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Identifying disease associated genes by network propagation
Background Genome-wide association studies have identified many individual genes associated with complex traits. However, pathway and network information have not been fully exploited in searches for genetic determinants, and including this information may increase our understanding of the underlying biology of common diseases. Results In this study, we propose a framework to address this problem in a principled way, with the underlying hypothesis that complex disease operates through multiple connected genes. Associations inferred from GWAS are translated into prior scores for vertices in a protein-protein interaction network, and these scores are propagated through the network. Permutation is used to select genes that are guilty-by-association and thus consistently obtain high scores after network propagation. We apply the approach to data of Crohn's disease and call candidate genes that have been reported by other independent GWAS, but not in the analysed data set. A prediction model based on these candidate genes show good predictive power as measured by Area Under the Receiver Operating Curve (AUC) in 10 fold cross-validations. Conclusions Our network propagation method applied to a genome-wide association study increases association findings over other approaches. PMID:24565229
Identifying disease genes by integrating multiple data sources
Background Now multiple types of data are available for identifying disease genes. Those data include gene-disease associations, disease phenotype similarities, protein-protein interactions, pathways, gene expression profiles, etc.. It is believed that integrating different kinds of biological data is an effective method to identify disease genes. Results In this paper, we propose a multiple data integration method based on the theory of Markov random field (MRF) and the method of Bayesian analysis for identifying human disease genes. The proposed method is not only flexible in easily incorporating different kinds of data, but also reliable in predicting candidate disease genes. Conclusions Numerical experiments are carried out by integrating known gene-disease associations, protein complexes, protein-protein interactions, pathways and gene expression profiles. Predictions are evaluated by the leave-one-out method. The proposed method achieves an AUC score of 0.743 when integrating all those biological data in our experiments. PMID:25350511
Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes
; Accepted September 20, 2013 Using a Drosophila model of Alzheimer's disease (AD), we systematically, cell-based strategies, as well as model organism studies. These efforts To whom correspondence shouldFunctional screening in Drosophila identifies Alzheimer's disease susceptibility genes
Perrimon, Norbert
Identifying Mendelian disease genes with the Variant Effect Scoring Tool
Background Whole exome sequencing studies identify hundreds to thousands of rare protein coding variants of ambiguous significance for human health. Computational tools are needed to accelerate the identification of specific variants and genes that contribute to human disease. Results We have developed the Variant Effect Scoring Tool (VEST), a supervised machine learning-based classifier, to prioritize rare missense variants with likely involvement in human disease. The VEST classifier training set comprised ~ 45,000 disease mutations from the latest Human Gene Mutation Database release and another ~45,000 high frequency (allele frequency >1%) putatively neutral missense variants from the Exome Sequencing Project. VEST outperforms some of the most popular methods for prioritizing missense variants in carefully designed holdout benchmarking experiments (VEST ROC AUC = 0.91, PolyPhen2 ROC AUC = 0.86, SIFT4.0 ROC AUC = 0.84). VEST estimates variant score p-values against a null distribution of VEST scores for neutral variants not included in the VEST training set. These p-values can be aggregated at the gene level across multiple disease exomes to rank genes for probable disease involvement. We tested the ability of an aggregate VEST gene score to identify candidate Mendelian disease genes, based on whole-exome sequencing of a small number of disease cases. We used whole-exome data for two Mendelian disorders for which the causal gene is known. Considering only genes that contained variants in all cases, the VEST gene score ranked dihydroorotate dehydrogenase (DHODH) number 2 of 2253 genes in four cases of Miller syndrome, and myosin-3 (MYH3) number 2 of 2313 genes in three cases of Freeman Sheldon syndrome. Conclusions Our results demonstrate the potential power gain of aggregating bioinformatics variant scores into gene-level scores and the general utility of bioinformatics in assisting the search for disease genes in large-scale exome sequencing studies. VEST is available as a stand-alone software package at http://wiki.chasmsoftware.org and is hosted by the CRAVAT web server at http://www.cravat.us PMID:23819870
Hum Genet . Author manuscript Identifying modifier genes of monogenic disease: strategies and
Hum Genet . Author manuscript Page /1 11 Identifying modifier genes of monogenic disease modifier gene, Mendelian disorders, disease expression, linkage, association Introduction Genetic factors determined diseases, and this variability may itself involve genetic factors, the so-called modifier genes
Boyer, Edmond
Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here ...
Daly, Mark J.
Gene-Based Rare Allele Analysis Identified a Risk Gene of Alzheimer's Disease
Alzheimer�s disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer�s Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency?3%). The genome-wide significance level was defined as meta P<1.8�10�6 (0.05/number of genes in human genome?=?0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ?4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies. PMID:25329708
Kim, Jong Hun; Song, Pamela; Lim, Hyunsun; Lee, Jae-Hyung; Lee, Jun Hong; Park, Sun Ah
Transcriptomic and genetic studies identify IL33 as a candidate gene for Alzheimer's disease
The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the ?4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two
J Chapuis; D Hot; F Hansmannel; O Kerdraon; S Ferreira; C Hubans; C A Maurage; L Huot; F Bensemain; G Laumet; A M Ayral; N Fievet; J J Hauw; S T DeKosky; Y Lemoine; T Iwatsubo; F Wavrant-Devri�ze; J F Dartigues; C Tzourio; L Bu�e; F Pasquier; C Berr; D Mann; C Lendon; A Alp�rovitch; M I Kamboh; P Amouyel; J C Lambert
Background Although many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. Nearly half of all human genes remain poorly studied, yet these genes may contribute to a number of disease processes. Genes involved in common biological processes and diseases are often co-expressed. Using known disease-associated genes in a co-expression analysis may help identify and prioritize novel candidate genes for further study. Results We have created an online tool, called GeneFriends, which identifies co-expressed genes in over 1,000 mouse microarray datasets. GeneFriends can be used to assign putative functions to poorly studied genes. Using a seed list of disease-associated genes and a guilt-by-association method, GeneFriends allows users to quickly identify novel genes and transcription factors associated with a disease or process. We tested GeneFriends using seed lists for aging, cancer, and mitochondrial complex I disease. We identified several candidate genes that have previously been predicted as relevant targets. Some of the genes identified are already being tested in clinical trials, indicating the effectiveness of this approach. Co-expressed transcription factors were investigated, identifying C/ebp genes as candidate regulators of aging. Furthermore, several novel candidate genes, that may be suitable for experimental or clinical follow-up, were identified. Two of the novel candidates of unknown function that were co-expressed with cancer-associated genes were selected for experimental validation. Knock-down of their human homologs (C1ORF112 and C12ORF48) in HeLa cells slowed growth, indicating that these genes of unknown function, identified by GeneFriends, may be involved in cancer. Conclusions GeneFriends is a resource for biologists to identify and prioritize novel candidate genes involved in biological processes and complex diseases. It is an intuitive online resource that will help drive experimentation. GeneFriends is available online at: http://genefriends.org/. PMID:23039964
Using the mouse to identify genes involved in human disease Jenny Murdoch
Lab, School of Biological Sciences, Royal Holloway-University of London, Egham, TW20 0EX ABSTRACT: Allows us to identify the genetic defect that causes the disease Mouse mutant with severe spina bifidaUsing the mouse to identify genes involved in human disease Jenny Murdoch Neural Tube Development
Royal Holloway, University of London
Background Understanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes. Methodology We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J�DBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development. Principal Findings From the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 Mb. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC) and those covered by copy number variations (CNV) yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F?=?22.48, p<9.87*10?5). Conclusion This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia. PMID:21572526
Poot, Martin; Badea, Alexandra; Williams, Robert W.; Kas, Martien J.
ABSTRACT Genomics and bioinformatics have the vast potential to identify genes that cause disease by investigating whole-genome databases. Comparison of an individual's geno- type with a genomic database these metabolic profiles with genomic, expression, and proteomic databases. Application of the knowledge of indi
Hammock, Bruce D.
Fatigue-related HIV Disease Gene-Networks identified in CD14+ cells isolated from HIV
1 Fatigue-related HIV Disease Gene-Networks identified in CD14+ cells isolated from HIV to solve the issue of limited experimental data to generate new hypotheses in CD14 cells of HIV of low versus high fatigued, NRTI-treated HIV patients to healthy controls (n=5 each). With novel
Dobra, Adrian
Fine Mapping of Loci Linked to Autoimmune Thyroid Disease Identifies Novel Susceptibility Genes
Context: Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively. Objectives: The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci. Design and Participants: Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls. Results: Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively. Conclusions: Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology. PMID:23118423
Hasham, Alia; Davies, Terry F.; Stefan, Mihaela; Concepcion, Erlinda; Keddache, Mehdi; Greenberg, David A.
Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (P < 10(-4)) from published human genome-wide association studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS. PMID:24067533
Shulman, Joshua M; Imboywa, Selina; Giagtzoglou, Nikolaos; Powers, Martin P; Hu, Yanhui; Devenport, Danelle; Chipendo, Portia; Chibnik, Lori B; Diamond, Allison; Perrimon, Norbert; Brown, Nicholas H; De Jager, Philip L; Feany, Mel B
DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease
The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer�s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5�-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer�s disease. We were able to translate these findings to patients with Alzheimer�s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease. PMID:24030951
Sanchez-Mut, Jose V.; Aso, Ester; Panayotis, Nicolas; Lott, Ira; Dierssen, Mara; Rabano, Alberto; Urdinguio, Rocio G.; Fernandez, Agustin F.; Astudillo, Aurora; Martin-Subero, Jose I.; Balint, Balazs; Fraga, Mario F.; Gomez, Antonio; Gurnot, Cecile; Roux, Jean-Christophe; Avila, Jesus; Hensch, Takao K.; Ferrer, Isidre
Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease
Background Alzheimer�s disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi-dimensional data and protein-protein interaction (PPI) network modelling. Results Our approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108�AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes. Conclusions With the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD. PMID:24628925
The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer�s disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-? signaling pathways that have been associated with neuroprotection as well as a neurodegeneration mediator, TRPM7. Further, for each disease model, we discovered collections of differentially expressed genes that provide novel insight into the individual pathology and its associated mechanisms. Our data provide a resource for exploring the complex molecular mechanisms that underlie brain neurodegeneration and a new approach for identifying generic and disease-specific targets for therapy. PMID:20435134
Tseveleki, Vivian; Rubio, Renee; Vamvakas, Sotiris-Spyros; White, Joseph; Taoufik, Era; Petit, Edwige; Quackenbush, John; Probert, Lesley
Identifying disease-specific genes based on their topological significance in protein networks
Background The identification of key target nodes within complex molecular networks remains a common objective in scientific research. The results of pathway analyses are usually sets of fairly complex networks or functional processes that are deemed relevant to the condition represented by the molecular profile. To be useful in a research or clinical laboratory, the results need to be translated to the level of testable hypotheses about individual genes and proteins within the condition of interest. Results In this paper we describe novel computational methodology capable of predicting key regulatory genes and proteins in disease- and condition-specific biological networks. The algorithm builds shortest path network connecting condition-specific genes (e.g. differentially expressed genes) using global database of protein interactions from MetaCore. We evaluate the number of all paths traversing each node in the shortest path network in relation to the total number of paths going via the same node in the global network. Using these numbers and the relative size of the initial data set, we determine the statistical significance of the network connectivity provided through each node. We applied this method to gene expression data from psoriasis patients and identified many confirmed biological targets of psoriasis and suggested several new targets. Using predicted regulatory nodes we were able to reconstruct disease pathways that are in excellent agreement with the current knowledge on the pathogenesis of psoriasis. Conclusion The systematic and automated approach described in this paper is readily applicable to uncovering high-quality therapeutic targets, and holds great promise for developing network-based combinational treatment strategies for a wide range of diseases. PMID:19309513
Dezs?, Zolt�n; Nikolsky, Yuri; Nikolskaya, Tatiana; Miller, Jeremy; Cherba, David; Webb, Craig; Bugrim, Andrej
In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oA?). To identify immediate molecular targets downstream of oA? binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric A? (dA?). These patients also showed increased expression of neuroplasticity related genes, many encoding 3?UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the ?-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dA?. PMID:19295912
Williams, Celia; Mehrian Shai, Ruty; Wu, Yongchun; Hsu, Ya-Hsuan; Sitzer, Traci; Spann, Bryan; McCleary, Carol; Mo, Yi; Miller, Carol A.
Functional Genomics Complements Quantitative Genetics in Identifying Disease-Gene Associations
An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype. PMID:21085640
Guan, Yuanfang; Ackert-Bicknell, Cheryl L.; Kell, Braden; Troyanskaya, Olga G.; Hibbs, Matthew A.
The identification of susceptibility genes for human disease is a major goal of current biomedical research. Both sequence and structural variation have emerged as major genetic sources of phenotypic variability and growing evidence points to copy number variation as a particularly important source of susceptibility for disease. Here we propose and validate a strategy to identify genes in which changes in dosage alter susceptibility to disease-relevant phenotypes in the mouse. Our approach relies on sensitized phenotypic screening of megabase-sized chromosomal deletion and deficiency lines carrying altered copy numbers of ?30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the feasibility of such a screen, we performed sensitized phenotyping in five therapeutic areas (metabolic syndrome, immune dysfunction, atherosclerosis, cancer and behaviour) of a 0.8 Mb reciprocal chromosomal duplication and deficiency on chromosome 11 containing 27 genes. Gene dosage in the region significantly affected risk for high-fat diet-induced metabolic syndrome, antigen-induced immune hypersensitivity, ApoE-induced atherosclerosis, and home cage activity. Follow up studies on individual gene knockouts for two candidates in the region showed that copy number variation in Stat5 was responsible for the phenotypic variation in antigen-induced immune hypersensitivity and metabolic syndrome. These data demonstrate the power of sensitized phenotypic screening of segmental aneuploidy lines to identify disease susceptibility genes. PMID:21204268
Ermakova, Olga; Piszczek, Lukasz; Luciani, Luisa; Cavalli, Florence M G; Ferreira, Tiago; Farley, Dominika; Rizzo, Stefania; Paolicelli, Rosa Chiara; Al-Banchaabouchi, Mumna; Nerlov, Claus; Moriggl, Richard; Luscombe, Nicholas M; Gross, Cornelius
The identification of susceptibility genes for human disease is a major goal of current biomedical research. Both sequence and structural variation have emerged as major genetic sources of phenotypic variability and growing evidence points to copy number variation as a particularly important source of susceptibility for disease. Here we propose and validate a strategy to identify genes in which changes in dosage alter susceptibility to disease-relevant phenotypes in the mouse. Our approach relies on sensitized phenotypic screening of megabase-sized chromosomal deletion and deficiency lines carrying altered copy numbers of ?30 linked genes. This approach offers several advantages as a method to systematically identify genes involved in disease susceptibility. To examine the feasibility of such a screen, we performed sensitized phenotyping in five therapeutic areas (metabolic syndrome, immune dysfunction, atherosclerosis, cancer and behaviour) of a 0.8?Mb reciprocal chromosomal duplication and deficiency on chromosome 11 containing 27 genes. Gene dosage in the region significantly affected risk for high-fat diet-induced metabolic syndrome, antigen-induced immune hypersensitivity, ApoE-induced atherosclerosis, and home cage activity. Follow up studies on individual gene knockouts for two candidates in the region showed that copy number variation in Stat5 was responsible for the phenotypic variation in antigen-induced immune hypersensitivity and metabolic syndrome. These data demonstrate the power of sensitized phenotypic screening of segmental aneuploidy lines to identify disease susceptibility genes. PMID:21204268
Ermakova, Olga; Piszczek, Lukasz; Luciani, Luisa; Cavalli, Florence M G; Ferreira, Tiago; Farley, Dominika; Rizzo, Stefania; Paolicelli, Rosa Chiara; Al-Banchaabouchi, Mumna; Nerlov, Claus; Moriggl, Richard; Luscombe, Nicholas M; Gross, Cornelius
Systematic Association Mapping Identifies NELL1 as a Novel IBD Disease Gene
Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an
Andre Franke; Jochen Hampe; Philip Rosenstiel; Christian Becker; Florian Wagner; Robert H�sler; Randall D. Little; Klaus Huse; Andreas Ruether; Tobias Balschun; Michael Wittig; Abdou ElSharawy; Gabriele Mayr; Mario Albrecht; Natalie J. Prescott; Clive M. Onnie; H�l�ne Fournier; Tim Keith; Uwe Radelof; Matthias Platzer; Christopher G. Mathew; Monika Stoll; Michael Krawczak; Peter N�rnberg; Stefan Schreiber
Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus
Taye H. Hamza; Honglei Chen; Erin M. Hill-Burns; Shannon L. Rhodes; Jennifer Montimurro; Denise M. Kay; Albert Tenesa; Victoria I. Kusel; Patricia Sheehan; Muthukrishnan Eaaswarkhanth; Dora Yearout; Ali Samii; John W. Roberts; Pinky Agarwal; Yvette Bordelon; Liyong Wang; Jianjun Gao; Jeffery M. Vance; Kenneth S. Kendler; Silviu-Alin Bacanu; William K. Scott; Beate Ritz; John Nutt; Stewart A. Factor; Haydeh Payami
Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20-25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants. PMID:25339316
Juang, Jyh-Ming Jimmy; Lu, Tzu-Pin; Lai, Liang-Chuan; Ho, Chia-Chuan; Liu, Yen-Bin; Tsai, Chia-Ti; Lin, Lian-Yu; Yu, Chih-Chieh; Chen, Wen-Jone; Chiang, Fu-Tien; Yeh, Shih-Fan Sherri; Lai, Ling-Ping; Chuang, Eric Y; Lin, Jiunn-Lee
Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20�25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants. PMID:25339316
Juang, Jyh-Ming Jimmy; Lu, Tzu-Pin; Lai, Liang-Chuan; Ho, Chia-Chuan; Liu, Yen-Bin; Tsai, Chia-Ti; Lin, Lian-Yu; Yu, Chih-Chieh; Chen, Wen-Jone; Chiang, Fu-Tien; Yeh, Shih-Fan Sherri; Lai, Ling-Ping; Chuang, Eric Y.; Lin, Jiunn-Lee
The important role that cilia and flagella play in human disease creates an urgent need to identify genes involved in ciliary assembly and function. The strong and specific induction of flagellar-coding genes during flagellar regeneration in Chlamydomonas reinhardtii suggests that transcriptional profiling of such cells would reveal new flagella-related genes. We have conducted a genome-wide analysis of RNA transcript levels during flagellar regeneration in Chlamydomonas by using maskless photolithography method-produced DNA oligonucleotide microarrays with unique probe sequences for all exons of the 19,803 predicted genes. This analysis represents previously uncharacterized whole-genome transcriptional activity profiling study in this important model organism. Analysis of strongly induced genes reveals a large set of known flagellar components and also identifies a number of important disease-related proteins as being involved with cilia and flagella, including the zebrafish polycystic kidney genes Qilin, Reptin, and Pontin, as well as the testis-expressed tubby-like protein TULP2. PMID:15738400
Stolc, Viktor; Samanta, Manoj Pratim; Tongprasit, Waraporn; Marshall, Wallace F
NASA Technical Reports Server (NTRS)
The important role that cilia and flagella play in human disease creates an urgent need to identify genes involved in ciliary assembly and function. The strong and specific induction of flagellar-coding genes during flagellar regeneration in Chlamydomonas reinhardtii suggests that transcriptional profiling of such cells would reveal new flagella-related genes. We have conducted a genome-wide analysis of RNA transcript levels during flagellar regeneration in Chlamydomonas by using maskless photolithography method-produced DNA oligonucleotide microarrays with unique probe sequences for all exons of the 19,803 predicted genes. This analysis represents previously uncharacterized whole-genome transcriptional activity profiling study in this important model organism. Analysis of strongly induced genes reveals a large set of known flagellar components and also identifies a number of important disease-related proteins as being involved with cilia and flagella, including the zebrafish polycystic kidney genes Qilin, Reptin, and Pontin, as well as the testis-expressed tubby-like protein TULP2.
Stolc, Viktor; Samanta, Manoj Pratim; Tongprasit, Waraporn; Marshall, Wallace F.
Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404?467 variants, n=6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal P<0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404?467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, P<0.001) and sulfur amino-acid metabolic process (GO:0000096, P<0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD. PMID:22510845
de las Fuentes, Lisa; Yang, Wei; Davila-Roman, Victor G; Charles Gu, C
Diseases such as obesity, diabetes, and athero- sclerosis result from multiple genetic and environmental factors, and importantly, interactions between genetic and environmental factors. Identifying susceptibility genes for these diseases using genetic and genomic technologies is accelerating, and the expectation over the next several years is that a number of genes will be identified for common dis- eases. However, the identification
Eric E. Schadt; Pek Y. Lum
Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA�B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine�cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression. PMID:24403257
Thomas, Asha; Mahantshetty, Umesh; Kannan, Sadhana; Deodhar, Kedar; Shrivastava, Shyam K; Kumar-Sinha, Chandan; Mulherkar, Rita
Background Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn�s disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique. Methods Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family. Results From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play mutiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1. Conclusions We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients. PMID:24937328
Song, Lu; NG, Siew Chien; Wang, Xiaobing; Chen, Liping; Yi, Fengming; Ran, Zhihua; Zhou, Rui; Xia, Bing
Background Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. Objective To investigate the genetic background of a family affected by inherited CCD. Methods and Results We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model. Conclusions Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases. PMID:24349489
Hsieh, Wen-Ping; Kuo, Chi-Tai; Wang, Wen-Ching; Chu, Chia-Han; Hung, Chiu-Lien; Cheng, Chia-Yang; Tsai, Hsin-Yi; Lee, Jia-Lin; Tang, Chuan-Yi; Hsu, Lung-An
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy. PMID:23418020
Schmidts, Miriam; Frank, Valeska; Eisenberger, Tobias; Al Turki, Saeed; Bizet, Albane A; Antony, Dinu; Rix, Suzanne; Decker, Christian; Bachmann, Nadine; Bald, Martin; Vinke, Tobias; Toenshoff, Burkhard; Di Donato, Natalia; Neuhann, Theresa; Hartley, Jane L; Maher, Eamonn R; Bogdanovi?, Radovan; Peco-Anti?, Amira; Mache, Christoph; Hurles, Matthew E; Joksi?, Ivana; Gu?-�?eki?, Marija; Dobricic, Jelena; Brankovic-Magic, Mirjana; Bolz, Hanno J; Pazour, Gregory J; Beales, Philip L; Scambler, Peter J; Saunier, Sophie; Mitchison, Hannah M; Bergmann, Carsten
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy. PMID:23418020
Schmidts, Miriam; Frank, Valeska; Eisenberger, Tobias; al Turki, Saeed; Bizet, Albane A.; Antony, Dinu; Rix, Suzanne; Decker, Christian; Bachmann, Nadine; Bald, Martin; Vinke, Tobias; Toenshoff, Burkhard; Donato, Natalia Di; Neuhann, Theresa; Hartley, Jane L.; Maher, Eamonn R.; Bogdanovic, Radovan; Peco-Antic, Amira; Mache, Christoph; Hurles, Matthew E.; Joksic, Ivana; Guc-Scekic, Marija; Dobricic, Jelena; Brankovic-Magic, Mirjana; Bolz, Hanno J.; Pazour, Gregory J.; Beales, Philip L.; Scambler, Peter J.; Saunier, Sophie; Mitchison, Hannah M.; Bergmann, Carsten
Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease. PMID:20419147
Carney, Thomas J.; Feitosa, Natalia Martins; Sonntag, Carmen; Slanchev, Krasimir; Kluger, Johannes; Kiyozumi, Daiji; Gebauer, Jan M.; Coffin Talbot, Jared; Kimmel, Charles B.; Sekiguchi, Kiyotoshi; Wagener, Raimund; Schwarz, Heinz; Ingham, Phillip W.; Hammerschmidt, Matthias
Hirschsprung's disease (HSCR) is a complex developmental defect characterized by the absence of enteric ganglia in the gastrointestinal tract. Although the genetic defect of enteric nervous system (ENS) was identified to play a critical role in the progress of HSCR, the systemic genetic dissection of HSCR still needs to be clarified. In this study, we firstly performed exome sequencing of two HSCR patients from a Han Chinese family, including the affected mother and son. After the initial quality filtering (coverage? ??5X and SNP quality score???40) of the raw data, we identified 13,948 and 13,856 single nucleotide variants (SNVs), respectively. We subsequently compared the SNVs against public databases (dbSNP130, HapMap, and 1000 Genome Project) and obtained a total of 15 novel nonsynonymous SNVs in 15 genes, which were shared between these two patients. Follow-up Sanger sequencing and bioinformatics analysis highlighted variant c.853G>A (p.E285K) in NRG3, a gene involved in the development of ENS. In the validation phase, we sequenced all nine exons of NRG3 in 96 additional sporadic HSCR cases and 110 healthy individuals and identified another nonsynonymous variant c.1329G>A (p.M443I) and two synonymous variants c.828G>A (p.T276T) and c.1365T>A (p.P455P) only in the cases. Our results indicated that NRG3 may be a susceptibility gene for HSCR in a Chinese population. PMID:23315268
Yang, Jun; Duan, Shengyu; Zhong, Rong; Yin, Jieyun; Pu, Jiarui; Ke, Juntao; Lu, Xuzai; Zou, Li; Zhang, Hongmei; Zhu, Zhidong; Wang, Depeng; Xiao, Huasheng; Guo, Anyuan; Xia, Jiahong; Miao, Xiaoping; Tang, Shaotao; Wang, Guobin
Introduction A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the sampled cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort. Methods A total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs). Results A total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P-value <0.0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300, which modulate cartilage and bone metabolism. Conclusions We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease. PMID:21470430
Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute to the development of ovarian cancer. PMID:21423607
Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna
Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the
Thomas J. Carney; Nat�lia Martins Feitosa; Carmen Sonntag; Krasimir Slanchev; Johannes Kluger; Daiji Kiyozumi; Jan M. Gebauer; Jared Coffin Talbot; Charles B. Kimmel; Kiyotoshi Sekiguchi; Raimund Wagener; Heinz Schwarz; Phillip W. Ingham; Matthias Hammerschmidt
Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS). The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions) identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-� therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases. PMID:18030350
Palacios, Ricardo; Goni, Joaquin; Martinez-Forero, Ivan; Iranzo, Jaime; Sepulcre, Jorge; Melero, Ignacio; Villoslada, Pablo
Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus that causes disease that is both a cancer model and a continuing threat to the world's poultry industry. This comprehensive gene expression study analyzes the host response to infection in both resistant and susceptible lines of chickens and inherent expression differences between the two lines following the infection of the host. A novel pathogenicity mechanism, involving the downregulation of genes containing HIC1 transcription factor binding sites as early as 4 days postinfection, was suggested from this analysis. HIC1 drives antitumor mechanisms, suggesting that MDV infection switches off genes involved in antitumor regulation several days before the expression of the MDV oncogene meq. The comparison of the gene expression data to previous QTL data identified several genes as candidates for involvement in resistance to MD. One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Understanding which genes are involved in susceptibility/resistance to MD and defining the pathological mechanisms of the disease gives us a much greater ability to try to reduce the incidence of this virus, which is costly to the poultry industry in terms of both animal welfare and economics. PMID:21865384
Smith, Jacqueline; Sadeyen, Jean-Remy; Paton, Ian R.; Hocking, Paul M.; Salmon, Nigel; Fife, Mark; Nair, Venugopal; Burt, David W.; Kaiser, Pete
Disease response genes (DRGs) diverge under recurrent positive selection as a result of a molecular arms race between hosts and pathogens. Most of these studies were conducted in animals, and few defense genes have been shown to evolve adaptively in plants. To test for adaptation in the molecules mediating disease resistance in the cereals, we first combined information from the expression pattern of Sorghum bicolor genes and from divergence to the full genome of rice to identify candidate DRGs. We then used evolutionary analyses of orthologous gene sets from several grass species, to determine whether the DRGs show signals of positive selection and the residues targeted. We found 140 divergent genes upregulated under biotic stress in S. bicolor by evaluating the relative abundance of expressed sequence tags in different libraries and comparing them with rice genes. For 10 of these genes, we found sets of orthologs including sequences from rice and three other cereals; six genes showed a pattern of substitution that was consistent with positive selection. Three of these genes, a thaumatin, a peroxidase, and a barley mlo homolog, are known antifungal proteins. The other three genes with evidence of positive selection were a MCM-1 agamous deficiens SRF- (MADS) box transcription factor, an eIF5 translation initiation factor, and a gene of unknown function but with evidence of expression during stress. Permutation analyses, using different ortholog and paralog sequences, consistently identified five positively selected codons in the peroxidase, a member of a cluster of genes and a large gene family. We mapped the positively selected residues onto the structure of the peroxidase and thaumatin and found that all sites are on the surface of these proteins and several are close to biochemically determined active sites. Identifying new positively selected plant disease resistance genes and the critical amino acid sites provides a basis for functional studies that may increase our understanding of their underlying molecular mechanisms of action. Additionally, it may lead to the identification of individuals having variation at functionally important sites, as well as eventually using this information in the rational design and engineering of proteins involved in plant disease resistance. PMID:19506000
Zamora, Alejandro; Sun, Qi; Hamblin, Martha T.; Aquadro, Charles F.; Kresovich, Stephen
Hashimoto's thyroiditis has been shown to be associated with the HLA-specificities DR4 and DR5. Since former association studies yielded variable results, we used novel molecular typing methods to assess predisposing immunogenetic factors. Gene analysis of the HLA-DR-DQ and tumor necrosis factor region was performed in a group of Hashimoto's thyroiditis patients and randomly chosen controls using standards and nomenclature of the 10th International Histocompatibility Workshop. Genomic DNA of patients and controls was analyzed using a cDNA probe of the DQB1 gene. The resulting restriction fragment patterns allowed the determination of newly defined DQw-types 1-9. We find the strongest relative risk conferred by DQw7 (RR = 4.7), that is observed in 36 of 64 patients (56%) and only 21 of 98 controls (21%) (P corr less than 0.002). Comparison of DNA sequence variation in the DQB1 gene, that is found predominantly in Hashimoto's thyroiditis patients, indicates that codons 45 and 57 are critical features in DQw7 which distinguish it from other DQw specificities. The adjacent DQA1 genes also display a significant association with Hashimoto's thyroiditis (DQA1*0201/*0301 heterozygotes were found in 37% of patients and 15% controls, P less than 0.03). No significant association could be found with polymorphisms of the tumor necrosis factor gene. These results provide a new basis for the concept of genetic susceptibility in Hashimoto's thyroiditis and will help to elucidate the underlying autoimmune mechanisms that lead to disease at the functional level. PMID:1977755
Badenhoop, K; Schwarz, G; Walfish, P G; Drummond, V; Usadel, K H; Bottazzo, G F
Background An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions. Results We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns. We tested our algorithm on 140 subjects with Chronic Obstructive Pulmonary Disease (COPD) and found four distinct, biologically and clinically meaningful combinations of clinical characteristics that are associated with large gene expression differences. The dominant characteristic in these combinations was the severity of airflow limitation. Other frequently identified measures included emphysema, fibrinogen levels, phlegm, BMI and age. A pathway analysis of the differentially expressed genes in the identified subtypes suggests that VIStA is capable of capturing specific molecular signatures within in each group. Conclusions The introduced methodology allowed us to identify combinations of clinical characteristics that correspond to clear gene expression differences. The resulting subtypes for COPD contribute to a better understanding of its heterogeneity. PMID:25032995
Genes that underlie human disease are important subjects of systems biology research. In the present study, we demonstrate that Mendelian and complex disease genes have distinct and consistent protein�protein interaction (PPI) properties. We show that five different network properties can be reduced to two independent metrics when applied to the human PPI network. These two metrics largely coincide with the degree (number of connections) and the clustering coefficient (the number of connections among the neighbors of a particular protein). We demonstrate that disease genes have simultaneously unusually high degree and unusually low clustering coefficient. Such genes can be described as brokers in that they connect many proteins that would not be connected otherwise. We show that these results are robust to the effect of gene age and inspection bias variation. Notably, genes identified in genome-wide association study (GWAS) have network patterns that are almost indistinguishable from the network patterns of nondisease genes and significantly different from the network patterns of complex disease genes identified through non-GWAS means. This suggests either that GWAS focused on a distinct set of diseases associated with an unusual set of genes or that mapping of GWAS-identified single nucleotide polymorphisms onto the causally affected neighboring genes is error prone. PMID:20937604
Cai, James J.; Borenstein, Elhanan; Petrov, Dmitri A.
1. Information and technologies derived from genomic research are beginning to revolutionize the study of disease. It is now being predicted that the human genome sequencing project will be more than 90% complete by the end of this decade and that most of the major genes involved in common diseases will have been identified by that time. Correlations between genetic mutations, disease susceptibility, and adverse reactions to drugs are already being established and it seems inevitable that this will lead to the development of novel therapies accurately targeted at subsets of patients most likely to show a favourable response. 2. Targeted therapies present a significant challenge to the pharmaceutical industry because the potential market for such drugs is likely to be smaller than for current 'phenotypic' treatments. However, application of molecular genetic technologies may allow parallel reductions in development costs since it should be more straightforward to demonstrate efficacy and safety in accurately selected patient groups, reducing the requirement for large clinical trials. 3. Gene-based diagnostics have the potential to radically improve medical practice, and progress in genetic testing technology has been impressive. Yet there is growing concern that commercial and other pressures may result in genetic testing being made widely available before the biological consequences of mutations in disease susceptibility genes are fully understood and before the legal, ethical and psychological consequences of testing have been fully debated. PMID:8971423
Dykes, C W
NSDL National Science Digital Library
The National Center for Biotechnology Information of the National Library of Medicine (part of the National Institutes of Health) has posted this webpage, Genes and Disease, which provides information "for some 60 diseases associated with specific genes, and has links to the 1998 Gene Map as well as to PubMed, protein sequences, Online Mendelian Inheritance in Man, and associations related to each disease."
Identifying proteins controlling key disease signaling pathways
Motivation: Several types of studies, including genome-wide association studies and RNA interference screens, strive to link genes to diseases. Although these approaches have had some success, genetic variants are often only present in a small subset of the population, and screens are noisy with low overlap between experiments in different labs. Neither provides a mechanistic model explaining how identified genes impact the disease of interest or the dynamics of the pathways those genes regulate. Such mechanistic models could be used to accurately predict downstream effects of knocking down pathway members and allow comprehensive exploration of the effects of targeting pairs or higher-order combinations of genes. Results: We developed methods to model the activation of signaling and dynamic regulatory networks involved in disease progression. Our model, SDREM, integrates static and time series data to link proteins and the pathways they regulate in these networks. SDREM uses prior information about proteins� likelihood of involvement in a disease (e.g. from screens) to improve the quality of the predicted signaling pathways. We used our algorithms to study the human immune response to H1N1 influenza infection. The resulting networks correctly identified many of the known pathways and transcriptional regulators of this disease. Furthermore, they accurately predict RNA interference effects and can be used to infer genetic interactions, greatly improving over other methods suggested for this task. Applying our method to the more pathogenic H5N1 influenza allowed us to identify several strain-specific targets of this infection. Availability: SDREM is available from http://sb.cs.cmu.edu/sdrem Contact: email@example.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23812988
Gitter, Anthony; Bar-Joseph, Ziv
To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundaci� ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19�1.44); P=9.74 � 10?9). PMID:24495969
Ruiz, A; Heilmann, S; Becker, T; Hernandez, I; Wagner, H; Thelen, M; Mauleon, A; Rosende-Roca, M; Bellenguez, C; Bis, J C; Harold, D; Gerrish, A; Sims, R; Sotolongo-Grau, O; Espinosa, A; Alegret, M; Arrieta, J L; Lacour, A; Leber, M; Becker, J; Lafuente, A; Ruiz, S; Vargas, L; Rodriguez, O; Ortega, G; Dominguez, M-A; Mayeux, R; Haines, J L; Pericak-Vance, M A; Farrer, L A; Schellenberg, G D; Chouraki, V; Launer, L J; van Duijn, C; Seshadri, S; Antunez, C; Breteler, M M; Serrano-Rios, M; Jessen, F; Tarraga, L; Nothen, M M; Maier, W; Boada, M; Ramirez, A
), adenoma (Ade), inflammatory bowel disease (IBD) and CRC with protein-protein interaction database and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have
Lee, H.C. Paul
Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in �second hit� hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH. PMID:24743702
Zain, Shamsul Mohd; Mohamed, Rosmawati; Cooper, David N.; Razali, Rozaimi; Rampal, Sanjay; Mahadeva, Sanjiv; Chan, Wah-Kheong; Anwar, Arif; Rosli, Nurul Shielawati Mohamed; Mahfudz, Anis Shafina; Cheah, Phaik-Leng; Basu, Roma Choudhury; Mohamed, Zahurin
NIH Researchers Identify OCD Risk Gene
... News From NIH NIH Researchers Identify OCD Risk Gene Past Issues / Summer 2006 Table of Contents For ... and Alcoholism (NIAAA) have identified a previously unknown gene variant that doubles an individual's risk for obsessive- ...
Cilia and flagella are microtubule-based structures nucleated by modified centrioles termed basal bodies. These biochemically complex organelles have more than 250 and 150 polypeptides, respectively. To identify the proteins involved in ciliary and basal body biogenesis and function, we undertook a comparative genomics approach that subtracted the nonflagellated proteome of Arabidopsis from the shared proteome of the ciliated\\/flagellated organisms Chlamydomonas
Jin Billy Li; Jantje M. Gerdes; Courtney J. Haycraft; Yanli Fan; Tanya M. Teslovich; Helen May-Simera; Haitao Li; Oliver E. Blacque; Linya Li; Carmen C. Leitch; Richard Allan Lewis; Jane S Green; Patrick S Parfrey; Michel R Leroux; William S Davidson; Philip L Beales; Lisa M Guay-Woodford; Bradley K Yoder; Gary D Stormo; Nicholas Katsanis; Susan K Dutcher
Identifying future zoonotic disease threats
Background and objectives: Emerging infectious diseases often originate in wildlife, making it important to identify infectious agents in wild populations. It is widely acknowledged that wild animals are incompletely sampled for infectious agents, especially in developing countries, but it is unclear how much more sampling is needed, and where that effort should focus in terms of host species and geographic locations. Here, we identify these gaps in primate parasites, many of which have already emerged as threats to human health. Methodology: We obtained primate host�parasite records and other variables from existing databases. We then investigated sampling effort within primates relative to their geographic range size, and within countries relative to their primate species richness. We used generalized linear models, controlling for phylogenetic or spatial autocorrelation, to model variation in sampling effort across primates and countries. Finally, we used species richness estimators to extrapolate parasite species richness. Results: We found uneven sampling effort within all primate groups and continents. Sampling effort among primates was influenced by their geographic range size and substrate use, with terrestrial species receiving more sampling. Our parasite species richness estimates suggested that, among the best sampled primates and countries, almost half of primate parasites remain to be sampled; for most primate hosts, the situation is much worse. Conclusions and implications: Sampling effort for primate parasites is uneven and low. The sobering message is that we know little about even the best studied primates, and even less regarding the spatial and temporal distribution of parasitism within species. PMID:24481184
Cooper, Natalie; Nunn, Charles L.
Identifying potential cancer driver genes by genomic data integration
NASA Astrophysics Data System (ADS)
Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis.
Chen, Yong; Hao, Jingjing; Jiang, Wei; He, Tong; Zhang, Xuegong; Jiang, Tao; Jiang, Rui
Identifying potential cancer driver genes by genomic data integration.
Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis. PMID:24346768
Chen, Yong; Hao, Jingjing; Jiang, Wei; He, Tong; Zhang, Xuegong; Jiang, Tao; Jiang, Rui
Identifying potential cancer driver genes by genomic data integration
Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis. PMID:24346768
Chen, Yong; Hao, Jingjing; Jiang, Wei; He, Tong; Zhang, Xuegong; Jiang, Tao; Jiang, Rui
New Gene Variants for Prostate Cancer Identified
Two Chinese patients with mild and moderate Hb H disease were investigated for rare mutations on the ?-globin genes (HBA1, HBA2) in addition to the - -(SEA) deletion. One patient was a 41-year old man with mild anemia (Hb 11.3?g/dL). Multiplex ligation-dependent probe amplification (MLPA) revealed a rare 2392?bp deletion involving the entire HBA1 gene. Mapping by gap-polymerase chain reaction (gap-PCR) defined the exact breakpoints of this deletion (HBA1: g36859_39252del2392) and confirmed its identity with a recently reported HBA1 deletion found in a Southern Chinese. The other patient was a 53-year old man with moderate anemia (Hb 9.5?g/dL). Automated direct nucleotide (nt) sequencing identified a novel single nt deletion at codon 40 (HBA2: c.123delG). This leads to a frameshift that modifies the C-terminal sequence to (40)Lys-Pro-Thr-Ser-Arg-Thr-Ser-Thr(47)COOH and the introduction of a stop codon TGA 23 nts downstream. These two cases demonstrate the power of MLPA and direct nt sequencing to detect and characterize rare and novel mutations. They also highlight the differential effect of HBA1 and HBA2 gene mutations on an ?-thalassemia (?-thal) phenotype due to their different transcriptional activity. PMID:24826793
So, Chi-Chiu; Chan, Amy Y Y; Ma, Edmond S K
Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here ...
Raychaudhuri, Soumya
Network Topology Reveals Key Cardiovascular Disease Genes
The structure of protein-protein interaction (PPI) networks has already been successfully used as a source of new biological information. Even though cardiovascular diseases (CVDs) are a major global cause of death, many CVD genes still await discovery. We explore ways to utilize the structure of the human PPI network to find important genes for CVDs that should be targeted by drugs. The hope is to use the properties of such important genes to predict new ones, which would in turn improve a choice of therapy. We propose a methodology that examines the PPI network wiring around genes involved in CVDs. We use the methodology to identify a subset of CVD-related genes that are statistically significantly enriched in drug targets and �driver genes.� We seek such genes, since driver genes have been proposed to drive onset and progression of a disease. Our identified subset of CVD genes has a large overlap with the Core Diseasome, which has been postulated to be the key to disease formation and hence should be the primary object of therapeutic intervention. This indicates that our methodology identifies �key� genes responsible for CVDs. Thus, we use it to predict new CVD genes and we validate over 70% of our predictions in the literature. Finally, we show that our predicted genes are functionally similar to currently known CVD drug targets, which confirms a potential utility of our methodology towards improving therapy for CVDs. PMID:23977067
Stojkovic, Neda; Radak, Djordje; Przulj, Natasa
Systems biology approaches to identify developmental bases for lung diseases
A greater understanding of the regulatory processes contributing to lung development could be helpful to identify strategies to ameliorate morbidity and mortality in premature infants and to identify individuals at risk for congenital and/or chronic lung diseases. Over the past decade, genomics technologies have enabled the production of rich gene expression databases providing information for all genes across developmental time or in diseased tissue. These data sets facilitate systems biology approaches for identifying underlying biological modules and programs contributing to the complex processes of normal development, and those that may be associated with disease states. The next decade will undoubtedly see rapid and significant advances in redefining both lung development and disease at the systems level. PMID:23314295
Bhattacharya, Soumyaroop; Mariani, Thomas J.
Disease gene identification strategies for exome sequencing
Next generation sequencing can be used to search for Mendelian disease genes in an unbiased manner by sequencing the entire protein-coding sequence, known as the exome, or even the entire human genome. Identifying the pathogenic mutation amongst thousands to millions of genomic variants is a major challenge, and novel variant prioritization strategies are required. The choice of these strategies depends on the availability of well-phenotyped patients and family members, the mode of inheritance, the severity of the disease and its population frequency. In this review, we discuss the current strategies for Mendelian disease gene identification by exome resequencing. We conclude that exome strategies are successful and identify new Mendelian disease genes in approximately 60% of the projects. Improvements in bioinformatics as well as in sequencing technology will likely increase the success rate even further. Exome sequencing is likely to become the most commonly used tool for Mendelian disease gene identification for the coming years. PMID:22258526
Gilissen, Christian; Hoischen, Alexander; Brunner, Han G; Veltman, Joris A
Methods to determine blood-meal sources of hematophagous Triatominae bugs (Chagas disease vectors) are serological or based on PCR employing species-specific primers or heteroduplex analysis, but these are expensive, inaccurate, or problematic when the insect has fed on more than one species. To solve those problems, we developed a technique based on HRM analysis of the mitochondrial gene cytochrome B (Cyt b). This technique recognized 14 species involved in several ecoepidemiological cycles of the transmission of Trypanosoma cruzi and it was suitable with DNA extracted from intestinal content and feces 30 days after feeding, revealing a resolution power that can display mixed feedings. Field samples were analyzed showing blood meal sources corresponding to domestic, peridomiciliary and sylvatic cycles. The technique only requires a single pair of primers that amplify the Cyt b gene in vertebrates and no other standardization, making it quick, easy, relatively inexpensive, and highly accurate. PMID:22389739
Pena, Victor H.; Fernandez, Geysson J.; Gomez-Palacio, Andres M.; Mejia-Jaramillo, Ana M.; Cantillo, Omar; Triana-Chavez, Omar
Gene Therapy and Cardiovascular Diseases
Gene therapy is a promising new field in modern medicine and holds great potential for the treatment of cardiovascular diseases.\\u000a This chapter will discuss the principles and methods of gene-based therapy and the use of gene transfer in research and in\\u000a treatment of cardiovascular diseases.
Yi Chu; Neal L. Weintraub; Donald D. Heistad
Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isolation of many disease genes. To facilitate the molecular cytogenetic characterisation of DBCRs, we have generated a set of >1200 non-chimeric, cytogenetically and genetically anchored CEPH YACs, on average one per 3�cM, spaced over the entire human genome. By fluorescence in situ hybridisation (FISH), we have performed a systematic search for YACs spanning translocation breakpoints. Patients with DBCRs and either syndromic or non-syndromic mental retardation (MR) were ascertained through the Mendelian Cytogenetics Network (MCN), a collaborative effort of, at present, 270�cytogenetic laboratories throughout the world. In this pilot study, we have characterised 10�different MR associated chromosome regions delineating candidate regions for MR. Five of these regions are narrowed to breakpoint spanning YACs, three of which are located on chromosomes 13q21, 13q22, and 13q32, respectively, one on chromosome 4p14, and one on 6q25. In two out of six DBCRs, we found cytogenetically cryptic deletions of 3-5�Mb on one or both translocation chromosomes. Thus, cryptic deletions may be an important cause of disease in seemingly balanced chromosome rearrangements that are associated with a disease phenotype. Our region specific FISH probes, which are available to MCN members, can be a powerful tool in clinical cytogenetics and positional cloning.???Keywords: chromosomal translocation; fluorescence in situ hybridisation (FISH); Mendelian Cytogenetics Network (MCN); mental retardation (MR) PMID:10227392
Wirth, J; Nothwang, H; van der Maarel, S; Menzel, C; Borck, G; Lopez-Pajares, I; Brondum-Nielsen, K; Tommerup, N; Bugge, M; Ropers, H; Haaf, T
We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8�10?157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4�10?9) and rs3851179, a SNP 5? to the PICALM gene (p= 1.9�10?8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5�10?10, odds ratio= 0.86; rs3851179: p= 1.3�10?9, odds ratio= 0.86). We also observed more variants associated at p< 1�10?5 than expected by chance (p=7.5�10?6), including polymorphisms at the BIN1, DAB1 and CR1 loci. PMID:19734902
Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian; Singh Pahwa, Jaspreet; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K; Brayne, Carol; Rubinsztein, David C.; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle; Passmore, Peter; Craig, David; McGuinness, Bernadette; Todd, Stephen; Holmes, Clive; Mann, David; Smith, A. David; Love, Seth; Kehoe, Patrick G.; Hardy, John; Mead, Simon; Fox, Nick; Rossor, Martin; Collinge, John; Maier, Wolfgang; Jessen, Frank; Schurmann, Britta; van den Bussche, Hendrik; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frolich, Lutz; Hampel, Harald; Hull, Michael; Rujescu, Dan; Goate, Alison; Kauwe, John S.K.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin; Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter; van Broeckhoven, Christine; Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christopher E.; Tsolaki, Magda; Singleton, Andrew; Guerreiro, Rita; Muhleisen, Thomas W.; Nothen, Markus M.; Moebus, Susanne; Jockel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Carrasquillo, Minerva M.; Pankratz, V. Shane; Younkin, Steven G.; Holmans, Peter; O'Donovan, Michael; Owen, Michael J.; Williams, Julie
In late-onset Alzheimer's disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with low topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases. PMID:25147748
Perry, George; Ray, Monika
Targetability of Human Disease Genes
The availability of complete genome sequences and the wealth of large-scale biological datasets provide an un- precedented opportunity to elucidate the genetic basis of human diseases. Therapeutically relevant targets should be both 'druggable' and 'disease modifying'. In this review we examine the application of computational biology towards the ex- ploration of druggability, targetability and evolutionary conservation of human disease genes.
Meena K. Sakharkar; Kishore R. Sakharkar
Identifying clusters in Bayesian disease mapping.
Disease mapping is the field of spatial epidemiology interested in estimating the spatial pattern in disease risk across [Formula: see text] areal units. One aim is to identify units exhibiting elevated disease risks, so that public health interventions can be made. Bayesian hierarchical models with a spatially smooth conditional autoregressive prior are used for this purpose, but they cannot identify the spatial extent of high-risk clusters. Therefore, we propose a two-stage solution to this problem, with the first stage being a spatially adjusted hierarchical agglomerative clustering algorithm. This algorithm is applied to data prior to the study period, and produces [Formula: see text] potential cluster structures for the disease data. The second stage fits a separate Poisson log-linear model to the study data for each cluster structure, which allows for step-changes in risk where two clusters meet. The most appropriate cluster structure is chosen by model comparison techniques, specifically by minimizing the Deviance Information Criterion. The efficacy of the methodology is established by a simulation study, and is illustrated by a study of respiratory disease risk in Glasgow, Scotland. PMID:24622038
Anderson, Craig; Lee, Duncan; Dean, Nema
Prediction of disease genes using tissue-specified gene-gene network
Background Tissue specificity is an important aspect of many genetic diseases in the context of genetic disorders as the disorder affects only few tissues. Therefore tissue specificity is important in identifying disease-gene associations. Hence this paper seeks to discuss the impact of using tissue specificity in predicting new disease-gene associations and how to use tissue specificity along with phenotype information for a particular disease. Methods In order to find out the impact of using tissue specificity for predicting new disease-gene associations, this study proposes a novel method called tissue-specified genes to construct tissues-specific gene-gene networks for different tissue samples. Subsequently, these networks are used with phenotype details to predict disease genes by using Katz method. The proposed method was compared with three other tissue-specific network construction methods in order to check its effectiveness. Furthermore, to check the possibility of using tissue-specific gene-gene network instead of generic protein-protein network at all time, the results are compared with three other methods. Results In terms of leave-one-out cross validation, calculation of the mean enrichment and ROC curves indicate that the proposed approach outperforms existing network construction methods. Furthermore tissues-specific gene-gene networks make a more positive impact on predicting disease-gene associations than generic protein-protein interaction networks. Conclusions In conclusion by integrating tissue-specific data it enabled prediction of known and unknown disease-gene associations for a particular disease more effectively. Hence it is better to use tissue-specific gene-gene network whenever possible. In addition the proposed method is a better way of constructing tissue-specific gene-gene networks. PMID:25350876
Application of gene therapy to the field of cardiovascular disorders has been the subject of intensive work over the recent period. Gene therapy for cardiovascular disorders is now fast developing with most therapies being devoted to the consequences (ischemia) rather than the causes of atherosclerotic diseases. Recent human clinical trials have shown that injection of naked DNA encoding vascular endothelial
E Teiger; I Deprez; V Fataccioli; S Champagne; J. L Dubois-Rand�; M Eloit; S Adnot
Subtle changes among presymptomatic carriers of the Huntington's disease gene
OBJECTIVESTo compare the neurological and psychometric characteristics of presymptomatic gene carriers and non-gene carriers who are at risk for developing Huntington's disease so as to characterise early signs of disease and to identify markers of neurological function that could be used to assess the impact of experimental therapies on the progression of disease, even among those who are clinically presymptomatic.METHODSA
S C Kirkwood; E Siemers; M E Hodes; P M Conneally; J C Christian; T Foroud
[Laminopathies: one gene, several diseases].
Lamins A and C, encoded by the LMNA gene, are nuclear proteins expressed in all post-mitotic cells. Together with B-type lamins, they form a meshwork of proteins beneath the inner nuclear membrane, the lamina, in connection with the cytoskeleton. Lamins A/C also interact with chromatin and numerous proteins, including transcription factors. Mutations in LMNA are responsible for more than ten different disorders, commonly called "laminopathies". These diseases affect tissues in a specific (striated muscle, adipose tissue, peripheral nerve) or in a systemic manner (premature ageing syndromes). This wide spectrum of phenotypes is associated to a wide variety of mutations. This large clinical and genetic heterogeneity, unique to the LMNA gene, makes genotype-phenotype relations particularly difficult to establish. However, correlations have been obtained in several cases. Hence, LMNA mutations identified in premature ageing syndromes lead to the accumulation of immature proteins with a toxic effect for cells. Mutations in laminopathies of the adipose tissue mainly localize in the Ig-like domain of the proteins, potentially affecting the interaction with the SREBP-1 transcription factor. In laminopathies of the striated muscles, the mutations are spread throughout the gene. These mutations are thought to induce structural modifications of the proteins, thereby affecting their polymerization into nuclear lamina. Such defect would lead to a mechanical weakness of the nuclear lamina and of the cells, particularly in striated muscles continuously stretching. The exploration of pathophysiological mechanisms of LMNA mutations largely benefits from the numerous mouse models created, which have been widely used to analyze affected molecular pathways and to test putative therapeutic treatments. PMID:21982404
Bertrand, Anne T; Chikhaoui, Khadija; Ben Yaou, Rabah; Bonne, Gis�le
Gene therapy for Fabry disease.
Fabry disease is an X-linked metabolic disorder caused by a deficiency of alpha-galactosidase A (alpha-Gal A). Lack of this lysosomal hydrolase results in the accumulation of galactose-terminal glycosphingolipids in a number of tissues, including vascular endothelial cells. Premature death is predominantly associated with vascular conditions of the heart, kidneys and brain. Historically, treatment has largely been palliative. Alternative treatments for many lysosomal storage diseases have been developed, including allogeneic organ and bone marrow transplantation, enzyme replacement therapy, and gene therapy. Significant clinical risks still exist with allogeneic transplantations. Alpha-Gal A enzyme replacement therapy has been implemented in clinical trials. This approach has been effective but may have limitations for long-term systemic or cost-effective correction. As an alternative, gene therapy approaches, involving a variety of gene delivery systems, have been pursued for the amelioration of Fabry disease. Fabry disease is a compelling disorder for gene therapy, as target cells are readily accessible and relatively low levels of enzyme correction may suffice to reduce storage. Importantly, metabolic cooperativity effects are also manifested in Fabry disease, wherein corrected cells secrete alpha-Gal A that can correct bystander cells. In addition, a broad therapeutic window probably exists, and mouse models of Fabry disease have been generated to assist studies. As an example, in vitro and in vivo studies using alpha-Gal A-transduced haematopoietic cells from Fabry mice have demonstrated enzymatic correction of recipient cells and dissemination of alpha-Gal A upon transplantation, leading to reduced lipid storage in a number of clinically relevant organs. This corrective enzymatic effect has recently been shown to be even further enhanced upon pre-selection of therapeutically transduced cells prior to transplantation. This review will briefly detail current gene delivery methods and summarize results to date in the context of gene therapy for Fabry disease. PMID:11758676
Siatskas, C; Medin, J A
Gene therapy for retinal disease
Gene therapy strategies for the treatment of inherited retinal diseases have made major advances in recent years. This review focuses on adeno-associated viral (AAV) vector approaches to treat retinal degeneration and thus prevent or delay the onset of blindness. Data from human clinical trials of gene therapy for retinal disease show encouraging signs of safety and efficacy from AAV vectors. Recent progress in enhancing cell-specific targeting and transduction efficiency of the various retinal layers plus the use of AAV-delivered growth factors to augment the therapeutic effect and limit cell death suggest even greater success in future human trials is possible. PMID:23305707
McClements, Michelle E; MacLaren, Robert E
Gene Preference in Maple Syrup Urine Disease
Untreated maple syrup urine disease (MSUD) results in mental and physical disabilities and often leads to neonatal death. Newborn-screening programs, coupled with the use of protein-modified diets, have minimized the severity of this phenotype and allowed affected individuals to develop into productive adults. Although inheritance of MSUD adheres to rules for single-gene traits, mutations in the genes for E1?, E1?, or E2 of the mitochondrial branched-chain ?-ketoacid dehydrogenase complex can cause the disease. Randomly selected cell lines from 63 individuals with clinically diagnosed MSUD were tested by retroviral complementation of branched-chain ?-ketoacid dehydrogenase activity to identify the gene locus for mutant alleles. The frequencies of the mutations were 33% for the E1? gene, 38% for the E1? gene, and 19% for the E2 gene. Ten percent of the tested cell lines gave ambiguous results by showing no complementation or restoration of activity with two gene products. These results provide a means to establish a genotype/phenotype relationship in MSUD, with the ultimate goal of unraveling the complexity of this single-gene trait. This represents the largest study to date providing information on the genotype for MSUD. PMID:11112664
Nellis, Mary M.; Danner, Dean J.
Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies
-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune and high-quality cell-type-specific gene expression is available. Introduction Autoimmune diseases
Raychaudhuri, Soumya
Bayesian gene set analysis for identifying significant biological pathways.
We propose a hierarchical Bayesian model for analyzing gene expression data to identify pathways differentiating between two biological states (e.g., cancer vs. non-cancer and mutant vs. normal). Finding significant pathways can improve our understanding of biological processes. When the biological process of interest is related to a specific disease, eliciting a better understanding of the underlying pathways can lead to designing a more effective treatment. We apply our method to data obtained by interrogating the mutational status of p53 in 50 cancer cell lines (33 mutated and 17 normal). We identify several significant pathways with strong biological connections. We show that our approach provides a natural framework for incorporating prior biological information, and it has the best overall performance in terms of correctly identifying significant pathways compared to several alternative methods. PMID:21857748
Shahbaba, Babak; Tibshirani, Robert; Shachaf, Catherine M; Plevritis, Sylvia K
Phenol sulfotransferases: Candidate genes for Batten disease
Batten disease (juvenile-onset neuronal ceroid lipofuscinosis; JNCL) is an autosomal recessive neurodegenerative disorder, characterized by the cytosomal accumulation of autofluorescent protolipopigments in neurons and other cell types. The Batten disease gene (CLN3) has not yet been identified, but has been mapped to a small region of human chromosome area 16p12.1-p11.2. We recently reported the fortuitous discovery that the cytosolic phenol sulfotransferase gene (STP) is located within this same interval of chromosome 16p. Since phenol sulfotransferase is expressed in neurons, can sulfate lipophilic phenolic compounds, and is mapped near CLN3, STP is considered as a candidate gene for Batten disease. YAC and cosmid cloning results have further substantiated the close proximity of STP and a highly related sulfotransferase (STM), encoding the catecholamine-preferring enzyme, to the CLN3 region of chromosome 16p. In this report, we summarize some of the recent progress in the identification of two phenol sulfotransferase genes (STP and STM) as positional candidate genes for Batten disease. 42 refs., 1 tab.
Dooley, T.P.; Probst, P.; Obermoeller, R.D. [M.D. Anderson Cancer Center, Houston, TX (United States)] [and others
Patching genes to fight disease
The National Institutes of Health has approved the first gene therapy experiments, one of which will try to cure cancer by bolstering the immune system. The applications of such therapy are limited, but the potential aid to people with genetic diseases is great.
Holzman, D.
Disease Resistance Mechanism Identified in Plants
... gene (AvrPto) enters the plant cell by moving across the plant cell wall and its inner lining, the ... plant cell, it directly interacts with the tomato plant's Pto resistance gene. To test this, the ...
Disease-specific gene repositioning in breast cancer
Genomes are nonrandomly organized within the three-dimensional space of the cell nucleus. Here, we have identified several genes whose nuclear positions are altered in human invasive breast cancer compared with normal breast tissue. The changes in positioning are gene specific and are not a reflection of genomic instability within the cancer tissue. Repositioning events are specific to cancer and do not generally occur in noncancerous breast disease. Moreover, we show that the spatial positions of genes are highly consistent between individuals. Our data indicate that cancer cells have disease-specific gene distributions. These interphase gene positioning patterns may be used to identify cancer tissues. PMID:19995938
Meaburn, Karen J.; Gudla, Prabhakar R.; Khan, Sameena; Lockett, Stephen J.
Identifying differentially expressed genes using false discovery rate controlling procedures
Motivation: DNA microarrays have recently been used for the purpose of monitoring expression levels of thousands of genes simultaneously and identifying those genes that are differentially expressed. The probability that a false identification (type I error) is committed can increase sharply when the number of tested genes gets large. Correlation between the test statistics attributed to gene co-regulation and dependency
Anat Reiner; Daniel Yekutieli; Yoav Benjamini
Marek's disease virus serotype 1 (MDV-1) is an oncogenic alphaherpesvirus causing fatal T-cell lymphoma in chickens. MDV latency is characterized by the production of latency-associated transcripts (LATs), a family of non-protein-coding spliced RNAs. A cluster of four microRNAs (cluster mdv1-miR-M8-M10) was identified, but not formally mapped, at the predicted LAT 5' end. We established a LAT cDNA library from latently MDV-infected cell line MSB-1. We identified 22 highly variable LATs, which were due to the extensive alternative splicing of a total of 14 introns. RACE PCR confirmed the predicted 3' end and allowed identification of the 5' end, 400 nt upstream of the previously predicted LAT end. The LATs share their transcription start site with the microRNA-expressing transcript described previously, localizing the microRNAs to the first LAT intron and identifying the LATs as the primary transcripts of the microRNAs. We identified MDV immediate-early (IE) genes ICP4 and ICP27 as putative targets of mdv1-miR-M7-5p, the third microRNA of the cluster mdv1-miR-M8-M10. Endogenously expressed mdv1-miR-M7-5p in MSB-1 cells reduced luciferase activity significantly when microRNA-responsive elements from ICP4 or ICP27 were cloned in the 3' UTR of the firefly luciferase gene. ICP27 protein levels were decreased by 70?% when the mdv1-miR-M7-5p precursor was co-expressed with an ICP27 expression plasmid. Additionally, we showed a negative correlation between the decreased expression of mdv1-miR-M7-5p and an increase in ICP27 expression during virus reactivation. Our results suggest that, by targeting two IE genes, MDV microRNAs produced from LAT transcripts may contribute to establish and/or maintain latency. PMID:22513387
Strassheim, S; Stik, G; Rasschaert, D; Laurent, S
BACKGROUND: Once specific genes are identified through high throughput genomics technologies there is a need to sort the final gene list to a manageable size for validation studies. The triaging and sorting of genes often relies on the use of supplemental information related to gene structure, metabolic pathways, and chromosomal location. Yet in disease states where the genes may not
Guohui Zhou; Xinyu Wen; Hang Liu; Michael J. Schlicht; Martin J. Hessner; Peter J. Tonellato; Milton W. Datta
Feline polycystic kidney disease mutation identified in PKD1.
Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder in humans that causes the formation of fluid-filled renal cysts, often leading to renal failure. PKD1 mutations cause 85% of ADPKD. Feline PKD is autosomal dominant and has clinical presentations similar to humans. PKD affects approximately 38% of Persian cats worldwide, which is approximately 6% of cats, making it the most prominent inherited feline disease. Previous analyses have shown significant linkage between the PKD phenotype and microsatellite markers linked to the feline homolog for PKD1. In this report, the feline PKD1 gene was scanned for causative mutations and a C>A transversion was identified at c.10063 (human ref NM_000296) in exon 29, resulting in a stop mutation at position 3284, which suggests a loss of approximately 25% of the C-terminus of the protein. The same mutation has not been identified in humans, although similar regions of the protein are truncated. The C>A transversion has been identified in the heterozygous state in 48 affected cats examined, including 41 Persians, a Siamese, and several other breeds that have been known to outcross with Persians. In addition, the mutation is segregating concordantly in all available PKD families. No unaffected cats have been identified with the mutation. No homozygous cats have been identified, supporting the suggestion that the mutation is embryonic lethal. These data suggest that the stop mutation causes feline PKD, providing a test to identify cats that will develop PKD and demonstrating that the domestic cat is an ideal model for human PKD. PMID:15466259
Lyons, Leslie A; Biller, David S; Erdman, Carolyn A; Lipinski, Monika J; Young, Amy E; Roe, Bruce A; Qin, Baifang; Grahn, Robert A
An RNAi screen identifies genes that regulate GABA synapses.
GABA synapses play a critical role in many aspects of circuit development and function. For example, conditions that perturb GABA transmission have been implicated in epilepsy. To identify genes that regulate GABA transmission, we performed an RNAi screen for genes whose inactivation increases the activity of C. elegans body muscles, which receive direct input from GABAergic motor neurons. We identified 90 genes, 21 of which were previously implicated in seizure syndromes, suggesting that this screen has effectively identified candidate genes for epilepsy. Electrophysiological recordings and imaging of excitatory and inhibitory synapses indicate that several genes alter muscle activity by selectively regulating GABA transmission. In particular, we identify two humoral pathways and several protein kinases that modulate GABA transmission but have little effect on excitatory transmission at cholinergic neuromuscular junctions. Our data suggest these conserved genes are components of signaling pathways that regulate GABA transmission and consequently may play a role in epilepsy and other cognitive or psychiatric disorders. PMID:18466746
Vashlishan, Amy B; Madison, Jon M; Dybbs, Mike; Bai, Jihong; Sieburth, Derek; Ch'ng, Queelim; Tavazoie, Masoud; Kaplan, Joshua M
Exploiting Blind Matrix Decomposition Techniques to Identify Diagnostic Marker Genes
Exploratory matrix factorization methods like ICA and LNMF are applied to identify marker genes and classify gene expression\\u000a data sets into different categories for diagnostic purposes or group genes into functional categories for further investigation\\u000a of related regulatory pathways. Gene expression levels of either human breast cancer (HBC) cell lines [5] mediating bone metastasis\\u000a or cell lines from Niemann Pick
Reinhard Schachtner; Dominik Lutter; Fabian J. Theis; Elmar Wolfgang Lang; Ana Maria Tom�; Gerd Schmitz
Congenital heart disease (CHD) is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect (ASD) is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 (TBX20) contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G>A (p.D176N), was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs (SIFT, Polyphen2, and MutationTaster). This mutation was also not presented in the current Single Nucleotide Polymorphism Database (dbSNP) or National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree. PMID:25183037
Liu, Ji-jia; Fan, Liang-liang; Chen, Jin-lan; Tan, Zhi-ping; Yang, Yi-feng
Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles
Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease-causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles. PMID:23685542
Boone, Philip M.; Campbell, Ian M.; Baggett, Brett C.; Soens, Zachry T.; Rao, Mitchell M.; Hixson, Patricia M.; Patel, Ankita; Bi, Weimin; Cheung, Sau Wai; Lalani, Seema R.; Beaudet, Arthur L.; Stankiewicz, Pawel; Shaw, Chad A.; Lupski, James R.
Identifying multiple causative genes at a single GWAS locus
Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same locus, prompting us to adopt an alternative approach to testing multiple GWAS genes empirically. We used gene targeting in a disease-susceptible rat model of genetic hypertension to test all six genes at the Agtrap-Plod1 locus (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) for blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (five out of six) can impact hypertension by modifying BP and renal phenotypes. Mutations of Nppa, Plod1, and Mthfr increased disease susceptibility, whereas Agtrap and Clcn6 mutations decreased hypertension risk. Reanalysis of the human AGTRAP-PLOD1 locus also implied that disease-associated haplotype blocks with polygenic effects were not only possible, but rather were highly plausible. Combined, these data demonstrate for the first time that multiple modifiers of hypertension can cosegregate at a single GWAS locus. PMID:24006081
Flister, Michael J.; Tsaih, Shirng-Wern; O'Meara, Caitlin C.; Endres, Bradley; Hoffman, Matthew J.; Geurts, Aron M.; Dwinell, Melinda R.; Lazar, Jozef; Jacob, Howard J.; Moreno, Carol
Blood pressure loci identified with a gene-centric array.
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56�� 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56�� 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. PMID:22100073
Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gon�alo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-Fran�ois; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; S�ber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Bj�rn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B
Gene expression profiling identifies clinically relevant subtypes of prostate cancer
Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing 26,000 genes. Unsupervised hierarchical
Jacques Lapointe; Chunde Li; John P. Higgins; Matt van de Rijn; Eric Bair; Kelli Montgomery; Michelle Ferrari; Lars Egevad; Walter Rayford; Ulf Bergerheim; Peter Ekman; Angelo M. Demarzo; Robert Tibshirani; David Botstein; Patrick O. Brown; James D. Brooks; Jonathan R. Pollack
Computational methods play an important role in the disease genes prioritisation by integrating many kinds of data sources such as gene expression, functional annotations and protein-protein interactions. However, the existing methods usually perform well in predicting highly linked genes, whereas they work quite poorly for loosely linked genes. Motivated by this observation, a degree-adjusted strategy is applied to improve the algorithm that was proposed earlier for the prediction of disease genes from gene expression and protein interactions. The authors also showed that the modified method is good at identifying loosely linked disease genes and the overall performance gets enhanced accordingly. This study suggests the importance of statistically adjusting the degree distribution bias in the background network for network-based modelling of complex diseases. PMID:25014224
Wang, Yichuan; Fang, Haiyang; Yang, Tinghong; Wu, Duzhi; Zhao, Jing
Identifying Candidate Hirschsprung Disease-Associated RET Variants
Patients with sporadic Hirschsprung disease (HSCR) show increased allele sharing at markers in the 5? region of the RET locus, indicating the presence of a common ancestral RET mutation. In a previous study, we found a haplotype of six SNPs that was transmitted to 55.6% of our patients, whereas it was present in only 16.2% of the controls we used. Among the patients with that haplotype, 90.8% had it on both chromosomes, which led to a much higher risk of developing HSCR than when the haplotype occurred heterozygously. To more precisely define the HSCR-associated region and to identify candidate disease-associated variant(s), we sequenced the shared common haplotype region from 10 kb upstream of the RET gene through intron 1 and exon 2 (in total, 33 kb) in a patient homozygous for the common risk haplotype and in a control individual homozygous for the most common nonrisk haplotype. A comparison of these sequences revealed 86 sequence differences. Of these 86 variations, 8 proved to be in regions highly conserved among different vertebrates and within putative transcription factor binding sites. We therefore considered these as candidate disease-associated variants. Subsequent genotyping of these eight variants revealed a strong disease association for six of the eight markers. These six markers also showed the largest distortions in allele transmission. Interspecies comparison showed that only one of the six variations was located in a region also conserved in a nonmammalian species, making it the most likely candidate HSCR-associated variant. PMID:15759212
Burzynski, Grzegorz M.; Nolte, Ilja M.; Bronda, Agnes; Bos, Krista K.; Osinga, Jan; Plaza Menacho, Ivan; Twigt, Bas; Maas, Saskia; Brooks, Alice S.; Verheij, Joke B. G. M.; Buys, Charles H. C. M.; Hofstra, Robert M. W.
Background Many methods have been developed to identify disease genes and further module biomarkers of complex diseases based on gene expression data. It is generally difficult to distinguish whether the variations in gene expression are causative or merely the effect of a disease. The limitation of relying on gene expression data alone highlights the need to develop new approaches that can explore various data to reflect the casual relationship between network modules and disease traits. Methods In this work, we developed a novel network-based approach to identify putative causal module biomarkers of complex diseases by integrating heterogeneous information, for example, epigenomic data, gene expression data, and protein�protein interaction network. We first formulated the identification of modules as a mathematical programming problem, which can be solved efficiently and effectively in an accurate manner. Then, we applied our approach to colorectal cancer (CRC) and identified several network modules that can serve as potential module biomarkers for characterizing CRC. Further validations using three additional gene expression datasets verified their candidate biomarker properties and the effectiveness of the method. Functional enrichment analysis also revealed that the identified modules are strongly related to hallmarks of cancer, and the enriched functions, such as inflammatory response, receptor and signaling pathways, are specific to CRC. Results Through constructing a transcription factor (TF)-module network, we found that aberrant DNA methylation of genes encoding TF considerably contributes to the activity change of some genes, which may function as causal genes of CRC, and that can also be exploited to develop efficient therapies or effective drugs. Conclusion Our method can potentially be extended to the study of other complex diseases and the multiclassification problem. PMID:22967703
Wen, Zhenshu; Liu, Zhi-Ping; Liu, Zhengrong; Zhang, Yan; Chen, Luonan
Intermediate Phenotypes Identify Divergent Pathways to Alzheimer's Disease
Background Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden. Methods/Principal Findings Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p?=?0.009) and global cognition (p?=?0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p?=?3.57�10?4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts. Conclusions/Significance The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder. PMID:20574532
Shulman, Joshua M.; Chibnik, Lori B.; Aubin, Cristin; Schneider, Julie A.; Bennett, David A.; De Jager, Philip L.
Background Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches. Results Here we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM). Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128) of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any � yet non-associated � gene. Conclusion In our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have explored the relation of these genes to disease relevant information and � using enrichment analysis � we have identified biological networks on different layers of cellular information such as signaling and metabolic pathways, gene regulatory networks and protein-protein interactions. The web interface is accessible via . PMID:18590522
Rasche, Axel; Al-Hasani, Hadi; Herwig, Ralf
Scientists Identify Four Candidate Obesity Genes in Mice
NSDL National Science Digital Library
Press release on a recent study where researchers developed a strain of mice more likely to be obese and then, using this strain, identified four genes in mouse chromosome 7 that may relate to obesity. This study, ��Four Out of Eight Genes in a Mouse Chromosome 7 Congenic Donor Region are Candidate Obesity Genes,�� was conducted by Craig H. Warden, Kari A. Sarahan, and Janis S. Fisler of the University of California, Davis. The study is published in Physiologic Genomics.
APS Communications Office (American Physiological Society Communications Office)
Identifying local co-regulation relationships in gene expression data.
Identifying interesting relationships between pairs of genes, presented over some of experimental conditions in gene expression data set, is useful for discovering novel functional gene interactions. In this paper, we introduce a new method for id entifying L ocal C o-regulation R elationships (IdLCR). These local relationships describe the behaviors of pairwise genes, which are either up- or down-regulated throughout the identified condition subset. IdLCR firstly detects the pairwise gene-gene relationships taking functional forms and the condition subsets by using a regression spline model. Then it measures the relationships using a penalized Pearson correlation and ranks the responding gene pairs by their scores. By this way, those relationships without clearly biological interpretations can be filtered out and the local co-regulation relationships can be obtained. In the simulation data sets, ten different functional relationships are embedded. Applying IdLCR to these data sets, the results show its ability to identify functional relationships and the condition subsets. For micro-array and RNA-seq gene expression data, IdLCR can identify novel biological relationships which are different from those uncovered by IFGR and MINE. PMID:25042175
Pei, Yonggang; Gao, Qinghui; Li, Juntao; Zhao, Xiting
Broker Genes in Human Disease James J. Cai*,1,2
variation. Notably, genes identified in genome-wide association study (GWAS) have network patterns the network patterns of complex disease genes identified through non-GWAS means. This suggests either that GWAS focused on a distinct set of diseases associated with an unusual set of genes or that mapping
Petrov, Dmitri
Systematic analysis of new drug indications by drug-gene-disease coherent subnetworks.
Drug targets and disease genes may work as driver factors at the transcriptional level, which propagate signals through gene regulatory network and cause the downstream genes' differential expression. How to analyze transcriptional response data to identify meaningful gene modules shared by both drugs and diseases is still a critical issue for drug-disease associations and molecular mechanism. In this article, we propose the drug-gene-disease coherent subnetwork concept to group the biological function related drugs, diseases, and genes. It was defined as the subnetwork with drug, gene, and disease as nodes and their interactions coherently crossing three data layers as edges. Integrating differential expression profiles of 418 drugs and 84 diseases, we develop a computational framework and identify 13 coherent subnetworks such as inflammatory bowel disease and melanoma relevant subnetwork. The results demonstrate that our coherent subnetwork approach is able to identify novel drug indications and highlight their molecular basis. PMID:25390685
Wang, L; Wang, Y; Hu, Q; Li, S
Candidate Gene for the Chromosome 1 Familial Alzheimer's Disease Locus
A candidate gene for the chromosome 1 Alzheimer's disease (AD) locus was identified (STM2). The predicted amino acid sequence for STM2 is homologous to that of the recently cloned chromosome 14 AD gene (S182). A point mutation in STM2, resulting in the substitution of an isoleucine for an asparagine (N141l), was identified in affected people from Volga German AD kindreds.
Ephrat Levy-Lahad; Wilma Wasco; Parvoneh Poorkaj; Donna M. Romano; Junko Oshima; Warren H. Pettingell; Chang-En Yu; Paul D. Jondro; Stephen D. Schmidt; Kai Wang; Annette C. Crowley; Ying-Hui Fu; Suzanne Y. Guenette; David Galas; Ellen Nemens; Ellen M. Wijsman; Thomas D. Bird; Gerard D. Schellenberg; Rudolph E. Tanzi
Gene therapy for ischemic heart disease
Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such
Madhav Lavu; Susheel Gundewar; David J. Lefer
Identifying new human oocyte marker genes: a microarray approach
Efficiency in classical IVF (cIVF) techniques is still impaired by poor implantation and pregnancy rates after embryo transfer. This is mostly due to a lack of reliable criteria for the selection of embryos with sufficient development potential. Several studies have provided evidence that some genes� expression levels could be used as objective markers of oocytes and embryos competence and of their capacity to sustain a successful pregnancy. These analyses usually used reverse transcription-polymerase chain reaction to look at small sets of pre-selected genes. However, microarray approaches permit to identify a wider range of cellular marker genes. Thus they allow the identification of additional and perhaps more suited genes that could serve as embryo selection markers. Microarray screenings of circa 30 000 genes on U133P Affymetrix� gene chips made it possible to establish the expression profile of these genes as well as other related genes in human oocytes and cumulus cells. In this study, we identified new potential regulators and marker genes such as BARD1, RBL2, RBBP7, BUB3 or BUB1B, which are involved in oocyte maturation. PMID:17298719
Gasca, Stephan; Pellestor, Franck; Assou, Said; Loup, Vanessa; Anahory, Tal; Dechaud, Herve; De Vos, John; Hamamah, Samir
Gene Duplication Identified in an Uncommon Form of Bone Cancer
Scientists have discovered that a familial form of a rare bone cancer called chordoma is explained not by typical types of changes or mutations in the sequence of DNA in a gene, but rather by the presence of a second copy of an entire gene. Inherited large structural changes, known as copy number variations (CNVs), have been implicated in some hereditary diseases but have seldom been reported as the underlying basis for a familial cancer.
'Gene shaving' as a method for identifying distinct sets of genes with similar expression patterns
BACKGROUND: Large gene expression studies, such as those conducted using DNA arrays, often provide millions of different pieces of data. To address the problem of analyzing such data, we describe a statistical method, which we have called 'gene shaving'. The method identifies subsets of genes with coherent expression patterns and large variation across conditions. Gene shaving differs from hierarchical clustering
Trevor Hastie; Robert Tibshirani; Michael B. Eisen; Ash Alizadeh; Ronald Levy; Louis Staudt; Wing C. Chan; David Botstein; Patrick Brown
Conceptual importance of identifying alcoholic liver disease as a lifestyle disease
The concept that alcoholic liver disease (ALD) is as a toxic disease does not mirror the exact nature of the disease. ALD\\u000a should be defined as an alcohol-associated lifestyle disease, the predisposition to which is largely governed by gene�environment\\u000a interactions, much like other chronic diseases such as diabetes, atherosclerosis, and neurodegenerative diseases. The epidemiology\\u000a and pathogenesis of ALD need to
Hidekazu Tsukamoto
Transposon tagging of disease resistance genes
We are developing a transposon mutagenesis system for lettuce to clone genes for resistance to the fungal pathogen, Bremia lactucae. Activity of heterologous transposons is being studied in transgenic plants. Southern analysis of T{sub 1} and T{sub 2} plants containing Tam3 from Antirrhinum provided ambiguous results. Multiple endonuclease digests indicated that transposition had occurred; however, in no plant were all endonuclease digests consistent with a simple excision event. Southern or PCR analysis of over 50 plans containing Ac from maize have also failed to reveal clear evidence of transposition; this is contrast to experiments by others with the same constructs who have observed high rates of Ac excision in other plant species. Nearly all of 65 T{sub 2} families containing Ac interrupting a chimeric streptomycin resistance gene (Courtesy J. Jones, Sainsbury Lab., UK) clearly segregated for streptomycin resistance. Southern analyses, however, showed no evidence of transposition, indicating restoration of a functional message by other mechanisms, possibly mRNA processing. Transgenic plants have also been generated containing CaMV 35S or hsp70 promoters fused to transposase coding sequences or a Ds element interrupting a chimeric GUS gene (Courtesy M. Lassner, UC Davis). F{sub 1} plants containing both constructs were analyzed for transposition. Only two plants containing both constructs were obtained from 48 progeny, far fewer than expected, and neither showed evidence of transposition in Southerns and GUS assays. We are currently constructing further chimeric transposase fusions. To test for the stability of the targeted disease resistance genes, 50,000 F{sub 1} plants heterozygous for three resistance genes were generated; no mutants have been identified in the 5000 so far screened.
Michelmore, R.W. (California Univ., Davis, CA (USA). Dept. of Physics)
Axon Regeneration Genes Identified by RNAi Screening in C. elegans
Axons of the mammalian CNS lose the ability to regenerate soon after development due to both an inhibitory CNS environment and the loss of cell-intrinsic factors necessary for regeneration. The complex molecular events required for robust regeneration of mature neurons are not fully understood, particularly in vivo. To identify genes affecting axon regeneration in Caenorhabditis elegans, we performed both an RNAi-based screen for defective motor axon regeneration in unc-70/?-spectrin mutants and a candidate gene screen. From these screens, we identified at least 50 conserved genes with growth-promoting or growth-inhibiting functions. Through our analysis of mutants, we shed new light on certain aspects of regeneration, including the role of ?-spectrin and membrane dynamics, the antagonistic activity of MAP kinase signaling pathways, and the role of stress in promoting axon regeneration. Many gene candidates had not previously been associated with axon regeneration and implicate new pathways of interest for therapeutic intervention. PMID:24403161
Nix, Paola; Hammarlund, Marc; Hauth, Linda; Lachnit, Martina; Jorgensen, Erik M.
DCEG Scientists Identify New Gene Mutation Related to Familial Melanoma
Scientists have identified a rare inherited mutation in a gene that can increase the risk of familial melanoma, according to a study that appeared online in Nature Genetics on March 30, 2014. Although the finding does not offer immediate benefit to patients, variation in the Protection of Telomeres-1 (POT1) gene provides additional clues as to the origins of melanoma and may open new avenues in prevention and treatment research. Read the full NCI Benchmarks blog post about this study.
Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer's disease
Uncovering the underlying genetic component of any disease is key to the understanding of its pathophysiology and may open new avenues for development of therapeutic strategies and biomarkers. In the past several years, there has been an explosion of genome-wide association studies (GWAS) resulting in the discovery of novel candidate genes conferring risk for complex diseases, including neurodegenerative diseases. Despite this success, there still remains a substantial genetic component for many complex traits and conditions that is unexplained by the GWAS findings. Additionally, in many cases, the mechanism of action of the newly discovered disease risk variants is not inherently obvious. Furthermore, a genetic region with multiple genes may be identified via GWAS, making it difficult to discern the true disease risk gene. Several alternative approaches are proposed to overcome these potential shortcomings of GWAS, including the use of quantitative, biologically relevant phenotypes. Gene expression levels represent an important class of endophenotypes. Genetic linkage and association studies that utilize gene expression levels as endophenotypes determined that the expression levels of many genes are under genetic influence. This led to the postulate that there may exist many genetic variants that confer disease risk via modifying gene expression levels. Results from the handful of genetic studies which assess gene expression level endophenotypes in conjunction with disease risk suggest that this combined phenotype approach may both increase the power for gene discovery and lead to an enhanced understanding of their mode of action. This review summarizes the evidence in support of gene expression levels as promising endophenotypes in the discovery and characterization of novel candidate genes for complex diseases, which may also represent a novel approach in the genetic studies of Alzheimer's and other neurodegenerative diseases. PMID:21569597
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping
M�lissa Beaudoin; Agnes Gardet; Christine Stevens; Yashoda Sharma; Clarence K Zhang; Gabrielle Boucher; Stephan Ripke; David Ellinghaus; Noel Burtt; Tim Fennell; Andrew Kirby; Anna Latiano; Philippe Goyette; Todd Green; Jonas Halfvarson; Talin Haritunians; Joshua M Korn; Finny Kuruvilla; Caroline Lagac�; Benjamin Neale; Ken Sin Lo; Phil Schumm; Leif T�rkvist; Marla C Dubinsky; Steven R Brant; Mark S Silverberg; Richard H Duerr; David Altshuler; Stacey Gabriel; Guillaume Lettre; Andre Franke; Mauro D'Amato; Dermot P B McGovern; Judy H Cho; John D Rioux; Ramnik J Xavier; Manuel A Rivas; Mark J Daly; D. J. de Jong
Stargardt's disease and the ABCR gene.
Stargardt's disease is an autosomal recessive form of juvenile macular degeneration. The clinical presentation, relevant ancillary tests, and classic histologic features will be reviewed. The role of genetic mutations in the pathophysiology of Stargardt's disease will also be explored. Stargardt's disease is caused by mutations in the ABCR (ABCA4) gene on chromosome 1. Mutations in this gene have also been attributed to some cases of cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. The genetic and molecular pathways that produce Stargardt's disease will be discussed. Future diagnostic and therapeutic objectives for this visually disabling condition will also be presented. PMID:18214793
Westerfeld, Corey; Mukai, Shizuo
A Pilot Study of Gene/Gene and Gene/Environment Interactions in Alzheimer Disease
Background: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. Methods: The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1,and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. Results: The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. Conclusions: These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study. PMID:20682755
Ghebranious, Nader; Mukesh, Bickol; Giampietro, Philip F.; Glurich, Ingrid; Mickel, Susan F.; Waring, Stephen C.; McCarty, Catherine A.
the gene encoding apolipoprotein e (APOE) on chromosome 19 is the only confirmed susceptibility locus for late-onset Alzheimer's disease. to identify other risk loci, we conducted a large genome-wide association study of 2,032 individuals from France with Alzheimer's disease (cases) and 5,328 controls. Markers outside APO e with suggestive evidence of association (P < 10 ?5 ) were examined in
Denise Harold; Richard Abraham; Paul Hollingworth; Rebecca Sims; Amy Gerrish; Marian L Hamshere; Jaspreet Singh Pahwa; Valentina Moskvina; Kimberley Dowzell; Amy Williams; Nicola Jones; Charlene Thomas; Alexandra Stretton; Angharad R Morgan; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K Lupton; Carol Brayne; David C Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kevin Morgan; Kristelle S Brown; Peter A Passmore; David Craig; Bernadette McGuinness; Stephen Todd; Clive Holmes; David Mann; A David Smith; Seth Love; Patrick G Kehoe; John Hardy; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Britta Sch�rmann; Hendrik van den Bussche; Isabella Heuser; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Fr�lich; Harald Hampel; Michael H�ll; Dan Rujescu; Alison M Goate; John S K Kauwe; Carlos Cruchaga; Petra Nowotny; John C Morris; Kevin Mayo; Kristel Sleegers; Karolien Bettens; Sebastiaan Engelborghs; Peter P De Deyn; Christine Van Broeckhoven; Gill Livingston; Nicholas J Bass; Hugh Gurling; Andrew McQuillin; Rhian Gwilliam; Panagiotis Deloukas; Ammar Al-Chalabi; Christopher E Shaw; Magda Tsolaki; Andrew B Singleton; Rita Guerreiro; Thomas W M�hleisen; Markus M N�then; Susanne Moebus; Karl-Heinz J�ckel; Norman Klopp; H-Erich Wichmann; Minerva M Carrasquillo; V Shane Pankratz; Steven G Younkin; Peter A Holmans; Michael O'Donovan; Michael J Owen; Julie Williams
Gene expression profiling identifies molecular subtypes of gliomas
Identification of distinct molecular subtypes is a critical challenge for cancer biology. In this study, we used Affymetrix high-density oligonucleotide arrays to identify the global gene expression signatures associated with gliomas of different types and grades. Here, we show that the global transcriptional profiles of gliomas of different types and grades are distinct from each other and from the normal
Ruty Shai; Tao Shi; Thomas J Kremen; Steve Horvath; Linda M Liau; Timothy F Cloughesy; Paul S Mischel; Stanley F Nelson
ORIGINAL PAPER Identifying differentially expressed genes in human acute leukemia
ORIGINAL PAPER Identifying differentially expressed genes in human acute leukemia and mouse brain the experimental-wise false discovery rate. A human acute leukemia dataset corrected from 38 leukemia patients, a mouse brain dataset collected from six brain regions of two inbred strains (two- treatment factors
Gu, Xun
Gene identified that sensitizes cancer cells to chemotherapy drugs
NCI scientists have found that a gene, Schlafen-11 (SLFN11), sensitizes cells to substances known to cause irreparable damage to DNA. �As part of their study, the researchers used a repository of 60 cell types to identify predictors of cancer cell response to classes of DNA damaging agents, widely used as chemotherapy treatments for many cancers.
International team identifies critical genes mutated in stomach cancer
An international team of scientists, led by researchers from the Duke-NUS Graduate Medical School in Singapore and National Cancer Centre of Singapore, has identified hundreds of novel genes that are mutated in stomach cancer, the second-most lethal cancer worldwide.
Gene Conversion in Human Genetic Disease
Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a �donor� sequence to a highly homologous �acceptor�. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102
Chen, Jian-Min; Ferec, Claude; Cooper, David N.
A genomics approach identifies senescence-specific gene expression regulation.
Replicative senescence is a fundamental tumor-suppressive mechanism triggered by telomere erosion that results in a permanent cell cycle arrest. To understand the impact of telomere shortening on gene expression, we analyzed the transcriptome of diploid human fibroblasts as they progressed toward and entered into senescence. We distinguished novel transcription regulation due to replicative senescence by comparing senescence-specific expression profiles to profiles from cells arrested by DNA damage or serum starvation. Only a small specific subset of genes was identified that was truly senescence-regulated and changes in gene expression were exacerbated from presenescent to senescent cells. The majority of gene expression regulation in replicative senescence was shown to occur due to telomere shortening, as exogenous telomerase activity reverted most of these changes. PMID:24863242
Lackner, Daniel H; Hayashi, Makoto T; Cesare, Anthony J; Karlseder, Jan
DAWN: a framework to identify autism genes and subnetworks using gene expression and genetics
Background De novo loss-of-function (dnLoF) mutations are found twofold more often in autism spectrum disorder (ASD) probands than their unaffected siblings. Multiple independent dnLoF mutations in the same gene implicate the gene in risk and hence provide a systematic, albeit arduous, path forward for ASD genetics. It is likely that using additional non-genetic data will enhance the ability to identify ASD genes. Methods To accelerate the search for ASD genes, we developed a novel algorithm, DAWN, to model two kinds of data: rare variations from exome sequencing and gene co-expression in the mid-fetal prefrontal and motor-somatosensory neocortex, a critical nexus for risk. The algorithm casts the ensemble data as a hidden Markov random field in which the graph structure is determined by gene co-expression and it combines these interrelationships with node-specific observations, namely gene identity, expression, genetic data and the estimated effect on risk. Results Using currently available genetic data and a specific developmental time period for gene co-expression, DAWN identified 127 genes that plausibly affect risk, and a set of likely ASD subnetworks. Validation experiments making use of published targeted resequencing results demonstrate its efficacy in reliably predicting ASD genes. DAWN also successfully predicts known ASD genes, not included in the genetic data used to create the model. Conclusions Validation studies demonstrate that DAWN is effective in predicting ASD genes and subnetworks by leveraging genetic and gene expression data. The findings reported here implicate neurite extension and neuronal arborization as risks for ASD. Using DAWN on emerging ASD sequence data and gene expression data from other brain regions and tissues would likely identify novel ASD genes. DAWN can also be used for other complex disorders to identify genes and subnetworks in those disorders. PMID:24602502
Introduction Blood leukocytes play a major role in mediating local and systemic inflammation during acute pancreatitis. We hypothesize that peripheral blood mononuclear cells (PBMC) in circulation exhibit unique changes in gene expression, and could provide a �reporter� function that reflects the inflammatory response in pancreas of acute pancreatitis. Methods To determine specific changes in blood leukocytes during acute pancreatitis, we studied gene transcription profile of in peripheral blood mononuclear cells (PBMC) in a rat model of experimental pancreatitis (sodium taurocholate). Normal rats, saline controls and a model of septic shock were used as a controls. cRNA obtained from PBMC of each group (n = 3) were applied to Affymetrix rat genome DNA Gene Chip Arrays. Results From the 8,799 rat genes analyzed, 140 genes showed unique significant changes in their expression in PBMC during the acute phase of pancreatitis, but not in sepsis. Among the 140 genes, 57 were upregulated, while 69 were downregulated. Platelet-derived growth factor receptor, prostaglandin E2 receptor and phospholipase D1 are among the top upregulated genes. Others include genes involved in G protein-coupled receptor and TGF-?-mediated signaling pathways, while genes associated with apoptosis, glucocorticoid receptors and even the cholecystokinin receptor are downregulated. Conclusions Microarray analysis in transcriptional profiling of PBMC showed that genes that are uniquely related to molecular and pancreatic function display differential expression in acute pancreatitis. Profiling genes obtained from an easily accessible source during severe pancreatitis may identify surrogate markers for disease severity. PMID:18347268
Bluth, Martin; Lin, Yin-yao; Zhang, Hong; Viterbo, Dominick; Zenilman, Michael
A Genome-wide screen identifies frequently methylated genes in haematological and epithelial cancers
Background Genetic as well as epigenetic alterations are a hallmark of both epithelial and haematological malignancies. High throughput screens are required to identify epigenetic markers that can be useful for diagnostic and prognostic purposes across malignancies. Results Here we report for the first time the use of the MIRA assay (methylated CpG island recovery assay) in combination with genome-wide CpG island arrays to identify epigenetic molecular markers in childhood acute lymphoblastic leukemia (ALL) on a genome-wide scale. We identified 30 genes demonstrating methylation frequencies of ?25% in childhood ALL, nine genes showed significantly different methylation frequencies in B vs T-ALL. For majority of the genes expression could be restored in methylated leukemia lines after treatment with 5-azaDC. Forty-four percent of the genes represent targets of the polycomb complex. In chronic myeloid leukemia (CML) two of the genes, (TFAP2A and EBF2), demonstrated increased methylation in blast crisis compared to chronic phase (P < 0.05). Furthermore hypermethylation of an autophagy related gene ATG16L2 was associated with poorer prognosis in terms of molecular response to Imatinib treatment. Lastly we demonstrated that ten of these genes were also frequently methylated in common epithelial cancers. Conclusion In summary we have identified a large number of genes showing frequent methylation in childhood ALL, methylation status of two of these genes is associated with advanced disease in CML and methylation status of another gene is associated with prognosis. In addition a subset of these genes may act as epigenetic markers across hematological malignancies as well as common epithelial cancers. PMID:20184741
Huntington's disease Between genes and
when the disease will strike. But there's the question of why people with identical repeats nonetheless that people who are susceptible to Huntington's disease might be able to minimize their exposure, they say,of ancient water on its parent asteroidVesta. Vesta lies in the main asteroid belt, between Mars
Levin, Yan
Automatically identifying and annotating mouse embryo gene expression patterns
Motivation: Deciphering the regulatory and developmental mechanisms for multicellular organisms requires detailed knowledge of gene interactions and gene expressions. The availability of large datasets with both spatial and ontological annotation of the spatio-temporal patterns of gene expression in mouse embryo provides a powerful resource to discover the biological function of embryo organization. Ontological annotation of gene expressions consists of labelling images with terms from the anatomy ontology for mouse development. If the spatial genes of an anatomical component are expressed in an image, the image is then tagged with a term of that anatomical component. The current annotation is done manually by domain experts, which is both time consuming and costly. In addition, the level of detail is variable, and inevitably errors arise from the tedious nature of the task. In this article, we present a new method to automatically identify and annotate gene expression patterns in the mouse embryo with anatomical terms. Results: The method takes images from in situ hybridization studies and the ontology for the developing mouse embryo, it then combines machine learning and image processing techniques to produce classifiers that automatically identify and annotate gene expression patterns in these images. We evaluate our method on image data from the EURExpress study, where we use it to automatically classify nine anatomical terms: humerus, handplate, fibula, tibia, femur, ribs, petrous part, scapula and head mesenchyme. The accuracy of our method lies between 70% and 80% with few exceptions. We show that other known methods have lower classification performance than ours. We have investigated the images misclassified by our method and found several cases where the original annotation was not correct. This shows our method is robust against this kind of noise. Availability: The annotation result and the experimental dataset in the article can be freely accessed at http://www2.docm.mmu.ac.uk/STAFF/L.Han/geneannotation/. Contact: email@example.com Supplementary Information: Supplementary data are available at Bioinformatics online. PMID:21357576
Han, Liangxiu; van Hemert, Jano I.; Baldock, Richard A.
Identifying critical transitions and their leading biomolecular networks in complex diseases
Identifying a critical transition and its leading biomolecular network during the initiation and progression of a complex disease is a challenging task, but holds the key to early diagnosis and further elucidation of the essential mechanisms of disease deterioration at the network level. In this study, we developed a novel computational method for identifying early-warning signals of the critical transition and its leading network during a disease progression, based on high-throughput data using a small number of samples. The leading network makes the first move from the normal state toward the disease state during a transition, and thus is causally related with disease-driving genes or networks. Specifically, we first define a state-transition-based local network entropy (SNE), and prove that SNE can serve as a general early-warning indicator of any imminent transitions, regardless of specific differences among systems. The effectiveness of this method was validated by functional analysis and experimental data. PMID:23230504
Liu, Rui; Li, Meiyi; Liu, Zhi-Ping; Wu, Jiarui; Chen, Luonan; Aihara, Kazuyuki
Animal Models of GWAS-Identified Type 2 Diabetes Genes
More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics. PMID:23710470
da Silva Xavier, Gabriela; Bellomo, Elisa A.; McGinty, James A.; French, Paul M.; Rutter, Guy A.
Identification of the von Hippel-Lindau Disease Tumor Suppressor Gene
A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients
Farida Latif; Kalman Tory; James Gnarra; Masahiro Yao; Fuh-Mei Duh; Mary Lou Orcutt; Thomas Stackhouse; Igor Kuzmin; William Modi; Laura Geil; Laura Schmidt; Fangwei Zhou; Hua Li; Ming Hui Wei; Fan Chen; Gladys Glenn; Peter Choyke; Mcclellan M. Walther; Yongkai Weng; Dah-Shuhn R. Duan; Michael Dean; Damjan Glavac; Frances M. Richards; Paul A. Crossey; Malcolm A. Ferguson-Smith; Denis Le Paslier; Iiya Chumakov; Daniel Cohen; A. Craig Chinault; Eamonn R. Maher; W. Marston Linehan; Berton Zbar; Michael I. Lerman
Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity. PMID:25217958
Coe, Bradley P; Witherspoon, Kali; Rosenfeld, Jill A; van Bon, Bregje W M; Vulto-van Silfhout, Anneke T; Bosco, Paolo; Friend, Kathryn L; Baker, Carl; Buono, Serafino; Vissers, Lisenka E L M; Schuurs-Hoeijmakers, Janneke H; Hoischen, Alex; Pfundt, Rolph; Krumm, Nik; Carvill, Gemma L; Li, Deana; Amaral, David; Brown, Natasha; Lockhart, Paul J; Scheffer, Ingrid E; Alberti, Antonino; Shaw, Marie; Pettinato, Rosa; Tervo, Raymond; de Leeuw, Nicole; Reijnders, Margot R F; Torchia, Beth S; Peeters, Hilde; Thompson, Elizabeth; O'Roak, Brian J; Fichera, Marco; Hehir-Kwa, Jayne Y; Shendure, Jay; Mefford, Heather C; Haan, Eric; G�cz, Jozef; de Vries, Bert B A; Romano, Corrado; Eichler, Evan E
Translatome analysis of CHO cells to identify key growth genes.
We report the first investigation of translational efficiency on a global scale, also known as translatome, of a Chinese hamster ovary (CHO) DG44 cell line producing monoclonal antibodies (mAb). The translatome data was generated via combined use of high resolution and streamlined polysome profiling technology and proprietary Nimblegen microarrays probing for more than 13K annotated CHO-specific genes. The distribution of ribosome loading during the exponential growth phase revealed the translational activity corresponding to the maximal growth rate, thus allowing us to identify stably and highly translated genes encoding heterogeneous nuclear ribonucleoproteins (Hnrnpc and Hnrnpa2b1), protein regulator of cytokinesis 1 (Prc1), glucose-6-phosphate dehydrogenase (G6pdh), UTP6 small subunit processome (Utp6) and RuvB-like protein 1 (Ruvbl1) as potential key players for cellular growth. Moreover, correlation analysis between transcriptome and translatome data sets showed that transcript level and translation efficiency were uncoupled for 95% of investigated genes, suggesting the implication of translational control mechanisms such as the mTOR pathway. Thus, the current translatome analysis platform offers new insights into gene expression in CHO cell cultures by bridging the gap between transcriptome and proteome data, which will enable researchers of the bioprocessing field to prioritize in high-potential candidate genes and to devise optimal strategies for cell engineering toward improving culture performance. PMID:23876478
Courtes, Franck C; Lin, Joyce; Lim, Hsueh Lee; Ng, Sze Wai; Wong, Niki S C; Koh, Geoffrey; Vardy, Leah; Yap, Miranda G S; Loo, Bernard; Lee, Dong-Yup
Researchers Find Gene Mutation That May Protect Against Heart Disease
... Researchers Find Gene Mutation That May Protect Against Heart Disease Rare genetic variation appears to cut the risk ... 2014 Related MedlinePlus Pages Genes and Gene Therapy Heart Diseases WEDNESDAY, Nov. 12, 2014 (HealthDay News) -- Mutations that ...
Gene therapy: prospects for glycolipid storage diseases.
Lysosomal storage diseases comprise a group of about 40 disorders, which in most cases are due to the deficiency of a lysosomal enzyme. Since lysosomal enzymes are involved in the degradation of various compounds, the diseases can be further subdivided according to which pathway is affected. Thus, enzyme deficiencies in the degradation pathway of glycosaminoglycans cause mucopolysaccharidosis, and deficiencies affecting glycopeptides cause glycoproteinosis. In glycolipid storage diseases enzymes are deficient that are involved in the degradation of sphingolipids. Mouse models are available for most of these diseases, and some of these mouse models have been used to study the applicability of in vivo gene therapy. We review the rationale for gene therapy in lysosomal disorders and present data, in particular, about trials in an animal model of metachromatic leukodystrophy. The data of these trials are compared with those obtained with animal models of other lysosomal diseases. PMID:12803926
Gieselmann, Volkmar; Matzner, Ulrich; Klein, Diana; Mansson, Jan Eric; D'Hooge, Rudi; DeDeyn, Peter D; Lullmann Rauch, Renate; Hartmann, Dieter; Harzer, Klaus
Network Analysis Identifies SOD2 mRNA as a Potential Biomarker for Parkinson's Disease
Increasing evidence indicates that Parkinson's disease (PD) and type 2 diabetes (T2DM) share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2), is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE). The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted. PMID:25279756
Santiago, Jose A.; Scherzer, Clemens R.; Potashkin, Judith A.
Gene therapy for Fabry disease
Fabry disease is an X-linked metabolic disorder caused by a deficiency of?-galactosidase A (?-Gal A). Lack of this lysosomal\\u000a hydrolase results in the accumulation of galactose-terminal glycosphingolipids in a number of tissues, including vascular\\u000a endothelial cells. Premature death is predominantly associated with vascular conditions of the heart, kidneys and brain. Historically,\\u000a treatment has largely been palliative. Alternative treatments for many
C. Sitaskas; J. A. Medin
Reverse engineering gene network identifies new dysferlin-interacting proteins.
Dysferlin (DYSF) is a type II transmembrane protein implicated in surface membrane repair of muscle. Mutations in dysferlin lead to Limb Girdle Muscular Dystrophy 2B (LGMD2B), Miyoshi Myopathy (MM), and Distal Myopathy with Anterior Tibialis onset (DMAT). The DYSF protein complex is not well understood, and only a few protein-binding partners have been identified thus far. To increase the set of interacting protein partners for DYSF we recovered a list of predicted interacting protein through a systems biology approach. The predictions are part of a "reverse-engineered" genome-wide human gene regulatory network obtained from experimental data by computational analysis. The reverse-engineering algorithm behind the analysis relates genes to each other based on changes in their expression patterns. DYSF and AHNAK were used to query the system and extract lists of potential interacting proteins. Among the 32 predictions the two genes share, we validated the physical interaction between DYSF protein with moesin (MSN) and polymerase I and transcript release factor (PTRF) in mouse heart lysate, thus identifying two novel Dysferlin-interacting proteins. Our strategy could be useful to clarify Dysferlin function in intracellular vesicles and its implication in muscle membrane resealing. PMID:21119217
Cacciottolo, Mafalda; Belcastro, Vincenzo; Laval, Steve; Bushby, Kate; di Bernardo, Diego; Nigro, Vincenzo
Alzheimer disease (AD) is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD). Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and �rokimi�, encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either �rokimi�, or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than �rokimi� which had no detectable expression in brain. PMID:24349219
Murdock, Deborah G.; Bradford, Yuki; Schnetz-Boutaud, Nathalie; Mayo, Ping; Allen, Melissa J.; D'Aoust, Laura N.; Liang, Xueying; Mitchell, Sabrina L.; Zuchner, Stephan; Small, Gary W.; Gilbert, John R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.
Identifying Neighborhoods of Coordinated Gene Expression and Metabolite Profiles
In this paper we investigate how metabolic network structure affects any coordination between transcript and metabolite profiles. To achieve this goal we conduct two complementary analyses focused on the metabolic response to stress. First, we investigate the general size of any relationship between metabolic network gene expression and metabolite profiles. We find that strongly correlated transcript-metabolite profiles are sustained over surprisingly long network distances away from any target metabolite. Secondly, we employ a novel pathway mining method to investigate the structure of this transcript-metabolite relationship. The objective of this method is to identify a minimum set of metabolites which are the target of significantly correlated gene expression pathways. The results reveal that in general, a global regulation signature targeting a small number of metabolites is responsible for a large scale metabolic response. However, our method also reveals pathway specific effects that can degrade this global regulation signature and complicates the observed coordination between transcript-metabolite profiles. PMID:22355360
Hancock, Timothy; Wicker, Nicolas; Takigawa, Ichigaku; Mamitsuka, Hiroshi
Screening for Noise in Gene Expression Identifies Drug Synergies
Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We used such fluctuations to modulate reactivation of HIV from latency�a quiescent state that is a major barrier to an HIV cure. By screening a diverse library of bioactive small molecules, we identified over 80 compounds that modulated HIV gene-expression fluctuations (i.e. �noise�), without changing mean expression. These noise-modulating compounds would be neglected in conventional screens and strikingly they synergized with conventional transcriptional activators. Noise enhancers reactivated latent cells significantly better than existing best-in-class reactivation cocktails (and with reduced off-target cytotoxicity), while noise suppressors stabilized latency. Noise-modulating chemicals may provide novel probes for the physiological consequences of noise and an unexplored axis for drug discovery, allowing enhanced control over diverse cell-fate decisions. PMID:24903562
Dar, Roy D.; Hosmane, Nina N.; Arkin, Michelle R.; Siliciano, Robert F.; Weinberger, Leor S.
Two major genes, linked to HLA and Gm, control susceptibility to Graves' disease
Graves' disease is a multifactorial disease in which immunogenetic as well as environmental factors have important roles. Recently, cumulative evidence has shown that genes controlling immune responses are linked to the MHC (major histocompatibility complex)1 and\\/or immunoglobulin allotype genes2,3. To identify the genes governing susceptibility to Graves' disease, we have studied 30 Japanese families where more than two first degree
Hisamitsu Uno; Takehiko Sasazuki; Hajime Tamai; Hideo Matsumoto
Hypertrophic cardiomyopathy: from gene defect to clinical disease.
Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man. PMID:12643345
Chung, Man-Wei; Tsoutsman, Tatiana; Semsarian, Christopher
Weighted gene co-expression network analysis identifies biomarkers in glycerol kinase deficient mice
Symptomatic glycerol kinase deficiency (GKD) is associated with episodic metabolic and central nervous system deterioration. We report here the first application of weighted gene co-expression network analysis (WGCNA) to investigate a knockout (KO) murine model of a human genetic disease. WGCNA identified networks and key hub transcripts from liver mRNA of glycerol kinase (Gyk) KO and wild-type (WT) mice. Day
Nicole K. MacLennan; Jun Dong; Jason E. Aten; Steve Horvath; Lola Rahib; Loren Ornelas; Katrina M. Dipple; Edward R. B. McCabe
Based on time series gene expressions, cyclic genes can be recognized via spectral analysis and statistical periodicity detection tests. These cyclic genes are usually associated with cyclic biological processes, for example, cell cycle and circadian rhythm. The power of a scheme is practically measured by comparing the detected periodically expressed genes with experimentally verified genes participating in a cyclic process. However, in the above mentioned procedure the valuable prior knowledge only serves as an evaluation benchmark, and it is not fully exploited in the implementation of the algorithm. In addition, partial data sets are also disregarded due to their nonstationarity. This paper proposes a novel algorithm to identify cyclic-process-involved genes by integrating the prior knowledge with the gene expression analysis. The proposed algorithm is applied on data sets corresponding to Saccharomyces cerevisiae and Drosophila melanogaster, respectively. Biological evidences are found to validate the roles of the discovered genes in cell cycle and circadian rhythm. Dendrograms are presented to cluster the identified genes and to reveal expression patterns. It is corroborated that the proposed novel identification scheme provides a valuable technique for unveiling pathways related to cyclic processes. PMID:19390635
Gene therapy for Stargardt disease associated with ABCA4 gene.
Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt's disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8�kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4 (-/-) murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt's disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach. PMID:24664763
Han, Zongchao; Conley, Shannon M; Naash, Muna I
Exome Sequencing Identifies Three Novel Candidate Genes Implicated in Intellectual Disability
Intellectual disability (ID) is a major health problem mostly with an unknown etiology. Recently exome sequencing of individuals with ID identified novel genes implicated in the disease. Therefore the purpose of the present study was to identify the genetic cause of ID in one syndromic and two non-syndromic Pakistani families. Whole exome of three ID probands was sequenced. Missense variations in two plausible novel genes implicated in autosomal recessive ID were identified: lysine (K)-specific methyltransferase 2B (KMT2B), zinc finger protein 589 (ZNF589), as well as hedgehog acyltransferase (HHAT) with a de novo mutation with autosomal dominant mode of inheritance. The KMT2B recessive variant is the first report of recessive Kleefstra syndrome-like phenotype. Identification of plausible causative mutations for two recessive and a dominant type of ID, in genes not previously implicated in disease, underscores the large genetic heterogeneity of ID. These results also support the viewpoint that large number of ID genes converge on limited number of common networks i.e. ZNF589 belongs to KRAB-domain zinc-finger proteins previously implicated in ID, HHAT is predicted to affect sonic hedgehog, which is involved in several disorders with ID, KMT2B associated with syndromic ID fits the epigenetic module underlying the Kleefstra syndromic spectrum. The association of these novel genes in three different Pakistani ID families highlights the importance of screening these genes in more families with similar phenotypes from different populations to confirm the involvement of these genes in pathogenesis of ID. PMID:25405613
Azam, Maleeha; Ayub, Humaira; Vissers, Lisenka E. L. M.; Gilissen, Christian; Ali, Syeda Hafiza Benish; Riaz, Moeen; Veltman, Joris A.; Pfundt, Rolph; van Bokhoven, Hans; Qamar, Raheel
Gene that controls aggressiveness in breast cancer cells identified
In a discovery that sheds new light on the aggressiveness of certain breast cancers, Whitehead Institute and MIT researchers have identified a transcription factor, known as ZEB1, that is capable of converting non-aggressive basal-type cancer cells into highly malignant, tumor-forming cancer stem cells (CSCs). Intriguingly, luminal breast cancer cells, which are associated with a much better clinical prognosis, carry this gene in a state in which it seems to be permanently shut down. MIT is home to the David H. Koch Institute for Integrative Cancer Research.
Approaches for Recognizing Disease Genes Based on Network
Diseases are closely related to genes, thus indicating that genetic abnormalities may lead to certain diseases. The recognition of disease genes has long been a goal in biology, which may contribute to the improvement of health care and understanding gene functions, pathways, and interactions. However, few large-scale gene-gene association datasets, disease-disease association datasets, and gene-disease association datasets are available. A number of machine learning methods have been used to recognize disease genes based on networks. This paper states the relationship between disease and gene, summarizes the approaches used to recognize disease genes based on network, analyzes the core problems and challenges of the methods, and outlooks future research direction. PMID:24707485
Zou, Quan; Li, Jinjin; Wang, Chunyu; Zeng, Xiangxiang
Genes, environment, and cardiovascular disease.
In this essay, we call to attention what every medical researcher knows about the etiology of cardiovascular disease but most deny, or choose to ignore, when designing, carrying out, and reporting genetic studies. Medical research is entering an era of synthesis that will take advantage of the successes of reductionism over the past decade in defining and describing human genome variations. Meaningful insights into the role of such variation requires a biological model of genome-phenotype relationships that incorporates interactions between subsets of possible genetic and environmental agents as causations in particular contexts indexed by time and space. We make recommendations for what needs to be done to cope with these complexities. PMID:12730090
Sing, Charles F; Steng�rd, Jari H; Kardia, Sharon L R
Fox Chase Cancer Center researchers have identified a gene that predicts disease recurrence in individuals with squamous cell carcinoma of the head and neck. The new findings, presented at the American Association for Cancer Research Annual Meeting 2012 on Monday, April 2, show that patients with one common variant of a gene which encodes the cytochrome P450 (CYP1B1) protein are likely to have a longer time-to-recurrence than those with the more typical form of the gene.
Screening for Single Gene Genetic Disease
The screening and directed testing for genetic disease caused by single gene mutations is an expanding part of the overall scheme of prenatal care. In addition to reproductive choice, carrier screening and fetal diagnostic testing afford the important opportunity for preparation of the family and the delivery site for the birth of a fetus with a known genetic disorder. Increasingly
Thomas J. Musci
Gene therapy for autoimmune diseases: quo vadis?
Biological therapies using antibodies and cytokines are becoming widespread for the treatment of chronic inflammatory autoimmune diseases. However, these treatments have several limitations � such as expense, the need for repeated injections and unwanted side-effects � that can be overcome by genetic delivery. This review summarizes the ingenuity, sophistication and variety of gene-therapy approaches that have been taken in the
David J. Gould; Osvaldo L. Podhajcer; Yuti Chernajovsky
Gene-Environment Interactions and Epigenetic Basis of Human Diseases
Most human diseases are related in some way to the loss or gain in gene functions. Regulation of gene expression is a complex process. In addition to genetic mechanisms, epigenetic causes are gaining new perspectives in human diseases related to gene deregulation. Most eukaryotic genes are packed into chromatin structures, which lead to high condensations of the genes that require
Liang Liu; Yuanyuan Li; Trygve O. Tollefsbol
Cilia are small cellular projections that either act as sensors (primary cilia) or propel fluid over the epithelia of various\\u000a organs (motile cilia). The organellum has gained much attention lately because of its involvement in a group of human diseases\\u000a called ciliopathies. Primary ciliary dyskinesia (PCD) is an autosomal recessive ciliopathy caused by mutations in cilia motility\\u000a genes. The disease
Maciej Geremek; Marcel Bruinenberg; Ewa Zi?tkiewicz; Andrzej Pogorzelski; Micha? Witt; Cisca Wijmenga
Complex biological systems usually pose a trade-off between robustness and fragility where a small number of perturbations can substantially disrupt the system. Although biological systems are robust against changes in many external and internal conditions, even a single mutation can perturb the system substantially, giving rise to a pathophenotype. Recent advances in identifying and analyzing the sequential variations beneath human disorders help to comprehend a systemic view of the mechanisms underlying various disease phenotypes. Network-based disease-gene prioritization methods rank the relevance of genes in a disease under the hypothesis that genes whose proteins interact with each other tend to exhibit similar phenotypes. In this study, we have tested the robustness of several network-based disease-gene prioritization methods with respect to the perturbations of the system using various disease phenotypes from the Online Mendelian Inheritance in Man database. These perturbations have been introduced either in the protein-protein interaction network or in the set of known disease-gene associations. As the network-based disease-gene prioritization methods are based on the connectivity between known disease-gene associations, we have further used these methods to categorize the pathophenotypes with respect to the recoverability of hidden disease-genes. Our results have suggested that, in general, disease-genes are connected through multiple paths in the human interactome. Moreover, even when these paths are disturbed, network-based prioritization can reveal hidden disease-gene associations in some pathophenotypes such as breast cancer, cardiomyopathy, diabetes, leukemia, parkinson disease and obesity to a greater extend compared to the rest of the pathophenotypes tested in this study. Gene Ontology (GO) analysis highlighted the role of functional diversity for such diseases. PMID:24733074
Guney, Emre; Oliva, Baldo
Identification of Human Disease Genes from Interactome Network Using Graphlet Interaction
Identifying genes related to human diseases, such as cancer and cardiovascular disease, etc., is an important task in biomedical research because of its applications in disease diagnosis and treatment. Interactome networks, especially protein-protein interaction networks, had been used to disease genes identification based on the hypothesis that strong candidate genes tend to closely relate to each other in some kinds of measure on the network. We proposed a new measure to analyze the relationship between network nodes which was called graphlet interaction. The graphlet interaction contained 28 different isomers. The results showed that the numbers of the graphlet interaction isomers between disease genes in interactome networks were significantly larger than random picked genes, while graphlet signatures were not. Then, we designed a new type of score, based on the network properties, to identify disease genes using graphlet interaction. The genes with higher scores were more likely to be disease genes, and all candidate genes were ranked according to their scores. Then the approach was evaluated by leave-one-out cross-validation. The precision of the current approach achieved 90% at about 10% recall, which was apparently higher than the previous three predominant algorithms, random walk, Endeavour and neighborhood based method. Finally, the approach was applied to predict new disease genes related to 4 common diseases, most of which were identified by other independent experimental researches. In conclusion, we demonstrate that the graphlet interaction is an effective tool to analyze the network properties of disease genes, and the scores calculated by graphlet interaction is more precise in identifying disease genes. PMID:24465923
Yang, Lun; Wei, Dong-Qing; Qi, Ying-Xin; Jiang, Zong-Lai
CD40 ligand gene and Kawasaki disease
Kawasaki disease (KD) is an acute systemic vasculitis syndrome of infants and young children. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KD. To identify genetic factors, affected sib-pair analysis has been performed. One of the identified peaks was located on the Xq26 region. A recent report of elevated
Yoshihiro Onouchi; Sakura Onoue; Mayumi Tamari; Keiko Wakui; Yoshimitsu Fukushima; Mayumi Yashiro; Yoshikazu Nakamura; Hiroshi Yanagawa; Fumio Kishi; Kazunobu Ouchi; Masaru Terai; Kunihiro Hamamoto; Fumiyo Kudo; Hiroyuki Aotsuka; Yoshitake Sato; Akiyoshi Nariai; Yoichi Kaburagi; Masaru Miura; Tsutomu Saji; Tomisaku Kawasaki; Yusuke Nakamura; Akira Hata
Gene expression profiling identifies different sub-types of retinoblastoma
Background: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. Methods: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. Results: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. Conclusion: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics. PMID:23756868
Kapatai, G; Brundler, M-A; Jenkinson, H; Kearns, P; Parulekar, M; Peet, A C; McConville, C M
Preselective gene therapy for Fabry disease
Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme ?-galactosidase A (?-gal A; EC 22.214.171.124). We previously have demonstrated long-term ?-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic ?-gal A gene and the human IL-2R? chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted ?-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34+ peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased ?-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders. PMID:11248095
Qin, Gangjian; Takenaka, Toshihiro; Telsch, Kimberly; Kelley, Leslie; Howard, Tazuko; Levade, Thierry; Deans, Robert; Howard, Bruce H.; Malech, Harry L.; Brady, Roscoe O.; Medin, Jeffrey A.
Preselective gene therapy for Fabry disease.
Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme alpha-galactosidase A (alpha-gal A; EC ). We previously have demonstrated long-term alpha-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic alpha-gal A gene and the human IL-2Ralpha chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted alpha-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34(+) peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased alpha-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders. PMID:11248095
Qin, G; Takenaka, T; Telsch, K; Kelley, L; Howard, T; Levade, T; Deans, R; Howard, B H; Malech, H L; Brady, R O; Medin, J A
Gene therapy for cardiovascular disease: perspectives and potential.
Cardiovascular disease is the most frequent cause of mortality in the western world, accounting for over 800,000 premature deaths per year in the EU alone. Cardiovascular disease is the second most common application for gene therapy clinical trials, which most frequently employ adenovirus serotype 5 (Ad5)-based vectors as delivery vehicles. Although interactions of Ad5 vectors with circulating proteins and cells can limit their efficacy after systemic administration, local gene delivery strategies show great potential in the cardiovascular setting, notably in the context of vascular delivery. Here we review the pathogenesis of bypass graft failure and in-stent restenosis, identifying potential therapeutic targets and discussing recent advances in the field of adenovirus biology and retargeting that, in concert, will potentially translate in coming years to more effective gene therapies for cardiovascular applications. PMID:23142171
Bradshaw, Angela C; Baker, Andrew H
Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)-which encodes a vital negative regulatory molecule of the immune system-as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism
Hironori Ueda; Joanna M. M. Howson; Laura Esposito; Joanne Heward; Hywel Snook; Giselle Chamberlain; Daniel B. Rainbow; Kara M. D. Hunter; Annabel N. Smith; Gianfranco Di Genova; Mathias H. Herr; Ingrid Dahlman; Felicity Payne; Deborah Smyth; Christopher Lowe; Rebecca C. J. Twells; Sarah Howlett; Barry Healy; Sarah Nutland; Helen E. Rance; Vin Everett; Luc J. Smink; Alex C. Lam; Heather J. Cordell; Neil M. Walker; Cristina Bordin; John Hulme; Costantino Motzo; Francesco Cucca; J. Fred Hess; Michael L. Metzker; Jane Rogers; Simon Gregory; Amit Allahabadia; Ratnasingam Nithiyananthan; Eva Tuomilehto-Wolf; Jaakko Tuomilehto; Polly Bingley; Kathleen M. Gillespie; Dag E. Undlien; Kjersti S. R�nningen; Cristian Guja; Constantin Ionescu-T�rgoviste; David A. Savage; A. Peter Maxwell; Dennis J. Carson; Chris C. Patterson; Jayne A. Franklyn; David G. Clayton; Laurence B. Peterson; Linda S. Wicker; John A. Todd; Stephen C. L. Gough
A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI) in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI. PMID:23874995
Uddin, Raihan K.; Singh, Shiva M.
De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support. PMID:23966865
He, Xin; Sanders, Stephan J.; Liu, Li; De Rubeis, Silvia; Lim, Elaine T.; Sutcliffe, James S.; Schellenberg, Gerard D.; Gibbs, Richard A.; Daly, Mark J.; Buxbaum, Joseph D.; State, Matthew W.; Devlin, Bernie; Roeder, Kathryn
Analysis of human genes with protein-protein interaction network for detecting disease genes
NASA Astrophysics Data System (ADS)
The topological features of disease genes and non-disease genes were widely utilized in disease genes prediction. However, previous studies neglected to exploit essential genes to distinguish disease genes and non-disease genes. Therefore, this paper firstly takes essential genes as reference to analyze the topological properties of human genes with protein-protein interaction network. Empirical results demonstrate that nonessential disease genes are topologically more important and closer to the center of the network than other genes (unknown genes, which are deemed as non-disease genes in disease genes prediction). Although disease genes are closer to essential genes, we find that the influence of disease genes on essential genes is similar with other genes, or even weaker. Further, we generate new topological features according to our findings and validate the effectiveness of combining the additional features for detecting disease genes. In addition, we find that the k-shell index (ks) of protein-protein network follows a power law distribution, and the function of the proteins with the largest ks may deserve further research.
Wu, Shun-yao; Shao, Feng-jing; Sun, Ren-cheng; Sui, Yi; Wang, Ying; Wang, Jin-long
Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean?=?4.4 Mb) that contain many genes (mean?=?79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data. PMID:22279524
Puffenberger, Erik G.; Jinks, Robert N.; Sougnez, Carrie; Cibulskis, Kristian; Willert, Rebecca A.; Achilly, Nathan P.; Cassidy, Ryan P.; Fiorentini, Christopher J.; Heiken, Kory F.; Lawrence, Johnny J.; Mahoney, Molly H.; Miller, Christopher J.; Nair, Devika T.; Politi, Kristin A.; Worcester, Kimberly N.; Setton, Roni A.; DiPiazza, Rosa; Sherman, Eric A.; Eastman, James T.; Francklyn, Christopher; Robey-Bond, Susan; Rider, Nicholas L.; Gabriel, Stacey; Morton, D. Holmes; Strauss, Kevin A.
Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.
Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Southern hybridization analysis of the alpha-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to greater than 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan356 substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease. Images PMID:2539398
Bernstein, H S; Bishop, D F; Astrin, K H; Kornreich, R; Eng, C M; Sakuraba, H; Desnick, R J
Gene Therapy Shows Potential for 'Bubble Boy' Disease
Identifying Unstable Regions of Proteins Involved in Misfolding Diseases
NASA Astrophysics Data System (ADS)
Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.
Guest, Will; Cashman, Neil; Plotkin, Steven
Background The basidiomycete fungus Microbotryum violaceum is responsible for the anther-smut disease in many plants of the Caryophyllaceae family and is a model in genetics and evolutionary biology. Infection is initiated by dikaryotic hyphae produced after the conjugation of two haploid sporidia of opposite mating type. This study describes M. violaceum ESTs corresponding to nuclear genes expressed during conjugation and early hyphal production. Results A normalized cDNA library generated 24,128 sequences, which were assembled into 7,765 unique genes; 25.2% of them displayed significant similarity to annotated proteins from other organisms, 74.3% a weak similarity to the same set of known proteins, and 0.5% were orphans. We identified putative pheromone receptors and genes that in other fungi are involved in the mating process. We also identified many sequences similar to genes known to be involved in pathogenicity in other fungi. The M. violaceum EST database, MICROBASE, is available on the Web and provides access to the sequences, assembled contigs, annotations and programs to compare similarities against MICROBASE. Conclusion This study provides a basis for cloning the mating type locus, for further investigation of pathogenicity genes in the anther smut fungi, and for comparative genomics. PMID:17692127
Yockteng, Roxana; Marthey, Sylvain; Chiapello, Helene; Gendrault, Annie; Hood, Michael E; Rodolphe, Francois; Devier, Benjamin; Wincker, Patrick; Dossat, Carole; Giraud, Tatiana
Inferring Gene Family Histories in Yeast Identifies Lineage Specific Expansions
The complement of genes found in the genome is a balance between gene gain and gene loss. Knowledge of the specific genes that are gained and lost over evolutionary time allows an understanding of the evolution of biological functions. Here we use...
Ames, Ryan M.; Money, Daniel; Lovell, Simon C.
Fluid Mechanics, Arterial Disease, and Gene Expression
NASA Astrophysics Data System (ADS)
This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow-induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid mechanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs.
Tarbell, John M.; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong
Fluid Mechanics, Arterial Disease, and Gene Expression
This review places modern research developments in vascular mechanobiology in the context of hemodynamic phenomena in the cardiovascular system and the discrete localization of vascular disease. The modern origins of this field are traced, beginning in the 1960s when associations between flow characteristics, particularly blood flow�induced wall shear stress, and the localization of atherosclerotic plaques were uncovered, and continuing to fluid shear stress effects on the vascular lining endothelial) cells (ECs), including their effects on EC morphology, biochemical production, and gene expression. The earliest single-gene studies and genome-wide analyses are considered. The final section moves from the ECs lining the vessel wall to the smooth muscle cells and fibroblasts within the wall that are fluid me chanically activated by interstitial flow that imposes shear stresses on their surfaces comparable with those of flowing blood on EC surfaces. Interstitial flow stimulates biochemical production and gene expression, much like blood flow on ECs.
Tarbell, John M.; Shi, Zhong-Dong; Dunn, Jessilyn; Jo, Hanjoong
Retinitis Pigmentosa: Genes and Disease Mechanisms
Retinitis pigmentosa (RP) is a group of inherited disorders affecting 1 in 3000-7000 people and characterized by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium of the retina which lead to progressive visual loss. RP can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. While usually limited to the eye, RP may also occur as part of a syndrome as in the Usher syndrome and Bardet-Biedl syndrome. Over 40 genes have been associated with RP so far, with the majority of them expressed in either the photoreceptors or the retinal pigment epithelium. The tremendous heterogeneity of the disease makes the genetics of RP complicated, thus rendering genotype-phenotype correlations not fully applicable yet. In addition to the multiplicity of mutations, in fact, different mutations in the same gene may cause different diseases. We will here review which genes are involved in the genesis of RP and how mutations can lead to retinal degeneration. In the future, a more thorough analysis of genetic and clinical data together with a better understanding of the genotype-phenotype correlation might allow to reveal important information with respect to the likelihood of disease development and choices of therapy. PMID:22131869
Ferrari, Stefano; Di Iorio, Enzo; Barbaro, Vanessa; Ponzin, Diego; Sorrentino, Francesco S; Parmeggiani, Francesco
An algorithm for identifying clusters of functionally related genes in genomes
An increasing body of literature shows that genomes of eukaryotes can contain clusters of functionally related genes. Most approaches to identify gene clusters utilize microarray data or metabolic pathway databases to find groups of genes on chromo...
Yi, Gang Man
Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C?Locus
Usher syndrome 1C (USH1C) is a congenital condition manifesting profound hearing loss, the absence of vestibular function, and eventual retinal degeneration. The USH1C locus has been mapped genetically to a 2- to 3-cM interval in 11p14�15.1 between D11S899 and D11S861. In an effort to identify the USH1C disease gene we have isolated the region between these markers in yeast artificial chromosomes (YACs) using a combination of STS content mapping and Alu�PCR hybridization. The YAC contig is ?3.5 Mb and has located several other loci within this interval, resulting in the order CEN-LDHA-SAA1-TPH-D11S1310-(D11S1888/KCNC1)-MYOD1-D11S902D11S921-D11S1890-TEL. Subsequent haplotyping and homozygosity analysis refined the location of the disease gene to a 400-kb interval between D11S902 and D11S1890 with all affected individuals being homozygous for the internal marker D11S921. To facilitate gene identification, the critical region has been converted into P1 artificial chromosome (PAC) clones using sequence-tagged sites (STSs) mapped to the YAC contig, Alu�PCR products generated from the YACs, and PAC end probes. A contig of >50 PAC clones has been assembled between D11S1310 and D11S1890, confirming the order of markers used in haplotyping. Three PAC clones representing nearly two-thirds of the USH1C critical region have been sequenced. PowerBLAST analysis identified six clusters of expressed sequence tags (ESTs), two known genes (BIR,SUR1) mapped previously to this region, and a previously characterized but unmapped gene NEFA (DNA binding/EF hand/acidic amino-acid-rich). GRAIL analysis identified 11 CpG islands and 73 exons of excellent quality. These data allowed the construction of a transcription map for the USH1C critical region, consisting of three known genes and six or more novel transcripts. Based on their map location, these loci represent candidate disease loci for USH1C. The NEFA gene was assessed as the USH1C locus by the sequencing of an amplified NEFA cDNA from an USH1C patient; however, no mutations were detected. [The sequence data described in this paper have been submitted to GenBank under accession numbers AC000406�AC000407.] PMID:9445488
Higgins, Michael J.; Day, Colleen D.; Smilinich, Nancy J.; Ni, L.; Cooper, Paul R.; Nowak, Norma J.; Davies, Chris; de Jong, Pieter J.; Hejtmancik, Fielding; Evans, Glen A.; Smith, Richard J.H.; Shows, Thomas B.
Autoimmune diseases are often intractable because their causes are unknown. Identifying which genes contribute to these diseases may allow us to understand the pathogenesis, but it is difficult to determine which genes contribute to disease. Recently, epigenetic information has been considered to activate/deactivate disease-related genes. Thus, it may also be useful to study epigenetic information that differs between healthy controls and patients with autoimmune disease. Among several types of epigenetic information, promoter methylation is believed to be one of the most important factors. Here, we propose that principal component analysis is useful to identify specific gene promoters that are differently methylated between the normal healthy controls and patients with autoimmune disease. Full Automatic Modeling System (FAMS) was used to predict the three-dimensional structures of selected proteins and successfully inferred relatively confident structures. Several possibilities of the application to the drug discovery based on obtained structures are discussed. PMID:23855671
Ishida, Shigeharu; Umeyama, Hideaki; Iwadate, Mitsuo; Y-h, Taguchi
Genetic interaction networks that underlie most human diseases are highly complex and poorly defined. Better-defined networks will allow identification of a greater number of therapeutic targets. Here we introduce our Yeast Augmented Network Analysis (YANA) approach and test it with the X-linked spinal muscular atrophy (SMA) disease gene UBA1.�First, we express UBA1 and a mutant variant in fission yeast and use high-throughput methods to identify fission yeast genetic modifiers of UBA1. Second, we analyze available protein-protein interaction network databases in both fission yeast and human to construct UBA1 genetic networks. Third, from these networks we identified potential therapeutic targets for SMA. Finally, we validate one of these targets in a vertebrate (zebrafish) SMA model. This study demonstrates the power of combining synthetic and chemical genetics with a simple model system to identify human disease gene networks that can be exploited for treating human diseases. PMID:25075304
Wiley, David J.; Juan, Ilona; Le, Hao; Cai, Xiaodong; Baumbach, Lisa; Beattie, Christine; D'Urso, Gennaro
A rule-based approach for automatically identifying gene/protein terms
Identifying gene and protein terms is important for obtaining biological knowledge from literature. We have developed GPmarkup (for gene and proteinname mark up), a system that automatically identifies gene and protein terms and maps gene and protein symbols (e.g., DR3) to names (e.g., Death Receptor 3) in MEDLINE abstracts.
Hong Yu; Vasileios Hatzivassiloglou; Carol Friedman; Ivan H. Iossifov; Andrey Rzhetsky
A rule-based approach for automatically identifying gene and protein names in MEDLINE abstracts
Identifying gene and protein terms is important for obtaining biological knowledge from literature. We have developed GPmarkup (for gene and proteinname mark up), a system that automatically identifies gene and protein terms and maps gene and protein symbols (e.g., DR3) to names (e.g., Death Receptor 3) in MEDLINE abstracts.
Hong Yu Vasileios; Hong Yu; Vasileios Hatzivassiloglou; Carol Friedman; Ivan H. Iossifov; Andrey Rzhetsky
Elevating crop disease resistance with cloned genes
Essentially all plant species exhibit heritable genetic variation for resistance to a variety of plant diseases caused by fungi, bacteria, oomycetes or viruses. Disease losses in crop monocultures are already significant, and would be greater but for applications of disease-controlling agrichemicals. For sustainable intensification of crop production, we argue that disease control should as far as possible be achieved using genetics rather than using costly recurrent chemical sprays. The latter imply CO2 emissions from diesel fuel and potential soil compaction from tractor journeys. Great progress has been made in the past 25 years in our understanding of the molecular basis of plant disease resistance mechanisms, and of how pathogens circumvent them. These insights can inform more sophisticated approaches to elevating disease resistance in crops that help us tip the evolutionary balance in favour of the crop and away from the pathogen. We illustrate this theme with an account of a genetically modified (GM) blight-resistant potato trial in Norwich, using the Rpi-vnt1.1 gene isolated from a wild relative of potato, Solanum venturii, and introduced by GM methods into the potato variety Desiree. PMID:24535396
Jones, Jonathan D. G.; Witek, Kamil; Verweij, Walter; Jupe, Florian; Cooke, David; Dorling, Stephen; Tomlinson, Laurence; Smoker, Matthew; Perkins, Sara; Foster, Simon
A yeast functional screen predicts new candidate ALS disease genes
Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782
Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.
The identification and study of evolutionarily con- served genomic sequences that surround disease- related genes is a valuable tool to gain insight into the functional role of these genes and to better eluci- date the pathogenetic mechanisms of disease. We created the DG-CST (Disease Gene Conserved Sequence Tags) database for the identification and detailed annotation of human-mouse conserved genomic sequences
Angelo Boccia; Mauro Petrillo; Diego Di Bernardo; Alessandro Guffanti; Flavio Mignone; Stefano Confalonieri; Lucilla Luzi; Graziano Pesole; Giovanni Paolella; Andrea Ballabio; Sandro Banfi
Clostridium difficile is a common cause of infectious diarrhea in hospitalized patients. A severe and increased incidence of C. difficile infection (CDI) is associated predominantly with the NAP1 strain; however, the existence of other severe-disease-associated (SDA) strains and the extensive genetic diversity across C. difficile complicate reliable detection and diagnosis. Comparative genome analysis of 14 sequenced genomes, including those of a subset of NAP1 isolates, allowed the assessment of genetic diversity within and between strain types to identify DNA markers that are associated with severe disease. Comparative genome analysis of 14 isolates, including five publicly available strains, revealed that C. difficile has a core genome of 3.4 Mb, comprising ?3,000 genes. Analysis of the core genome identified candidate DNA markers that were subsequently evaluated using a multistrain panel of 177 isolates, representing more than 50 pulsovars and 8 toxinotypes. A subset of 117 isolates from the panel had associated patient data that allowed assessment of an association between the DNA markers and severe CDI. We identified 20 candidate DNA markers for species-wide detection and 10,683 single nucleotide polymorphisms (SNPs) associated with the predominant SDA strain (NAP1). A species-wide detection candidate marker, the sspA gene, was found to be the same across 177 sequenced isolates and lacked significant similarity to those of other species. Candidate SNPs in genes CD1269 and CD1265 were found to associate more closely with disease severity than currently used diagnostic markers, as they were also present in the toxin A-negative and B-positive (A-B+) strain types. The genetic markers identified illustrate the potential of comparative genomics for the discovery of diagnostic DNA-based targets that are species specific or associated with multiple SDA strains. PMID:21508155
Forgetta, Vincenzo; Oughton, Matthew T.; Marquis, Pascale; Brukner, Ivan; Blanchette, Ruth; Haub, Kevin; Magrini, Vince; Mardis, Elaine R.; Gerding, Dale N.; Loo, Vivian G.; Miller, Mark A.; Mulvey, Michael R.; Rupnik, Maja; Dascal, Andre; Dewar, Ken
CFTR gene mutations in isolated chronic obstructive pulmonary disease
In order to identify a possible hereditary predisposition to the development of chronic obstructive pulmonary disease (COPD), we have looked for the presence of cystic fibrosis transmembrane regulator (CFTR) gene DNA sequence modifications in 28 unrelated patients with no signs of cystic fibrosis. The known mutations in Italian CF patients, as well as the most frequent worldwide CF mutations, were investigated. In addition, a denaturing gradient gel electrophoresis analysis of about half of the coding sequence of the gene in 56 chromosomes from the patients and in 102 chromosomes from control individuals affected by other pulmonary diseases and from normal controls was performed. Nine different CFTR gene mutations and polymorphisms were found in seven patients, a highly significant increase over controls. Two of the patients were compound heterozygotes. Two frequent CF mutations were detected: deletion F508 and R117H; two rare CF mutations: R1066C and 3667ins4; and five CF sequence variants: R75Q (which was also described as a disease-causing mutation in male sterility cases due to the absence of the vasa deferentia), G576A, 2736 A{r_arrow}G, L997F, and 3271+18C{r_arrow}T. Seven (78%) of the mutations are localized in transmembrane domains. Six (86%) of the patients with defined mutations and polymorphisms had bronchiectasis. These results indicate that CFTR gene mutations and sequence alterations may be involved in the etiopathogenesis of some cases of COPD.
Pignatti, P.F.; Bombien, C.; Marigo, C. [and others
Gene Profiling of Mta1 Identifies Novel Gene Targets and Functions
Background Metastasis-associated protein 1 (MTA1), a master dual co-regulatory protein is found to be an integral part of NuRD (Nucleosome Remodeling and Histone Deacetylation) complex, which has indispensable transcriptional regulatory functions via histone deacetylation and chromatin remodeling. Emerging literature establishes MTA1 to be a valid DNA-damage responsive protein with a significant role in maintaining the optimum DNA-repair activity in mammalian cells exposed to genotoxic stress. This DNA-damage responsive function of MTA1 was reported to be a P53-dependent and independent function. Here, we investigate the influence of P53 on gene regulation function of Mta1 to identify novel gene targets and functions of Mta1. Methods Gene expression analysis was performed on five different mouse embryonic fibroblasts (MEFs) samples (i) the Mta1 wild type, (ii) Mta1 knock out (iii) Mta1 knock out in which Mta1 was reintroduced (iv) P53 knock out (v) P53 knock out in which Mta1 was over expressed using Affymetrix Mouse Exon 1.0 ST arrays. Further Hierarchical Clustering, Gene Ontology analysis with GO terms satisfying corrected p-value<0.1, and the Ingenuity Pathway Analysis were performed. Finally, RT-qPCR was carried out on selective candidate genes. Significance/Conclusion This study represents a complete genome wide screen for possible target genes of a coregulator, Mta1. The comparative gene profiling of Mta1 wild type, Mta1 knockout and Mta1 re-expression in the Mta1 knockout conditions define �bona fide� Mta1 target genes. Further extensive analyses of the data highlights the influence of P53 on Mta1 gene regulation. In the presence of P53 majority of the genes regulated by Mta1 are related to inflammatory and anti-microbial responses whereas in the absence of P53 the predominant target genes are involved in cancer signaling. Thus, the presented data emphasizes the known functions of Mta1 and serves as a rich resource which could help us identify novel Mta1 functions. PMID:21364872
Eswaran, Jeyanthy; Kumar, Rakesh
Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-? inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFN-primed iDCs. PMID:24039940
Szasz, Andras; Tubak, Vilmos; Kemeny, Lajos; Kondorosi, Eva; Nagy, Istvan
Background High-throughput profiling of human tissues typically yield as results the gene lists comprised of a mix of relevant molecular entities with multiple false positives that obstruct the translation of such results into mechanistic hypotheses. From general probabilistic considerations, gene lists distilled for the mechanistically relevant components can be far more useful for subsequent experimental design or data interpretation. Results The input candidate gene lists were processed into different tiers of evidence consistency established by enrichment analysis across subsets of the same experiments and across different experiments and platforms. The cut-offs were established empirically through ontological and semantic enrichment; resultant shortened gene list was re-expanded by Ingenuity Pathway Assistant tool. The resulting sub-networks provided the basis for generating mechanistic hypotheses that were partially validated by literature search. This approach differs from previous consistency-based studies in that the cut-off on the Receiver Operating Characteristic of the true-false separation process is optimized by flexible selection of the consistency building procedure. The gene list distilled by this analytic technique and its network representation were termed Compact Disease Model (CDM). Here we present the CDM signature for the study of early-stage Alzheimer�s disease. The integrated analysis of this gene signature allowed us to identify the protein traffic vesicles as prominent players in the pathogenesis of Alzheimer�s. Considering the distances and complexity of protein trafficking in neurons, it is plausible that spontaneous protein misfolding along with a shortage of growth stimulation result in neurodegeneration. Several potentially overlapping scenarios of early-stage Alzheimer pathogenesis have been discussed, with an emphasis on the protective effects of AT-1 mediated antihypertensive response on cytoskeleton remodeling, along with neuronal activation of oncogenes, luteinizing hormone signaling and insulin-related growth regulation, forming a pleiotropic model of its early stages. Alignment with emerging literature confirmed many predictions derived from early-stage Alzheimer�s disease� CDM. Conclusions A flexible approach for high-throughput data analysis, the Compact Disease Model generation, allows extraction of meaningful, mechanism-centered gene sets compatible with instant translation of the results into testable hypotheses. PMID:24196233
Link-based quantitative methods to identify differentially coexpressed genes and gene Pairs
Background Differential coexpression analysis (DCEA) is increasingly used for investigating the global transcriptional mechanisms underlying phenotypic changes. Current DCEA methods mostly adopt a gene connectivity-based strategy to estimate differential coexpression, which is characterized by comparing the numbers of gene neighbors in different coexpression networks. Although it simplifies the calculation, this strategy mixes up the identities of different coexpression neighbors of a gene, and fails to differentiate significant differential coexpression changes from those trivial ones. Especially, the correlation-reversal is easily missed although it probably indicates remarkable biological significance. Results We developed two link-based quantitative methods, DCp and DCe, to identify differentially coexpressed genes and gene pairs (links). Bearing the uniqueness of exploiting the quantitative coexpression change of each gene pair in the coexpression networks, both methods proved to be superior to currently popular methods in simulation studies. Re-mining of a publicly available type 2 diabetes (T2D) expression dataset from the perspective of differential coexpression analysis led to additional discoveries than those from differential expression analysis. Conclusions This work pointed out the critical weakness of current popular DCEA methods, and proposed two link-based DCEA algorithms that will make contribution to the development of DCEA and help extend it to a broader spectrum. PMID:21806838
Evolution of the rice Xa21 disease resistance gene family.
The rice disease resistance gene Xa21, encoding a receptor-like kinase, is a member of a multigene family. Sequence analysis of seven family members revealed two distinct classes of genes. One member from each class encodes a receptor kinase-like open reading frame. The other five members encode truncated open reading frames of the predicted receptor kinase. A highly conserved 233-bp sequence (HC) was also identified among the seven family members. Recombination at the HC region between family members apparently resulted in the precise swapping of promoter regions. Large sequence duplications were generated by a presumed unequal crossover event in intergenic regions. Insertions of transposon-like sequences truncated two of the predicted open reading frames. A model for amplification and diversification of the Xa21 gene family is presented. PMID:9286106
Song, W Y; Pi, L Y; Wang, G L; Gardner, J; Holsten, T; Ronald, P C
Symptomatic glycerol kinase deficiency (GKD) is associated with episodic metabolic and central nervous system deterioration. We report here the first application of weighted gene co-expression network analysis (WGCNA) to investigate a knockout (KO) murine model of a human genetic disease. WGCNA identified networks and key hub transcripts from liver mRNA of glycerol kinase (Gyk) KO and wild-type (WT) mice. Day of life 1 (dol1) samples from KO mice contained a network module enriched for organic acid metabolism before Gyk KO mice develop organic acidemia and die on dol3-4. Furthermore, the module containing Gyk was enriched with apoptotic genes. We used causal testing to elucidate the causal relationships between intramodular hub genes Acot, Psat and Plk3. Important causal relationships are confirmed in cell cultures. We provide evidence that GK may have an apoptotic moonlighting role that is lost in GKD. This first application of WGCNA to mouse knockout data provides insights into the molecular mechanisms of GKD pathogenesis. The resulting systems-genetic gene screening method identifies candidate biomarkers for GKD. PMID:19546021
MacLennan, Nicole K; Dong, Jun; Aten, Jason E; Horvath, Steve; Rahib, Lola; Ornelas, Loren; Dipple, Katrina M; McCabe, Edward R B
Dietary restriction (DR), limiting nutrient intake from diet without causing malnutrition, delays the aging process and extends lifespan in multiple organisms. The conserved life-extending effect of DR suggests the involvement of fundamental mechanisms, although these remain a subject of debate. To help decipher the life-extending mechanisms of DR, we first compiled a list of genes that if genetically altered disrupt or prevent the life-extending effects of DR. We called these DR�essential genes and identified more than 100 in model organisms such as yeast, worms, flies, and mice. In order for other researchers to benefit from this first curated list of genes essential for DR, we established an online database called GenDR (http://genomics.senescence.info/diet/). To dissect the interactions of DR�essential genes and discover the underlying lifespan-extending mechanisms, we then used a variety of network and systems biology approaches to analyze the gene network of DR. We show that DR�essential genes are more conserved at the molecular level and have more molecular interactions than expected by chance. Furthermore, we employed a guilt-by-association method to predict novel DR�essential genes. In budding yeast, we predicted nine genes related to vacuolar functions; we show experimentally that mutations deleting eight of those genes prevent the life-extending effects of DR. Three of these mutants (OPT2, FRE6, and RCR2) had extended lifespan under ad libitum, indicating that the lack of further longevity under DR is not caused by a general compromise of fitness. These results demonstrate how network analyses of DR using GenDR can be used to make phenotypically relevant predictions. Moreover, gene-regulatory circuits reveal that the DR�induced transcriptional signature in yeast involves nutrient-sensing, stress responses and meiotic transcription factors. Finally, comparing the influence of gene expression changes during DR on the interactomes of multiple organisms led us to suggest that DR commonly suppresses translation, while stimulating an ancient reproduction-related process. PMID:22912585
Wuttke, Daniel; Connor, Richard; Vora, Chintan; Craig, Thomas; Li, Yang; Wood, Shona; Vasieva, Olga; Shmookler Reis, Robert; Tang, Fusheng; de Magalhaes, Joao Pedro
Leber congenital amaurosis: genes, proteins and disease mechanisms.
Leber congenital amaurosis (LCA) is the most severe retinal dystrophy causing blindness or severe visual impairment before the age of 1 year. Linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 14 genes mutated in patients with LCA and juvenile retinal degeneration, which together explain approximately 70% of the cases. Several of these genes have also been implicated in other non-syndromic or syndromic retinal diseases, such as retinitis pigmentosa and Joubert syndrome, respectively. CEP290 (15%), GUCY2D (12%), and CRB1 (10%) are the most frequently mutated LCA genes; one intronic CEP290 mutation (p.Cys998X) is found in approximately 20% of all LCA patients from north-western Europe, although this frequency is lower in other populations. Despite the large degree of genetic and allelic heterogeneity, it is possible to identify the causative mutations in approximately 55% of LCA patients by employing a microarray-based, allele-specific primer extension analysis of all known DNA variants. The LCA genes encode proteins with a wide variety of retinal functions, such as photoreceptor morphogenesis (CRB1, CRX), phototransduction (AIPL1, GUCY2D), vitamin A cycling (LRAT, RDH12, RPE65), guanine synthesis (IMPDH1), and outer segment phagocytosis (MERTK). Recently, several defects were identified that are likely to affect intra-photoreceptor ciliary transport processes (CEP290, LCA5, RPGRIP1, TULP1). As the eye represents an accessible and immune-privileged organ, it appears to be uniquely suitable for human gene replacement therapy. Rodent (Crb1, Lrat, Mertk, Rpe65, Rpgrip1), avian (Gucy2D) and canine (Rpe65) models for LCA and profound visual impairment have been successfully corrected employing adeno-associated virus or lentivirus-based gene therapy. Moreover, phase 1 clinical trials have been carried out in humans with RPE65 deficiencies. Apart from ethical considerations inherently linked to treating children, major obstacles for the treatment of LCA could be the putative developmental deficiencies in the visual cortex in persons blind from birth (amblyopia), the absence of sufficient numbers of viable photoreceptor or RPE cells in LCA patients, and the unknown and possibly toxic effects of overexpression of transduced genes. Future LCA research will focus on the identification of the remaining causal genes, the elucidation of the molecular mechanisms of disease in the retina, and the development of gene therapy approaches for different genetic subtypes of LCA. PMID:18632300
den Hollander, Anneke I; Roepman, Ronald; Koenekoop, Robert K; Cremers, Frans P M
Expression Sensitivity Analysis of Human Disease Related Genes
Background. Genome-wide association studies (GWAS) have shown its revolutionary power in seeking the influenced loci on complex diseases genetically. Thousands of replicated loci for common traits are helpful in diseases risk assessment. However it is still difficult to elucidate the variations in these loci that directly cause susceptibility to diseases by disrupting the expression or function of a protein currently. Results. We evaluate the expression features of disease related genes and find that different diseases related genes show different expression perturbation sensitivities in various conditions. It is worth noting that the expression of some robust disease-genes doesn't show significant change in their corresponding diseases, these genes might be easily ignored in the expression profile analysis. Conclusion. Gene ontology enrichment analysis indicates that robust disease-genes execute essential function in comparison with sensitive disease-genes. The diseases associated with robust genes seem to be relatively lethal like cancer and aging. On the other hand, the diseases associated with sensitive genes are apparently nonlethal like psych and chemical dependency diseases. PMID:24350280
Ma, Liang-Xiao; Wang, Ya-Jun; Li, Xuan; Hao, Pei
The molecular complexity of genetic diseases requires novel approaches to break it down into coherent biological modules. For this purpose, many disease network models have been created and analyzed. We highlight two of them, "the human diseases networks" (HDN) and "the orphan disease networks" (ODN). However, in these models, each single node represents one disease or an ambiguous group of diseases. In these cases, the notion of diseases as unique entities reduces the usefulness of network-based methods. We hypothesize that using the clinical features (pathophenotypes) to define pathophenotypic connections between disease-causing genes improve our understanding of the molecular events originated by genetic disturbances. For this, we have built a pathophenotypic similarity gene network (PSGN) and compared it with the unipartite projections (based on gene-to-gene edges) similar to those used in previous network models (HDN and ODN). Unlike these disease network models, the PSGN uses semantic similarities. This pathophenotypic similarity has been calculated by comparing pathophenotypic annotations of genes (human abnormalities of HPO terms) in the "Human Phenotype Ontology". The resulting network contains 1075 genes (nodes) and 26197 significant pathophenotypic similarities (edges). A global analysis of this network reveals: unnoticed pairs of genes showing significant pathophenotypic similarity, a biological meaningful re-arrangement of the pathological relationships between genes, correlations of biochemical interactions with higher similarity scores and functional biases in metabolic and essential genes toward the pathophenotypic specificity and the pleiotropy, respectively. Additionally, pathophenotypic similarities and metabolic interactions of genes associated with maple syrup urine disease (MSUD) have been used to merge into a coherent pathological module.Our results indicate that pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity. PMID:23437198
Reyes-Palomares, Armando; Rodr�guez-L�pez, Roc�o; Ranea, Juan A G; S�nchez Jim�nez, Francisca; Medina, Miguel Angel
The molecular complexity of genetic diseases requires novel approaches to break it down into coherent biological modules. For this purpose, many disease network models have been created and analyzed. We highlight two of them, �the human diseases networks� (HDN) and �the orphan disease networks� (ODN). However, in these models, each single node represents one disease or an ambiguous group of diseases. In these cases, the notion of diseases as unique entities reduces the usefulness of network-based methods. We hypothesize that using the clinical features (pathophenotypes) to define pathophenotypic connections between disease-causing genes improve our understanding of the molecular events originated by genetic disturbances. For this, we have built a pathophenotypic similarity gene network (PSGN) and compared it with the unipartite projections (based on gene-to-gene edges) similar to those used in previous network models (HDN and ODN). Unlike these disease network models, the PSGN uses semantic similarities. This pathophenotypic similarity has been calculated by comparing pathophenotypic annotations of genes (human abnormalities of HPO terms) in the �Human Phenotype Ontology�. The resulting network contains 1075 genes (nodes) and 26197 significant pathophenotypic similarities (edges). A global analysis of this network reveals: unnoticed pairs of genes showing significant pathophenotypic similarity, a biological meaningful re-arrangement of the pathological relationships between genes, correlations of biochemical interactions with higher similarity scores and functional biases in metabolic and essential genes toward the pathophenotypic specificity and the pleiotropy, respectively. Additionally, pathophenotypic similarities and metabolic interactions of genes associated with maple syrup urine disease (MSUD) have been used to merge into a coherent pathological module. Our results indicate that pathophenotypes contribute to identify underlying co-dependencies among disease-causing genes that are useful to describe disease modularity. PMID:23437198
Reyes-Palomares, Armando; Rodriguez-Lopez, Rocio; Ranea, Juan A. G.; Jimenez, Francisca Sanchez; Medina, Miguel Angel
We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms. PMID:22057235
Trynka, Gosia; Hunt, Karen A; Bockett, Nicholas A; Romanos, Jihane; Mistry, Vanisha; Szperl, Agata; Bakker, Sjoerd F; Bardella, Maria Teresa; Bhaw-Rosun, Leena; Castillejo, Gemma; de la Concha, Emilio G.; de Almeida, Rodrigo Coutinho; Dias, Kerith-Rae M; van Diemen, Cleo C.; Dubois, Patrick CA; Duerr, Richard H.; Edkins, Sarah; Franke, Lude; Fransen, Karin; Gutierrez, Javier; Heap, Graham AR; Hrdlickova, Barbara; Hunt, Sarah; Izurieta, Leticia Plaza; Izzo, Valentina; Joosten, Leo AB; Langford, Cordelia; Mazzilli, Maria Cristina; Mein, Charles A; Midah, Vandana; Mitrovic, Mitja; Mora, Barbara; Morelli, Marinita; Nutland, Sarah; Nunez, Concepcion; Onengut-Gumuscu, Suna; Pearce, Kerra; Platteel, Mathieu; Polanco, Isabel; Potter, Simon; Ribes-Koninckx, Carmen; Ricano-Ponce, Isis; Rich, Stephen S.; Rybak, Anna; Santiago, Jose Luis; Senapati, Sabyasachi; Sood, Ajit; Szajewska, Hania; Troncone, Riccardo; Varade, Jezabel; Wallace, Chris; Wolters, Victorien M; Zhernakova, Alexandra; Thelma, B.K.; Cukrowska, Bozena; Urcelay, Elena; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Barrett, Jeffrey C; Plagnol, Vincent; Deloukas, Panos; Wijmenga, Cisca; van Heel, David A
Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary
J. H. Duncan Bassett; Apostolos Gogakos; Jacqueline K. White; Holly Evans; Richard M. Jacques; Anne H. van der Spek; Edward Ryder; David Sunter; Alan Boyde; Michael J. Campbell; Peter I. Croucher; Graham R. Williams
The role of FUS gene variants in neurodegenerative diseases.
The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders. PMID:24840975
Deng, Hao; Gao, Kai; Jankovic, Joseph
Hashimoto's Thyroiditis: From Genes to the Disease
Hashimoto�s thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated. Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with T-cell mediated cytotoxicity. PMID:22654557
Zaletel, Katja; Gaberscek, Simona
In a non-model staple crop like wheat (Triticum aestivumI L.), functional validation of potential drought stress responsive genes identified in Arabidopsis could provide gene targets for breeding. Virus-induced gene silencing (VIGS) of genes of interest can overcome the inherent problems of polyploidy and limited transformation potential that hamper functional validation studies in wheat. In this study, three potential candidate genes shown to be involved in abiotic stress response pathways in Arabidopsis thaliana were selected for VIGS experiments in wheat. These include Era1 (enhanced response to abscisic acid), Cyp707a (ABA 8'-hydroxylase), and Sal1 (inositol polyphosphate 1-phosphatase). Gene homologues for these three genes were identified in wheat and cloned in the viral vector barley stripe mosaic virus (BSMV) in the antisense direction, followed by rub inoculation of BSMV viral RNA transcripts onto wheat plants. Quantitative real-time PCR showed that VIGS-treated wheat plants had significant reductions in target gene transcripts. When VIGS-treated plants generated for Era1 and Sal1 were subjected to limiting water conditions, they showed increased relative water content, improved water use efficiency, reduced gas exchange, and better vigour compared to water-stressed control plants inoculated with RNA from the empty viral vector (BSMV0). In comparison, the Cyp707a-silenced plants showed no improvement over BSMV0-inoculated plants under limited water condition. These results indicate that Era1 and Sal1 play important roles in conferring drought tolerance in wheat. Other traits affected by Era1 silencing were also studied. Delayed seed germination in Era1-silenced plants suggests this gene may be a useful target for developing resistance to pre-harvest sprouting. PMID:23364940
Manmathan, Harish; Shaner, Dale; Snelling, Jacob; Tisserat, Ned; Lapitan, Nora
Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families. PMID:23028338
Thompson, Ella R.; Doyle, Maria A.; Ryland, Georgina L.; Rowley, Simone M.; Choong, David Y. H.; Tothill, Richard W.; Thorne, Heather; Barnes, Daniel R.; Li, Jason; Ellul, Jason; Philip, Gayle K.; Antill, Yoland C.; James, Paul A.; Trainer, Alison H.; Mitchell, Gillian; Campbell, Ian G.
A set-based association test identifies sex-specific gene sets associated with type 2 diabetes
Single variant analysis in genome-wide association studies (GWAS) has been proven to be successful in identifying thousands of genetic variants associated with hundreds of complex diseases. However, these identified variants only explain a small fraction of inheritable variability in many diseases, suggesting that other resources, such as multilevel genetic variations, may contribute to disease susceptibility. In this work, we proposed to combine genetic variants that belong to a gene set, such as at gene- and pathway-level to form an integrated signal aimed to identify major players that function in a coordinated manner conferring disease risk. The integrated analysis provides novel insight into disease etiology while individual signals could be easily missed by single variant analysis. We applied our approach to a genome-wide association study of type 2 diabetes (T2D) with male and female data analyzed separately. Novel sex-specific genes and pathways were identified to increase the risk of T2D. We also demonstrated the performance of signal integration through simulation studies.
He, Tao; Zhong, Ping-Shou; Cui, Yuehua
Sleeping Beauty Plays a Significant Role in Identifying Cancer Genes
Researchers at the University of Minnesota Cancer Center and the National Cancer Institute (NCI), part of the National Institutes of Health, have discovered a new method that could accelerate the way cancer-causing genes are found and could lead to a more accurate identification of the genes
The ACE gene and Alzheimer's disease susceptibility
A recent study suggested that the insertion (I) allele in intron 16�of the angiotensin converting enzyme gene (ACE) is associated with Alzheimer's disease (AD) risk. In our series of 239�necropsy confirmed late onset AD cases and 342�elderly non-demented controls aged >73 years, we found significantly different ACE genotype distributions in the case and control groups (p=0.007). Homozygotes for both the I and D alleles were associated with a higher risk compared to DI heterozygotes. While the APOE ?4 allele was strongly associated with AD risk in our series, we found no evidence for an interaction between the APOE and ACE loci. In addition, no interactions were observed between ACE and gender or age at death of the AD cases. A meta-analysis of all published reports (12�case-control series in total) suggested that both the II and ID ACE genotypes are associated with increased AD risk (odds ratio (OR) for II v DD 1.36,�95% confidence interval (CI)=1.13-1.63, OR for DI v DD 1.33,�95% CI=1.14-1.53, p=0.0002).???Keywords: Alzheimer's disease; ACE gene; I allele PMID:10978362
Narain, Y.; Yip, A.; Murphy, T.; Brayne, C.; Easton, D.; Evans, J. G.; Xuereb, J.; Cairns, N.; Esiri, M.; Furlong, R.; Rubinsztein, D.
Using Frequent Coexpression Network to Identify Gene Clusters for Breast Cancer Prognosis
In this paper, we investigated the use of gene coexpression network analyses to identify potential biomarkers for breast carcinoma prognosis. The network mining algorithm CODENSE is used to identify highly connected genome-wide gene co-expression networks among a variety of cancer types, and the resulted gene clusters are applied to a series of breast cancer microarray sets to categorize the patients
Jie Zhang; Kun Huang; Yang Xiang; Ruoming Jin
Much of a cell's activity is organized as a network of interacting modules: sets of genes coregulated to respond to different conditions. We present a probabilistic method for identifying regulatory modules from gene expression data. Our procedure identifies modules of coregulated genes, their regulators and the conditions under which regulation occurs, generating testable hypotheses in the form 'regulator X regulates
Michael Shapira; Aviv Regev; Dana Pe'er; David Botstein; Nir Friedman; Eran Segal; Daphne Koller
A Computational Study Identifies HIV Progression-Related Genes Using mRMR and Shortest Path Tracing
Since statistical relationships between HIV load and CD4+ T cell loss have been demonstrated to be weak, searching for host factors contributing to the pathogenesis of HIV infection becomes a key point for both understanding the disease pathology and developing treatments. We applied Maximum Relevance Minimum Redundancy (mRMR) algorithm to a set of microarray data generated from the CD4+ T cells of viremic non-progressors (VNPs) and rapid progressors (RPs) to identify host factors associated with the different responses to HIV infection. Using mRMR algorithm, 147 gene had been identified. Furthermore, we constructed a weighted molecular interaction network with the existing protein-protein interaction data from STRING database and identified 1331 genes on the shortest-paths among the genes identified with mRMR. Functional analysis shows that the functions relating to apoptosis play important roles during the pathogenesis of HIV infection. These results bring new insights of understanding HIV progression. PMID:24244287
Liu, Lei
To identify genes that enable the enteric redmouth disease bacterium, Yersinia ruckeri, to persist in salmonid fish, 1056 signature-tagged mini-Tn5Km2 transposon mutants of a serotype 1 strain of Y. ruckeri, RS1154, were screened in rainbow trout by immersion infection. Two rounds of screening in fish identified 25 mutants that were not re-isolated from the kidney, 7 days post-infection. Six mutants
Indervesh Dahiya; R. M. W. Stevenson
Apolipoprotein A1 Gene Polymorphisms and Risk of Early Coronary Disease
Genetic studies have identified polymorphisms at the apolipoprotein (Apo) A1 gene associated with HDL cholesterol and apolipoprotein levels, and a relationship between the severity of coronary artery disease and polymorphisms at the 5?-end of Apo A1 has been also reported. This study was designed to examine the relationship between polymorphism at the Apo A1 gene and the risk of early
Juli�n R. Reguero; Gustavo Iglesias Cubero; Alberto Batalla; Victoria Alvarez; Sergio Hevia; Arturo Cortina; Eliecer Coto
Prioritisation and Network Analysis of Crohn's Disease Susceptibility Genes
Recent Genome-Wide Association Studies (GWAS) have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development ...
Muraro, Daniele
Automatically identifying gene\\/protein terms in MEDLINE abstracts
Motivation. Natural language processing (NLP) techniques are used to extract information automatically from computer- readable literature. In biology, the identification of terms corresponding to biological substances (e.g., genes and proteins) is a necessary step that precedes the application of other NLP systems that extract biological information (e.g., protein-protein in- teractions, gene regulation events, and biochemical pathways). We have developed GPmarkup
Hong Yu; Vasileios Hatzivassiloglou; Andrey Rzhetsky; W. John Wilbur
Infectious salmon anemia (ISA) has been described as the hoof and mouth disease of salmon farming. ISA is caused by a lethal and highly communicable virus, which can have a major impact on salmon aquaculture, as demonstrated by an outbreak in Chile in 2007. A quantitative trait locus (QTL) for ISA resistance has been mapped to three microsatellite markers on linkage group (LG) 8 (Chr 15) on the Atlantic salmon genetic map. We identified bacterial artificial chromosome (BAC) clones and three fingerprint contigs from the Atlantic salmon physical map that contains these markers. We made use of the extensive BAC end sequence database to extend these contigs by chromosome walking and identified additional two markers in this region. The BAC end sequences were used to search for conserved synteny between this segment of LG8 and the fish genomes that have been sequenced. An examination of the genes in the syntenic segments of the tetraodon and medaka genomes identified candidates for association with ISA resistance in Atlantic salmon based on differential expression profiles from ISA challenges or on the putative biological functions of the proteins they encode. One gene in particular, HIV-EP2/MBP-2, caught our attention as it may influence the expression of several genes that have been implicated in the response to infection by infectious salmon anemia virus (ISAV). Therefore, we suggest that HIV-EP2/MBP-2 is a very strong candidate for the gene associated with the ISAV resistance QTL in Atlantic salmon and is worthy of further study. PMID:20396924
Li, Jieying; Boroevich, Keith A; Koop, Ben F; Davidson, William S
Gene Promoter Scan Methodology for Identifying and Classifying Coregulated Promoters
A critical challenge of the postgenomic era is to understand how genes are differentially regulated. Genetic and genomic approaches have been used successfully to assign genes to distinct regulatory networks in both prokaryotes and eukaryotes. However, little is known about what determines the differential expression of genes within a particular network, even when it involves a single transcription factor. The fact that coregulated genes may be differentially expressed suggests that subtle differences in the shared cis-acting regulatory elements are likely to be significant. This chapter describes a method, termed gene promoter scan (GPS), that discriminates among coregulated promoters by simultaneously considering a variety of cis-acting regulatory features. Application of this method to the PhoP/PhoQ two-component regulatory system of Escherichia coli and Salmonella enterica uncovered novel members of the PhoP regulon, as well as regulatory interactions that had not been discovered using previous approaches. The predictions made by GPS were validated experimentally to establish that the PhoP protein uses multiple mechanisms to control gene transcription and is a central element in a highly connected network. PMID:17628149
Zwir, Igor; Harari, Oscar; Groisman, Eduardo A.
Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice
A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.
Moyer, J.H.; Lee-Tischler, M.J.; Kwon, H.Y.; Schrick, J.J. (Univ. of Tennessee Graduate School of Biomedical Sciences, Oak Ridge, TN (United States)); Avner, E.D.; Sweeney, W.E. (Univ. of Washington, Seattle, WA (United States)); Godfrey, V.L.; Cacheiro, N.L.A.; Woychik, R.P. (Oak Ridge National Lab., TN (United States)); Wilkinson, J.E. (Univ. of Tennessee, Knoxville, TN (United States))
Disease Gene Characterization through Large-Scale Co-Expression Analysis
Background In the post genome era, a major goal of biology is the identification of specific roles for individual genes. We report a new genomic tool for gene characterization, the UCLA Gene Expression Tool (UGET). Results Celsius, the largest co-normalized microarray dataset of Affymetrix based gene expression, was used to calculate the correlation between all possible gene pairs on all platforms, and generate stored indexes in a web searchable format. The size of Celsius makes UGET a powerful gene characterization tool. Using a small seed list of known cartilage-selective genes, UGET extended the list of known genes by identifying 32 new highly cartilage-selective genes. Of these, 7 of 10 tested were validated by qPCR including the novel cartilage-specific genes SDK2 and FLJ41170. In addition, we retrospectively tested UGET and other gene expression based prioritization tools to identify disease-causing genes within known linkage intervals. We first demonstrated this utility with UGET using genetically heterogeneous disorders such as Joubert syndrome, microcephaly, neuropsychiatric disorders and type 2 limb girdle muscular dystrophy (LGMD2) and then compared UGET to other gene expression based prioritization programs which use small but discrete and well annotated datasets. Finally, we observed a significantly higher gene correlation shared between genes in disease networks associated with similar complex or Mendelian disorders. Discussion UGET is an invaluable resource for a geneticist that permits the rapid inclusion of expression criteria from one to hundreds of genes in genomic intervals linked to disease. By using thousands of arrays UGET annotates and prioritizes genes better than other tools especially with rare tissue disorders or complex multi-tissue biological processes. This information can be critical in prioritization of candidate genes for sequence analysis. PMID:20046828
Funari, Vincent A.; Harry, Bret; Strom, Samuel P.; Cohn, Dan H.; Nelson, Stanley F.
Research of Maize Leaf Disease Identifying Models Based Image Recognition
\\u000a The methods of recognition and diagnosis of main maize leaf diseases using machine vision were studied in the paper. Threshold\\u000a method was adopted to do image segmentation, and area-marking method was used calculating the num of disease as well as wiping\\u000a off redundancy dots. And then Freeman link code was used to calculate form feature. Finally diseases were deduced according
Yu-Xia Zhao; Ke-Ru Wang; Zhong-Ying Bai; Shao-Kun Li; Rui-Zhi Xie; Shi-Ju Gao
Identifying Functional Modules Using MST-Based Weighted Gene CoExpression Networks
This paper proposes an effective method for identifying functional modules of the weighted gene co-expression network using a minimum spanning tree (MST) approach coupled with network neighborhood connectivity. The MST-based gene co-expression network was reconstructed to serve as the backbone of gene co-expression network. Highly connected hub genes were identified based on the connectivity of the backbone network. All sub-networks
Atthawut Chanthaphan; Santitham Prom-on; Asawin Meechai; Jonathan Hoyin Chan
Gene sequencing project identifies abnormal gene that launches rare childhood leukemia
Research led by the St. Jude Children�s Research Hospital � Washington University Pediatric Cancer Genome Project has identified a fusion gene responsible for almost 30 percent of a rare subtype of childhood leukemia with an extremely poor prognosis. The finding offers the first evidence of a mistake that gives rise to a significant percentage of acute megakaryoblastic leukemia (AMKL) cases in children. AMKL accounts for about 10 percent of pediatric acute myeloid leukemia (AML). The discovery paves the way for desperately needed treatment advances.
Detecting differential gene expression in subgroups of a disease population.
In many disease settings, it is likely that only a subset of the disease population will exhibit certain genetic or phenotypic differences from the healthy population. Therefore, when seeking to identify genes or other explanatory factors that might be related to the disease state, we might expect a mixture distribution of the variable of interest in the disease group. A number of methods have been proposed for performing tests to identify situations for which only a subgroup of samples or patients exhibit differential expression levels. Our discussion here focuses on how inattention to standard statistical theory can lead to approaches that exhibit some serious drawbacks. We present and discuss several approaches motivated by theoretical derivations and compare to an ad hoc approach based upon identification of outliers. We find that the outlier-sum statistic proposed by Tibshirani and Hastie offers little benefit over a t-test even in the most idealized scenarios and suffers from a number of limitations including difficulty of calibration, lack of robustness to underlying distributions, high false positive rates owing to its asymmetric treatment of groups, and poor power or discriminatory ability under many alternatives. PMID:24049787
Emerson, Sarah C; Emerson, Scott S
The etiology of autoimmune thyroid disease: a story of genes and environment.
Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are prevalent autoimmune diseases, affecting up to 5% of the general population. Autoimmune thyroid diseases arise due to complex interactions between environmental and genetic factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. However, the interactions between genes and environment are yet to be defined. Among the major AITD susceptibility genes that have been identified and characterized is the HLA-DR gene locus, as well as non-MHC genes including the CTLA-4, CD40, PTPN22, thyroglobulin, and TSH receptor genes. The major environmental triggers of AITD include iodine, medications, infection, smoking, and possibly stress. Recent data on the genetic predisposition to AITD lead to novel putative mechanisms by which the genetic-environmental interactions may lead to the development of thyroid autoimmunity. PMID:19307103
Tomer, Yaron; Huber, Amanda
Clustering Gene Expression Regulators: New Approach to Disease Subtyping
One of the main challenges in modern medicine is to stratify different patient groups in terms of underlying disease molecular mechanisms as to develop more personalized approach to therapy. Here we propose novel method for disease subtyping based on analysis of activated expression regulators on a sample-by-sample basis. Our approach relies on Sub-Network Enrichment Analysis algorithm (SNEA) which identifies gene subnetworks with significant concordant changes in expression between two conditions. Subnetwork consists of central regulator and downstream genes connected by relations extracted from global literature-extracted regulation database. Regulators found in each patient separately are clustered together and assigned activity scores which are used for final patients grouping. We show that our approach performs well compared to other related methods and at the same time provides researchers with complementary level of understanding of pathway-level biology behind a disease by identification of significant expression regulators. We have observed the reasonable grouping of neuromuscular disorders (triggered by structural damage vs triggered by unknown mechanisms), that was not revealed using standard expression profile clustering. For another experiment we were able to suggest the clusters of regulators, responsible for colorectal carcinoma vs adenoma discrimination and identify frequently genetically changed regulators that could be of specific importance for the individual characteristics of cancer development. Proposed approach can be regarded as biologically meaningful feature selection, reducing tens of thousands of genes down to dozens of clusters of regulators. Obtained clusters of regulators make possible to generate valuable biological hypotheses about molecular mechanisms related to a clinical outcome for individual patient. PMID:24416320
Pyatnitskiy, Mikhail; Mazo, Ilya; Shkrob, Maria; Schwartz, Elena; Kotelnikova, Ekaterina
Clustering gene expression regulators: new approach to disease subtyping.
One of the main challenges in modern medicine is to stratify different patient groups in terms of underlying disease molecular mechanisms as to develop more personalized approach to therapy. Here we propose novel method for disease subtyping based on analysis of activated expression regulators on a sample-by-sample basis. Our approach relies on Sub-Network Enrichment Analysis algorithm (SNEA) which identifies gene subnetworks with significant concordant changes in expression between two conditions. Subnetwork consists of central regulator and downstream genes connected by relations extracted from global literature-extracted regulation database. Regulators found in each patient separately are clustered together and assigned activity scores which are used for final patients grouping. We show that our approach performs well compared to other related methods and at the same time provides researchers with complementary level of understanding of pathway-level biology behind a disease by identification of significant expression regulators. We have observed the reasonable grouping of neuromuscular disorders (triggered by structural damage vs triggered by unknown mechanisms), that was not revealed using standard expression profile clustering. For another experiment we were able to suggest the clusters of regulators, responsible for colorectal carcinoma vs adenoma discrimination and identify frequently genetically changed regulators that could be of specific importance for the individual characteristics of cancer development. Proposed approach can be regarded as biologically meaningful feature selection, reducing tens of thousands of genes down to dozens of clusters of regulators. Obtained clusters of regulators make possible to generate valuable biological hypotheses about molecular mechanisms related to a clinical outcome for individual patient. PMID:24416320
Pyatnitskiy, Mikhail; Mazo, Ilya; Shkrob, Maria; Schwartz, Elena; Kotelnikova, Ekaterina
Identifying Families with Likely Genetic Protective Factors against Alzheimer Disease
Summary Elderly individuals who lived beyond the age of 90 years without dementia were hypothesized to have increased concentrations of genetic protective factors against Alz- heimer disease (AD), conferring a reduced liability for this disease relative to less-aged nondemented elderly. However, testing this hypothesis is complicated by hav- ing to distinguish such a group from those who may lack genetic
Jeremy M. Silverman; Christopher J. Smith; Deborah B. Marin; Sandra Birstein; Marlene Mare; Richard C. Mohs; Kenneth L. Davis
The influence of disease categories on gene candidate predictions from model organism phenotypes
Background The molecular etiology is still to be identified for about half of the currently described Mendelian diseases in humans, thereby hindering efforts to find treatments or preventive measures. Advances, such as new sequencing technologies, have led to increasing amounts of data becoming available with which to address the problem of identifying disease genes. Therefore, automated methods are needed that reliably predict disease gene candidates based on available data. We have recently developed Exomiser as a tool for identifying causative variants from exome analysis results by filtering and prioritising using a number of criteria including the phenotype similarity between the disease and mouse mutants involving the gene candidates. Initial investigations revealed a variation in performance for different medical categories of disease, due in part to a varying contribution of the phenotype scoring component. Results In this study, we further analyse the performance of our cross-species phenotype matching algorithm, and examine in more detail the reasons why disease gene filtering based on phenotype data works better for certain disease categories than others. We found that in addition to misleading phenotype alignments between species, some disease categories are still more amenable to automated predictions than others, and that this often ties in with community perceptions on how well the organism works as model. Conclusions In conclusion, our automated disease gene candidate predictions are highly dependent on the organism used for the predictions and the disease category being studied. Future work on computational disease gene prediction using phenotype data would benefit from methods that take into account the disease category and the source of model organism data. PMID:25093073
Seven newly identified loci for autoimmune thyroid disease.
Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 � 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases. PMID:22922229
Cooper, Jason D; Simmonds, Matthew J; Walker, Neil M; Burren, Oliver; Brand, Oliver J; Guo, Hui; Wallace, Chris; Stevens, Helen; Coleman, Gillian; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L
Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n?=?228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer. PMID:25411967
Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.
Moffitt Cancer Center researchers identify unique immune gene signature
Researchers at Moffitt Cancer Center have discovered a unique immune gene signature that can predict the presence of microscopic lymph node-like structures in metastatic melanoma. The presence of these immune structures, the researchers said, appears to be associated with better survival and may indicate the possibility of selecting patients for immunotherapy based solely on the immune-related makeup of their tumors.
Gene expression in normal and disease states--identification of therapeutic targets.
Analysis of gene-expression patterns derived from large expressed sequence tag (EST) databases has become a valuable tool in the discovery of therapeutic targets and diagnostic markers. Sequence data derived from a wide variety of cDNA libraries offer a wealth of information for identifying genes for pharmaceutical product development. Collecting, storing, organizing, analyzing and presenting cDNA expression data requires advanced bioinformatics methods and high-performance computational equipment. Comparison of expression patterns from normal and disease tissues enables inferences about gene function to be made, and medically relevant genes as candidates for therapeutics research and development programs to be identified. PMID:8987461
Fannon, M R
Network-based global inference of human disease genes.
Deciphering the genetic basis of human diseases is an important goal of biomedical research. On the basis of the assumption that phenotypically similar diseases are caused by functionally related genes, we propose a computational framework that integrates human protein-protein interactions, disease phenotype similarities, and known gene-phenotype associations to capture the complex relationships between phenotypes and genotypes. We develop a tool named CIPHER to predict and prioritize disease genes, and we show that the global concordance between the human protein network and the phenotype network reliably predicts disease genes. Our method is applicable to genetically uncharacterized phenotypes, effective in the genome-wide scan of disease genes, and also extendable to explore gene cooperativity in complex diseases. The predicted genetic landscape of over 1000 human phenotypes, which reveals the global modular organization of phenotype-genotype relationships. The genome-wide prioritization of candidate genes for over 5000 human phenotypes, including those with under-characterized disease loci or even those lacking known association, is publicly released to facilitate future discovery of disease genes. PMID:18463613
Wu, Xuebing; Jiang, Rui; Zhang, Michael Q; Li, Shao
Network-based global inference of human disease genes
Deciphering the genetic basis of human diseases is an important goal of biomedical research. On the basis of the assumption that phenotypically similar diseases are caused by functionally related genes, we propose a computational framework that integrates human protein�protein interactions, disease phenotype similarities, and known gene�phenotype associations to capture the complex relationships between phenotypes and genotypes. We develop a tool named CIPHER to predict and prioritize disease genes, and we show that the global concordance between the human protein network and the phenotype network reliably predicts disease genes. Our method is applicable to genetically uncharacterized phenotypes, effective in the genome-wide scan of disease genes, and also extendable to explore gene cooperativity in complex diseases. The predicted genetic landscape of over 1000 human phenotypes, which reveals the global modular organization of phenotype�genotype relationships. The genome-wide prioritization of candidate genes for over 5000 human phenotypes, including those with under-characterized disease loci or even those lacking known association, is publicly released to facilitate future discovery of disease genes. PMID:18463613
Wu, Xuebing; Jiang, Rui; Zhang, Michael Q; Li, Shao
Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles
Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865
Candidate genes for limiting cholestatic intestinal injury identified by gene expression profiling
The lack of bile flow from the liver into the intestine can have devastating complications including hepatic failure, sepsis, and even death. This pathologic condition known as cholestasis can result from etiologies as diverse as total parenteral nutrition (TPN), hepatitis, and pancreatic cancer. The intestinal injury associated with cholestasis has been shown to result in decreased intestinal resistance, increased bacterial translocation, and increased endotoxemia. Anecdotal clinical evidence suggests a genetic predisposition to exaggerated injury. Recent animal research on two different strains of inbred mice demonstrating different rates of bacterial translocation with different mortality rates supports this premise. In this study, a microarray analysis of intestinal tissue following common bile duct ligation (CBDL) performed under general anesthesia on these same two strains of inbred mice was done with the goal of identifying the potential molecular mechanistic pathways responsible. Over 500 genes were increased more than 2.0-fold following CBDL. The most promising candidate genes included major urinary proteins (MUPs), serine protease-1-inhibitor (Serpina1a), and lipocalin-2 (LCN-2). Quantitative polymerase chain reaction (qPCR) validated the microarray results for these candidate genes. In an in vitro experiment using differentiated intestinal epithelial cells, inhibition of MUP-1 by siRNA resulted in increased intestinal epithelial cell permeability. Diverse novel mechanisms involving the growth hormone pathway, the acute phase response, and the innate immune response are thus potential avenues for limiting cholestatic intestinal injury. Changes in gene expression were at times found to be not only due to the CBDL but also due to the murine strain. Should further studies in cholestatic patients demonstrate interindividual variability similar to what we have shown in mice, then a �personalized medicine� approach to cholestatic patients may become possible. PMID:24179676
Alaish, Samuel M; Timmons, Jennifer; Smith, Alexis; Buzza, Marguerite S; Murphy, Ebony; Zhao, Aiping; Sun, Yezhou; Turner, Douglas J; Shea-Donahue, Terez; Antalis, Toni M; Cross, Alan; Dorsey, Susan G
Recent studies have identified more than 160 inflammatory bowel disease susceptibility loci and provided evidence for genetic heritability in disease pathogenesis. Here we describe a case of a 47-year-old White woman suffering from Crohn's disease (CD), who had four children, two with CD and two with a factor V Leiden variation. We analysed the presence of single nucleotide polymorphisms in several CD susceptibility genes. SNP analysis was carried out using commercially available assays. The female CD patient had a positive inflammatory bowel disease family history. All of the patients had a mild disease course, without fistulae or symptomatic stenosis. The patient was heterozygous for risk variants of the genes encoding nucleotide oligomerization domain 2 (NOD2) and Toll-like receptor 5 (TLR5) and a homozygous carrier of both of the identified protein tyrosine phosphatase nonreceptor type 2 (PTPN2) risk alleles. The CD-affected daughter carried heterozygous risk alleles of the genes encoding TLR5, NOD2 and PTPN2. The son, with the earliest onset of disease in the family at the age of 12 years, was heterozygous for risk alleles of autophagy 16 like 1 (ATG16L1), TLR5, NOD2 and PTPN2. This study reports an interesting pattern of CD-associated single nucleotide polymorphisms in a family with CD. This report clearly supports the observation that genetic variations, especially in genes associated with the innate immune system, contribute to disease onset. PMID:24901824
Barthel, Christiane; Spalinger, Marianne R; Brunner, Jakob; Lang, Silvia; Fried, Michael; Rogler, Gerhard; Scharl, Michael
A Multistep Screening Method to Identify Genes Using Evolutionary Transcriptome of Plants
We introduced a multistep screening method to identify the genes in plants using microarrays and ribonucleic acid (RNA)-seq transcriptome data. Our method describes the process for identifying genes using the salt-tolerance response pathways of the potato (Solanum tuberosum) plant. Gene expression was analyzed using microarrays and RNA-seq experiments that examined three potato lines (high, intermediate, and low salt tolerance) under conditions of salt stress. We screened the orthologous genes and pathway genes involved in salinity-related biosynthetic pathways, and identified nine potato genes that were candidates for salinity-tolerance pathways. The nine genes were selected to characterize their phylogenetic reconstruction with homologous genes of Arabidopsis thaliana, and a Circos diagram was generated to understand the relationships among the selected genes. The involvement of the selected genes in salt-tolerance pathways was verified by reverse transcription polymerase chain reaction analysis. One candidate potato gene was selected for physiological validation by generating dehydration-responsive element-binding 1 (DREB1)-overexpressing transgenic potato plants. The DREB1 overexpression lines exhibited increased salt tolerance and plant growth when compared to that of the control. Although the nine genes identified by our multistep screening method require further characterization and validation, this study demonstrates the power of our screening strategy after the initial identification of genes using microarrays and RNA-seq experiments. PMID:24812480
Kim, Chang-Kug; Lim, Hye-Min; Na, Jong-Kuk; Choi, Ji-Weon; Sohn, Seong-Han; Park, Soo-Chul; Kim, Young-Hwan; Kim, Yong-Kab; Kim, Dool-Yi
Identifying reference genes with stable expression from high throughput sequence data
Genes that are constitutively expressed across multiple environmental stimuli are crucial to quantifying differentially expressed genes, particularly when employing quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) assays. However, the identification of these potential reference genes in non-model organisms is challenging and is often guided by expression patterns in distantly related organisms. Here, transcriptome datasets from the diatom Thalassiosira pseudonana grown under replete, phosphorus-limited, iron-limited, and phosphorus and iron co-limited nutrient regimes were analyzed through literature-based searches for homologous reference genes, k-means clustering, and analysis of sequence counts (ASC) to identify putative reference genes. A total of 9759 genes were identified and screened for stable expression. Literature-based searches surveyed 18 generally accepted reference genes, revealing 101 homologs in T. pseudonana with variable expression and a wide range of mean tags per million. k-means analysis parsed the whole transcriptome into 15 clusters. The two most stable clusters contained 709 genes, but still had distinct patterns in expression. ASC analyses identified 179 genes that were stably expressed (posterior probability < 0.1 for 1.25 fold change). Genes known to have a stable expression pattern across the test treatments, like actin, were identified in this pool of 179 candidate genes. ASC can be employed on data without biological replicates and was more robust than the k-means approach in isolating genes with stable expression. The intersection of the genes identified through ASC with commonly used reference genes from the literature suggests that actin and ubiquitin ligase may be useful reference genes for T. pseudonana and potentially other diatoms. With the wealth of transcriptome sequence data becoming available, ASC can be easily applied to transcriptome datasets from other phytoplankton to identify reference genes. PMID:23162540
Alexander, Harriet; Jenkins, Bethany D.; Rynearson, Tatiana A.; Saito, Mak A.; Mercier, Melissa L.; Dyhrman, Sonya T.
Individually identifiable health information needs to be masked or deleted in the secondary use of data for research. We defined and identified rare visible disorders as part of de-identification of individually identifiable health information. The prevalence of these disorders was evaluated using an administrative database and conformed to our definition. Due emphasis should be given to rare visible disorders in the de-identification process of health information. PMID:16779234
Eguale, Tewodros; Bartlett, Gillian; Tamblyn, Robyn
Correctly identifying associations of genes with diseases has long been a goal in biology. With the emergence of large-scale gene-phenotype association datasets in biology, we can leverage statistical and machine learning methods to help us achieve this goal. In this paper, we present two methods for predicting gene-disease associations based on functional gene associations and gene-phenotype associations in model organisms. The first method, the Katz measure, is motivated from its success in social network link prediction, and is very closely related to some of the recent methods proposed for gene-disease association inference. The second method, called Catapult (Combining dATa Across species using Positive-Unlabeled Learning Techniques), is a supervised machine learning method that uses a biased support vector machine where the features are derived from walks in a heterogeneous gene-trait network. We study the performance of the proposed methods and related state-of-the-art methods using two different evaluation strategies, on two distinct data sets, namely OMIM phenotypes and drug-target interactions. Finally, by measuring the performance of the methods using two different evaluation strategies, we show that even though both methods perform very well, the Katz measure is better at identifying associations between traits and poorly studied genes, whereas Catapult is better suited to correctly identifying gene-trait associations overall [corrected]. PMID:23650495
Singh-Blom, U Martin; Natarajan, Nagarajan; Tewari, Ambuj; Woods, John O; Dhillon, Inderjit S; Marcotte, Edward M
Identifying mechanistic indicators of childhood asthma from blood gene expression
Asthmatic individuals have been identified as a susceptible subpopulation for air pollutants. However, asthma represents a syndrome with multiple probable etiologies, and the identification of these asthma endotypes is critical to accurately define the most susceptible subpopula...
Despite considerable progress in understanding the molecular origins of hereditary human diseases, the molecular basis of several thousand genetic diseases still remains unknown. High-throughput phenotype studies are underway to systematically assess the phenotype outcome of targeted mutations in model organisms. Thus, comparing the similarity between experimentally identified phenotypes and the phenotypes associated with human diseases can be used to suggest causal genes underlying a disease. In this manuscript, we present a method for disease gene prioritization based on comparing phenotypes of mouse models with those of human diseases. For this purpose, either human disease phenotypes are �translated� into a mouse-based representation (using the Mammalian Phenotype Ontology), or mouse phenotypes are �translated� into a human-based representation (using the Human Phenotype Ontology). We apply a measure of semantic similarity and rank experimentally identified phenotypes in mice with respect to their phenotypic similarity to human diseases. Our method is evaluated on manually curated and experimentally verified gene�disease associations for human and for mouse. We evaluate our approach using a Receiver Operating Characteristic (ROC) analysis and obtain an area under the ROC curve of up to . Furthermore, we are able to confirm previous results that the Vax1 gene is involved in Septo-Optic Dysplasia and suggest Gdf6 and Marcks as further potential candidates. Our method significantly outperforms previous phenotype-based approaches of prioritizing gene�disease associations. To enable the adaption of our method to the analysis of other phenotype data, our software and prioritization results are freely available under a BSD licence at http://code.google.com/p/phenomeblast/wiki/CAMP. Furthermore, our method has been integrated in PhenomeNET and the results can be explored using the PhenomeBrowser at http://phenomebrowser.net. PMID:22719993
Oellrich, Anika; Hoehndorf, Robert; Gkoutos, Georgios V.; Rebholz-Schuhmann, Dietrich
Positional cloning studies to identify disease genes are being carried out for many human genetic diseases. Such studies often include a genome-scan linkage analysis to identify the rough chromosomal location of a disease gene, fine structure genetic mapping to define and narrow the chromosomal interval in which the disease gene may be located, and physical mapping and gene identification in the genetically defined interval to clone the disease gene. During the planning of a positional cloning study, it is important to know that, if linkage is found, the genetic interval identified is likely to be sufficiently narrow to be dissected efficiently by methods of physical mapping and gene identification. Thus, one wishes to know the limits of resolution of a genetic linkage study. In this paper, the author determines for Mendelian diseases the distributions and moments of three measures of linkage resolution: (1) in a set of N chromosomes, the distance between the nearest crossovers that flank a disease locus, (2) the distance between the nearest genetic markers that flank the pair of flanking crossovers after a genome scan, and (3) the distance between the nearest flanking markers after additional randomly placed markers are generated and typed in an identified interval. These results provide explicit sample-size guidelines for future positional cloning studies of Mendelian diseases and make possible a more objective evaluation of whether a proposed positional cloning study is likely to be successful. The author also briefly discusses the more difficult problem of linkage resolution for complex genetic diseases. 14 refs., 1 fig., 6 tabs.
Boehnke, M. (Univ. of Michigan, Ann Arbor, MI (United States))
Mutational Analysis of Angiogenin Gene in Parkinson's Disease
Mutations in the angiogenic factor, angiogenin (ANG), have been identified in patients with both familial and sporadic amyotrophic lateral sclerosis (ALS) and are thought to have a neuroprotective function. Parkinsonism has been noted in kindreds with ANG mutations and variants in the ANG gene have been found to associate with PD in two Caucasian populations. We therefore hypothesized that mutations in ANG may also contribute to idiopathic Parkinson's disease (PD). We sequenced ANG gene in a total of 1498 participants comprising 750 PD patients and 748 age/gender matched controls from Taiwan. We identified one novel synonymous substitution, c.C100T (p.L10L), in a single heterozygous state in one PD patient, which was not observed in controls. The clinical phenotypes and [99mTc]-TORDAT-SPECT images of the p.L10L carrier were similar to that seen in idiopathic PD. In addition, we also identified one common variant, c.T330G (p.G110G, rs11701), which was previously reported to associate with PD risk in Caucasians. However, the frequency of TG/GG genotype was comparable between PD cases and controls (odds ratio: 0.85, 95% confidence interval: 0.29�2.55, P?=?0.78). Our results did not support that ANG rs11701 variant is a genetic risk factor for PD in our population. We conclude that mutations in ANG are not a common cause for idiopathic PD. PMID:25386690
Chen, Meng-Ling; Wu, Ruey-Meei; Tai, Chun-Hwei; Lin, Chin-Hsien
Disease candidate gene identification and prioritization using protein interaction networks
BACKGROUND: Although most of the current disease candidate gene identification and prioritization methods depend on functional annotations, the coverage of the gene functional annotations is a limiting factor. In the current study, we describe a candidate gene prioritization method that is entirely based on protein-protein interaction network (PPIN) analyses. RESULTS: For the first time, extended versions of the PageRank and
Jing Chen; Bruce J. Aronow; Anil G. Jegga
Genes in congenital heart disease: atrioventricular valve formation
Through the use of animal studies, many candidate genes (mainly encoding transcriptional factors and receptors) have been\\u000a implicated in the development of congenital heart disease. Thus far, only a minority of these genes have been shown to carry\\u000a mutations associated with congenital disease in humans, e.g., GATA 4, TBX-5, NOTCH1 and NKX2-5. Mutations in these genes can cause a variety
Irene C. Joziasse; Jasper J. van de Smagt; Kelly Smith; Jeroen Bakkers; Gert-Jan Sieswerda; Barbara J. M. Mulder; Peter A. Doevendans
Harnessing genomics to identify environmental determinants of heritable disease
De novo mutation is increasingly being recognized as the cause for a range of human genetic diseases and disorders. Important examples of this include inherited genetic disorders such as autism, schizophrenia, mental retardation, epilepsy, and a broad range of adverse reproductiv...
Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers of
NF can undergo transformationto malignant peripheral nerve sheath tumors (MPNST). There are no identified to quantify. pNF can undergo malignant transfor- mation to malignant peripheral nerve sheath tumors (MPNST- ment of Schwann cell precursor/Schwann cellderived pe- ripheral nerve sheath tumors, the formation
Hammerton, James
Large-scale association analysis identifies new risk loci for coronary artery disease.
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. PMID:23202125
Deloukas, Panos; Kanoni, Stavroula; Willenborg, Christina; Farrall, Martin; Assimes, Themistocles L; Thompson, John R; Ingelsson, Erik; Saleheen, Danish; Erdmann, Jeanette; Goldstein, Benjamin A; Stirrups, Kathleen; K�nig, Inke R; Cazier, Jean-Baptiste; Johansson, Asa; Hall, Alistair S; Lee, Jong-Young; Willer, Cristen J; Chambers, John C; Esko, T�nu; Folkersen, Lasse; Goel, Anuj; Grundberg, Elin; Havulinna, Aki S; Ho, Weang K; Hopewell, Jemma C; Eriksson, Niclas; Kleber, Marcus E; Kristiansson, Kati; Lundmark, Per; Lyytik�inen, Leo-Pekka; Rafelt, Suzanne; Shungin, Dmitry; Strawbridge, Rona J; Thorleifsson, Gudmar; Tikkanen, Emmi; Van Zuydam, Natalie; Voight, Benjamin F; Waite, Lindsay L; Zhang, Weihua; Ziegler, Andreas; Absher, Devin; Altshuler, David; Balmforth, Anthony J; Barroso, In�s; Braund, Peter S; Burgdorf, Christof; Claudi-Boehm, Simone; Cox, David; Dimitriou, Maria; Do, Ron; Doney, Alex S F; El Mokhtari, NourEddine; Eriksson, Per; Fischer, Krista; Fontanillas, Pierre; Franco-Cereceda, Anders; Gigante, Bruna; Groop, Leif; Gustafsson, Stefan; Hager, J�rg; Hallmans, G�ran; Han, Bok-Ghee; Hunt, Sarah E; Kang, Hyun M; Illig, Thomas; Kessler, Thorsten; Knowles, Joshua W; Kolovou, Genovefa; Kuusisto, Johanna; Langenberg, Claudia; Langford, Cordelia; Leander, Karin; Lokki, Marja-Liisa; Lundmark, Anders; McCarthy, Mark I; Meisinger, Christa; Melander, Olle; Mihailov, Evelin; Maouche, Seraya; Morris, Andrew D; M�ller-Nurasyid, Martina; Nikus, Kjell; Peden, John F; Rayner, N William; Rasheed, Asif; Rosinger, Silke; Rubin, Diana; Rumpf, Moritz P; Sch�fer, Arne; Sivananthan, Mohan; Song, Ci; Stewart, Alexandre F R; Tan, Sian-Tsung; Thorgeirsson, Gudmundur; van der Schoot, C Ellen; Wagner, Peter J; Wells, George A; Wild, Philipp S; Yang, Tsun-Po; Amouyel, Philippe; Arveiler, Dominique; Basart, Hanneke; Boehnke, Michael; Boerwinkle, Eric; Brambilla, Paolo; Cambien, Francois; Cupples, Adrienne L; de Faire, Ulf; Dehghan, Abbas; Diemert, Patrick; Epstein, Stephen E; Evans, Alun; Ferrario, Marco M; Ferri�res, Jean; Gauguier, Dominique; Go, Alan S; Goodall, Alison H; Gudnason, Villi; Hazen, Stanley L; Holm, Hilma; Iribarren, Carlos; Jang, Yangsoo; K�h�nen, Mika; Kee, Frank; Kim, Hyo-Soo; Klopp, Norman; Koenig, Wolfgang; Kratzer, Wolfgang; Kuulasmaa, Kari; Laakso, Markku; Laaksonen, Reijo; Lee, Ji-Young; Lind, Lars; Ouwehand, Willem H; Parish, Sarah; Park, Jeong E; Pedersen, Nancy L; Peters, Annette; Quertermous, Thomas; Rader, Daniel J; Salomaa, Veikko; Schadt, Eric; Shah, Svati H; Sinisalo, Juha; Stark, Klaus; Stefansson, Kari; Tr�gou�t, David-Alexandre; Virtamo, Jarmo; Wallentin, Lars; Wareham, Nicholas; Zimmermann, Martina E; Nieminen, Markku S; Hengstenberg, Christian; Sandhu, Manjinder S; Pastinen, Tomi; Syv�nen, Ann-Christine; Hovingh, G Kees; Dedoussis, George; Franks, Paul W; Lehtim�ki, Terho; Metspalu, Andres; Zalloua, Pierre A; Siegbahn, Agneta; Schreiber, Stefan; Ripatti, Samuli; Blankenberg, Stefan S; Perola, Markus; Clarke, Robert; Boehm, Bernhard O; O'Donnell, Christopher; Reilly, Muredach P; M�rz, Winfried; Collins, Rory; Kathiresan, Sekar; Hamsten, Anders; Kooner, Jaspal S; Thorsteinsdottir, Unnur; Danesh, John; Palmer, Colin N A; Roberts, Robert; Watkins, Hugh; Schunkert, Heribert; Samani, Nilesh J
Large-scale association analysis identifies new risk loci for coronary artery disease
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. PMID:23202125
Background Interactions among genomic loci (also known as epistasis) have been suggested as one of the potential sources of missing heritability in single locus analysis of genome-wide association studies (GWAS). The computational burden of searching for interactions is compounded by the extremely low threshold for identifying significant p-values due to multiple hypothesis testing corrections. Utilizing prior biological knowledge to restrict the set of candidate SNP pairs to be tested can alleviate this problem, but systematic studies that investigate the relative merits of integrating different biological frameworks and GWAS data have not been conducted. Results We developed four biologically based frameworks to identify pairwise interactions among candidate SNP pairs as follows: (1) for each human protein-coding gene, a set of SNPs associated with that gene was constructed providing a gene-based interaction model, (2) for each known biological pathway, a set of SNPs associated with the genes in the pathway was constructed providing a pathway-based interaction model, (3) a set of SNPs associated with genes in a disease-related subnetwork provides a network-based interaction model, and (4) a framework is based on the function of SNPs. The last approach uses expression SNPs (eSNPs or eQTLs), which are SNPs or loci that have defined effects on the abundance of transcripts of other genes. We constructed pairs of eSNPs and SNPs located in the target genes whose expression is regulated by eSNPs. For all four frameworks the SNP sets were exhaustively tested for pairwise interactions within the sets using a traditional logistic regression model after excluding genes that were previously identified to associate with the trait. Using previously published GWAS data for type 2 diabetes (T2D) and the biologically based pair-wise interaction modeling, we identify twelve genes not seen in the previous single locus analysis. Conclusion We present four approaches to detect interactions associated with complex diseases. The results show our approaches outperform the traditional single locus approaches in detecting genes that previously did not reach significance; the results also provide novel drug targets and biomarkers relevant to the underlying mechanisms of disease. PMID:23281810
The NACP/synuclein gene: Chromosomal assignment and screening for alterations in Alzheimer disease
The major component of the vascular and plaque amyloid deposits in Alzheimer disease is the amyloid {beta} peptide (A{beta}). A second intrinsic component of amyloid, the NAC (non-A{beta} component of amyloid) peptide, has recently been identified, and its precursor protein was named NACP. A computer homology search allowed us to establish that the human NACP gene was homologous to the rat synuclein gene. We mapped the NACP/synuclein gene to chromosome 4 and cloned three alternatively spliced transcripts in lymphocytes derived from a normal subject. We analyzed by RT-PCR and direct sequencing the entire coding region of the NACP/synuclein gene in a group of patients with familial early onset Alzheimer disease. No mutation was found in 26 unrelated patients. Further studies are required to investigate the implication of the NACP/synuclein gene in Alzheimer disease. 21 refs., 3 tabs.
Campion, D. [CHR, Rouen (France)] [CHR, Rouen (France); Martin, C.; Charbonnier, F. [Unite de Genetique, Rouen (France)] [and others] [Unite de Genetique, Rouen (France); and others
Effector CD4+ T Cell Expression Signatures and Immune-Mediated Disease Associated Genes
Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in na�ve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to na�ve CD4+ T cells of genes contained among immune�mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis. PMID:22715389
Ng, Sok Meng; Hui, Ken; Goh, Gerald; Lin, Aiping; Esplugues, Enric; Flavell, Richard A.; Abraham, Clara; Zhao, Hongyu; Cho, Judy H.
Streptococcus mutans, the primary etiological agent of human dental caries, is an obligate biofilm-forming bacterium. The goals of this study were to identify the gene(s) required for biofilm formation by this organism and to elucidate the role(s) that some of the known global regulators of gene expression play in controlling biofilm formation. In S. mutans UA159, the brpA gene (for
Zezhang T. Wen; Robert A. Burne
[The study of candidates' genes in psychiatric diseases. I. Schizophrenia].
The study concerning the importance of genetic factors in etiopathogenesis of schizophrenia is presented below. In molecular genetics research there are two most frequently applied strategies: searching of the whole genome in order to find new genes; and molecular analysis of a candidate gene. Candidate gene analysis consist in choosing a gene which could theoretically have a connection with a given certain disease. The presented reference review includes the results of study concerning candidate genes analysis referring to biochemical hypothesis of schizophrenia. The aim of the study is to find changes at the level of nucleotide sequence in DNA, which have a connection with the disease. It was stated in many medical centres that in case of schizophrenia the polymorphism of gene's receptor D3 and gene's receptor 5HT2A can be of etiological importance. It was also proved that the clinical effect of clozapine could be connected with polymorphism of gene's receptor 5HT2A. PMID:10786238
Hauser, J; Czarny, M
Using registries to identify adverse events in rheumatic diseases.
The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring. PMID:24144710
Lionetti, Geraldina; Kimura, Yukiko; Schanberg, Laura E; Beukelman, Timothy; Wallace, Carol A; Ilowite, Norman T; Winsor, Jane; Fox, Kathleen; Natter, Marc; Sundy, John S; Brodsky, Eric; Curtis, Jeffrey R; Del Gaizo, Vincent; Iyasu, Solomon; Jahreis, Angelika; Meeker-O'Connell, Ann; Mittleman, Barbara B; Murphy, Bernard M; Peterson, Eric D; Raymond, Sandra C; Setoguchi, Soko; Siegel, Jeffrey N; Sobel, Rachel E; Solomon, Daniel; Southwood, Taunton R; Vesely, Richard; White, Patience H; Wulffraat, Nico M; Sandborg, Christy I
Using Registries to Identify Adverse Events in Rheumatic Diseases
The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short- and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multicenter longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring. PMID:24144710
Lionetti, Geraldina; Kimura, Yukiko; Schanberg, Laura E.; Beukelman, Timothy; Wallace, Carol A.; Ilowite, Norman T.; Winsor, Jane; Fox, Kathleen; Natter, Marc; Sundy, John S.; Brodsky, Eric; Curtis, Jeffrey R.; Del Gaizo, Vincent; Iyasu, Solomon; Jahreis, Angelika; Meeker-O'Connell, Ann; Mittleman, Barbara B.; Murphy, Bernard M.; Peterson, Eric D.; Raymond, Sandra C.; Setoguchi, Soko; Siegel, Jeffrey N.; Sobel, Rachel E.; Solomon, Daniel; Southwood, Taunton R.; Vesely, Richard; White, Patience H.; Wulffraat, Nico M.; Sandborg, Christy I.
Ensemble Positive Unlabeled Learning for Disease Gene Identification
An increasing number of genes have been experimentally confirmed in recent years as causative genes to various human diseases. The newly available knowledge can be exploited by machine learning methods to discover additional unknown genes that are likely to be associated with diseases. In particular, positive unlabeled learning (PU learning) methods, which require only a positive training set P (confirmed disease genes) and an unlabeled set U (the unknown candidate genes) instead of a negative training set N, have been shown to be effective in uncovering new disease genes in the current scenario. Using only a single source of data for prediction can be susceptible to bias due to incompleteness and noise in the genomic data and a single machine learning predictor prone to bias caused by inherent limitations of individual methods. In this paper, we propose an effective PU learning framework that integrates multiple biological data sources and an ensemble of powerful machine learning classifiers for disease gene identification. Our proposed method integrates data from multiple biological sources for training PU learning classifiers. A novel ensemble-based PU learning method EPU is then used to integrate multiple PU learning classifiers to achieve accurate and robust disease gene predictions. Our evaluation experiments across six disease groups showed that EPU achieved significantly better results compared with various state-of-the-art prediction methods as well as ensemble learning classifiers. Through integrating multiple biological data sources for training and the outputs of an ensemble of PU learning classifiers for prediction, we are able to minimize the potential bias and errors in individual data sources and machine learning algorithms to achieve more accurate and robust disease gene predictions. In the future, our EPU method provides an effective framework to integrate the additional biological and computational resources for better disease gene predictions. PMID:24816822
Yang, Peng; Li, Xiaoli; Chua, Hon-Nian; Kwoh, Chee-Keong; Ng, See-Kiong
Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p?=?0.004; Bonferroni p?=?0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p?=?0.03; Odds ratio (OR)?=?3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p?=?0.056; OR?=?1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS. PMID:25116239
Campbell, Catarina D.; Mohajeri, Kiana; Malig, Maika; Hormozdiari, Fereydoun; Nelson, Benjamin; Du, Gaixin; Patterson, Kristen M.; Eng, Celeste; Torgerson, Dara G.; Hu, Donglei; Herman, Catherine; Chong, Jessica X.; Ko, Arthur; O'Roak, Brian J.; Krumm, Niklas; Vives, Laura; Lee, Choli; Roth, Lindsey A.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose; Brigino-Buenaventura, Emerita; Davis, Adam; Meade, Kelley; LeNoir, Michael A.; Thyne, Shannon; Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.; Shendure, Jay; Abney, Mark; Burchard, Esteban G.; Ober, Carole; Eichler, Evan E.
Elevations of circulating Fibroblast growth factor 23 (FGF23) are associated with adverse cardiovascular outcomes and progression of renal failure in chronic kidney disease (CKD). Efforts to identify gene products whose transcription is directly regulated by FGF23 stimulation of fibroblast growth factor receptors (FGFR)/?-Klotho complexes in the kidney is confounded by both systemic alterations in calcium, phosphorus and vitamin D metabolism and intrinsic alterations caused by the underlying renal pathology in CKD. To identify FGF23 responsive genes in the kidney that might explain the association between FGF23 and adverse outcomes in CKD, we performed comparative genome wide analysis of gene expression profiles in the kidney of the Collagen 4 alpha 3 null mice (Col4a3?/?) model of progressive kidney disease with kidney expression profiles of Hypophosphatemic (Hyp) and FGF23 transgenic mouse models of elevated FGF23. The different complement of potentially confounding factors in these models allowed us to identify genes that are directly targeted by FGF23. This analysis found that ?-Klotho, an anti-aging hormone and FGF23 co-receptor, was decreased by FGF23. We also identified additional FGF23-responsive transcripts and activation of networks associated with renal damage and chronic inflammation, including lipocalin 2 (Lcn2), transforming growth factor beta (TGF-?) and tumor necrosis factor-alpha (TNF-?) signaling pathways. Finally, we found that FGF23 suppresses angiotensin-converting enzyme 2 (ACE2) expression in the kidney, thereby providing a pathway for FGF23 regulation of the renin-angiotensin system. These gene products provide a possible mechanistic links between elevated FGF23 and pathways responsible for renal failure progression and cardiovascular diseases. PMID:22970174
Martin, Aline; Huang, Jinsong; Li, Hua; Jiao, Yan; Gu, Weikuan; Quarles, L. Darryl
Inductive matrix completion for predicting gene-disease associations
Motivation: Most existing methods for predicting causal disease genes rely on specific type of evidence, and are therefore limited in terms of applicability. More often than not, the type of evidence available for diseases varies�for example, we may know linked genes, keywords associated with the disease obtained by mining text, or co-occurrence of disease symptoms in patients. Similarly, the type of evidence available for genes varies�for example, specific microarray probes convey information only for certain sets of genes. In this article, we apply a novel matrix-completion method called Inductive Matrix Completion to the problem of predicting gene-disease associations; it combines multiple types of evidence (features) for diseases and genes to learn latent factors that explain the observed gene�disease associations. We construct features from different biological sources such as microarray expression data and disease-related textual data. A crucial advantage of the method is that it is inductive; it can be applied to diseases not seen at training time, unlike traditional matrix-completion approaches and network-based inference methods that are transductive. Results: Comparison with state-of-the-art methods on diseases from the Online Mendelian Inheritance in Man (OMIM) database shows that the proposed approach is substantially better�it has close to one-in-four chance of recovering a true association in the top 100 predictions, compared to the recently proposed Catapult method (second best) that has <15% chance. We demonstrate that the inductive method is particularly effective for a query disease with no previously known gene associations, and for predicting novel genes, i.e. genes that are previously not linked to diseases. Thus the method is capable of predicting novel genes even for well-characterized diseases. We also validate the novelty of predictions by evaluating the method on recently reported OMIM associations and on associations recently reported in the literature. Availability: Source code and datasets can be downloaded from http://bigdata.ices.utexas.edu/project/gene-disease. Contact: firstname.lastname@example.com PMID:24932006
Natarajan, Nagarajan; Dhillon, Inderjit S.
NIH Researchers Identify New Gene Mutation Associated with ALS and Dementia
... in the March 30, 2014, issue of Nature Neuroscience. ALS, often referred to as Lou Gehrig's disease, ... 3 gene cause familial amyotrophic lateral sclerosis. Nature Neuroscience . Published online March 30, 2014. doi:10.1038/ ...
Network Topology Reveals Key Cardiovascular Disease Genes Anida Sarajlic1,
) is a group of diseases of the heart and blood vessels and a major global cause of death, with more people1 Network Topology Reveals Key Cardiovascular Disease Genes Anida Sarajli´c1, , Vuk Janji´c1, SW72AZ, UK 2 Institute for Cardiovascular Disease "Dedinje," University of Belgrade, Serbia E
Przulj, Natasa
Variation within the Huntington's Disease Gene Influences Normal Brain Structure
Variation within the Huntington's Disease Gene Influences Normal Brain Structure Mark Mu¨ hlau1 cause neurodegenerative disorders of which Huntington's disease constitutes the most common example causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we
Gaser, Christian
Objective Identify gene expression profiles associated with OA processes in articular cartilage and determine pathways changing during the disease process. Methods Genome wide gene expression was determined in paired samples of OA affected and preserved cartilage of the same joint using microarray analysis for 33 patients of the RAAK study. Results were replicated in independent samples by RT-qPCR and immunohistochemistry. Profiles were analyzed with the online analysis tools DAVID and STRING to identify enrichment for specific pathways and protein-protein interactions. Results Among the 1717 genes that were significantly differently expressed between OA affected and preserved cartilage we found significant enrichment for genes involved in skeletal development (e.g. TNFRSF11B and FRZB). Also several inflammatory genes such as CD55, PTGES and TNFAIP6, previously identified in within-joint analyses as well as in analyses comparing preserved cartilage from OA affected joints versus healthy cartilage were among the top genes. Of note was the high up-regulation of NGF in OA cartilage. RT-qPCR confirmed differential expression for 18 out of 19 genes with expression changes of 2-fold or higher, and immunohistochemistry of selected genes showed a concordant change in protein expression. Most of these changes associated with OA severity (Mankin score) but were independent of joint-site or sex. Conclusion We provide further insights into the ongoing OA pathophysiological processes in cartilage, in particular into differences in macroscopically intact cartilage compared to OA affected cartilage, which seem relatively consistent and independent of sex or joint. We advocate that development of treatment could benefit by focusing on these similarities in gene expression changes and/or pathways. PMID:25054223
Bovee, Judith V. M. G.; Bomer, Nils; van der Breggen, Ruud; Lakenberg, Nico; Keurentjes, J. Christiaan; Goeman, Jelle J.; Slagboom, P. Eline; Nelissen, Rob G. H. H.; Bos, Steffan D.; Meulenbelt, Ingrid
Identifying Early Changes in Myocardial Microstructure in Hypertensive Heart Disease
The transition from healthy myocardium to hypertensive heart disease is characterized by a series of poorly understood changes in myocardial tissue microstructure. Incremental alterations in the orientation and integrity of myocardial fibers can be assessed using advanced ultrasonic image analysis. We used a modified algorithm to investigate left ventricular myocardial microstructure based on analysis of the reflection intensity at the myocardial-pericardial interface on B-mode echocardiographic images. We evaluated the extent to which the novel algorithm can differentiate between normal myocardium and hypertensive heart disease in humans as well as in a mouse model of afterload resistance. The algorithm significantly differentiated between individuals with uncomplicated essential hypertension (N?=?30) and healthy controls (N?=?28), even after adjusting for age and sex (P?=?0.025). There was a trend in higher relative wall thickness in hypertensive individuals compared to controls (P?=?0.08), but no difference between groups in left ventricular mass (P?=?0.98) or total wall thickness (P?=?0.37). In mice, algorithm measurements (P?=?0.026) compared with left ventricular mass (P?=?0.053) more clearly differentiated between animal groups that underwent fixed aortic banding, temporary aortic banding, or sham procedure, on echocardiography at 7 weeks after surgery. Based on sonographic signal intensity analysis, a novel imaging algorithm provides an accessible, non-invasive measure that appears to differentiate normal left ventricular microstructure from myocardium exposed to chronic afterload stress. The algorithm may represent a particularly sensitive measure of the myocardial changes that occur early in the course of disease progression. PMID:24831515
Hiremath, Pranoti; Bauer, Michael; Aguirre, Aaron D.; Cheng, Hui-Wen; Unno, Kazumasa; Patel, Ravi B.; Harvey, Bethany W.; Chang, Wei-Ting; Groarke, John D.; Liao, Ronglih; Cheng, Susan
Genome-wide identification of pseudogenes capable of disease-causing gene conversion.
Pseudogenes are remnants of gene duplication (nonprocessed pseudogenes) and retrotransposition (processed pseudogenes) events. This study describes methods for identifying gene conversion candidates from predicted pseudogenes. Pseudogenes may accumulate and harbor sequence variations over time that become disease-causing mutations when transferred to genes by gene conversion. A total of 14,476 pseudogenes were identified, including 3,426 nonprocessed pseudogenes. In addition, 1,945 nonprocessed pseudogenes that are localized near their progenitor gene were evaluated for their possible role in gene conversion and disease. All 11 known, human cases of gene conversion (with deleterious effects) involving pseudogenes were successfully identified by these methods. Among the pseudogenes identified is a retinitis pigmentosa 9 (RP9) pseudogene that carries a c.509A>G mutation which produces a p.Asp170Gly substitution that is associated with the RP9 form of autosomal dominant retinitis pigmentosa (adRP). The c.509A>G mutation in RP9 is a previously unrecognized example of gene conversion between the progenitor gene and its pseudogene. Notably, two processed pseudogenes also contain mutations associated with diseases. An inosine monophosphate dehydrogenase 1 (IMPDH1) pseudogene carries a c.676G>A mutation that produces a p.Asp226Asn substitution that causes the retinitis pigmentosa 10 (RP10) form of adRP; and a phosphoglycerate kinase 1 (PGK1) pseudogene (PGK1P1) carries a c.837T>C mutation that produces a p.Ile252Thr substitution that is associated with a phosphoglycerate kinase deficiency. Ranking of nonprocessed pseudogenes as candidates for gene conversion was also performed based on the sequence characteristics of published cases of pseudogene-mediated gene conversion. All results and tools produced by this study are available for download at: http://genome.uiowa.edu/pseudogenes. PMID:16671097
Bischof, Jared M; Chiang, Annie P; Scheetz, Todd E; Stone, Edwin M; Casavant, Thomas L; Sheffield, Val C; Braun, Terry A
Identification of Genes Expressed in Premalignant Breast Disease by Microscopy-Directed Cloning
NASA Astrophysics Data System (ADS)
Histopathologic study of human breast biopsy samples has identified specific lesions which are associated with a high risk of development of invasive breast cancer. Presumably, these lesions (collectively termed premalignant breast disease) represent the earliest recognizable morphologic expression of fundamental molecular events that lead to the development of invasive breast cancer. To study molecular events underlying premalignant breast disease, we have developed a method for isolating RNA from histologically identified lesions from frozen human breast tissue. This method specifically obtains mRNA from breast epithelial cells and has identified three genes which are differentially expressed in premalignant breast epithelial lesions. One gene identified by this method is overexpressed in four of five noncomedo ductal carcinoma in situ lesions and appears to be the human homologue of the gene encoding the M2 subunit of ribonucleotide reductase, an enzyme involved in DNA synthesis.
Jensen, Roy A.; Page, David L.; Holt, Jeffrey T.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking expression of estrogen and progesterone receptors (ER/PR) and HER2, thus limiting therapy options. We hypothesized that meta-analysis of TNBC gene expression profiles would illuminate mechanisms underlying the aggressive nature of this disease and identify therapeutic targets. Meta-analysis in the Oncomine database identified 206 genes that were recurrently deregulated in TNBC compared with non-TNBC and in tumors that metastasized or led to death within 5 years. This �aggressiveness gene list' was enriched for two core functions/metagenes: chromosomal instability (CIN) and ER signaling metagenes. We calculated an �aggressiveness score' as the ratio of the CIN metagene to the ER metagene, which identified aggressive tumors in breast cancer data sets regardless of subtype or other clinico-pathological indicators. A score calculated from six genes from the CIN metagene and two genes from the ER metagene recapitulated the aggressiveness score. By multivariate survival analysis, we show that our aggressiveness scores (from 206 genes or the 8 representative genes) outperformed several published prognostic signatures. Small interfering RNA screen revealed that the CIN metagene holds therapeutic targets against TNBC. Particularly, the inhibition of TTK significantly reduced the survival of TNBC cells and synergized with docetaxel in vitro. Importantly, mitosis-independent expression of TTK protein was associated with aggressive subgroups, poor survival and further stratified outcome within grade 3, lymph node-positive, HER2-positive and TNBC patients. In conclusion, we identified the core components of CIN and ER metagenes that identify aggressive breast tumors and have therapeutic potential in TNBC and aggressive breast tumors. Prognostication from these metagenes at the mRNA level was limited to ER-positive tumors. However, we provide evidence that mitosis-independent expression of TTK protein was prognostic in TNBC and other aggressive breast cancer subgroups, suggesting that protection of CIN/aneuploidy drives aggressiveness and treatment resistance. PMID:24752235
Al-Ejeh, F; Simpson, P T; Sanus, J M; Klein, K; Kalimutho, M; Shi, W; Miranda, M; Kutasovic, J; Raghavendra, A; Madore, J; Reid, L; Krause, L; Chenevix-Trench, G; Lakhani, S R; Khanna, K K
Genetic interactions and modifier genes in Hirschsprung's disease.
Hirschsprung's disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung's disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung's disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung's disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung's disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes. PMID:22174542
Wallace, Adam S; Anderson, Richard B
Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids
Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms �breast cancer� and �lung cancer� in conjunction with 14 separate �biofluids� (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms �(biofluid) NOT breast cancer� or �(biofluid) NOT lung cancer.� More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method�s performance. Results Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI�s On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI�s Genes & Disease, NCI�s Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer. Conclusions We developed a semi-automated process for determining a list of putative biomarkers for breast and lung cancer. New knowledge is presented in the form of biomarker lists; ranked, newly discovered biomarker-disease-biofluid relationships; and biomarker specificity across biofluids. PMID:25379168
Thoracic aortic aneurysms involving the aortic root and/or ascending aorta can lead to acute aortic dissections. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of the disease, referred to as familial TAAD (FTAAD) that can be inherited in an autosomal dominant manner with variable expression with respect to disease presentation, age of onset and associated features. Whole exome sequencing (WES) has been used to identify causative mutations in novel genes for TAAD. The strategy used to reduce the large number of rare variants identified using WES is to sequence distant relatives with TAAD and filter for heterozygous rare variants that are shared between the relatives, predicted to disrupt protein function and segregate with the TAAD phenotype in other family members. Putative genes are validated by identifying additional families with a causative mutation in the genes. This approach has successfully identified novel genes for FTAAD. PMID:23953976
Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay; Nickerson, Deborah A; Guo, Dong-chuan
Strategies for evaluating idiopathic inflammatory myopathy disease susceptibility genes.
This review outlines the progress that has been made in understanding the genetics of the idiopathic inflammatory myopathies in the previous 2 years, with a particular focus on dermatomyositis and polymyositis. A recent genome-wide association study in dermatomyositis has confirmed the importance of the major histocompatibility region in this disease, and has suggested a shared genetic etiology with other autoimmune disorders. This has led to an ongoing study of additional immune-related loci using the Immunochip array. Candidate gene studies have identified novel risk associations in non-Europeans, such as STAT4 and HLA-DRB1 in the Japanese population. Evidence for gene-environment interactions has come from two recent studies implicating smoking status and statin use with HLA alleles. This review also touches on future approaches to genetic research in myositis, including bioinformatics tools to identify causal variants, HLA imputation from existing genetic data and statistical methods to investigate shared effects between subgroups of myositis. PMID:25182674
Rothwell, Simon; Cooper, Robert G; Lamb, Janine A; Chinoy, Hector
The impact of self-identified race on epidemiologic studies of gene expression.
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4(+) lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10(-16)). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV(1)). Though unadjusted linear models of FEV(1) identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV(1) and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association. PMID:21254216
Sharma, Sunita; Murphy, Amy; Howrylak, Judie; Himes, Blanca; Cho, Michael H; Chu, Jen-Hwa; Hunninghake, Gary M; Fuhlbrigge, Anne; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Liu, Andy; Szefler, Stanley J; Strunk, Robert; Castro, Mario; Hansel, Nadia N; Diette, Gregory B; Vonakis, Becky M; Adkinson, N Franklin; Carey, Vincent J; Raby, Benjamin A
Solving genetic heterogeneity in extended families by identifying sub-types of complex diseases
The study of genetic properties of a disease requires the collection of information concerning the subjects in a set of pedigrees.\\u000a The main focus of this study was the detection of susceptible genes. However, even with large pedigrees, the heterogeneity\\u000a of phenotypes in complex diseases such as Schizophrenia, Bipolar and Autism, makes the detection of susceptible genes difficult\\u000a to accomplish.
Arafat Tayeb; Aur�lie Labbe; Alexandre Bureau; Chantal M�rette
Expression of dishevelled gene in Hirschsprung's disease
Hirschsprung�s disease (HSCR) is a congenital disorder of the enteric nervous system and is characterized by an absence of enteric ganglion cells in terminal regions of the gut during development. Dishevelled (DVL) protein is a cytoplasmic protein which plays pivotal roles in the embryonic development. In this study, we explore the cause of HSCR by studying the expression of DVL-1 and DVL-3 genes and their proteins in the aganglionic segment and the ganglionic segment of colon in HSCR patients. Materials and Methods: Specimen of aganglionic segment and ganglionic segment of colon in 50 cases of HSCR patients. Expression levels of mRNA and proteins of DVL-1 and DVL-3 were confirmed by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry staining between the aganglionic segment and the ganglionic segment of colon in HSCR patients. Results: The mRNA expression of DVL-1 and DVL-3 were 2.06 fold and 3.12 fold in the aganglionic segment colon tissues compared to the ganglionic segment, respectively. Similarly, the proteins expression of DVL-1 and DVL-3 were higher (39.71 � 4.53 vs and 53.90 � 6.79 vs) in the aganglionic segment colon tissues than in the ganglionic segment (15.01 � 2.66 and 20.13 � 3.63) by western blot. Besides, immunohistochemical staining showed that DVL-1 and DVL-3 have a significant increase in mucous and submucous layers from aganglionic colon segments compared with ganglionic segments. Conclusion: The study showed an association of DVL-1 and DVL-3 with HSCR, it may play an important role in the pathogenesis of HSCR. PMID:24040443
Chen, Dong; Mi, Jie; Wu, Mei; Wang, Weilin; Gao, Hong
We present a genome-wide association study of ileal Crohn's disease (CD) and two independent replication studies that identify five novel regions of association to CD. Specifically, in addition to the previously established CARD15 and IL23R associations, we report strong associations with independent replication to variation in the genomic regions encoding the PHOX2B, NCF4 and ATG16L1 genes, as well as a predicted gene on 16q24.1 (FAM92B) and an intergenic region on 10q21.1. We further demonstrate that the ATG16L1 gene is expressed in intestinal epithelial cell lines and that functional knock down of this gene abrogates autophagy of Salmonella typhimurium. Together these findings suggest that autophagy and host cell responses to intra-cellular microbes are involved in the pathogenesis of CD. PMID:17435756
Rioux, John D.; Xavier, Ramnik J.; Taylor, Kent D.; Silverberg, Mark S.; Goyette, Philippe; Huett, Alan; Green, Todd; Kuballa, Petric; Barmada, M. Michael; Datta, Lisa Wu; Shugart, Yin Yao; Griffiths, Anne M.; Targan, Stephan R.; Ippoliti, Andrew F.; Bernard, Edmond-Jean; Mei, Ling; Nicolae, Dan L.; Regueiro, Miguel; Schumm, L. Philip; Steinhart, A. Hillary; Rotter, Jerome I.; Duerr, Richard H.; Cho, Judy H.; Daly, Mark J.; Brant, Steven R.
Rapid in vivo forward genetic approach for identifying axon death genes in Drosophila.
Axons damaged by acute injury, toxic insults, or neurodegenerative diseases execute a poorly defined autodestruction signaling pathway leading to widespread fragmentation and functional loss. Here, we describe an approach to study Wallerian degeneration in the Drosophila L1 wing vein that allows for analysis of axon degenerative phenotypes with single-axon resolution in vivo. This method allows for the axotomy of specific subsets of axons followed by examination of progressive axonal degeneration and debris clearance alongside uninjured control axons. We developed new Flippase (FLP) reagents using proneural gene promoters to drive FLP expression very early in neural lineages. These tools allow for the production of mosaic clone populations with high efficiency in sensory neurons in the wing. We describe a collection of lines optimized for forward genetic mosaic screens using MARCM (mosaic analysis with a repressible cell marker; i.e., GFP-labeled, homozygous mutant) on all major autosomal arms (?95% of the fly genome). Finally, as a proof of principle we screened the X chromosome and identified a collection eight recessive and two dominant alleles of highwire, a ubiquitin E3 ligase required for axon degeneration. Similar unbiased forward genetic screens should help rapidly delineate axon death genes, thereby providing novel potential drug targets for therapeutic intervention to prevent axonal and synaptic loss. PMID:24958874
Neukomm, Lukas J; Burdett, Thomas C; Gonzalez, Michael A; Z�chner, Stephan; Freeman, Marc R
Genetic strains of mice represent an important resource for research on the biological determinants of complex diseases and behavioral phenotypes. To date, the approaches used have had little success in identifying causal genes. We have evaluated brain gene expression in C57BL\\/6J (B6) and DBA\\/2J (D2) inbred mouse strains using differential display to identify a number of sequences showing significant expression
Julie A. Treadwell; Kara B. Pagniello; Shiva M. Singh
Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals
Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection by different influenza A virus subtypes which would allow the identification of potential antiviral drugs with a broad anti-influenza spectrum of activity. We analyzed the cellular gene expression response to infection with five different human and avian influenza A virus strains and identified 300 genes as differentially expressed between infected and non-infected samples. The most 20 dysregulated genes were used to screen the connectivity map, a database of drug-associated gene expression profiles. Candidate antivirals were then identified by their inverse correlation to the query signature. We hypothesized that such molecules would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified and their effects were tested in vitro on five influenza A strains. Six of the molecules inhibited influenza viral growth. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five out of the eight identified molecules, demonstrating that this strategy could contribute to identifying new broad anti-influenza agents acting on cellular gene expression. The identified infection signature genes, the expression of which are modified upon infection, could encode cellular proteins involved in the viral life cycle. This is the first study showing that gene expression-based screening can be used to identify antivirals. Such an approach could accelerate drug discovery and be extended to other pathogens. PMID:20957181
Josset, Laurence; Textoris, Julien; Loriod, Beatrice; Ferraris, Olivier; Moules, Vincent; Lina, Bruno; N'Guyen, Catherine; Diaz, Jean-Jacques; Rosa-Calatrava, Manuel
Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder. PMID:16385451
Grupe, Andrew; Li, Yonghong; Rowland, Charles; Nowotny, Petra; Hinrichs, Anthony L; Smemo, Scott; Kauwe, John S K; Maxwell, Taylor J; Cherny, Sara; Doil, Lisa; Tacey, Kristina; van Luchene, Ryan; Myers, Amanda; Wavrant-De Vri�ze, Fabienne; Kaleem, Mona; Hollingworth, Paul; Jehu, Luke; Foy, Catherine; Archer, Nicola; Hamilton, Gillian; Holmans, Peter; Morris, Chris M; Catanese, Joseph; Sninsky, John; White, Thomas J; Powell, John; Hardy, John; O'Donovan, Michael; Lovestone, Simon; Jones, Lesley; Morris, John C; Thal, Leon; Owen, Michael; Williams, Julie; Goate, Alison
Rapidly evolving R genes in diverse grass species confer resistance to rice blast disease
We show that the genomes of maize, sorghum, and brachypodium contain genes that, when transformed into rice, confer resistance to rice blast disease. The genes are resistance genes (R genes) that encode proteins with nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domains (NBS�LRR proteins). By using criteria associated with rapid molecular evolution, we identified three rapidly evolving R-gene families in these species as well as in rice, and transformed a randomly chosen subset of these genes into rice strains known to be sensitive to rice blast disease caused by the fungus Magnaporthe oryzae. The transformed strains were then tested for sensitivity or resistance to 12 diverse strains of M. oryzae. A total of 15 functional blast R genes were identified among 60 NBS�LRR genes cloned from maize, sorghum, and brachypodium; and 13 blast R genes were obtained from 20 NBS�LRR paralogs in rice. These results show that abundant blast R genes occur not only within species but also among species, and that the R genes in the same rapidly evolving gene family can exhibit an effector response that confers resistance to rapidly evolving fungal pathogens. Neither conventional evolutionary conservation nor conventional evolutionary convergence supplies a satisfactory explanation of our findings. We suggest a unique mechanism termed �constrained divergence,� in which R genes and pathogen effectors can follow only limited evolutionary pathways to increase fitness. Our results open avenues for R-gene identification that will help to elucidate R-gene vs. effector mechanisms and may yield new sources of durable pathogen resistance. PMID:24145399
Yang, Sihai; Li, Jing; Zhang, Xiaohui; Zhang, Qijun; Huang, Ju; Chen, Jian-Qun; Hartl, Daniel L.; Tian, Dacheng
NASA Astrophysics Data System (ADS)
The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.
Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk
Plant disease resistance genes are a key component of defending plants from a range of pathogens. The majority of these resistance genes belong to the super-family that harbors a Nucleotide-binding site (NBS). A number of studies have focused on NBS-encoding genes in disease resistant breeding programs for diverse plants. However, little information has been reported with an emphasis on systematic analysis and comparison of NBS-encoding genes in cotton. To fill this gap of knowledge, in this study, we identified and investigated the NBS-encoding resistance genes in cotton using the whole genome sequence information of Gossypium raimondii. Totally, 355 NBS-encoding resistance genes were identified. Analyses of the conserved motifs and structural diversity showed that the most two distinct features for these genes are the high proportion of non-regular NBS genes and the high diversity of N-termini domains. Analyses of the physical locations and duplications of NBS-encoding genes showed that gene duplication of disease resistance genes could play an important role in cotton by leading to an increase in the functional diversity of the cotton NBS-encoding genes. Analyses of phylogenetic comparisons indicated that, in cotton, the NBS-encoding genes with TIR domain not only have their own evolution pattern different from those of genes without TIR domain, but also have their own species-specific pattern that differs from those of TIR genes in other plants. Analyses of the correlation between disease resistance QTL and NBS-encoding resistance genes showed that there could be more than half of the disease resistance QTL associated to the NBS-encoding genes in cotton, which agrees with previous studies establishing that more than half of plant resistance genes are NBS-encoding genes. PMID:23936305
Wei, Hengling; Li, Wei; Sun, Xiwei; Zhu, Shuijin; Zhu, Jun
Positional cloning of disease genes on chromosome 16
The project seeks to elucidate the molecular basis of an important genetic disease (Batten`s disease) by molecular cloning of the affected gene by utilizing an overlapping clone map of chromosome 16. Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a recessively inherited neurodegenerative disorder of childhood characterized by progressive loss of vision, seizures, and psychomoter disturbances. The Batten disease gene was genetically mapped to the chromosome region 16p 12.1 in close linkage with the genetic markers D16S299 and D16S298. Exon amplification of a cosmid containing D16S298 yielded a candidate gene that was disrupted by a 1 kb genomic deletion in all patients containing the most common haplotype for the disease. Two separate deletions and a point mutation altering a splice site in three unrelated families have confirmed the gene as the Batten disease gene. The disease gene encodes a novel 438 amino acid membrane binding protein of unknown function.
Doggett, N. [Los Alamos National Lab., NM (United States); Bruening, M. [Leiden Univ. (Netherlands); Callen, D. [Adelaide Women`s and Children`s Hospital, North Adelaide, South Australia (Australia); Gardiner, M. [University Coll., London (United Kingdom); Lerner, T. [Massachusetts General Hospital, Boston, MA (United States)
Gene Expression Profiling in Familial Adenomatous Polyposis Adenomas and Desmoid Disease
Gene expression profiling is a powerful method by which alterations in gene expression can be interrogated in a single experiment. The disease familial adenomatous polyposis (FAP) is associated with germline mutations in the APC gene, which result in aberrant ?-catenin control. The molecular mechanisms underlying colorectal cancer development in FAP are being characterised but limited information is available about other symptoms that occur in this disorder. Although extremely rare in the general population, desmoid tumours in approximately 10% of FAP patients. The aim of this study was to determine the similarities and differences in gene expression profiles in adenomas and compare them to those observed in desmoid tumours. Illumina whole genome gene expression BeadChips were used to measure gene expression in FAP adenomas and desmoid tumours. Similarities between gene expression profiles and mechanisms important in regulating formation of FAP adenomas and desmoid tumours were identified. This study furthers our understanding of the mechanisms underlying FAP and desmoid tumour formation. PMID:19725988
Bowden, Nikola A; Croft, Amanda; Scott, Rodney J
Adeno-associated virus mediated gene therapy for retinal degenerative diseases.
Retinal gene therapy holds great promise for the treatment of inherited and noninherited blinding diseases such as retinitis pigmentosa and age-related macular degeneration. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV) because it mediates long-term transgene expression in a variety of retinal cell types and elicits minimal immune responses. Inherited retinal diseases are nonlethal and have a wide level of genetic heterogeneity. Many of the genes have now been identified and their function elucidated, providing a major step towards the development of gene-based treatments. Extensive preclinical evaluation of gene transfer strategies in small and large animal models is key to the development of successful gene-based therapies for the retina. These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial.In this chapter, we focus on AAV-mediated specific gene therapy for inherited retinal degenerative diseases, describing the disease targets, the preclinical studies in animal models and the recent success of the LCA-RPE65 clinical trials. PMID:22034031
Stieger, Knut; Cronin, Therese; Bennett, Jean; Rolling, Fabienne
Background Parkinson�s disease (PD) is affecting 5 million people worldwide, but the response mechanisms of the striatum are still unclear. Therefore, identification of gene expression alterations in the striatum will greatly assist the development of novel therapy strategies. Methods We performed a comprehensive gene expression analysis in 15 PD patients and 15 normal controls to identify differentially expressed genes (DEGs) using the expression profile GSE20291 from Gene Expression Omnibus (GEO). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis were used to define functions and pathways altered in PD. Protein-protein interaction network was constructed to find out the modules with close interactions. Results Total715 DEGs including 268 up-regulated and 447 down-regulated genes were obtained. GO functional enrichment analysis indicated that the genes related with neurons function and cell morphogenesis might be changed upon PD. KEGG pathway enrichment analysis showed that most of the genes were enriched in the nodes of Gap junction, calcium signaling pathway, phosphatidylinositol signaling system, long-term potentiation, Alzheimer�s disease and GnRH signaling pathway. Protein-protein interaction network and module analysis suggested that some apoptosis related genes, such as PRKCA, CDC42 and BCL2 may play critical roles in striatal neurons growth. Conclusion Intrinsic striatal tyrosine hydroxylase interneurons growth may be promoted by changes in several genes expression and thus reduce the functional excitatory synapses. PMID:24256571
Bipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 � 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD. PMID:25136889
Witt, S H; Juraeva, D; Sticht, C; Strohmaier, J; Meier, S; Treutlein, J; Dukal, H; Frank, J; Lang, M; Deuschle, M; Schulze, T G; Degenhardt, F; Mattheisen, M; Brors, B; Cichon, S; N�then, M M; Witt, C C; Rietschel, M
BACKGROUND AND AIMS:Emerging data indicate that alterations in cytokine synthesis may play a role in inflammatory bowel disease (IBD) pathogenesis. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. The aim of this study was to assess the relationship between polymorphisms involving five cytokine genes (TNF-?, TGF-?, IL-10,
Michael J. Cantor; Peter Nickerson; Charles N. Bernstein
Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression
Background Prostate cancer is one of the most common complex diseases with high leading cause of death in men. Identifications of prostate cancer associated genes and biomarkers are thus essential as they can gain insights into the mechanisms underlying disease progression and advancing for early diagnosis and developing effective therapies. Methods In this study, we presented an integrative analysis of gene expression profiling and protein interaction network at a systematic level to reveal candidate disease-associated genes and biomarkers for prostate cancer progression. At first, we reconstructed the human prostate cancer protein-protein interaction network (HPC-PPIN) and the network was then integrated with the prostate cancer gene expression data to identify modules related to different phases in prostate cancer. At last, the candidate module biomarkers were validated by its predictive ability of prostate cancer progression. Results Different phases-specific modules were identified for prostate cancer. Among these modules, transcription Androgen Receptor (AR) nuclear signaling and Epidermal Growth Factor Receptor (EGFR) signalling pathway were shown to be the pathway targets for prostate cancer progression. The identified candidate disease-associated genes showed better predictive ability of prostate cancer progression than those of published biomarkers. In context of functional enrichment analysis, interestingly candidate disease-associated genes were enriched in the nucleus and different functions were encoded for potential transcription factors, for examples key players as AR, Myc, ESR1 and hidden player as Sp1 which was considered as a potential novel biomarker for prostate cancer. Conclusions The successful results on prostate cancer samples demonstrated that the integrative analysis is powerful and useful approach to detect candidate disease-associate genes and modules which can be used as the potential biomarkers for prostate cancer progression. The data, tools and supplementary files for this integrative analysis are deposited at http://www.ibio-cn.org/HPC-PPIN/. PMID:25080090
A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis
Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, pcombined = 6.23 � 10?10, is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis. PMID:19230858
Schrauwen, Isabelle; Ealy, Megan; Huentelman, Matthew J.; Thys, Melissa; Homer, Nils; Vanderstraeten, Kathleen; Fransen, Erik; Corneveaux, Jason J.; Craig, David W.; Claustres, Mireille; Cremers, Cor W.R.J.; Dhooge, Ingeborg; Van de Heyning, Paul; Vincent, Robert; Offeciers, Erwin; Smith, Richard J.H.; Van Camp, Guy
A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis.
Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, p(combined) = 6.23 x 10(-10), is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis. PMID:19230858
Schrauwen, Isabelle; Ealy, Megan; Huentelman, Matthew J; Thys, Melissa; Homer, Nils; Vanderstraeten, Kathleen; Fransen, Erik; Corneveaux, Jason J; Craig, David W; Claustres, Mireille; Cremers, Cor W R J; Dhooge, Ingeborg; Van de Heyning, Paul; Vincent, Robert; Offeciers, Erwin; Smith, Richard J H; Van Camp, Guy
Regulatory elements for the mouse growth hormone (GH) gene are located distally in a putative locus control region (LCR) in addition to key elements in the promoter proximal region. The role of promoter DNA methylation for GH gene regulation is not well understood. Pit-1 is a POU transcription factor required for normal pituitary development and obligatory for GH gene expression. In mammals, Pit-1 mutations eliminate GH production resulting in a dwarf phenotype. In this study, dwarf mice illustrated that Pit-1 function was obligatory for GH promoter hypomethylation. By monitoring promoter methylation levels during developmental GH expression we found that the GH promoter became hypomethylated coincident with gene expression. We identified a promoter differentially methylated region (DMR) that was used to characterize a methylation-dependent DNA binding activity. Upon DNA affinity purification using the DMR and nuclear extracts, we identified structural maintenance of chromosomes hinge domain containing -1 (SmcHD1). To better understand the role of SmcHD1 in genome-wide gene expression, we performed microarray analysis and compared changes in gene expression upon reduced levels of SmcHD1 in human cells. Knock-down of SmcHD1 in human embryonic kidney (HEK293) cells revealed a disproportionate number of up-regulated genes were located on the X-chromosome, but also suggested regulation of genes on non-sex chromosomes. Among those, we identified several genes located in the protocadherin ? cluster. In addition, we found that imprinted genes in the H19/Igf2 cluster associated with Beckwith-Wiedemann and Silver-Russell syndromes (BWS & SRS) were dysregulated. For the first time using human cells, we showed that SmcHD1 is an important regulator of imprinted and clustered genes. PMID:24818964
Massah, Shabnam; Hollebakken, Robert; Labrecque, Mark P.; Kolybaba, Addie M.; Beischlag, Timothy V.; Prefontaine, Gratien G.
[Genetic epidemiology--from gene to disease understanding].
Both genetic and environmental factors contribute to the aetiology of many common diseases. Recently, progress has been made in the identification of susceptibility genes by candidate gene and genome-wide association studies. Thereby, a further molecular understanding of pathophysiological pathways has been obtained and the development of new therapeutic modalities based on rational drug design has been initiated. However, a host of methods and approaches are necessary to further increase the knowledge on the aetiology of the complex diseases. PMID:20122331
Andersen, Vibeke Charlotte; Vogel, Ulla
Osteosarcoma is the most common primary malignant bone tumour. Currently osteosarcoma classification is based on histological\\u000a appearance. It was the aim of this study to use a more systematic approach to osteosarcoma classification based on gene expression\\u000a analysis and to identify subtype specific differentially expressed genes. We analysed the global gene expression profiles\\u000a of ten osteosarcoma samples using Affymetrix U133A
Bernd Kubista; Florian Klinglmueller; Martin Bilban; Martin Pfeiffer; Richard Lass; Alexander Giurea; Phillipp T. Funovics; Cyril Toma; Martin Dominkus; Rainer Kotz; Theresia Thalhammer; Klemens Trieb; Teresa Zettl; Christian F. Singer
PCR-Based Strategy To Detect and Identify Species of Phaeoacremonium Causing Grapevine Diseases
Species of Phaeoacremonium (especially Phaeoacremonium aleophilum) are associated with two severe diseases in grapevines, Petri disease in young plants and Esca disease in adult plants. Phaeoacremonium species grow slowly on culture medium, and it is difficult to identify these species on the basis of morphological characteristics. Primers Pm1 and Pm2 were designed in the ribosomal DNA internal transcribed spacer (ITS)
Angeles Aroca; Rosa Raposo
1 Identifying Alzheimer's Disease-Related Brain Regions from Multi-Modality Neuroimaging Data using University, Tempe, USA {shuang31, jing.li.8, jieping.ye, email@example.com 4 Banner Alzheimer's firstname.lastname@example.com Abstract Diagnosis of Alzheimer's disease (AD) at the early stage of the disease development is of great
Ye, Jieping
Novel gene abnormalities discovered in a subpopulation of lung and colorectal tumors could potentially identify patients with a good chance of responding to highly specific "targeted" drugs already in use for treating other cancers, scientists report.
Salk scientists identify a new gene that could stop the spread of deadly cancer
Scientists at the Salk Institute have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world's deadliest cancers.
The primary determinant for telomere replication is the enzyme telomerase, responsible for elongating the Grich strand of the telomere. The only component of this enzyme that has been identified in Saccharomyces cermzsiae is the TLCl gene, encoding the telomerase RNA subunit. However, a yeast strain defective for the ESTl gene exhibits the same phenotypes (progressively shorter telomeres and a senes-
Thomas S. Lendvay; Jeannie Sah; Bhuvana Balasubramanian; Victoria Lundblad
Purpose Identify novel tumor suppressor genes in melanoma utilizing an integrative genomic approach Methods Data from: 1) prior reports of DNA loss and gain in malignant melanoma accompanied by CGH high-definition array data of the entire human genome, 2) Microarray expression data from melanoma derived cell lines identifying genes with significantly increased expression due to methylation using a pharmacologic demethylating strategy, and 3) publicly available RNA expression microarray data of primary tumors and benign nevi was integrated utilizing statistical tools in order to define a population of candidate tumor suppressor genes. Results 27 genes were identified in areas of deletion that demonstrated diminished expression in primary melanomas relative to benign nevi and were significantly increased in expression by �5-Aza treatment. Seven genes of these genes demonstrated methylation and deletion in a validation cohort of 14 separate primary tumors. These were: CHRDL1, SFRP1, TMEM47, LPL, RARRES1, PLCXD1, and KOX15. All of these genes demonstrated growth suppressive properties with transfection into melanoma derived cell lines. Conclusions 7 putative tumor suppressor genes in malignant melanoma were identified utilizing a novel integrative technique. PMID:21606880
Mithani, Suhail K.; Smith, Ian M.; Califano, Joseph A.
Mayo Clinic identifies gene critical to development and spread of lung cancer
A single gene that promotes initial development of the most common form of lung cancer and its lethal metastases has been identified by researchers at Mayo Clinic in Florida. Their study suggests other forms of cancer may also be driven by this gene, matrix metalloproteinase-10 (MMP-10).
A novel strategy termed habitat-inducible rescue of survival (HIRS) was developed to identify genes of Pseudomonas syringae that are induced during growth on bean leaves. This strategy is based on the comple- mentation of metXW, two cotranscribed genes that are necessary for methionine biosynthesis and required for survival of P. syringae on bean leaves exposed to conditions of low humidity.
Maria L. Marco; Jennifer Legac; Steven E. Lindow
Oligonucleotide array based analysis was conducted to examine the temporal pattern of gene expression across the various stages of lung development to identify regulatory pathways at key developmental time points. Whole embryo total RNA or embryonic lung total RNA was harvested from A/J mice at seven developmental stages. To investigate changes in gene expression during lung development, four samples from each stage were examined using Affymetrix U74Av2 murine oligonucleotide microarrays. From the over 12 000 genes and ESTs represented on the array, 1346 genes and ESTs were identified as having a significant change in expression between at least one time point and the others (p<0.001, Kruskal-Wallis test). Within this group of ?1300 genes, four patterns of expression were seen: (1) upregulation during the embryonic period of development (up-down); (2) upregulation during the postnatal period of lung development (down-up) and (3) fluctuating expression, up initially, down for one or more time points, and then up again (up-down-up); and (4) vice versa (down-up-down). Expression patterns of genes previously reported to be involved in pulmonary development were also examined. Using the pathway visualisation tool, GenMapp, at least three regulatory pathways were found to contain clusters of differentially expressed genes: Wnt signalling, cell cycle, and apoptosis. Furthermore, we have shown that many of the genes involved in lung development are either known oncogenes or tumour suppressor genes altered in lung cancer, such as Cyr61, Rassf1a, and Dutt1/Robo1, or putative lung cancer genes. In addition, the genes identified pertinent to early development may also serve as candidate susceptibility genes for various inherited lung cancer disorders as well as for various heritable disorders of lung development. These results will contribute to our understanding of novel aspects of the regulatory machinery for embryonic lung development and of the genes involved in lung tumorigenesis. PMID:12807961
Bonner, A; Lemon, W; You, M
Microarray Analysis Identifies Cerebellar Genes Sensitive to Chronic Ethanol Treatment in PKC? Mice
Neuroadaptive changes that occur in the development of ethanol tolerance may be the result of alterations in gene expression. We have shown that PKC? wild-type mice develop tolerance to the sedative-hypnotic effects of ethanol after chronic ethanol treatment; whereas, mutant mice do not, making these genotypes a suitable model for identifying changes in gene expression related to tolerance development. Using a two-stage process, several genes were initially identified using microarray analyses of cerebellar tissue from ethanol-treated PKC? mutant and wild-type mice. Subsequent confirmation of a subset of these genes using qRT-PCR was done to verify gene expression changes. A total of 109 genes from different functional classifications were identified in these groups on the microarrays. Eight genes were selected for verification: three, Twik-1, Plp, and Adk2, were chosen as genes related to tolerance; another three, Hsp70.2, Bdnf, and Th, were chosen as genes related to resistance to tolerance; and two genes, JunB and Nur77, were selected as candidate genes sensitive to chronic ethanol. The results from the verification experiments indicated that Twik-1, which codes for a potassium channel, was associated with tolerance and appeared to be dependent on the presence of PKC?. No genes were confirmed to be related to resistance to tolerance; however, expression of two of these, Hsp70.2 and Th, were found to be sensitive to chronic ethanol and were added to the transcription factors, JunB and Nur77, confirmed by qRT-PCR, as a subset of genes that respond to chronic ethanol. PMID:17157717
Bowers, Barbara J.; Radcliffe, Richard A.; Smith, Amy M.; Miyamoto-Ditmon, Jill; Wehner, Jeanne M.
WNT3A has been regarded as an activator of the canonical Wnt signaling pathway. It has been found Wnt signaling pathway is closely related with embrionic development and Hirschsprung disease (HSCR). A common haplotype consisting of minor SNPs alleles located in the WNT3A gene has been described as a risk factor for various genetic disorders. However, whether WNT3A contributes to the onset of HSCR has not been identified. The present study aims to detect the interactions of genetic variations in the WNT3A gene and examine the biological expression levels with Hirschsprung disease (HSCR) in the Chinese people. We analyzed WNT3A gene (rs61743220, rs192966556 and rs145882986) variants in the whole blood samples from HSCR patients and normal children (control groups). WNT3A expression was also examined by quantitative real-time PCR (qRT-PCR), western blotting and immunostaining. Consequently, when rs192966556 and rs145882986 alleles of the WNT3A gene lack the SNPs, they are especially associated with a greater risk of HSCR (OR [95% confidence interval] = 1.791, p = 0.001; OR [95% confidence interval] = 1.556, p = 0.003, respectively). The mRNA and protein expressions of WNT3A were higher in the aganglionic colon segment tissues than in the normal ganglionic segments tissues. Immunostaining indicates that the staining of WNT3A was much stronger (brown) in the aganglionic colon segment tissues than that in the normal ganglionic colon segment tissues (colorless or light yellow) in the mucous layer and muscular layer. Although preliminary, these results suggest that WNT3A may play an important role in the pathogenesis of HSCR. PMID:24817932
Chen, Dong; Mi, Jie; Liu, Xiaomei; Zhang, Juan; Wang, Weilin; Gao, Hong
Aging syndrome genes and premature coronary artery disease
BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A\\/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models
Adrian F Low; Christopher J O'Donnell; Sekar Kathiresan; Brendan Everett; Claudia U Chae; Stanley Y Shaw; Patrick T Ellinor; Calum A MacRae
Gene therapy in nonhuman primate models of human autoimmune disease
Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey models for rheumatoid arthritis and multiple sclerosis and the (few) gene
B A t'Hart; M. J. B. M. Vervoordeldonk; J. L. Heeney; P. P. Tak
Connections between Epigenetic Gene Silencing and Human Disease
Alterations in epigenetic gene regulation are associated with human disease. Here, we discuss connections between DNA methylation and histone methylation, providing examples in which defects in these processes are linked with disease. Mutations in genes encoding DNA methyltransferases and proteins that bind methylated cytosine residues cause changes in gene expression and alterations in the patterns of DNA methylation. These changes are associated with cancer and congenital diseases due to defects in imprinting. Gene silencing is also controlled through histone methylation. Altered levels of methyltransferases that modify lysine 27 of histone H3 (K27H3) and lysine 9 of histone H3 (K9H3) correlate with changes in Rb signaling and disruption of the cell cycle in cancer cells. The K27H3 mark recruits a Polycomb complex that is involved in regulating stem cell pluripotency, silencing of developmentally regulated genes, and controlling cancer progression. The K9H3 methyl mark recruits HP1, a structural protein that plays a role in heterochromatin formation, gene silencing, and viral latency. Cells exhibiting altered levels of HP1 are predicted to show a loss of silencing at genes regulating cancer progression. Gene silencing through K27H3 and K9H3 can involve histone deacetylation and DNA methylation, suggesting cross talk between epigenetic silencing systems through direct interactions among the various players. The reversible nature of these epigenetic modifications offers therapeutic possibilities for a wide spectrum of disease. PMID:17306846
Moss, Timothy J.; Wallrath, Lori L.
Delivery of Gene and Cellular Therapies for Heart Disease
Although there has been considerable interest in the utilization of gene and cellular therapy for heart disease in recent\\u000a years, there remain critical questions prior to widespread promotion of therapy, and key among these issues is the delivery\\u000a method used for both gene therapy and cellular therapy. Much of the failure of gene and cellular therapy can be explained\\u000a by
Justin A. Mariani; David M. Kaye
For complex diseases, the relationship between genotypes, environment factors, and phenotype is usually complex and nonlinear. Our understanding of the genetic architecture of diseases has considerably increased over the last years. However, both conceptually and methodologically, detecting gene-gene and gene-environment interactions remains a challenge, despite the existence of a number of efficient methods. One method that offers great promises but has not yet been widely applied to genomic data is the entropy-based approach of information theory. In this article, we first develop entropy-based test statistics to identify two-way and higher order gene-gene and gene-environment interactions. We then apply these methods to a bladder cancer data set and thereby test their power and identify strengths and weaknesses. For two-way interactions, we propose an information gain (IG) approach based on mutual information. For three-ways and higher order interactions, an interaction IG approach is used. In both cases, we develop one-dimensional test statistics to analyze sparse data. Compared to the naive chi-square test, the test statistics we develop have similar or higher power and is robust. Applying it to the bladder cancer data set allowed to investigate the complex interactions between DNA repair gene single nucleotide polymorphisms, smoking status, and bladder cancer susceptibility. Although not yet widely applied, entropy-based approaches appear as a useful tool for detecting gene-gene and gene-environment interactions. The test statistics we develop add to a growing body methodologies that will gradually shed light on the complex architecture of common diseases. PMID:22009792
Fan, R; Zhong, M; Wang, S; Zhang, Y; Andrew, A; Karagas, M; Chen, H; Amos, C I; Xiong, M; Moore, J H
Type 2 Diabetes Mellitus (T2DM) and obesity have become increasingly prevalent in recent years. Recent studies have focused on identifying causal variations or candidate genes for obesity and T2DM via analysis of expression quantitative trait loci (eQTL) within a single tissue. T2DM and obesity are affected by comprehensive sets of genes in multiple tissues. In the current study, gene expression levels in multiple human tissues from GEO datasets were analyzed, and 21 candidate genes displaying high percentages of differential expression were filtered out. Specifically, DENND1B, LYN, MRPL30, POC1B, PRKCB, RP4-655J12.3, HIBADH, and TMBIM4 were identified from the T2DM-control study, and BCAT1, BMP2K, CSRNP2, MYNN, NCKAP5L, SAP30BP, SLC35B4, SP1, BAP1, GRB14, HSP90AB1, ITGA5, and TOMM5 were identified from the obesity-control study. The majority of these genes are known to be involved in T2DM and obesity. Therefore, analysis of gene expression in various tissues using GEO datasets may be an effective and feasible method to determine novel or causal genes associated with T2DM and obesity. PMID:24455749
Meng, Yuhuan; Zhou, Jinghui; Zhuo, Min; Ling, Fei; Zhang, Yu; Du, Hongli; Wang, Xiaoning
Much remains unknown of molecular events controlling the plant hypersensitive defense response (HR), a rapid localized cell death that limits pathogen spread and is mediated by resistance (R-) genes. Genetic control of the HR is hard to quantify due to its microscopic and rapid nature. Natural modifiers of the ectopic HR phenotype induced by an aberrant auto-active R-gene (Rp1-D21), were mapped in a population of 3,381 recombinant inbred lines from the maize nested association mapping population. Joint linkage analysis was conducted to identify 32 additive but no epistatic quantitative trait loci (QTL) using a linkage map based on more than 7000 single nucleotide polymorphisms (SNPs). Genome-wide association (GWA) analysis of 26.5 million SNPs was conducted after adjusting for background QTL. GWA identified associated SNPs that colocalized with 44 candidate genes. Thirty-six of these genes colocalized within 23 of the 32 QTL identified by joint linkage analysis. The candidate genes included genes predicted to be in involved programmed cell death, defense response, ubiquitination, redox homeostasis, autophagy, calcium signalling, lignin biosynthesis and cell wall modification. Twelve of the candidate genes showed significant differential expression between isogenic lines differing for the presence of Rp1-D21. Low but significant correlations between HR-related traits and several previously-measured disease resistance traits suggested that the genetic control of these traits was substantially, though not entirely, independent. This study provides the first system-wide analysis of natural variation that modulates the HR response in plants. PMID:25166276
Olukolu, Bode A; Wang, Guan-Feng; Vontimitta, Vijay; Venkata, Bala P; Marla, Sandeep; Ji, Jiabing; Gachomo, Emma; Chu, Kevin; Negeri, Adisu; Benson, Jacqueline; Nelson, Rebecca; Bradbury, Peter; Nielsen, Dahlia; Holland, James B; Balint-Kurti, Peter J; Johal, Gurmukh
Summary/Abstract Genes that are highly overexpressed in tumor cells can be required for tumor cell survival, and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRC) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or shRNAs, i.e., HMGA1, TACSTD2, RRM2, RPS2, and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAi-specific gene expression signatures allowed the identification of the functional space in which the five genes operate, and showed enrichment for cancer specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas we could recapitulate these defined RNAi signatures, therefore establishing the biologically relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1, and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC. PMID:20473941
Grade, Marian; Hummon, Amanda B.; Camps, Jordi; Emons, Georg; Spitzner, Melanie; Gaedcke, Jochen; Hoermann, Patrick; Ebner, Reinhard; Becker, Heinz; Difilippantonio, Michael J.; Ghadimi, B. Michael; Beissbarth, Tim; Caplen, Natasha J.; Ried, Thomas
Background Peripheral arterial disease (PAD) is a relatively common manifestation of systemic atherosclerosis that leads to progressive narrowing of the lumen of leg arteries. Circulating monocytes are in contact with the arterial wall and can serve as reporters of vascular pathology in the setting of PAD. We performed gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with PAD and controls without PAD to identify differentially regulated genes. Methods PAD was defined as an ankle brachial index (ABI) ?0.9 (n = 19) while age and gender matched controls had an ABI > 1.0 (n = 18). Microarray analysis was performed using Affymetrix HG-U133 plus 2.0 gene chips and analyzed using GeneSpring GX 11.0. Gene expression data was normalized using Robust Multichip Analysis (RMA) normalization method, differential expression was defined as a fold change ?1.5, followed by unpaired Mann-Whitney test (P < 0.05) and correction for multiple testing by Benjamini and Hochberg False Discovery Rate. Meta-analysis of differentially expressed genes was performed using an integrated bioinformatics pipeline with tools for enrichment analysis using Gene Ontology (GO) terms, pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular event enrichment using Reactome annotations and network analysis using Ingenuity Pathway Analysis suite. Extensive biocuration was also performed to understand the functional context of genes. Results We identified 87 genes differentially expressed in the setting of PAD; 40 genes were upregulated and 47 genes were downregulated. We employed an integrated bioinformatics pipeline coupled with literature curation to characterize the functional coherence of differentially regulated genes. Conclusion Notably, upregulated genes mediate immune response, inflammation, apoptosis, stress response, phosphorylation, hemostasis, platelet activation and platelet aggregation. Downregulated genes included several genes from the zinc finger family that are involved in transcriptional regulation. These results provide insights into molecular mechanisms relevant to the pathophysiology of PAD. PMID:22409835
Peripheral Blood Mononuclear Cell Gene Expression in Chronic Obstructive Pulmonary Disease
Although most cases of chronic obstructive pulmonary disease (COPD) occur in smokers, only a fraction of smokers develop the disease. We hypothesized distinct molecular signatures for COPD and emphysema in the peripheral blood mononuclear cells (PBMCs) of current and former smokers. To test this hypothesis, we identified and validated PBMC gene expression profiles in smokers with and without COPD. We generated expression data on 136 subjects from the COPDGene study, using Affymetrix U133 2.0 microarrays (Affymetrix, Santa Clara, CA). Multiple linear regression with adjustment for covariates (gender, age, body mass index, family history, smoking status, and pack-years) was used to identify candidate genes, and ingenuity pathway analysis was used to identify candidate pathways. Candidate genes were validated in 149 subjects according to multiplex quantitative real-time polymerase chain reaction, which included 75 subjects not previously profiled. Pathways that were differentially expressed in subjects with COPD and emphysema included those that play a role in the immune system, inflammatory responses, and sphingolipid (ceramide) metabolism. Twenty-six of the 46 candidate genes (e.g., FOXP1, TCF7, and ASAH1) were validated in the independent cohort. Plasma metabolomics was used to identify a novel glycoceramide (galabiosylceramide) as a biomarker of emphysema, supporting the genomic association between acid ceramidase (ASAH1) and emphysema. COPD is a systemic disease whose gene expression signatures in PBMCs could serve as novel diagnostic or therapeutic targets. PMID:23590301
Bahr, Timothy M.; Hughes, Grant J.; Armstrong, Michael; Reisdorph, Rick; Coldren, Christopher D.; Edwards, Michael G.; Schnell, Christina; Kedl, Ross; LaFlamme, Daniel J.; Reisdorph, Nichole; Kechris, Katerina J.
The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar �Dr. Davis� and a brown rot resistant introgression line, �F8,1�42�, derived from an initial almond � peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329
Martinez-Garcia, Pedro J.; Parfitt, Dan E.; Bostock, Richard M.; Fresnedo-Ramirez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A.; Gradziel, Thomas M.; Crisosto, Carlos H.
The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar 'Dr. Davis' and a brown rot resistant introgression line, 'F8,1-42', derived from an initial almond � peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329
Mart�nez-Garc�a, Pedro J; Parfitt, Dan E; Bostock, Richard M; Fresnedo-Ram�rez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A; Gradziel, Thomas M; Crisosto, Carlos H
ORIGINAL ARTICLE Gene Disease Interaction on Orbitofrontal
- ume (GMV) as a function of lifetime drug use and the genotype of the monoamine oxidase A gene, MAOA neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regu
Homes, Christopher C.
Germline Missense Changes in the APC Gene and Their Relationship to Disease
Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of adenomas that carpet the entire colon and rectum. Nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene account for the majority of mutations identified to date and predispose primarily to the typical disease phenotype. Some APC mutations are associated with a milder form of
Rodney J Scott; Renee Crooks; Lindy Rose; John Attia; Ammarin Thakkinstian; Lesley Thomas; Allan D Spigelman; Cliff J Meldrum
Prothrombotic Gene Variation in Patients with Large and Small Vessel Disease
The classification of ischemic stroke into different subtypes is supported in genetic association studies. While several gene variants have been identified as being associated with ischemia subtypes, most studies have not been powered to study subtypes separately. We investigated 887 patients with nondisabling cerebral ischemia of arterial origin and classified ischemia as being caused by large or small vessel disease
D. Martijn O. Pruissen; L. Jaap Kappelle; Frits R. Rosendaal; Ale Algra
Missense Mutations in Disease Genes: A Bayesian Approach to Evaluate Causality
community to map the human genome and identify disease causing genes has been successful in advancing our knowledge in a number of areas, such as molecular technology leading to more rapid cloning and sequencing and characterization of mutations in affected persons (Cotton, 1997). The definitive methodology is DNA sequencing
West, Mike
Charcot-Marie-Tooth Disease: Seventeen Causative Genes
Charcot-Marie-Tooth disease (CMT) is the most common form of inherited motor and sensory neuropathy. Moreover, CMT is a genetically heterogeneous disorder of the peripheral nervous system, with many genes identified as CMT-causative. CMT has two usual classifications: type 1, the demyelinating form (CMT1); and type 2, the axonal form (CMT2). In addition, patients are classified as CMTX if they have an X-linked inheritance pattern and CMT4 if the inheritance pattern is autosomal recessive. A large amount of new information on the genetic causes of CMT has become available, and mutations causing it have been associated with more than 17 different genes and 25 chromosomal loci. Advances in our understanding of the molecular basis of CMT have revealed an enormous diversity in genetic mechanisms, despite a clinical entity that is relatively uniform in presentation. In addition, recent encouraging studies - shown in CMT1A animal models - concerning the therapeutic effects of certain chemicals have been published; these suggest potential therapies for the most common form of CMT, CMT1A. This review focuses on the inherited motor and sensory neuropathy subgroup for which there has been an explosion of new molecular genetic information over the past decade. PMID:20396492
Lee, Jung-Hwa
Genetic study of neurexin and neuroligin genes in Alzheimer's disease.
The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632-0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males. PMID:23403532
Martinez-Mir, Amalia; Gonz�lez-P�rez, Antonio; Gay�n, Javier; Ant�nez, Carmen; Mar�n, Juan; Boada, Merc�; Lopez-Arrieta, Jes�s Mar�a; Fern�ndez, Evaristo; Ram�rez-Lorca, Reposo; S�ez, Mar�a Eugenia; Ruiz, Agust�n; Scholl, Francisco G; Real, Luis Miguel
Quantitative trait loci analysis to identify modifiers genes of the gene opaque2 in maize endosperm
clusters for amino acid contents were located on chromosomes 7 and 8 that explained up to 39% of the observed variation. The product of the O2 gene is a transcription factor that affects the expression of a number of endosperm genes. A group of 29 endosperm...
Gutierrez Rojas, Libardo Andres
Credibility Analysis of Putative Disease-Causing Genes Using Bioinformatics
Background Genetic studies are challenging in many complex diseases, particularly those with limited diagnostic certainty, low prevalence or of old age. The result is that genes may be reported as disease-causing with varying levels of evidence, and in some cases, the data may be so limited as to be indistinguishable from chance findings. When there are large numbers of such genes, an objective method for ranking the evidence is useful. Using the neurodegenerative and complex disease amyotrophic lateral sclerosis (ALS) as a model, and the disease-specific database ALSoD, the objective is to develop a method using publicly available data to generate a credibility score for putative disease-causing genes. Methods Genes with at least one publication suggesting involvement in adult onset familial ALS were collated following an exhaustive literature search. SQL was used to generate a score by extracting information from the publications and combined with a pathogenicity analysis using bioinformatics tools. The resulting score allowed us to rank genes in order of credibility. To validate the method, we compared the objective ranking with a rank generated by ALS genetics experts. Spearman's Rho was used to compare rankings generated by the different methods. Results The automated method ranked ALS genes in the following order: SOD1, TARDBP, FUS, ANG, SPG11, NEFH, OPTN, ALS2, SETX, FIG4, VAPB, DCTN1, TAF15, VCP, DAO. This compared very well to the ranking of ALS genetics experts, with Spearman's Rho of 0.69 (P?=?0.009). Conclusion We have presented an automated method for scoring the level of evidence for a gene being disease-causing. In developing the method we have used the model disease ALS, but it could equally be applied to any disease in which there is genotypic uncertainty. PMID:23755159
Abel, Olubunmi; Powell, John F.; Andersen, Peter M.; Al-Chalabi, Ammar
DNA repair is essential to maintain genome integrity, and genes with roles in DNA repair are frequently mutated in a variety of human diseases. Repair via homologous recombination typically restores the original DNA sequence without introducing mutations, and a number of genes that are required for homologous recombination DNA double-strand break repair (HR-DSBR) have been identified. However, a systematic analysis of this important DNA repair pathway in mammalian cells has not been reported. Here, we describe a genome-scale endoribonuclease-prepared short interfering RNA (esiRNA) screen for genes involved in DNA double strand break repair. We report 61 genes that influenced the frequency of HR-DSBR and characterize in detail one of the genes that decreased the frequency of HR-DSBR. We show that the gene KIAA0415 encodes a putative helicase that interacts with SPG11 and SPG15, two proteins mutated in hereditary spastic paraplegia (HSP). We identify mutations in HSP patients, discovering KIAA0415/SPG48 as a novel HSP-associated gene, and show that a KIAA0415/SPG48 mutant cell line is more sensitive to DNA damaging drugs. We present the first genome-scale survey of HR-DSBR in mammalian cells providing a dataset that should accelerate the discovery of novel genes with roles in DNA repair and associated medical conditions. The discovery that proteins forming a novel protein complex are required for efficient HR-DSBR and are mutated in patients suffering from HSP suggests a link between HSP and DNA repair. PMID:20613862
Slabicki, Mikolaj; Theis, Mirko; Krastev, Dragomir B.; Samsonov, Sergey; Mundwiller, Emeline; Junqueira, Magno; Paszkowski-Rogacz, Maciej; Teyra, Joan; Heninger, Anne-Kristin; Poser, Ina; Prieur, Fabienne; Truchetto, Jeremy; Confavreux, Christian; Marelli, Cecilia; Durr, Alexandra; Camdessanche, Jean Philippe; Brice, Alexis; Shevchenko, Andrej; Pisabarro, M. Teresa; Stevanin, Giovanni; Buchholz, Frank
Network-based methods for human disease gene prediction
networks, with integration of other large-scale gen- omic data or disease phenotype information, to infer to the discovery of candidate genes [4]. Traditional genetic mapping methods include linkage analysis and genome to such systems may lead to various human diseases using both high-throughput experi- mental and integrative
Yu, Haiyuan
Gene and cell-based therapies for heart disease
Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent develop- ments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection
We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P?=?0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution. PMID:24615902
Gresle, Melissa M; Schulz, Katrin; Jonas, Anna; Perreau, Victoria M; Cipriani, Tania; Baxter, Alan G; Miranda-Hernandez, Socorro; Field, Judith; Jokubaitis, Vilija G; Cherny, Robert; Volitakis, Irene; David, Samuel; Kilpatrick, Trevor J; Butzkueven, Helmut
Background: We conducted a genome-wide association study (GWAS) to identify specific genetic variants that underlie susceptibility to diseases caused by Staphylococcus aureus in humans. Methods: Cases (n = 309) and controls (n = 2925) were genotyped at 508,921 single nucleotide polymorphisms (SNPs). Cases had at least one laboratory and clinician confirmed disease caused by S. aureus whereas controls did not. R-package (for SNP association), EIGENSOFT (to estimate and adjust for population stratification) and gene- (VEGAS) and pathway-based (DAVID, PANTHER, and Ingenuity Pathway Analysis) analyses were performed. Results: No SNP reached genome-wide significance. Four SNPs exceeded the p < 10?5 threshold including two (rs2455012 and rs7152530) reaching a p-value < 10?7. The nearby genes were PDE4B (rs2455012), TXNRD2 (rs3804047), VRK1 and BCL11B (rs7152530), and PNPLA5 (rs470093). The top two findings from the gene-based analysis were NMRK2 (pgene = 1.20E-05), which codes an integrin binding molecule (focal adhesion), and DAPK3 (pgene = 5.10E-05), a serine/threonine kinase (apoptosis and cytokinesis). The pathway analyses identified epithelial cell responses to mechanical and non-mechanical stress. Conclusion: We identified potential susceptibility genes for S. aureus diseases in this preliminary study but confirmation by other studies is needed. The observed associations could be relevant given the complexity of S. aureus as a pathogen and its ability to exploit multiple biological pathways to cause infections in humans. PMID:24847357
Ye, Zhan; Vasco, Daniel A.; Carter, Tonia C.; Brilliant, Murray H.; Schrodi, Steven J.; Shukla, Sanjay K.
Integrated analysis of recurrent properties of cancer genes to identify novel drivers
The heterogeneity of cancer genomes in terms of acquired mutations complicates the identification of genes whose modification may exert a driver role in tumorigenesis. In this study, we present a novel method that integrates expression profiles, mutation effects, and systemic properties of mutated genes to identify novel cancer drivers. We applied our method to ovarian cancer samples and were able to identify putative drivers in the majority of carcinomas without mutations in known cancer genes, thus suggesting that it can be used as a complementary approach to find rare driver mutations that cannot be detected using frequency-based approaches. PMID:23718799
Background During gene conversion, genetic information is transferred unidirectionally between highly homologous but non-allelic regions of DNA. While germ-line gene conversion has been implicated in the pathogenesis of some diseases, somatic gene conversion has remained technically difficult to investigate on a large scale. Methods A novel analysis technique is proposed for detecting the signature of somatic gene conversion from SNP microarray data. The Wellcome Trust Case Control Consortium has gathered SNP microarray data for two control populations and cohorts for bipolar disorder (BD), cardiovascular disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), type-1 diabetes (T1D) and type-2 diabetes (T2D). Using the new analysis technique, the seven disease cohorts are analyzed to identify cohort-specific SNPs at which conversion is predicted. The quality of the predictions is assessed by identifying known disease associations for genes in the homologous duplicons, and comparing the frequency of such associations with background rates. Results Of 28 disease/locus pairs meeting stringent conditions, 22 show various degrees of disease association, compared with only 8 of 70 in a mock study designed to measure the background association rate (P < 10-9). Additional candidate genes are identified using less stringent filtering conditions. In some cases, somatic deletions appear likely. RA has a distinctive pattern of events relative to other diseases. Similarities in patterns are apparent between BD and HT. Conclusions The associations derived represent the first evidence that somatic gene conversion could be a significant causative factor in each of the seven diseases. The specific genes provide potential insights about disease mechanisms, and are strong candidates for further study. Please see Commentary: http://www.biomedcentral.com/1741-7015/9/13/abstract. PMID:21291537
Gene Linked to Lou Gehrig's Disease
Scientists have just taken a big step toward understanding the cause of Lou Gehrig's disease, one of the most devastating nerve degenerative diseases. A large team of researchers, led by Robert Brown Jr. of Harvards's Massachusetts General Hospital and Robert Horvitz, a Howard Hughes Medical Institute investigator at the Massachusetts Institute of Technology, report in the 4 March Nature that
Jean Marx
Peripheral blood gene expression profiling for cardiovascular disease assessment
Whole blood gene expression profiling has the potential to be informative about dynamic changes in disease states and to provide information on underlying disease mechanisms. Having demonstrated proof of concept in animal models, a number of studies have now tried to tackle the complexity of cardiovascular disease in human hosts to develop better diagnostic and prognostic indicators. These studies show that genomic signatures are capable of classifying patients with cardiovascular diseases into finer categories based on the molecular architecture of a patient�s disease and more accurately predict the likelihood of a cardiovascular event than current techniques. To highlight the spectrum of potential applications of whole blood gene expression profiling approach in cardiovascular science, we have chosen to review the findings in a number of complex cardiovascular diseases such as atherosclerosis, hypertension and myocardial infarction as well as thromboembolism, aortic aneurysm, and heart transplant. PMID:18923935
Aziz, Hamza; Zaas, Aimee
The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-?) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-?. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. PMID:25268627
Liao, Juan; Jijon, Humberto B.; Kim, Ira R.; Goel, Gautam; Doan, Aivi; Sokol, Harry; Bauer, Hermann; Herrmann, Bernhard G.; Lassen, Kara G.; Xavier, Ramnik J.
A text-mining technique for extracting gene-disease associations from the biomedical literature.
We propose a new text mining technique to identify associations between biological entities, specifically genes-diseases associations, from the biomedical literature. The proposed method is very simple and straightforward; it uses two sets (a positive set and a negative set) of documents and utilises the concepts of expectation (ex), evidence (ev), and Z-scores in combining positive and negative evidences in determining the significant gene-disease associations from Medline documents. Moreover, the method offers an efficient way to handle gene names, aliases, symbols, and abbreviations. We evaluated the method in discovering gene-to-disease associations from literature and the experimental results are impressive. We verified our results and confirmed the effectiveness of the proposed technique by various ways. For example, we ran the technique on some discovered and known genes-diseases relationships. Our method was able to discover associations between genes and various diseases like Amyotrophic lateral sclerosis, Tuberous Sclerosis, Autism, Homocystinuria, Bipolar Disorder, Atherosclerosis and more. PMID:20615835
Al-Mubaid, Hisham; Singh, Rajit K
Background Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD). While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC) differentiation by tmem59 is explored on the genome-level. Results We identified regulators of tmem59 during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred tmem59 related gene network including 36 genes, pou6f1 was identified to regulate tmem59 significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that tmem59 locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of pou6f1 could significantly up-regulate tmem59 expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including Ace, aqp1, arrdc3, cd14, cd59a, cds1, cldn1, cox8b, defb11, folr1, gdi2, mmp3, mgp, myrip, Ripk4, rnd3, and sncg. The localization of tmem59 related genes and functional-related gene groups based on the Gene Ontology (GO) annotation was also identified. Conclusions Our findings suggest that the expression of tmem59 is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to identifying genes for AD. PMID:21955788
The extremely dismal prognosis of pancreatic cancer (PC) is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA)-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes) were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation. PMID:24376604
Guo, Jun-Chao; Li, Jian; Yang, Ying-Chi; Zhou, Li; Zhang, Tai-Ping; Zhao, Yu-Pei
The extremely dismal prognosis of pancreatic cancer (PC) is attributed, at least in part, to lack of early diagnosis. Therefore, identifying differentially expressed genes in multiple steps of tumorigenesis of PC is of great interest. In the present study, a 7,12-dimethylbenzanthraene (DMBA)-induced PC model was established in male Sprague-Dawley rats. The gene expression profile was screened using an oligonucleotide microarray, followed by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemical staining validation. A total of 661 differentially expressed genes were identified in stages of pancreatic carcinogenesis. According to GO classification, these genes were involved in multiple molecular pathways. Using two-way hierarchical clustering analysis, normal pancreas, acute and chronic pancreatitis, PanIN, early and advanced pancreatic cancer were completely discriminated. Furthermore, 11 upregulated and 142 downregulated genes (probes) were found by Mann-Kendall trend Monotone test, indicating homologous genes of rat and human. The qRT-PCR and immunohistochemistry analysis of CXCR7 and UBe2c, two of the identified genes, confirmed the microarray results. In human PC cell lines, knockdown of CXCR7 resulted in decreased migration and invasion. Collectively, our data identified several promising markers and therapeutic targets of PC based on a comprehensive screening and systemic validation. PMID:24376604
Zhou, Li; Zhang, Tai-Ping; Zhao, Yu-Pei
Gene Set Enrichment in eQTL Data Identifies Novel Annotations and Pathway Regulators
Genome-wide gene expression profiling has been extensively used to generate biological hypotheses based on differential expression. Recently, many studies have used microarrays to measure gene expression levels across genetic mapping populations. These gene expression phenotypes have been used for genome-wide association analyses, an analysis referred to as expression QTL (eQTL) mapping. Here, eQTL analysis was performed in adipose tissue from 28 inbred strains of mice. We focused our analysis on �trans-eQTL bands�, defined as instances in which the expression patterns of many genes were all associated to a common genetic locus. Genes comprising trans-eQTL bands were screened for enrichments in functional gene sets representing known biological pathways, and genes located at associated trans-eQTL band loci were considered candidate transcriptional modulators. We demonstrate that these patterns were enriched for previously characterized relationships between known upstream transcriptional regulators and their downstream target genes. Moreover, we used this strategy to identify both novel regulators and novel members of known pathways. Finally, based on a putative regulatory relationship identified in our analysis, we identified and validated a previously uncharacterized role for cyclin H in the regulation of oxidative phosphorylation. We believe that the specific molecular hypotheses generated in this study will reveal many additional pathway members and regulators, and that the analysis approaches described herein will be broadly applicable to other eQTL data sets. PMID:18464898
Wu, Chunlei; Delano, David L.; Mitro, Nico; Su, Stephen V.; Janes, Jeff; McClurg, Phillip; Batalov, Serge; Welch, Genevieve L.; Zhang, Jie; Orth, Anthony P.; Walker, John R.; Glynne, Richard J.; Cooke, Michael P.; Takahashi, Joseph S.; Shimomura, Kazuhiro; Kohsaka, Akira; Bass, Joseph; Saez, Enrique; Wiltshire, Tim; Su, Andrew I.
Prior expression quantitative trait locus (eQTL) studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM) data sets obtained from The Cancer Genome Atlas (TCGA) to systematically investigate germline variation�s contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05) mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05). Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05). Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis. PMID:25133526
Chen, Qing-Rong; Hu, Ying; Yan, Chunhua; Buetow, Kenneth; Meerzaman, Daoud
Prioritisation and Network Analysis of Crohn's Disease Susceptibility Genes
Recent Genome-Wide Association Studies (GWAS) have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greatest influence on pathological behaviour, in a manner recognizing how multiple relevant genes may yield integrative effect. In this work we apply mathematical analysis of networks involving the list of recently described Crohn's susceptibility genes, to prioritise pathways in relation to their potential development of this disease. Prioritisation was performed by applying a text mining and a diffusion based method (GRAIL, GPEC). Prospective biological significance of the resulting prioritised list of proteins is highlighted by changes in their gene expression levels in Crohn's patients intestinal tissue in comparison with healthy donors. PMID:25268122
Muraro, Daniele; Lauffenburger, Douglas A.; Simmons, Alison
A P-element insertion screen identified mutations in 455 novel essential genes in Drosophila.
With the completion of the nucleotide sequences of several complex eukaryotic genomes, tens of thousands of genes have been predicted. However, this information has to be correlated with the functions of those genes to enhance our understanding of biology and to improve human health care. The Drosophila transposon P-element-induced mutations are very useful for directly connecting gene products to their biological function. We designed an efficient transposon P-element-mediated gene disruption procedure and performed genetic screening for single P-element insertion mutations, enabling us to recover 2500 lethal mutations. Among these, 2355 are second chromosome mutations. Sequences flanking >2300 insertions that identify 850 different genes or ESTs (783 genes on the second chromosome and 67 genes on the third chromosome) have been determined. Among these, 455 correspond to genes for which no lethal mutation has yet been reported. The Drosophila genome is thought to contain approximately 3600 vital genes; 1400 are localized on the second chromosome. Our mutation collection represents approximately 56% of the second chromosome vital genes and approximately 24% of the total vital Drosophila genes. PMID:12586707
Oh, Su-Wan; Kingsley, Tracy; Shin, Hyun-hee; Zheng, Zhiyu; Chen, Hua-Wei; Chen, Xiu; Wang, Hong; Ruan, Peizheng; Moody, Michelle; Hou, Steven X
Fundamental questions about genes, inactivity, and chronic diseases
Booth FW, Lees SJ. Fundamental questions about genes, inactivity, and chronic diseases. Physiol Genomics 28: 146-157, 2007. First pub- lished October 10, 2006; doi:10.1152\\/physiolgenomics.00174.2006.� Currently our society is faced with the challenge of understanding the biological basis for the epidemics of obesity and many chronic diseases, including Type 2 diabetes. Physical inactivity increases the relative risk of coronary artery disease
Frank W. Booth; Simon J. Lees
Interaction between the ?-T catenin gene (VR22) and APOE in Alzheimer's disease
Background: APOE is the only gene that has been consistently replicated as a risk factor for late onset Alzheimer's disease. Several recent studies have identified linkage to chromosome 10 for both risk and age of onset, suggesting that this region harbours genes that influence the development of the disease. A recent study reported association between single nucleotide polymorphisms (SNPs) in the VR22 gene (CTNNA3) on chromosome 10 and plasma levels of A�42, an endophenotype related to Alzheimer's disease. Objective: To assess whether polymorphisms in the VR22 gene are associated with Alzheimer's disease in a large sample of Alzheimer's disease families and an independent set of unrelated cases and controls. Results: Several SNPs showed association in either the family based or case�control analyses (p<0.05). The most consistent findings were with SNP6, for which there was significant evidence of association in both the families and the unrelated cases and controls. Furthermore, there was evidence of significant interaction between APOE-4 and two of the VR22 SNPs, with the strongest evidence of association being concentrated in individuals carrying APOE-4. Conclusions: This study suggests that VR22 or a nearby gene influences susceptibility to Alzheimer's disease, and the effect is dependent on APOE status. PMID:16199552
Martin, E; Bronson, P; Li, Y; Wall, N; Chung, R; Schmechel, D; Small, G; Xu, P; Bartlett, J; Schnetz-Boutaud, N; Haines, J; Gilbert, J; Pericak-Vance, M
Celiac disease: a model disease for gene-environment interaction
Celiac sprue remains a model autoimmune disease for dissection of genetic and environmental influences on disease progression. The 2010 Congress of Autoimmunity included several key sessions devoted to genetics and environment. Several papers from these symposia were selected for in-depth discussion and publication. This issue is devoted to this theme. The goal is not to discuss genetic and environmental interactions, but rather to focus on key elements of diagnosis, the inflammatory response and the mechanisms of autoimmunity. PMID:21317918
Uibo, Raivo; Tian, Zhigang; Gershwin, M Eric
Methods for detecting additional genes underlying Alzheimer disease
Alzheimer`s disease (AD) is a complex inherited disorder with proven genetic heterogeneity. To date, genes on chromosome 21 (APP) and 14 (not yet identified) are associated with early-onset familial AD, while the APOE gene on chromosome 19 is associated with both late onset familial and sporadic AD and early onset sporadic AD. Although these genes likely account for the majority of AD, many familial cases cannot be traced to any of these genes. From a set of 127 late-onset multiplex families screened for APOE, 43 (34%) families have at least one affected individual with no APOE-4 allele, suggesting an alternative genetic etiology. Simulation studies indicated that additional loci could be identified through a genomic screen with a 10 cM sieve on a subset of 21 well documented, non-APOE-4 families. Given the uncertainties in the mode of inheritance, reliance on a single analytical method could result in a missed linkage. Therefore, we have developed a strategy of using multiple overlapping yet complementary methods to detect linkage. These include sib-pair analysis and affected-pedigree-member analysis, neither of which makes assumptions about mode of inheritance, and lod score analysis (using two predefined genetic models). In order for a marker to qualify for follow-up, it must fit at least two of three criteria. These are nominal P values of 0.05 or less for the non-parametric methods, and/or a lod score greater than 1.0. Adjacent markers each fulfilling a single criterion also warrant follow-up. To date, we have screened 61 markers on chromosomes 1, 2, 3, 18, 19, 21, and 22. One marker, D2S163, generated a lod score of 1.06 ({theta} = 0.15) and an APMT statistic of 3.68 (P < 0.001). This region is currently being investigated in more detail. Updated results of this region plus additional screening data will be presented.
Locke, P.A.; Haines, J.L.; Ter-Minassian, M. [Massachusetts General Hospital, Boston, MA (United States)] [and others
In a search for genes and pathways implicated in T-cell lymphoblastic lymphoma (T-LBL) development, we used a murine lymphoma model, where mice of the NMRI-inbred strain were inoculated with murine leukemia virus mutants. The resulting tumors were analyzed by integration analysis and global gene expression profiling to determine the effect of the retroviral integrations on the nearby genes, and the deregulated pathways in the tumors. Gene expression profiling identified increased expression of genes involved in the minichromosome maintenance and origin of recognition pathway as well as downregulation in negative regulators of G1/S transition, indicating increased S-phase initiation in murine T-LBLs. PMID:23896059
Dabrowska, Magdalena Julia; Ejegod, Ditte; Lassen, Louise Berkhoudt; Johnsen, Hans Erik; Wabl, Matthias; Pedersen, Finn Skou; Dybk�r, Karen
Science and Artificial Intelligence, University of Granada, E-18071 Granada, Spain tel: (34) (958) 240469Identifying the promoter features governing differential kinetics of co-regulated genes using fuzzy sites for a transcriptional regulator, and identify recurrent relationships among these features termed
Granada, Universidad de
Identification of the von Hippel-Lindau disease tumor suppressor gene
A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients and from sporadic renal cell carcinomas. The VHL gene is evolutionarily conserved and encodes two widely expressed transcripts of approximately 6 and 6.5 kilobases. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. 17 refs., 4 figs. 1 tab.
Latif, F.; Masahiro Yao; Orcutt, L.; Kuzmin, I.; Fangwei Zhou; Zbar, B.; Lerman, M.I.; Dean, M. (National Cancer Inst., Frederick, MD (United States)); Tory, K.; Fuhmei Duh; Stackhouse, T.; Modi, W.; Geil, L.; Schmidt, L.; Hua Li; Ming Hui Wei; Fan Chen; Glavac, D. (Program Resources, Inc./DynCorp, Frederick, MD (United States) National Cancer Inst., Frederick, MD (United States)); Gnarra, J.; Walther, M.M.; Yongkai Weng; Duan, D.S.R.; Linehan, W.M.; Glenn, G.; Choyke, P. (National Cancer Inst., Bethesda, MD (United States)); Richards, F.M.; Crossey, P.A.; Ferguson-Smith, M.A.; Maher, E.R. (Cambridge Univ. (United Kingdom)); Paslier D. Le; Chumakov, I.; Cohen, D. (Centre d'Etude du Polymorphisme Humain, Paris (France)); Chinault, A.C. (Baylor College, Houston, TX (United States))
Currently there is a lack of targeted therapies that lead to long-term attenuation or regression of disease in patients with advanced clear cell renal cell carcinoma (ccRCC). Our group has implemented a high-throughput genetic analysis coupled with a high-throughput proliferative screen in order to investigate the genetic contributions of a large cohort of overexpressed genes at the functional level in an effort to better understand factors involved in tumor initiation and progression. Patient gene array analysis identified transcripts that are consistently elevated in patient ccRCC as compared to matched normal renal tissues. This was followed by a high-throughput lentivirus screen, independently targeting 195 overexpressed transcripts identified in the gene array in four ccRCC cell lines. This revealed 31 �hits� that contribute to ccRCC cell proliferation. Many of the hits identified are not only presented in the context of ccRCC for the first time, but several have not been previously linked to cancer. We further characterize the function of a group of hits in tumor cell invasion. Taken together these findings reveal pathways that may be critical in ccRCC tumorigenicity, and identifies novel candidate factors that could serve as targets for therapeutic intervention or diagnostic/prognostic biomarkers for patients with advanced ccRCC. PMID:24979721
von Roemeling, Christina A.; Marlow, Laura A.; Radisky, Derek C.; Rohl, Austin; Larsen, Hege E.; Wei, Johnny; Sasinowska, Heather; Zhu, Heng; Drake, Richard; Sasinowski, Maciek; Tun, Han W.; Copland, John A.
[Gene analysis of maple syrup urine disease (MSUD)].
Maple syrup urine disease (MSUD), an autosomal recessive hereditary metabolic disorder, is due to defective oxidative decarboxylation of the branched-chain alpha-ketoacids (BCKAs) derived from transamination of the three branched-chain amino acids, valine, leucine and isoleucine. The oxidative decarboxylation of three BCKAs is catalysed by the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. BCKDH consists of three catalytic components: E1, E2 and E3. The E1 component is further composed of two subunits, E1 alpha and E1 beta. To clarify the mechanisms involved in MSUD, measurements of the enzyme activity in cultured cells, measurements of the generation time in cultured cells, complementation analysis and immunoblot analysis were performed. To further elucidate the molecular mechanisms of MSUD, we and others isolated and characterized cDNAs encoding BCKDH-E1 alpha, E1 beta, E2 and E3. The human genome structures of BCKDH -E1 alpha, E1 beta and E2 were also characterized. Gene mutations in E1 alpha, E1 beta and E2, respectively, were identified at the molecular level in three cases of classical MSUD. It became clear that the molecular mechanisms of MSUD involved not only the function of each subunit but also the protein-protein interactions between each subunit. In an attempt to further analyse the molecular basis of MSUD, we carried out complementation analyses by somatic cell hybridization, and identified the affected component of BCKDH complex in the MSUD patient. Furthermore, to rapidly screen for gene mutations, we used PCR-SSCP analysis. Seventeen patients with MSUD were examined using these methods. Defects of E1 alpha, E1 beta and E2 subunits were suspected in 8, 5, and 4 patients, respectively, by complementation analysis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8350511
Mitsubuchi, H; Nobukuni, Y; Hayashida, Y; Ohta, K; Indo, Y; Akaboshi, I; Endo, F; Matsuda, I
The MEN1 gene and associated diseases: An update
Heterozygous germline mutations of the tumor suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized\\u000a by the combined occurrence of pituitary, parathyroid, and enteropancreatic tumors. Various types of mutations likely causing\\u000a loss of the gene function have been identified throughout the entire gene region in patients with MEN1 and related
Toshihiko Tsukada; Ken Yamaguchi; Toru Kameya
Background Microbe-associated molecular patterns, such as those present in bacterial flagellin, are powerful inducers of the innate immune response in plants. Successful pathogens deliver virulence proteins, termed effectors, into the plant cell where they can interfere with the immune response and promote disease. Engineering the plant immune system to enhance disease resistance requires a thorough understanding of its components. Results We describe a high-throughput screen, using RNA sequencing and virus-induced gene silencing, to identify tomato genes whose expression is enhanced by the flagellin microbe-associated molecular pattern flgII-28, but reduced by activities of the Pseudomonas syringae pv. tomato (Pst) type III effectors AvrPto and AvrPtoB. Gene ontology terms for this category of Flagellin-induced repressed by effectors (FIRE) genes showed enrichment for genes encoding certain subfamilies of protein kinases and transcription factors. At least 25 of the FIRE genes have been implicated previously in plant immunity. Of the 92 protein kinase-encoding FIRE genes, 33 were subjected to virus-induced gene silencing and their involvement in pattern-triggered immunity was tested with a leaf-based assay. Silencing of one FIRE gene, which encodes the cell wall-associated kinase SlWAK1, compromised the plant immune response resulting in increased growth of Pst and enhanced disease symptoms. Conclusions Our transcriptomic approach identifies FIRE genes that represent a pathogen-defined core set of immune-related genes. The analysis of this set of candidate genes led to the discovery of a cell wall-associated kinase that participates in plant defense. The FIRE genes will be useful for further elucidation of the plant immune system. PMID:24359686
The Praomyini tribe is one of the most diverse and abundant groups of Old World rodents. Several species are known to be involved in crop damage and in the epidemiology of several human and cattle diseases. Due to the existence of sibling species their identification is often problematic. Thus an easy, fast and accurate species identification tool is needed for non-systematicians to correctly identify Praomyini species. In this study we compare the usefulness of three genes (16S, Cytb, CO1) for identifying species of this tribe. A total of 426 specimens representing 40 species (sampled across their geographical range) were sequenced for the three genes. Nearly all of the species included in our study are monophyletic in the neighbour joining trees. The degree of intra-specific variability tends to be lower than the divergence between species, but no barcoding gap is detected. The success rate of the statistical methods of species identification is excellent (up to 99% or 100% for statistical supervised classification methods as the k-Nearest Neighbour or Random Forest). The 16S gene is 2.5 less variable than the Cytb and CO1 genes. As a result its discriminatory power is smaller. To sum up, our results suggest that using DNA markers for identifying species in the Praomyini tribe is a largely valid approach, and that the CO1 and Cytb genes are better DNA markers than the 16S gene. Our results confirm the usefulness of statistical methods such as the Random Forest and the 1-NN methods to assign a sequence to a species, even when the number of species is relatively large. Based on our NJ trees and the distribution of all intraspecific and interspecific pairwise nucleotide distances, we highlight the presence of several potentially new species within the Praomyini tribe that should be subject to corroboration assessments. PMID:22574186
Nicolas, Violaine; Schaeffer, Brigitte; Missoup, Alain Didier; Kennis, Jan; Colyn, Marc; Denys, Christiane; Tatard, Caroline; Cruaud, Corinne; Laredo, Catherine
Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately ...
Hu, Xinli
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.
Background Non-coding DNA in and around the human Amyloid Precursor Protein (APP) gene that is central to Alzheimer�s disease (AD) shares little sequence similarity with that of appb in zebrafish. Identifying DNA domains regulating expression of the gene in such situations becomes a challenge. Taking advantage of the zebrafish system that allows rapid functional analyses of gene regulatory sequences, we previously showed that two discontinuous DNA domains in zebrafish appb are important for expression of the gene in neurons: an enhancer in intron 1 and sequences 28�31 kb upstream of the gene. Here we identify the putative transcription factor binding sites responsible for this distal cis-acting regulation, and use that information to identify a regulatory region of the human APP gene. Results Functional analyses of intron 1 enhancer mutations in enhancer-trap BACs expressed as transgenes in zebrafish identified putative binding sites of two known transcription factor proteins, E4BP4/ NFIL3 and Forkhead, to be required for expression of appb. A cluster of three E4BP4 sites at ?31?kb is also shown to be essential for neuron-specific expression, suggesting that the dependence of expression on upstream sequences is mediated by these E4BP4 sites. E4BP4/ NFIL3 and XFD1 sites in the intron enhancer and E4BP4/ NFIL3 sites at ?31?kb specifically and efficiently bind the corresponding zebrafish proteins in vitro. These sites are statistically over-represented in both the zebrafish appb and the human APP genes, although their locations are different. Remarkably, a cluster of four E4BP4 sites in intron 4 of human APP exists in actively transcribing chromatin in a human neuroblastoma cell-line, SHSY5Y, expressing APP as shown using chromatin immunoprecipitation (ChIP) experiments. Thus although the two genes share little sequence conservation, they appear to share the same regulatory logic and are regulated by a similar set of transcription factors. Conclusion The results suggest that the clock-regulated and immune system modulator transcription factor E4BP4/ NFIL3 likely regulates the expression of both appb in zebrafish and APP in humans. It suggests potential human APP gene regulatory pathways, not on the basis of comparing DNA primary sequences with zebrafish appb but on the model of conservation of transcription factors. PMID:22947103
Analysis of promoter regions of co-expressed genes identified by microarray analysis
Background The use of global gene expression profiling to identify sets of genes with similar expression patterns is rapidly becoming a widespread approach for understanding biological processes. A logical and systematic approach to study co-expressed genes is to analyze their promoter sequences to identify transcription factors that may be involved in establishing specific profiles and that may be experimentally investigated. Results We introduce promoter clustering i.e. grouping of promoters with respect to their high scoring motif content, and show that this approach greatly enhances the identification of common and significant transcription factor binding sites (TFBS) in co-expressed genes. We apply this method to two different dataset, one consisting of micro array data from 108 leukemias (AMLs) and a second from a time series experiment, and show that biologically relevant promoter patterns may be obtained using phylogenetic foot-printing methodology. In addition, we also found that 15% of the analyzed promoter regions contained transcription factors start sites for additional genes transcribed in the opposite direction. Conclusion Promoter clustering based on global promoter features greatly improve the identification of shared TFBS in co-expressed genes. We believe that the outlined approach may be a useful first step to identify transcription factors that contribute to specific features of gene expression profiles. PMID:16916454
Veerla, Srinivas; Hoglund, Mattias
Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene�gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein�protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected Pc?=?0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene�gene interaction in the European American cohorts from the Framingham Heart Study (Pc?=?0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; Pc?=?0.006). The interaction between these two loci is also significant in the African American sample from ARIC (Pc?=?0.004) and in the Hispanic American sample from MESA (Pc?=?0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene�gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations. PMID:22654671
Ma, Li; Brautbar, Ariel; Boerwinkle, Eric; Sing, Charles F.
Evolution of Disease Response Genes in Loblolly Pine: Insights from Candidate Genes
Background Host-pathogen interactions that may lead to a competitive co-evolution of virulence and resistance mechanisms present an attractive system to study molecular evolution because strong, recent (or even current) selective pressure is expected at many genomic loci. However, it is unclear whether these selective forces would act to preserve existing diversity, promote novel diversity, or reduce linked neutral diversity during rapid fixation of advantageous alleles. In plants, the lack of adaptive immunity places a larger burden on genetic diversity to ensure survival of plant populations. This burden is even greater if the generation time of the plant is much longer than the generation time of the pathogen. Methodology/Principal Findings Here, we present nucleotide polymorphism and substitution data for 41 candidate genes from the long-lived forest tree loblolly pine, selected primarily for their prospective influences on host-pathogen interactions. This dataset is analyzed together with 15 drought-tolerance and 13 wood-quality genes from previous studies. A wide range of neutrality tests were performed and tested against expectations from realistic demographic models. Conclusions/Significance Collectively, our analyses found that axr (auxin response factor), caf1 (chromatin assembly factor) and gatabp1 (gata binding protein 1) candidate genes carry patterns consistent with directional selection and erd3 (early response to drought 3) displays patterns suggestive of a selective sweep, both of which are consistent with the arm-race model of disease response evolution. Furthermore, we have identified patterns consistent with diversifying selection at erf1-like (ethylene responsive factor 1), ccoaoemt (caffeoyl-CoA-O-methyltransferase), cyp450-like (cytochrome p450-like) and pr4.3 (pathogen response 4.3), expected under the trench-warfare evolution model. Finally, a drought-tolerance candidate related to the plant cell wall, lp5, displayed patterns consistent with balancing selection. In conclusion, both arms-race and trench-warfare models seem compatible with patterns of polymorphism found in different disease-response candidate genes, indicating a mixed strategy of disease tolerance evolution for loblolly pine, a major tree crop in southeastern United States. PMID:21151911
Gonzalez-Martinez, Santiago C.; Langley, Charles H.; Neale, David B.
Genome-wide association identifies candidate genes that influence the human electroencephalogram
Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (?), beta (?), and theta (?) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of ? or ? power. SGIP1 was estimated to account for 8.8% of variance in ? power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with ? power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by ? EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism. PMID:20421487
Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Cummins-Oman, Justine S.; Ferrier, Cherisse; Iarikova, Polina; Sankararaman, Sriram; Yamini, Goli; Yuan, Qiaoping; Zhou, Zhifeng; Albaugh, Bernard; White, Kenneth V.; Shen, Pei-Hong; Goldman, David
NOD2/CARD15 gene mutation identified in a Chinese family with Blau syndrome
Purpose To characterize the clinical features of a Chinese pedigree with Blau syndrome and to identify mutations in the NOD2/CARD15 (nucleotide-binding oligomerization domain containing 2/caspase recruitment domain family, member 15) gene. Methods Clinical features of this family were evaluated. Genomic DNA was obtained from blood samples, and all exons of NOD2/CARD15 were amplified by polymerase chain reaction (PCR) and direct DNA sequencing of PCR products was performed for mutations in NOD2/CARD15. Results Granulomatous arthritis, uveitis, and skin granulomas were found in all affected members. Sequencing analysis demonstrated a heterozygous C>T mutation in exon 4 of NOD2/CARD15 in all patients of this pedigree, which resulted in an amino acid substitution at position 334 (p.R334W). Conclusions The R334W mutation in NOD2/CARD15 caused Blau syndrome in a Chinese pedigree. This is the first report of R334W mutation in NOD2/CARD15 in a Chinese pedigree of this disease. PMID:22509093
Xiang, Haotian; Zhang, Ting; Chen, Mengping; Zhou, Xiaomin; Li, Zhen; Yan, Naihong; Li, Shiguang; Han, Yu; Gong, Qiyong
Objective In current clinical practice, optimal treatment of inflammatory bowel disease (IBD) aims at the induction and maintenance of clinical remission. Clinical remission is apparent when laboratory markers of inflammation are normal and clinical symptoms are absent. However, sub-clinical inflammation can still be present. A detailed analysis of the immune status during this inactive state of disease may provide a useful tool to categorize patients with clinical remission into subsets with variable states of immune activation. Design By using Affymetrix GeneChips, we analysed RNA gene expression profiles of peripheral blood leukocytes from pediatric IBD patients in clinical remission and controls. We performed (un)supervised clustering analysis of IBD-associated genes and applied Ingenuity� pathway software to identify specific molecular profiles between patients. Results Pediatric IBD patients with disease in clinical remission display heterogeneously distributed gene expression profiles that are significantly distinct from controls. We identified three clusters of IBD patients, each displaying specific expression profiles of IBD-associated genes. Conclusion The expression of immune- and IBD-associated genes in peripheral blood leukocytes from pediatric IBD patients in clinical remission was different from healthy controls, indicating that sub-clinical immune mechanisms are still active during remission. As such, RNA profiling of peripheral blood may allow for non-invasive patient subclassification and new perspectives in treatment regimes of IBD patients in the future. PMID:24260248
van Lierop, Pieter P. E.; Swagemakers, Sigrid M.; de Bie, Charlotte I.; Middendorp, Sabine; van Baarlen, Peter; Samsom, Janneke N.; van IJcken, Wilfred F. J.; Escher, Johanna C.; van der Spek, Peter J.; Nieuwenhuis, Edward E. S.
Genes May Make Some More Prone to Heart Disease When Under Stress
The goal of our research is to identify genes and mutations causing auto-somal dominant retinitis pigmentosa (adRP). For this purpose we established a cohort of more than 250 independently ascertained families with adRP in the Houston Laboratory for Molecular Diagnosis of Inherited Eye Diseases. Affected members of each family were screened for disease-causing mutations in genes and gene regions that are commonly associated with adRP. By this approach, we detected mutations in 65 % of the families, leaving 85 families that are likely to harbor mutations outside of the �common� regions or in novel genes. Of these, 32 families were tested by several types of next-generation sequencing (NGS), including (a) targeted polymerase chain reaction (PCR) NGS, (b) whole exome NGS, and (c) targeted retinal-capture NGS. We detected mutations in 11 of these families (31 %) bringing the total detected in the adRP cohort to 70 %. Several large families have also been tested for linkage using Afymetrix single nucleotide polymorphism (SNP) arrays. PMID:24664689
Bowne, Sara J.; Sullivan, Lori S.; Blanton, Susan H.; Weinstock, George M.; Koboldt, Daniel C.; Fulton, Robert S.; Larsen, David; Humphries, Peter; Humphries, Marian M.; Pierce, Eric A.; Chen, Rui; Li, Yumei
The goal of our research is to identify genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). For this purpose we established a cohort of more than 250 independently ascertained families with adRP in the Houston Laboratory for Molecular Diagnosis of Inherited Eye Diseases. Affected members of each family were screened for disease-causing mutations in genes and gene regions that are commonly associated with adRP. By this approach, we detected mutations in 65?% of the families, leaving 85 families that are likely to harbor mutations outside of the "common" regions or in novel genes. Of these, 32 families were tested by several types of next-generation sequencing (NGS), including (a) targeted polymerase chain reaction (PCR) NGS, (b) whole exome NGS, and (c) targeted retinal-capture NGS. We detected mutations in 11 of these families (31?%) bringing the total detected in the adRP cohort to 70?%. Several large families have also been tested for linkage using Afymetrix single nucleotide polymorphism (SNP) arrays. PMID:24664689
Daiger, Stephen P; Bowne, Sara J; Sullivan, Lori S; Blanton, Susan H; Weinstock, George M; Koboldt, Daniel C; Fulton, Robert S; Larsen, David; Humphries, Peter; Humphries, Marian M; Pierce, Eric A; Chen, Rui; Li, Yumei
Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors. PMID:23698379
Rousseaux, Sophie; Debernardi, Alexandra; Jacquiau, Baptiste; Vitte, Anne-Laure; Vesin, Aur�lien; Nagy-Mignotte, H�l�ne; Moro-Sibilot, Denis; Brichon, Pierre-Yves; Lantuejoul, Sylvie; Hainaut, Pierre; Laffaire, Julien; de Reyni�s, Aur�lien; Beer, David G; Timsit, Jean-Fran�ois; Brambilla, Christian; Brambilla, Elisabeth; Khochbin, Saadi
Gene-Environment Interactions and Epigenetic Basis of Human Diseases
Most human diseases are related in some way to the loss or gain in gene functions. Regulation of gene expression is a complex process. In addition to genetic mechanisms, epigenetic causes are gaining new perspectives in human diseases related to gene deregulation. Most eukaryotic genes are packed into chromatin structures, which lead to high condensations of the genes that require dynamic chromatin remodeling processes to facilitate their transcription. DNA methylation and histone modifications represent two of the major chromatin remodeling processes. They also serve to integrate environmental signals for the cells to modulate the functional output of their genome. Complex human diseases such as cancer and type 2 diabetes are believed to have a strong environmental component in addition to genetic causes. Aberrancies in chromatin remodeling are associated with both genetically and environmentally-related diseases. We will focus on recent findings of the epigenetic basis of human metabolic disorders to facilitate further exploration of epigenetic mechanisms and better understandings of the molecular cues underlying such complex diseases. PMID:18525104
Liu, Liang; Li, Yuanyuan; Tollefsbol, Trygve O.
A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription.
In contrast to skeletal muscle, the mechanisms responsible for activation and maintenance of tissue-specific transcription in cardiac muscle remain poorly understood. A family of hormone-encoding genes is expressed in a highly specific manner in cardiac but not skeletal myocytes. This includes the A- and B-type natriuretic peptide (ANP and BNP) genes, which encode peptide hormones with crucial roles in the regulation of blood volume and pressure. Since these genes are markers of cardiac cells, we have used them to probe the mechanisms for cardiac muscle-specific transcription. Cloning and functional analysis of the rat BNP upstream sequences revealed unexpected structural resemblance to erythroid but not to muscle-specific promoters and enhancers, including a requirement for regulatory elements containing GATA motifs. A cDNA clone corresponding to a member of the GATA family of transcription factors was isolated from a cardiomyocyte cDNA library. Transcription of this GATA gene is restricted mostly to the heart and is undetectable in skeletal muscle. Within the heart, GATA transcripts are localized in ANP- and BNP-expressing myocytes, and forced expression of the GATA protein in heterologous cells markedly activates transcription from the natural cardiac muscle-specific ANP and BNP promoters. This GATA-dependent pathway defines the first mechanism for cardiac muscle-specific transcription. Moreover, the present findings reveal striking similarities between the mechanisms controlling gene expression in hematopoietic and cardiac cells and may have important implications for studies of cardiogenesis. Images PMID:8164667
Grepin, C; Dagnino, L; Robitaille, L; Haberstroh, L; Antakly, T; Nemer, M
Paleo-evolutionary plasticity of plant disease resistance genes
Background The recent access to a large set of genome sequences, combined with a robust evolutionary scenario of modern monocot (i.e. grasses) and eudicot (i.e. rosids) species from their founder ancestors, offered the opportunity to gain insights into disease resistance genes (R-genes) evolutionary plasticity. Results We unravel in the current article (i) a R-genes repertoire consisting in 7883 for monocots and 15758 for eudicots, (ii) a contrasted R-genes conservation with 23.8% for monocots and 6.6% for dicots, (iii) a minimal ancestral founder pool of 384 R-genes for the monocots and 150 R-genes for the eudicots, (iv) a general pattern of organization in clusters accounting for more than 60% of mapped R-genes, (v) a biased deletion of ancestral duplicated R-genes between paralogous blocks possibly compensated by clusterization, (vi) a bias in R-genes clusterization where Leucine-Rich Repeats act as a �glue� for domain association, (vii) a R-genes/miRNAs interome enriched toward duplicated R-genes. Conclusions Together, our data may suggest that R-genes family plasticity operated during plant evolution (i) at the structural level through massive duplicates loss counterbalanced by massive clusterization following polyploidization; as well as at (ii) the regulation level through microRNA/R-gene interactions acting as a possible source of functional diploidization of structurally retained R-genes duplicates. Such evolutionary shuffling events leaded to CNVs (i.e. Copy Number Variation) and PAVs (i.e. Presence Absence Variation) between related species operating in the decay of R-genes colinearity between plant species. PMID:24617999
Natural antisense transcripts of Alzheimer's disease associated genes.
Natural antisense transcripts (NATs), also named endogenous antisense transcripts, are a class of genes whose role in controlling gene expression is becoming more and more relevant. NATs might play important roles in gene expression and translation regulation. Present work investigated the presence of NATs of Alzheimer's disease associated genes including PRESENILIN1, PRESENILIN2, BACE1, BACE2, APP, APOE, TAU (MAPT), PRION, alpha-SYNUCLEIN (SNCA), NICASTRIN, PEN2, APH1A, APH1B as well as CD147 (BASIGIN), and the results revealed that APP, BACE2, APH1A, TAU, CD147 and alpha-SYNUCLEIN contain natural antisense transcripts. These NATs were characterized according to the sense-antisense overlapping information and potential functional mechanisms were proposed. Present findings provide preliminary but important information about transcription regulation of AD associated genes, which would further our understanding of the gene expression regulation of AD, and also suggest a novel potential strategy for the therapy of AD. PMID:17076261
Guo, Jin-Hu; Cheng, Hai-Peng; Yu, Long; Zhao, Shouyuan
Background The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. Design and Methods Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. Results Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. Conclusions ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval. PMID:21993670
Guarini, Anna; Marinelli, Marilisa; Tavolaro, Simona; Bellacchio, Emanuele; Magliozzi, Monia; Chiaretti, Sabina; De Propris, Maria Stefania; Peragine, Nadia; Santangelo, Simona; Paoloni, Francesca; Nanni, Mauro; Del Giudice, Ilaria; Mauro, Francesca Romana; Torrente, Isabella; Foa, Robin
Embryo development represents a crucial developmental period in the life cycle of flowering plants. To gain insights into the genetic programs that control embryo development in Brassica rapa L., RNA sequencing technology was used to perform transcriptome profiling analysis of B. rapa developing embryos. The results generated 42,906,229 sequence reads aligned with 32,941 genes. In total, 27,760, 28,871, 28,384, and 25,653