay for tomato and a 10-plex assay for Caenorhabditis elegans, detected on the MegaBACE 1000 capillary sequencer. PMID:15004220
van Eijk, Michiel J T; Broekhof, José L N; van der Poel, Hein J A; Hogers, René C J; Schneiders, Harrie; Kamerbeek, Judith; Verstege, Esther; van Aart, Joris W; Geerlings, Henk; Buntjer, Jaap B; van Oeveren, A Jan; Vos, Pieter
Armenia has been little-studied genetically, even though it is situated in an important area with respect to theories of ancient Middle Eastern population expansion and the spread of Indo-European languages. We screened 734 Armenian males for 11 biallelic and 6 microsatellite Y chromosome markers, segregated them according to paternal grandparental region of birth within or close to Armenia, and compared them with data from other population samples. We found significant regional stratification, on a level greater than that found in some comparisons between different ethno-national identities. A diasporan Armenian sub-sample (collected in London) was not sufficient to describe this stratified haplotype distribution adequately, warning against the use of such samples as surrogates for the non-diasporan population in future studies. The haplotype distribution and pattern of genetic distances suggest a high degree of genetic isolation in the mountainous southern and eastern regions, while in the northern, central and western regions there has been greater admixture with populations from neighbouring Middle Eastern countries. Georgia, to the north of Armenia, also appears genetically more distinct, suggesting that in the past Trans-Caucasia may have acted as a genetic barrier. A Bayesian full-likelihood analysis of the Armenian sample yields a mean estimate for the start of population growth of 4.8 thousand years ago (95% credible interval: 2.0-11.1), consistent with the onset of Neolithic farming. The more isolated southern and eastern regions have high frequencies of a microsatellite defined cluster within haplogroup 1 that is centred on a modal haplotype one step removed from the Atlantic Modal Haplotype, the centre of a cluster found at high frequencies in England, Friesland and Atlantic populations, and which may represent a remnant paternal signal of a Paleolithic migration event. PMID:11810279
Weale, M E; Yepiskoposyan, L; Jager, R F; Hovhannisyan, N; Khudoyan, A; Burbage-Hall, O; Bradman, N; Thomas, M G
A haplotype map of the human genome
Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution. PMID:16255080
How Genome-Wide SNP-SNP Interactions Relate to Nasopharyngeal Carcinoma Susceptibility
This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P<0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P?=?9.86×10?11) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease's genetic etiology, and possibly also that of other gene-related cancers. PMID:24376627
Su, Wen-Hui; Yao Shugart, Yin; Chang, Kai-Ping; Tsang, Ngan-Ming; Tse, Ka-Po; Chang, Yu-Sun
dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data
Motivation: Oligonucleotide microarrays allow genotyping of thousands of single-nucleotide polymorphisms (SNPs) in parallel. Recently, this technology has been applied to loss- of-heterozygosity (LOH) analysis of paired normal and tumor samples. However, methods and software for analyzing such data are not fully developed. Result: Here, we report automated methods for pooling SNP array replicates to make LOH calls, visualizing SNP and
Ming Lin; Lee-jen Wei; William R. Sellers; Marshall Lieberfarb; Wing Hung Wong; Cheng Li
SNPMeta: SNP annotation and SNP metadata collection without a reference genome.
The increase in availability of resequencing data is greatly accelerating SNP discovery and has facilitated the development of SNP genotyping assays. This, in turn, is increasing interest in annotation of individual SNPs. Currently, these data are only available through curation, or comparison to a reference genome. Many species lack a reference genome, but are still important genetic models or are significant species in agricultural production or natural ecosystems. For these species, it is possible to annotate SNPs through comparison with cDNA, or data from well-annotated genes in public repositories. We present SNPMeta, a tool which gathers information about SNPs by comparison with sequences present in GenBank databases. SNPMeta is able to annotate SNPs from contextual sequence in SNP assay designs, and SNPs discovered through genotyping by sequencing (GBS) approaches. However, SNPs discovered through GBS occur throughout the genome, rather than only in gene space, and therefore do not annotate at high rates. SNPMeta can therefore be used to annotate SNPs in nonmodel species or species that lack a reference genome. Annotations generated by SNPMeta are highly concordant with annotations that would be obtained from a reference genome. PMID:24237904
Kono, Thomas J Y; Seth, Kiran; Poland, Jesse A; Morrell, Peter L
SNP variation in the promoter of the PRKAG3 gene and association with meat quality traits in pig
Background The PRKAG3 gene encodes the ?3 subunit of adenosine monophosphate activated protein kinase (AMPK), a protein that plays a key role in energy metabolism in skeletal muscle. Non-synonymous single nucleotide polymorphisms (SNPs) in this gene such as I199V are associated with important pork quality traits. The objective of this study was to investigate the relationship between gene expression of the PRKAG3 gene, SNP variation in the PRKAG3 promoter and meat quality phenotypes in pork. Results PRKAG3 gene expression was found to correlate with a number of traits relating to glycolytic potential (GP) and intramuscular fat (IMF) in three phenotypically diverse F1 crosses comprising of 31 Large White, 23 Duroc and 32 Pietrain sire breeds. The majority of associations were observed in the Large White cross. There was a significant association between genotype at the g.-311A>G locus and PRKAG3 gene expression in the Large White cross. In the same population, ten novel SNPs were identified within a 1.3 kb region spanning the promoter and from this three major haplotypes were inferred. Two tagging SNPs (g.-995A>G and g.-311A>G) characterised the haplotypes within the promoter region being studied. These two SNPs were subsequently genotyped in larger populations consisting of Large White (n?=?98), Duroc (n?=?99) and Pietrain (n?=?98) purebreds. Four major haplotypes including promoter SNP's g.-995A>G and g.-311A>G and I199V were inferred. In the Large White breed, HAP1 was associated with IMF% in the M. longissmus thoracis et lumborum (LTL) and driploss%. HAP2 was associated with IMFL% GP-influenced traits pH at 24 hr in LTL (pHULT), pH at 45 min in LTL (pH45LT) and pH at 45 min in the M. semimembranosus muscle (pH45SM). HAP3 was associated with driploss%, pHULT pH45LT and b* Minolta. In the Duroc breed, associations were observed between HAP1 and driploss% and pHUSM. No associations were observed with the remaining haplotypes (HAP2, HAP3 and HAP4) in the Duroc breed. The Pietrain breed was monomorphic in the promoter region. The I199V locus was associated with several GP-influenced traits across all three breeds and IMF% in the Large White and Pietrain breed. No significant difference in promoter function was observed for the three main promoter haplotypes when tested in vitro. Conclusion Gene expression levels of the porcine PRKAG3 are associated with meat quality phenotypes relating to glycolytic potential and IMF% in the Large White breed, while SNP variation in the promoter region of the gene is associated with PRKAG3 gene expression and meat quality phenotypes. PMID:22831392
A Potential Relationship among Beta-Defensins Haplotype, SOX7 Duplication and Cardiac Defects
Objective To determine the pathogenesis of a patient born with congenital heart defects, who had appeared normal in prenatal screening. Methods In routine prenatal screening, G-banding was performed to analyse the karyotypes of the family and fluorescence in situ hybridization was used to investigate the 22q11.2 deletion in the fetus. After birth, the child was found to be suffering from heart defects by transthoracic echocardiography. In the following study, sequencing was used to search for potential mutations in pivotal genes. SNP-array was employed for fine mapping of the aberrant region and quantitative real-time PCR was used to confirm the results. Furthermore, other patients with a similar phenotype were screened for the same genetic variations. To compare with a control, these variations were also assessed in the general population. Results The child and his mother each had a region that was deleted in the beta-defensin repeats, which are usually duplicated in the general population. Besides, the child carried a SOX7-gene duplication. While this duplication was not detected in his mother, it was found in two other patients with cardiac defects who also had the similar deletion in the beta-defensin repeats. Conclusion The congenital heart defects of the child were probably caused by a SOX7-gene duplication, which may be a consequence of the partial haplotype of beta-defensin regions at 8p23.1. To our knowledge, this is the first congenital heart defect case found to have the haplotype of beta-defensin and the duplication of SOX7. PMID:24009689
Fang, Shaohai; Xu, Yuejuan; Sun, Kun; Chen, Sun; Xu, Rang
SNP GENOTYPING AND APPLICATIONS Sperm whale population structure in the eastern and central
SNP GENOTYPING AND APPLICATIONS Sperm whale population structure in the eastern and central North macrocephalus) in the eastern and central North Pacific. SNP markers, reproducible across technologies
Baird, Robin W.
Summary Background Psoriasis is an inflammatory disease characterized by increased squamous cell proliferation and impaired differentiation. Vitamin D, Calcitriol, and its analogues are successfully used for psoriasis therapy. However, it is unknown why some psoriasis patients are resistant to Vitamin D therapy. Vitamin D mediates its activity by a nuclear receptor. It is suggested that polymorphisms and haplotypes in the VDR gene may explain the differences in response to vitamin D therapy. Material/Methods In this study, 102 psoriasis patients and 102 healthy controls were studied for VDR gene polymorphisms. The Fok I, Bsm I, Apa I and Taq I polymorphisms were examined by PCR-RFLP, and 50 subjects received vitamin D therapy to evaluate the association between VDR gene polymorphisms and response to vitamin D therapy. Existence of cutting site is shown by capital letters, and lack was shown by lower case. The haplotypes were analysed by CHAPLIN. Results There was significant difference in allele frequency of T and genotype frequency of Tt between cases and controls (p values 0.038 and 0.04, respectively). The Aa and bb genotypes were significantly higher in early onset than late onset psoriasis (p values 0.008 and 0.04, respectively). The genotypes Ff, ff and TT are significantly different between vitamin D3 therapy responders and non-responders (p values 0.04, 0.0001, 0.009, respectively). To the best of our knowledge, this is the first report showing importance of VDR gene haplotypes in psoriasis, the significance of the Wald and LR (Likelihood Ratio) statistics (p=0,0042) suggest that FfBbAatt is a disease-susceptibility haplotype. Conclusions Haplotype analysis is a recent and commonly used method in genetic association studies. Our results reveal a previously unidentified susceptibility haplotype and indicate that certain haplotypes are important in the resistance to vitamin D3 therapy and the onset of psoriasis. The haplotypes can give valuable data where genotypes unable to do. PMID:23111742
Acikbas, Ibrahim; Sanl?, Berna; Tepeli, Emre; Ergin, Seniz; Aktan, Sebnem; Bagci, Huseyin
Human dopamine transporter gene: differential regulation of 18-kb haplotypes
Aim Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner. Materials & methods By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5? 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models. Results The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 ?-chains. Conclusion SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3. PMID:24024899
Zhao, Ying; Xiong, Nian; Liu, Yang; Zhou, Yanhong; Li, Nuomin; Qing, Hong; Lin, Zhicheng
Combining Markers into Haplotypes Can Improve Population Structure Inference
High-throughput genotyping and sequencing technologies can generate dense sets of genetic markers for large numbers of individuals. For most species, these data will contain many markers in linkage disequilibrium (LD). To utilize such data for population structure inference, we investigate the use of haplotypes constructed by combining the alleles at single-nucleotide polymorphisms (SNPs). We introduce a statistic derived from information theory, the gain of informativeness for assignment (GIA), which quantifies the additional information for assigning individuals to populations using haplotype data compared to using individual loci separately. Using a two-loci–two-allele model, we demonstrate that combining markers in linkage equilibrium into haplotypes always leads to nonpositive GIA, suggesting that combining the two markers is not advantageous for ancestry inference. However, for loci in LD, GIA is often positive, suggesting that assignment can be improved by combining markers into haplotypes. Using GIA as a criterion for combining markers into haplotypes, we demonstrate for simulated data a significant improvement of assigning individuals to candidate populations. For the many cases that we investigate, incorrect assignment was reduced between 26% and 97% using haplotype data. For empirical data from French and German individuals, the incorrectly assigned individuals can, for example, be decreased by 73% using haplotypes. Our results can be useful for challenging population structure and assignment problems, in particular for studies where large-scale population–genomic data are available. PMID:21868606
Gattepaille, Lucie M.; Jakobsson, Mattias
Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r (2), and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P?=?0.021). In addition, analysis of the haplotype of COL1A1 showed that the G-G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women. PMID:22174012
Rojano-Mejía, David; Coral-Vázquez, Ramón M; Espinosa, Leticia Cortes; López-Medina, Guillermo; Aguirre-García, María C; Coronel, Agustín; Canto, Patricia
Y-chromosomal STRs haplotypes in the Taiwanese Paiwan population
The distribution of Y-chromosomal short tandem repeat (Y-STR) haplotypes was determined in a population of Taiwanese Paiwan aboriginals. Using 17 Y-STR markers, a total of 135 haplotypes were observed, 102 of which were unique. The overall haplotype diversity for the 17 Y-STR loci tested was 0.9922 and the discrimination capacity was 0.6490. In addition, three novel intermediate alleles at the DYS448 locus were also found. Electronic supplementary material The online version of this article (doi:10.1007/s00414-009-0416-x) contains supplementary material, which is available to authorized users. PMID:20107827
Pu, Chang-En; Hu, Kuang-Yu; Willuweit, Sascha; Roewer, Lutz; Liu, David Hwang
Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed. PMID:9683608
Clark, A G; Weiss, K M; Nickerson, D A; Taylor, S L; Buchanan, A; Stengard, J; Salomaa, V; Vartiainen, E; Perola, M; Boerwinkle, E; Sing, C F
In Arabidopsis ecotype Landsberg erecta (Ler), RPP5 confers resistance to the pathogen Peronospora parasitica. RPP5 is part of a clustered multigene family encoding nucleotide binding-leucine-rich repeat (LRR) proteins. We compared 95 kb of DNA sequence carrying the Ler RPP5 haplotype with the corresponding 90 kb of Arabidopsis ecotype Columbia (Col-0). Relative to the remainder of the genome, the Ler and Col-0 RPP5 haplotypes exhibit remarkable intraspecific polymorphism. The RPP5 gene family probably evolved by extensive recombination between LRRs from an RPP5-like progenitor that carried only eight LRRs. Most members have variable LRR configurations and encode different numbers of LRRs. Although many members carry retroelement insertions or frameshift mutations, codon usage analysis suggests that regions of the genes have been subject to purifying or diversifying selection, indicating that these genes were, or are, functional. The RPP5 haplotypes thus carry dynamic gene clusters with the potential to adapt rapidly to novel pathogen variants by gene duplication and modification of recognition capacity. We propose that the extremely high level of polymorphism at this complex resistance locus is maintained by frequency-dependent selection. PMID:10559437
Noel, L; Moores, T L; van Der Biezen, E A; Parniske, M; Daniels, M J; Parker, J E; Jones, J D
The protein product of the myxovirus resistance 2 (MX2) gene restricts HIV-1 and simian retroviruses. We demonstrate that MX2 evolved adaptively in mammals with distinct sites representing selection targets in distinct branches; selection mainly involved residues in loop 4, previously shown to carry antiviral determinants. Modeling data indicated that positively selected sites form a continuous surface on loop 4, which folds into two antiparallel ?-helices protruding from the stalk domain. A population genetics-phylogenetics approach indicated that the coding region of MX2 mainly evolved under negative selection in the human lineage. Nonetheless, population genetic analyses demonstrated that natural selection operated on MX2 during the recent history of human populations: distinct selective events drove the frequency increase of two haplotypes in the populations of Asian and European ancestry. The Asian haplotype carries a susceptibility allele for melanoma; the European haplotype is tagged by rs2074560, an intronic variant. Analyses performed on three independent European cohorts of HIV-1-exposed seronegative individuals with different geographic origin and distinct exposure route showed that the ancestral (G) allele of rs2074560 protects from HIV-1 infection with a recessive effect (combined P = 1.55 × 10(-4)). The same allele is associated with lower in vitro HIV-1 replication and increases MX2 expression levels in response to IFN-?. Data herein exploit evolutionary information to identify a novel host determinant of HIV-1 infection susceptibility. PMID:24930137
Sironi, Manuela; Biasin, Mara; Cagliani, Rachele; Gnudi, Federica; Saulle, Irma; Ibba, Salomč; Filippi, Giulia; Yahyaei, Sarah; Tresoldi, Claudia; Riva, Stefania; Trabattoni, Daria; De Gioia, Luca; Lo Caputo, Sergio; Mazzotta, Francesco; Forni, Diego; Pontremoli, Chiara; Pineda, Juan Antonio; Pozzoli, Uberto; Rivero-Juarez, Antonio; Caruz, Antonio; Clerici, Mario
Haplotypes and effects on growth traits of bovine Wnt7a gene in Chinese Qinchuan cattle.
Wnt7a is a member of the WNT gene family, which encodes secreted signaling proteins and responds to many biological processes. Specifically Wnt7a influences satellite stem cells and regulates the regenerative potential of the muscle. However, similar researches about the bovine Wnt7a gene are lacking. Therefore, in this study, polymorphisms of the bovine Wnt7a gene were detected in 488 individuals from Chinese Qinchuan cattle by DNA pooling, forced PCR-RFLP, and DNA sequencing methods. 3 novel SNPs were identified, two SNPs (g.T4926C and g.A21943G) were in the intron and the last one (g.C63777T) was in the exon. Five haplotypes involved in these three variant sites in the Wnt7a gene were identified and their effects on growth traits were analyzed. The results revealed that haplotype 1 had the highest haplotype frequencies and was highly significantly associated with body height (P<0.01), body weight (P<0.05), chest width (P<0.05) and height at hip cross (P<0.01) respectively. PMID:23612250
Xue, Jing; Sun, Yujia; Guo, Wenjiao; Yang, Ziqi; Tian, Huibin; Zhang, Chunlei; Lei, Chuzhao; Lan, Xianyong; Chen, Hong
We performed a pairwise epistatic interaction test using the chicken 60 K single nucleotide polymorphism (SNP) chip for the 11th generation of the Northeast Agricultural University broiler lines divergently selected for abdominal fat content. A linear mixed model was used to test two dimensions of SNP interactions affecting abdominal fat weight. With a threshold of P<1.2×10?11 by a Bonferroni 5% correction, 52 pairs of SNPs were detected, comprising 45 pairs showing an Additive×Additive and seven pairs showing an Additive×Dominance epistatic effect. The contribution rates of significant epistatic interactive SNPs ranged from 0.62% to 1.54%, with 47 pairs contributing more than 1%. The SNP-SNP network affecting abdominal fat weight constructed using the significant SNP pairs was analyzed, estimated and annotated. On the basis of the network's features, SNPs Gga_rs14303341 and Gga_rs14988623 at the center of the subnet should be important nodes, and an interaction between GGAZ and GGA8 was suggested. Twenty-two quantitative trait loci, 97 genes (including nine non-coding genes), and 50 pathways were annotated on the epistatic interactive SNP-SNP network. The results of the present study provide insights into the genetic architecture underlying broiler chicken abdominal fat weight. PMID:24339942
Li, Fangge; Hu, Guo; Zhang, Hui; Wang, Shouzhi; Wang, Zhipeng; Li, Hui
The shift from outcrossing to self-fertilization is among the most common evolutionary transitions in flowering plants. Until recently, however, a genome-wide view of this transition has been obscured by both a dearth of appropriate data and the lack of appropriate population genomic methods to interpret such data. Here, we present a novel population genomic analysis detailing the origin of the selfing species, Capsella rubella, which recently split from its outcrossing sister, Capsella grandiflora. Due to the recency of the split, much of the variation within C. rubella is also found within C. grandiflora. We can therefore identify genomic regions where two C. rubella individuals have inherited the same or different segments of ancestral diversity (i.e. founding haplotypes) present in C. rubella's founder(s). Based on this analysis, we show that C. rubella was founded by multiple individuals drawn from a diverse ancestral population closely related to extant C. grandiflora, that drift and selection have rapidly homogenized most of this ancestral variation since C. rubella's founding, and that little novel variation has accumulated within this time. Despite the extensive loss of ancestral variation, the approximately 25% of the genome for which two C. rubella individuals have inherited different founding haplotypes makes up roughly 90% of the genetic variation between them. To extend these findings, we develop a coalescent model that utilizes the inferred frequency of founding haplotypes and variation within founding haplotypes to estimate that C. rubella was founded by a potentially large number of individuals between 50 and 100 kya, and has subsequently experienced a twenty-fold reduction in its effective population size. As population genomic data from an increasing number of outcrossing/selfing pairs are generated, analyses like the one developed here will facilitate a fine-scaled view of the evolutionary and demographic impact of the transition to self-fertilization. PMID:24068948
Brandvain, Yaniv; Slotte, Tanja; Hazzouri, Khaled M.; Wright, Stephen I.; Coop, Graham
Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity
Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3? untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3?UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures. PMID:25339953
Castelli, Erick C.; Ramalho, Jaqueline; Porto, Iane O. P.; Lima, Thalitta H. A.; Felicio, Leandro P.; Sabbagh, Audrey; Donadi, Eduardo A.; Mendes-Junior, Celso T.
The male-specific region of the ovine Y chromosome (MSY) remains poorly characterized, yet sequence variants from this region have the potential to reveal the wild progenitor of domestic sheep or examples of domestic and wild paternal introgression. The 5' promoter region of the sex-determining gene SRY was re-sequenced using a subset of wild sheep including bighorn (Ovis canadensis), thinhorn (Ovis dalli spp.), urial (Ovis vignei), argali (Ovis ammon), mouflon (Ovis musimon) and domestic sheep (Ovis aries). Seven novel SNPs (oY2-oY8) were revealed; these were polymorphic between but not within species. Re-sequencing and fragment analysis was applied to the MSY microsatellite SRYM18. It contains a complex compound repeat structure and sequencing of three novel size fragments revealed that a pentanucleotide element remained fixed, whilst a dinucleotide element displayed variability within species. Comparison of the sequence between species revealed that urial and argali sheep grouped more closely to the mouflon and domestic breeds than the pachyceriforms (bighorn and thinhorn). SNP and microsatellite data were combined to define six previously undetected haplotypes. Analysis revealed the mouflon as the only species to share a haplotype with domestic sheep, consistent with its status as a feral domesticate that has undergone male-mediated exchange with domestic animals. A comparison of the remaining wild species and domestic sheep revealed that O. aries is free from signatures of wild sheep introgression. PMID:19016675
Meadows, J R S; Kijas, J W
A worldwide survey of haplotype variation and linkage disequilibrium in the human genome
Recent genomic surveys have produced high-resolution haplotype information, but only in a small number of human populations. We report haplotype structure across 12 Mb of DNA sequence in 927 individuals representing 52 populations. The geographic distribution of haplotypes reflects human history, with a loss of haplotype diversity as distance increases from Africa. Although the extent of linkage disequilibrium (LD) varies
Donald F Conrad; Mattias Jakobsson; Graham Coop; Xiaoquan Wen; Jeffrey D Wall; Jonathan K Pritchard; Noah A Rosenberg
Original article New haplotypes for the non-coding region
. nigrocincta is distributed in Sulawesi and Mindanao. 25 * Correspondence and reprints E-mail: sasaki. koschevnikovi from Borneo has a single known haplotype (Smith and Hagen, 1996), and A. nigrocincta from Sulawesi
Paris-Sud XI, Université de
Background Several studies report about intra-specific trait variation of nitrogen-metabolism related traits, such as N(itrogen)-use efficiency, protein content, N-storage and remobilization in barley and related grass species. The goal of this study was to assess the intra-specific genetic diversity present in primary N-metabolism genes of barley and to investigate the associations of the detected haplotype diversity with malting and kernel quality related traits. Results Partial sequences of five genes related to N-metabolism in barley (Hordeum vulgare L.) were obtained, i.e. nitrate reductase 1, glutamine synthetase 2, ferredoxin-dependent glutamate synthase, aspartate aminotransferase and asparaginase. Two to five haplotypes in each gene were discovered in a set of 190 various varieties. The development of 33 SNP markers allowed the genotyping of all these barley varieties consisting of spring and winter types. Furthermore, these markers could be mapped in several doubled haploid populations. Cluster analysis based on haplotypes revealed a more uniform pattern of the spring barleys as compared to the winter barleys. Based on linear model approaches associations to several malting and kernel quality traits including soluble N and protein were identified. Conclusions A study was conducted to investigate the presence of sequence variation of several genes related to the primary N-metabolism in barley. The detected diversity could be related to particular phenotypic traits. Specific differences between spring and winter barleys most likely reflect different breeding aims. The developed markers can be used as tool for further genetic studies and marker-assisted selection during breeding of barley. PMID:24007272
The SNP genotypes of growth hormone gene associated with reproductive traits in Tsaiya ducks.
Our previous cDNA microarray study showed that the growth hormone (GH) gene may involve in the duck egg formation process. The purpose of this study was to investigate the relationship between GH genotypes of single nucleotide polymorphisms (SNPs) and reproductive traits of Tsaiya ducks. Primer pairs for the coding region in the GH were designed based on the duck genomic sequence. Polymorphisms were detected by polymerase chain reaction (PCR)-single strand polymorphism (SSCP) and were verified by DNA sequencing. Nineteen SNPs were identified in the duck GH gene, of which three coding SNPs (C3169T, C3700T and C5058G) were genotyped to investigate the associations with reproductive traits. The results showed that each SNP was associated with at least one duck fertility-related trait (p < 0.05). Haplotypes constructed on these three SNPs were associated with fertility rate (FR) and maximum duration of fertility (MDF) (p < 0.05). In particular, diplotype H1H1 was dominant for FR and MDF. This suggested that GH gene polymorphisms are associated with duck fertility-related traits. The SNPs in this gene may be used as potential markers for marker-assisted selection. PMID:22023026
Chang, Mu-Tzu; Cheng, Yu-Shin; Huang, Mu-Chiou
SNP discovery using Next Generation Transcriptomic Sequencing in Atlantic herring (Clupea harengus).
The introduction of Next Generation Sequencing (NGS) has revolutionised population genetics, providing studies of non-model species with unprecedented genomic coverage, allowing evolutionary biologists to address questions previously far beyond the reach of available resources. Furthermore, the simple mutation model of Single Nucleotide Polymorphisms (SNPs) permits cost-effective high-throughput genotyping in thousands of individuals simultaneously. Genomic resources are scarce for the Atlantic herring (Clupea harengus), a small pelagic species that sustains high revenue fisheries. This paper details the development of 578 SNPs using a combined NGS and high-throughput genotyping approach. Eight individuals covering the species distribution in the eastern Atlantic were bar-coded and multiplexed into a single cDNA library and sequenced using the 454 GS FLX platform. SNP discovery was performed by de novo sequence clustering and contig assembly, followed by the mapping of reads against consensus contig sequences. Selection of candidate SNPs for genotyping was conducted using an in silico approach. SNP validation and genotyping were performed simultaneously using an Illumina 1,536 GoldenGate assay. Although the conversion rate of candidate SNPs in the genotyping assay cannot be predicted in advance, this approach has the potential to maximise cost and time efficiencies by avoiding expensive and time-consuming laboratory stages of SNP validation. Additionally, the in silico approach leads to lower ascertainment bias in the resulting SNP panel as marker selection is based only on the ability to design primers and the predicted presence of intron-exon boundaries. Consequently SNPs with a wider spectrum of minor allele frequencies (MAFs) will be genotyped in the final panel. The genomic resources presented here represent a valuable multi-purpose resource for developing informative marker panels for population discrimination, microarray development and for population genomic studies in the wild. PMID:22879907
Helyar, Sarah J; Limborg, Morten T; Bekkevold, Dorte; Babbucci, Massimiliano; van Houdt, Jeroen; Maes, Gregory E; Bargelloni, Luca; Nielsen, Rasmus O; Taylor, Martin I; Ogden, Rob; Cariani, Alessia; Carvalho, Gary R; Consortium, Fishpoptrace; Panitz, Frank
Background The malaria parasite Plasmodium falciparum exhibits abundant genetic diversity, and this diversity is key to its success as a pathogen. Previous efforts to study genetic diversity in P. falciparum have begun to elucidate the demographic history of the species, as well as patterns of population structure and patterns of linkage disequilibrium within its genome. Such studies will be greatly enhanced by new genomic tools and recent large-scale efforts to map genomic variation. To that end, we have developed a high throughput single nucleotide polymorphism (SNP) genotyping platform for P. falciparum. Results Using an Affymetrix 3,000 SNP assay array, we found roughly half the assays (1,638) yielded high quality, 100% accurate genotyping calls for both major and minor SNP alleles. Genotype data from 76 global isolates confirm significant genetic differentiation among continental populations and varying levels of SNP diversity and linkage disequilibrium according to geographic location and local epidemiological factors. We further discovered that nonsynonymous and silent (synonymous or noncoding) SNPs differ with respect to within-population diversity, inter-population differentiation, and the degree to which allele frequencies are correlated between populations. Conclusions The distinct population profile of nonsynonymous variants indicates that natural selection has a significant influence on genomic diversity in P. falciparum, and that many of these changes may reflect functional variants deserving of follow-up study. Our analysis demonstrates the potential for new high-throughput genotyping technologies to enhance studies of population structure, natural selection, and ultimately enable genome-wide association studies in P. falciparum to find genes underlying key phenotypic traits. PMID:19077304
Neafsey, Daniel E; Schaffner, Stephen F; Volkman, Sarah K; Park, Daniel; Montgomery, Philip; Milner, Danny A; Lukens, Amanda; Rosen, David; Daniels, Rachel; Houde, Nathan; Cortese, Joseph F; Tyndall, Erin; Gates, Casey; Stange-Thomann, Nicole; Sarr, Ousmane; Ndiaye, Daouda; Ndir, Omar; Mboup, Soulyemane; Ferreira, Marcelo U; Moraes, Sandra do Lago; Dash, Aditya P; Chitnis, Chetan E; Wiegand, Roger C; Hartl, Daniel L; Birren, Bruce W; Lander, Eric S; Sabeti, Pardis C; Wirth, Dyann F
Major copy proportion analysis of tumor samples using SNP arrays
Background: Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the human genome and are useful as genomic markers. Oligonucleotide SNP microarrays have been developed for high-throughput ...
Li, Cheng
Characterization of Bison bison major histocompatibility complex class IIa haplotypes.
American bison (Bison bison) and domestic cattle (Bos taurus and Bos indicus) evolved from a common ancestor 1-1.4 million years ago. Nevertheless, they show dramatic differences in their susceptibility to infectious diseases, including malignant catarrhal fever (MCF). Although bison are highly susceptible to ovine herpesvirus-2 (OvHV-2) associated MCF, about 20% of healthy domesticated and wild bison are positive for OvHV-2 antibody. We are interested in testing the hypothesis that, within the bison population, the polymorphism of major histocompatibility complex (MHC) class II genes influences resistance to MCF. However, since little was known about the MHC class II genes of bison, it was necessary to first characterize class II haplotypes present in Bi. bison (Bibi). Thus, the MHC class II haplotypes carried by 14 bison were characterized by the PCR-based cloning and sequencing of their DRB3, DQA, and DQB alleles. Twelve MHC class II haplotypes were identified in the 14 bison. These haplotypes comprised six previously reported and six new Bibi-DRB3 alleles, along with 11 Bibi-DQA and 10 Bibi-DQB alleles. For each bison class II allele, it was possible to identify closely related cattle sequences. The closest bison and bovine DQA, DQB, and DRB3 alleles, on average, differed by only 1.3, 3.5, and 5.8 amino acids, respectively. Furthermore, bison MHC haplotypes with both nonduplicated and duplicated DQ genes were identified; these haplotypes appear to have originated from the same ancestral haplotypes as orthologous cattle haplotypes. PMID:16331512
Traul, Donald L; Bhushan, Bharat; Eldridge, Jennifer A; Crawford, Timothy B; Li, Hong; Davies, Christopher J
Bayesian Haplotype Inference for Multiple Linked Single-Nucleotide Polymorphisms
Haplotypes have gained increasing attention in the mapping of complex-disease genes, because of the abundance of single-nucleotide polymorphisms (SNPs) and the limited power of conventional single-locus analyses. It has been shown that haplotype-inference methods such as Clark's algorithm, the expectation-maximization algorithm, and a coalescence-based iterative-sampling algorithm are fairly effective and economical alternatives to molecular-hap-lotyping methods. To contend with some weaknesses
Tianhua Niu; Zhaohui S. Qin; Xiping Xu; Jun S. Liu
The detection of molecular signatures of selection is one of the major concerns of modern population genetics. A widely used strategy in this context is to compare samples from several populations and to look for genomic regions with outstanding genetic differentiation between these populations. Genetic differentiation is generally based on allele frequency differences between populations, which are measured by FST or related statistics. Here we introduce a new statistic, denoted hapFLK, which focuses instead on the differences of haplotype frequencies between populations. In contrast to most existing statistics, hapFLK accounts for the hierarchical structure of the sampled populations. Using computer simulations, we show that each of these two features—the use of haplotype information and of the hierarchical structure of populations—significantly improves the detection power of selected loci and that combining them in the hapFLK statistic provides even greater power. We also show that hapFLK is robust with respect to bottlenecks and migration and improves over existing approaches in many situations. Finally, we apply hapFLK to a set of six sheep breeds from Northern Europe and identify seven regions under selection, which include already reported regions but also several new ones. We propose a method to help identifying the population(s) under selection in a detected region, which reveals that in many of these regions selection most likely occurred in more than one population. Furthermore, several of the detected regions correspond to incomplete sweeps, where the favorable haplotype is only at intermediate frequency in the population(s) under selection. PMID:23307896
Fariello, Maria Ines; Boitard, Simon; Naya, Hugo; SanCristobal, Magali; Servin, Bertrand
Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P?=?1.2×10?10; odds ratio [OR] ?=?3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P?=?0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P?=?0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P?=?0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P?=?0.00057; OR?=?0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P?=?0.017; OR?=?6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P?=?0.034; OR?=?4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH. PMID:24956105
Umemura, Takeji; Katsuyama, Yoshihiko; Yoshizawa, Kaname; Kimura, Takefumi; Joshita, Satoru; Komatsu, Michiharu; Matsumoto, Akihiro; Tanaka, Eiji; Ota, Masao
Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans
The CYP3A locus encodes hepatic enzymes that metabolize many clinically used drugs. However, there is marked interindividual variability in enzyme expression and clearance of drugs metabolized by these enzymes. We utilized comparative genomics and computational prediction of transcriptional factor binding sites to evaluate regions within CYP3A that were most likely to contribute to this variation. We then used a haplotype tagging single-nucleotide polymorphisms (htSNPs) approach to evaluate the entire locus with the fewest number of maximally informative SNPs. We investigated the association between these htSNPs and in vivo CYP3A enzyme activity using a single-point IV midazolam clearance assay. We found associations between the midazolam phenotype and age, diagnosis of hypertension and one htSNP (141689) located upstream of CYP3A4. 141689 lies near the xenobiotic responsive enhancer module (XREM) regulatory region of CYP3A4. Cell-based studies show increased transcriptional activation with the minor allele at 141689, in agreement with the in vivo association study findings. This study marks the first systematic evaluation of coding and noncoding variation that may contribute to CYP3A phenotypic variability. PMID:18825162
Perera, MA; Thirumaran, RK; Cox, NJ; Hanauer, S; Das, S; Brimer-Cline, C; Lamba, V; Schuetz, EG; Ratain, MJ; Di Rienzo, A
The genetic architecture of post-traumatic stress disorder (PTSD) remains poorly understood with the vast majority of genetic association studies reporting on single candidate genes. We conducted a large genetic study in trauma-exposed European-American women (N=2538; 845 PTSD cases, 1693 controls) by testing 3742 SNPs across more than 300 genes and conducting polygenic analyses using results from the Psychiatric Genome-Wide Association Studies Consortium (PGC). We tested the association between each SNP and two measures of PTSD, a severity score and diagnosis. We found a significant association between PTSD (diagnosis) and SNPs (top SNP: rs363276, odds ratio (OR)=1.4, p=2.1E-05) in SLC18A2 (vesicular monoamine transporter 2). A haplotype analysis of 9 SNPs in SLC18A2, including rs363276, identified a risk haplotype (CGGCGGAAG, p=0.0046), and the same risk haplotype was associated with PTSD in an independent cohort of trauma-exposed African-Americans (p=0.049; N=748, men and women). SLC18A2 is involved in transporting monoamines to synaptic vesicles and has been implicated in a number of neuropsychiatric disorders including major depression. Eight genes previously associated with PTSD had SNPs with nominally significant associations (p<0.05). The polygenic analyses suggested that there are SNPs in common between PTSD severity and bipolar disorder. Our data are consistent with a genetic architecture for PTSD that is highly polygenic, influenced by numerous SNPs with weak effects, and may overlap with mood disorders. Genome-wide studies with very large samples sizes are needed to detect these types of effects. PMID:24525708
Solovieff, Nadia; Roberts, Andrea L; Ratanatharathorn, Andrew; Haloosim, Michelle; De Vivo, Immaculata; King, Anthony P; Liberzon, Israel; Aiello, Allison; Uddin, Monica; Wildman, Derek E; Galea, Sandro; Smoller, Jordan W; Purcell, Shaun M; Koenen, Karestan C
Background Several studies have shown overexpression of leptin in microarray experiments in pre-eclampsia (PE) and in hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. We decided to study four leptin receptor (LEPR) SNP polymorphisms in HELLP syndrome patients by using quantitative real-time PCR and melting curve analysis. Methods DNA was isolated from blood samples from 83 normotensive pregnant women and 75 HELLP syndrome patients. Four SNPs, LEPR c.326A>G (K109), LEPR c.668A>G (Q223R), LEPR c.1968G>C (K656N) and LEPR c.3024A>G (S1008) were determined by quantitative real-time PCR and melting curve analysis. Investigators were blinded to clinical outcomes. Results LEPR c.326A>G, LEPR c.668A>G, LEPR c.1968G>C and LEPR c.3024A>G allele, genotype and haplotype polymorphisms were not different in HELLP syndrome patients and normotensive healthy pregnants. There were strong linkage disequilibrium (LD) between loci c.326A>G and c.6687A>G (D' = 0.974), and c.668A>G and c.1968G>C (D' = 0.934), and c.326A>G and c.1968G>C (D' = 0.885), and c.1968G>C and c.3024A>G (D' = 1.0). However, linkages of c.3024A>G with c.668A>G (D' = 0.111) and c.326A>G (D' = 0.398) were weak. The Hardy-Weinberg equilibrium was observed for all polymorphisms. However the LEPR c.326A>G AG genotype was twice more frequent and the (AG AG GG AG) haplotype was three times more frequent in HELLP syndrome patients. The introduced quantitative real-time PCR combined with melting curve analysis is a fast and reliable method for the determination of LEPR SNPs. Conclusion Although certain LEPR haplotypes are more frequent in HELLP syndrome, we conclude that there is no compelling evidence that the four studied LEPR SNP polymorphisms associated with the development of HELLP syndrome. PMID:20149225
Variable responses of formyl peptide receptor haplotypes toward bacterial peptides
The chemoattractant neutrophil formyl peptide receptor (FPR) binds bacterial and mitochondrial N-formylated peptides, which allows the neutrophils to find the bacterial source and/or site of tissue damage. Certain inflammatory disorders may be due in part to an impaired innate immune system that does not respond to acute bacterial damage in a timely fashion. Since the human FPR is encoded by a large number of different haplotypes arising from ten single nucleotide polymorphisms, we examined the possibility that some of these haplotypes are functionally distinct. We analyzed the response of three common FPR haplotypes to peptides from Escherichia coli, Mycobacterium avium ssp. paratuberculosis and human mitochondria. All three haplotypes responded similarly to the E. coli and mitochondrial peptides, whereas one required a higher concentration of the M. avium peptide fMFEDAVAWF for receptor downregulation, receptor signaling and chemotaxis. This raises the possibility of additional bacterial species differences in functional responses among FPR variants, and establishes a precedent with potentially important implications for our innate immune response against bacterial infections. We also investigated whether certain FPR haplotypes are associated with rheumatoid arthritis (RA) by sequencing FPR1 from 148 Caucasian individuals. The results suggested that FPR haplotypes do not significantly contribute toward RA. PMID:18253729
Gripentrog, Jeannie M.; Mills, John S.; Saari, George J.; Miettinen, Heini M.
Haplotype Reconstruction in Large Pedigrees with Many Untyped Individuals
NASA Astrophysics Data System (ADS)
Haplotypes, as they specify the linkage patterns between dispersed genetic variations, provide important information for understanding the genetics of human traits. However haplotypes are not directly available from current genotyping platforms, and hence there are extensive investigations of computational methods to recover such information. Two major computational challenges arising in current family-based disease studies are large family sizes and many ungenotyped family members. Traditional haplotyping methods can neither handle large families nor families with missing members. In this paper, we propose a method which addresses these issues by integrating multiple novel techniques. The method consists of three major components: pairwise identical-bydescent (IBD) inference, global IBD reconstruction and haplotype restoring. By reconstructing the global IBD of a family from pairwise IBD and then restoring the haplotypes based on the inferred IBD, this method can scale to large pedigrees, and more importantly it can handle families with missing members. Compared with existing methods, this method demonstrates much higher power to recover haplotype information, especially in families with many untyped individuals.
Li, Xin; Li, Jing
LINEAR REDUCTION METHODS FOR TAG SNP SELECTION Jingwu He Alex Zelikovsky
LINEAR REDUCTION METHODS FOR TAG SNP SELECTION Jingwu He Alex Zelikovsky Department of Computer diseases with certain SNP's. Unfortunately, the number of SNP's is huge and it is very costly to sequence many individuals. There- fore, it is desirable to reduce the number of SNP's that should be sequenced
Zelikovsky, Alexander
A rapid, microplate SNP genotype assay for the Angie T. Oler and Alan D. Attie1
methods A rapid, microplate SNP genotype assay for the leptinob allele Angie T. Oler and Alan D (SNP) detection, we have devel- oped a gel-free microplate SNP assay for genotyping leptinwt and leptinob alleles.--Oler, A. T. and A. D. Attie. A rapid, microplate SNP genotype assay for the leptinob
Attie, Alan D.
SEARCH FOR MULTI-SNP DISEASE ASSOCIATION D. Brinza, A. Perelygin, M. Brinton, A. Zelikovsky*
SEARCH FOR MULTI-SNP DISEASE ASSOCIATION D. Brinza, A. Perelygin, M. Brinton, A. Zelikovsky: algorithm, disease association, SNP, genotypes Summary Motivation: Recent improvements in the accessibility for finding disease-associated multi-SNP combinations was developed. Multi-SNP combinations significantly
Zelikovsky, Alexander
Calibrating the Performance of SNP Arrays for Whole-Genome Association Studies
Calibrating the Performance of SNP Arrays for Whole- Genome Association Studies Ke Hao, Eric E To facilitate whole-genome association studies (WGAS), several high-density SNP genotyping arrays have been the performance of SNP arrays. Ideally, such evaluations would be done on a SNP set and a cohort of individuals
Storey, John D.
SNP Set Analysis for Detecting Disease Association Using Exon Sequence Data
SNP Set Analysis for Detecting Disease Association Using Exon Sequence Data Ru Wang1,2,* , Jie Peng of common and rare variants within a SNP set based on logistic regression models and logistic kernel machine models. Gene-environment interactions and SNP-SNP interactions are also considered in some
Peng, Jie
The Perils of SNP Microarray Testing: Uncovering Unexpected Consanguinity
Background While single nucleotide polymorphism (SNP) chromosomal microarrays identify areas of small genetic deletions/duplications, they can also reveal regions of homozygosity indicative of consanguinity. As more non-geneticists order SNP microarrays, they must prepare for the potential ethical, legal and social issues that result from revelation of unanticipated consanguinity. Patient An infant with multiple congenital anomalies underwent SNP microarray testing. Results The results of the SNP microarray revealed several large regions of homozygosity that indicated identity by descent most consistent with a second or third degree relative mating (e.g., uncle/ niece, half brother/sister, first cousins). Mother was not aware of the test's potential to reveal consanguinity. When informed of the test results, she reluctantly admitted to being raped by her half-brother around the time of conception. Conclusions During the pre-testing consent process, providers should inform parents that SNP microarray testing could reveal consanguinity. Providers must also understand the psychological implications, as well as the legal and moral obligations, that accompany SNP microarray results that indicate consanguinity. PMID:23827427
Tarini, Beth A.; Konczal, Laura; Goldenberg, Aaron J.; Goldman, Edward B.; McCandless, Shawn E.
Linkage disequilibrium structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity – Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) – in 15 Eurasian populations. Demographic events predicted to increase the LD level – genetic drift, bottleneck and admixture – had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasise the importance of understanding the history, structure and variation of a study population. PMID:15657606
Laan, Maris; Wiebe, Victor; Khusnutdinova, Elza; Remm, Maido; Paabo, Svante
Transcriptional factor Nrf2 and its cytosolic reservoir protein Keap1 play important roles in induction of the expression of genes for xenobiotic metabolism and disposition, many of which are involved in protection from oxidative stress. In this study, 5 NFE2L2 (encoding Nrf2) and 6 KEAP1 exons and their flanking introns were comprehensively screened for genetic variations in 84 Japanese subjects. As for NFE2L2, 14 genetic variations were found, including 9 novel ones: 7 were located in the 5'-flanking region, 1 in the 5'-untranslated region (5'-UTR), 3 (1 synonymous and 2 nonsynonymous) in the coding exons, 1 in the intron, and 2 in the 3'-UTR. Two novel nonsynonymous variations, 697C>T (Pro233Ser) and 1094G>T (Ser365Ile), were heterozygously found with allele frequencies of 0.012 and 0.006, respectively. Regarding KEAP1, 18 genetic variations were detected, including 13 novel ones: 2 were located in the 5'-flanking region, 4 in the coding exons (4 synonymous), 5 in the introns, 4 in the 3'-UTR, and 3 in the 3'-flanking region. Based on the linkage disequilibrium (LD) profiles, both genes were analyzed as single LD blocks, where 14 (NFE2L2) and 18 (KEAP1) haplotypes were inferred. Six (NFE2L2) and 5 (KEAP1) haplotypes were relatively prevalent (>or=0.03 frequencies) and accounted for >or=88% of the inferred haplotypes. Haplotype-tagging variations of each gene were identified to capture these prevalent haplotypes. These data would be fundamental and useful information for pharmacogenetic studies on Nrf2-regulated genes for xenobiotic metabolism and disposition. PMID:17603223
Fukushima-Uesaka, Hiromi; Saito, Yoshiro; Maekawa, Keiko; Kamatani, Naoyuki; Kajio, Hiroshi; Kuzuya, Nobuaki; Noda, Mitsuhiko; Yasuda, Kazuki; Sawada, Jun-ichi
We propose an incomplete-data, quasi-likelihood framework, for estimation and score tests, which accommodates both dependent and partially-observed data. The motivation comes from genetic association studies, where we address the problems of estimating haplotype frequencies and testing association between a disease and haplotypes of multiple tightly-linked genetic markers, using case-control samples containing related individuals. We consider a more general setting in which the complete data are dependent with marginal distributions following a generalized linear model. We form a vector Z whose elements are conditional expectations of the elements of the complete-data vector, given selected functions of the incomplete data. Assuming that the covariance matrix of Z is available, we form an optimal linear estimating function based on Z, which we solve by an iterative method. This approach addresses key difficulties in the haplotype frequency estimation and testing problems in related individuals: (1) dependence that is known but can be complicated; (2) data that are incomplete for structural reasons, as well as possibly missing, with different amounts of information for different observations; (3) the need for computational speed in order to analyze large numbers of markers; (4) a well-established null model, but an alternative model that is unknown and is problematic to fully specify in related individuals. For haplotype analysis, we give sufficient conditions for consistency and asymptotic normality of the estimator and asymptotic ?2 null distribution of the score test. We apply the method to test for association of haplotypes with alcoholism in the GAW 14 COGA data set. PMID:20428335
Wang, Zuoheng; McPeek, Mary Sara
Introduction Cytochrome P-450 2E1 (CYP2E1) is an important member of the CYP superfamily, which is involved in the metabolism and activation of many low molecular weight toxic compounds. We tried to investigate the possible association of CYP2E1 tag single nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese Han population. Methods The coding and flanking regions of the CYP2E1 gene were scanned for polymorphisms and tag SNPs were selected. A two-stage case-control study was performed to genotype a total of 876 SLE patients and 680 geographically matched healthy controls (265 cases and 288 controls in stage I and 611 cases and 392 controls in stage II). SLE associations of alleles, genotypes and haplotypes were tested by age and sex adjusted logistic regression. The gene transcription quantitation was carried out for peripheral blood mononuclear cell (PBMC) samples from 120 healthy controls. Results Tag SNP rs2480256 was found significantly associated with SLE in both stages of the study. The "A" allele was associated with slightly higher risk (odds ratio (OR) = 1.165, 95% confidence interval (CI) 1.073 to 1.265, P = 2.75E-4) and "A/A" genotype carriers were with even higher SLE risk (OR = 1.464 95% CI 1.259 to 1.702, P = 7.48E-7). When combined with another tag SNP rs8192772, we identified haplotype "rs8192772-rs2480256/TA" over presented in SLE patients (OR 1.407, 95% CI 1.182 to 1.675, P = 0.0001) and haplotype "TG" over presented in the controls (OR 0.771, 95% CI 0.667 to 0.890, P = 0.0004). The gene transcription quantitation analysis further proved the dominant effect of rs2480256 as the "A/A" genotype showed highest transcription. Conclusions Our results suggest the involvement of CYP2E1 as a susceptibility gene for SLE in the Chinese population. PMID:21281483
Background Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. Methods We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. Results We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. Conclusion The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family. PMID:17888175
Datta, Susmita R; McQuillin, Andrew; Puri, Vinay; Choudhury, Khalid; Thirumalai, Srinivasa; Lawrence, Jacob; Pimm, Jonathan; Bass, Nicholas; Lamb, Graham; Moorey, Helen; Morgan, Jenny; Punukollu, Bhaskar; Kandasami, Gomathinayagam; Kirwin, Simon; Sule, Akeem; Quested, Digby; Curtis, David; Gurling, Hugh MD
Prevalence of HLA-DQA1 alleles and haplotypes in blood donors resident in Wales.
Two hundred and fifty-four normal blood donors, from a largely UK European population, were sequence-based typed for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1 and HLA-DQB1. The fit to Hardy-Weinberg expectations was good for all loci (all P values >0.5). Fifteen DQA1 alleles were identified to the second field. DQA1 carriage, allele and DQA1-DQB1 and DRB1-DQA1-DQB1 haplotype frequencies, linkage disequilibria and related values are presented. PMID:25345618
Lemin, A J; Darke, C
Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome characterized by early cancer onset, diverse tumor types, and multiple primary tumors. Germ-line p53 mutations have been identified in most LFS families. A high-frequency genetic variant of single-nucleotide polymorphism (SNP) 309 in the MDM2 gene was recently confirmed to be a modifier of cancer risk in several case-control studies: substantially earlier cancer onset was observed in SNP309 G-allele carriers than in wild-type individuals by 7–16 years. However, risk analyses in family studies that jointly account for measured hereditary p53 mutations and SNP309 have not been evaluated. Here, we extended the statistical method that we recently developed to determine the combined effects of measured p53 mutations, SNP309, and gender and their interactions simultaneously. The method is structured for age-specific risk models based on Cox proportional hazards regression for censored age-of-onset traits. We analyzed the cancer incidence in 19 extended pedigrees with multiple germ-line p53 mutations ascertained through clinical LFS phenotype. The dataset consisted of 463 individuals with 129 p53 mutation carriers. Our analyses showed that the p53 germ-line mutation and its interaction with gender were strongly associated with familial cancer incidence and that the association between SNP309 and increased cancer risk was modest. In contrast with several outcomes in case-control studies, the interaction between SNP309 and p53 mutation was not statistically significant. The causal role of SNP309 in family studies was consistent with a previous finding that SNP309 G-alleles are associated with accelerated tumor formation in patients with sporadic and hereditary cancers. PMID:21305319
Wu, Chih-Chieh; Krahe, Ralf; Lozano, Guillermina; Zhang, Baili; Wilson, Charmaine D; Jo, Eun-Ji; Shete, Sanjay; Amos, Christopher I; Strong, Louise C
High-resolution Y chromosome haplotype analysis was performed in 143 paternally unrelated Israeli and Palestinian Moslem Arabs\\u000a (I&P Arabs) by screening for 11 binary polymorphisms and six microsatellite loci. Two frequent haplotypes were found among\\u000a the 83 detected: the modal haplotype of the I&P Arabs (?14%) was spread throughout the region, while its one-step microsatellite\\u000a neighbor, the modal haplotype of the
Almut Nebel; Dvora Filon; Deborah A. Weiss; Michael Weale; Marina Faerman; Ariella Oppenheim; Mark G. Thomas
Objective: To study the genetic variation and haplotype structure of Vitamin K epoxide reductase complex, subunit 1 (VKORC1) gene in the Tamilian population. Materials And Methods: The study was performed on 210 unrelated, healthy volunteers of the Tamilian population, of either sex between the age group of 18-60 years. Five ml of venous blood sample was collected using sodium ethylene diamine tetra acetic acid (EDTA) as anticoagulant. DNA was extracted using phenol-chloroform extraction method. Eight single nucleotide polymorphisms (SNPs) VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), rs23596121 (C), and rs7294 (A) were studied using real-time quantitative Polymerase Chain Reaction (qPCR) method and they were included for constructing five-major haplotype blocks of VKORC1 gene. Results: The major alleles of VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), and rs23596121 (C), were found to be at frequencies of 90.0%, 89.2%, 90.9%, 94.1%, 90.7%, 89.5% and 91.2%, respectively. The variant allele of VKORC1 rs7294 (A) was more frequent (83.6%) in the Tamilian population. The frequencies of haplotypes HAP1 (GTTCCGCA), HAP2 (ACGCTCTG), HAP3 (GTTTCGCG), HAP4 (GTTCCGCG) and HAP5 (GCTCCCCG) were found to be 80.0%, 7.4%, 4.7%, 1.5% and 1.1%, respectively. Conclusion: In the present study the allele- frequency distributions, genotype and haplotype frequencies of the VKORC1 gene was considered. The findings of this study provide the genetic information required for learning the association of VKORC1 genetic variation and oral anticoagulant dose variability among patients receiving oral anticoagulants in the Tamilian population. PMID:23662025
Kumar, Dhakchinamoorthi Krishna; Shewade, Deepak Gopal; Surendiran, Adithan; Adithan, Chandrasekaran
A SNP resource for Douglas-fir: de novo transcriptome assembly and SNP detection and validation
Background Douglas-fir (Pseudotsuga menziesii), one of the most economically and ecologically important tree species in the world, also has one of the largest tree breeding programs. Although the coastal and interior varieties of Douglas-fir (vars. menziesii and glauca) are native to North America, the coastal variety is also widely planted for timber production in Europe, New Zealand, Australia, and Chile. Our main goal was to develop a SNP resource large enough to facilitate genomic selection in Douglas-fir breeding programs. To accomplish this, we developed a 454-based reference transcriptome for coastal Douglas-fir, annotated and evaluated the quality of the reference, identified putative SNPs, and then validated a sample of those SNPs using the Illumina Infinium genotyping platform. Results We assembled a reference transcriptome consisting of 25,002 isogroups (unique gene models) and 102,623 singletons from 2.76 million 454 and Sanger cDNA sequences from coastal Douglas-fir. We identified 278,979 unique SNPs by mapping the 454 and Sanger sequences to the reference, and by mapping four datasets of Illumina cDNA sequences from multiple seed sources, genotypes, and tissues. The Illumina datasets represented coastal Douglas-fir (64.00 and 13.41 million reads), interior Douglas-fir (80.45 million reads), and a Yakima population similar to interior Douglas-fir (8.99 million reads). We assayed 8067 SNPs on 260 trees using an Illumina Infinium SNP genotyping array. Of these SNPs, 5847 (72.5%) were called successfully and were polymorphic. Conclusions Based on our validation efficiency, our SNP database may contain as many as ~200,000 true SNPs, and as many as ~69,000 SNPs that could be genotyped at ~20,000 gene loci using an Infinium II array—more SNPs than are needed to use genomic selection in tree breeding programs. Ultimately, these genomic resources will enhance Douglas-fir breeding and allow us to better understand landscape-scale patterns of genetic variation and potential responses to climate change. PMID:23445355
Because defects in the phenylalanine hydroxylase gene (PAH) cause phenylketonuria (PKU), PAH was studied for normal polymorphisms and linkage disequilibrium soon after the gene was cloned. Studies in the 1980s concentrated on European populations in which PKU was common and showed that haplotype-frequency variation exists between some regions of the world. In European populations, linkage disequilibrium generally was found not to exist between RFLPs at opposite ends of the gene but was found to exist among the RFLPs clustered at each end. We have now undertaken the first global survey of normal variation and disequilibrium across the PAH gene. Four well-mapped single-nucleotide polymorphisms (SNPs) spanning approximately 75 kb, two near each end of the gene, were selected to allow linkage disequilibrium across most of the gene to be examined. These SNPs were studied as PCR-RFLP markers in samples of, on average, 50 individuals for each of 29 populations, including, for the first time, multiple populations from Africa and from the Americas. All four sites are polymorphic in all 29 populations. Although all but 5 of the 16 possible haplotypes reach frequencies >5% somewhere in the world, no haplotype was seen in all populations. Overall linkage disequilibrium is highly significant in all populations, but di