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A highly conserved baculovirus gene p48 (ac103) is essential for BV production and ODV envelopment
Autographa californica multiple nucleopolyhedrovirus (AcMNPV) p48 (ac103) is a highly conserved baculovirus gene of unknown function. In the present study, we generated a knockout of the p48 gene in an AcMNPV bacmid and investigated the role of P48 in baculovirus life cycle. The p48-null Bacmid vAc{sup P48-KO-PH-GFP} was unable to propagate in cell culture, while a 'repair' Bacmid vAc{sup P48-REP-PH-GFP} was able to replicate in a manner similar to a wild-type Bacmid vAc{sup PH-GFP}. Titration assays and Western blotting confirmed that vAc{sup P48-KO-PH-GFP} was unable to produce budded viruses (BVs). qPCR analysis showed that p48 deletion did not affect viral DNA replication. Electron microscopy indicated that P48 was required for nucleocapsid envelopment to form occlusion-derived viruses (ODVs) and their subsequent occlusion. Confocal analysis showed that P48 prominently condensed in the centre of the nucleus. Our results demonstrate that P48 plays an essential role in BV production and ODV envelopment in the AcMNPV life cycle.
Yuan Meijin; Wu Wenbi; Liu Chao; Wang Yanjie; Hu Zhaoyang [State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou 510275 (China); Yang Kai [State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou 510275 (China)], E-mail: email@example.com; Pang Yi [State Key Laboratory of Biocontrol, Sun Yat-sen University, Guangzhou 510275 (China)
Molecular characterization of the Mycoplasma bovis p68 gene, encoding a basic membrane protein with homology to P48 of Mycoplasma agalactiae.
Mycoplasmal lipoproteins are considered to be potential virulence determinants, which may carry out numerous important functions in pathogenesis including adhesion and immunomodulation. The prototype mycoplasmal immunomodulin is the macrophage-activating lipoprotein (MALP) of Mycoplasma fermentans. In this study, a homolog of the malp gene, designated p68, was identified and characterized in Mycoplasma bovis strain PG45 clonal variant #6. P68 belongs to the family of basic membrane proteins, which have been identified in diverse prokaryotes, including mycoplasmas. P68 revealed significant similarity and shared conserved selective lipoprotein-associated motifs with the highly immunogenic MALP-related lipoproteins P48 of M. bovis and P48 of Mycoplasma agalactiae. Determination of the genomic distribution of both M. bovis malp-homologs showed that p48 was present in all M. bovis strains tested, whereas the p68 gene was missing in some. Sequence comparison of the p68 genomic region in strains with and without this gene revealed that the region is very dynamic, with multiple genetic changes. Reverse-transcription PCR and primer extension analysis indicated that both p68 and p48 are transcribed in M. bovis under in vitro growth conditions. Mycoplasma bovis is the first mycoplasma species in which two malp-related genes have been identified. PMID:18194339
Lysnyansky, Inna; Yogev, David; Levisohn, Sharon
Expression and antigenic characterization of recombinant Mycoplasma agalactiae P48 major surface protein
The gene encoding the P48 major surface lipoprotein of M. agalactiae has been recently characterised. Since its product plays an important role in the immune response of infected animals, in this study we analysed a recombinant P48 expressed in E. coli. Multiple point mutations were introduced by site directed mutagenesis in order to convert four tryptophan TGA codons, which are
S. Rosati; P. Robino; M. Fadda; S. Pozzi; A. Mannelli; M. Pittau
Essential and non-redundant roles of p48 (ISGF3gamma) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies
Background: Interferons (IFNs) are a class of cyto- kines which confer cellular resistance against viral infections. Type I (IFN- and - ) and type II (IFN- ) IFNs utilize distinct receptors, the stimulation of which results in the induction of downstream target genes. These target genes usually contain within their promoter region an IFN responsive element, termed ISRE (IFN stimulated
Tohru Kimura; Yuzo Kadokawa; Hisashi Harada; Masahito Matsumoto; Mitsuharu Sato; Yasuo Kashiwazaki; Masahito Tarutani; Rosemary Sok-Pin Tan; Tomohiro Takasugi; Toshifumi Matsuyama; Tak W. Mak; Shigeru Noguchi; Tadatsugu Taniguchi
Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.
The limited success of IFN-alpha therapy for clinical treatment of transitional cell carcinoma (TCC) has prompted us to investigate the responsiveness of TCC lines to IFN-alpha. The response to IFN-alpha in terms of 561 gene induction, an IFN-stimulated response element-containing IFN-alpha/beta-inducible gene, and IFN-stimulated gene factor 3 (ISGF3) formation was normal in primary human urothelial cells. We tested the antiproliferative effects of IFN-alpha in three TCC lines as a measure of IFN-alpha responsiveness, and variable patterns of growth inhibition were observed in three TCC lines. More than 90% growth inhibition was noted in TCCSUP cells, whereas only 40% and 10% inhibition by IFN-alpha was observed in 5637 and HT1197 cells, respectively. IFN-alpha treatment formed extremely low levels of ISGF3 in electrophoretic mobility shift assays in these later two relatively insensitive cells. In addition, expression of the 561 gene was significantly reduced in these two TCC lines by Northern blots. We have further identified a low expression level of Tyk2 in HT1197 cells compared with two other TCCs. This suggests that an extremely low ISGF3 level after IFN-alpha treatment may be due to low Tyk2 expression or other unidentified defects. In 5637 cells, p48 protein expression was undetectable. This undetectable p48 expression is not due to a deletion in the coding region because the correct size protein is detected following IFN-gamma treatment. Consequently, the ISGF3 complex formation and 561 gene induction were restored by IFN-gamma pretreatment plus IFN-alpha treatment. Introduction of p48 expressing plasmid into 5637 cells was sufficient to form the ISGF3 complex by IFN-alpha treatment, suggesting the defect lies in the expression of p48 protein in 5637 cells. Detailed mechanistic understanding of the action of IFNs in bladder cancer cell lines may explain the abrogated therapeutic response of IFN-alpha in the clinical treatment of TCCs. PMID:11280796
Matin, S F; Rackley, R R; Sadhukhan, P C; Kim, M S; Novick, A C; Bandyopadhyay, S K
The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas
We have generated a mouse bearing a null allele of the gene encoding basic helix�loop�helix (bHLH) protein p48, the cell-specific DNA-binding subunit of hetero-oligomeric transcription factor PTF1 that directs the expression of genes in the exocrine pancreas. The null mutation, which establishes a lethal condition shortly after birth, leads to a complete absence of exocrine pancreatic tissue and its specific products, indicating that p48 is required for differentiation and/or proliferation of the exocrine cell lineage. p48 is so far the only developmental regulator known to be required exclusively for committing cells to an exocrine fate. The hormone secreting cells of all four endocrine lineages are present in the mesentery that normally harbors the pancreatic organ until day 16 of gestation. Toward the end of embryonic life, cells expressing endocrine functions are no longer detected at their original location but are now found to colonize the spleen, where they persist in a functional state until postnatal death of the organism occurs. These findings suggest that the presence of the exocrine pancreas is required for the correct spatial assembly of the endocrine pancreas and that, in its absence, endocrine cells are directed by default to the spleen, a site that, in some reptiles, harbors part of this particular cellular compartment.
Krapp, Andrea; Knofler, Martin; Ledermann, Birgit; Burki, Kurt; Berney, Catherine; Zoerkler, Nicole; Hagenbuchle, Otto; Wellauer, Peter K.
Genetic immunization with the immunodominant antigen P48 of Mycoplasma agalactiae stimulates a mixed adaptive immune response in BALBc mice
A DNA vaccine against contagious agalactia was developed for the first time, encoding the P48 of Mycoplasma agalactiae. Specific immune responses elicited in BALB\\/c mice were evaluated. Both total IgG and IgG1 were detected in mice vaccinated with pVAX1\\/P48. Proliferation of mononuclear cells of the spleen, levels of gamma interferon, interleukin-12, and interleukin-2 mRNAs were enhanced in immunized animals. Results
Bernardo Chessa; Marco Pittau; Maria Puricelli; Rosanna Zobba; Elisabetta Coradduzza; Paola Dall�Ara; Sergio Rosati; Giorgio Poli; Alberto Alberti
Genetic immunization with the immunodominant antigen P48 of Mycoplasma agalactiae stimulates a mixed adaptive immune response in BALBc mice.
A DNA vaccine against contagious agalactia was developed for the first time, encoding the P48 of Mycoplasma agalactiae. Specific immune responses elicited in BALB/c mice were evaluated. Both total IgG and IgG1 were detected in mice vaccinated with pVAX1/P48. Proliferation of mononuclear cells of the spleen, levels of gamma interferon, interleukin-12, and interleukin-2 mRNAs were enhanced in immunized animals. Results indicate that pVAX1/P48 vaccination induced both T(h)1 and T(h)2 immune responses. Nucleic acid immunization could be a new strategy against M. agalactiae infections and may be potentially used to develop vaccines for other Mycoplasma diseases. PMID:19007952
Chessa, Bernardo; Pittau, Marco; Puricelli, Maria; Zobba, Rosanna; Coradduzza, Elisabetta; Dall'ara, Paola; Rosati, Sergio; Poli, Giorgio; Alberti, Alberto
Long isoform of ErbB3 binding protein, p48, mediates protein kinase B/Akt-dependent HDM2 stabilization and nuclear localization
p48 is a long isoform of the ErbB3 binding protein that has oncogenic functions including promotion of carcinogenesis and induction of malignant transformation through negative regulation of tumor suppressor p53. Here, we show that high level of p48 protein expression leads to enhance HDM2 phosphorylation by Akt and inhibits the self-ubiquitination of HDM2 by up-regulation of Akt activity, thereby promoting its protein stability. Moreover, p48 expression leads to accumulated nuclear localization of HDM2, whereas p48 depletion disturbs its nuclear localization. Hence, higher expression of p48 in cancer cells reduces p53 levels through modulation of HDM2 nuclear localization and protein stability via regulation of its Akt-mediated phosphorylation.
Kim, Chung Kwon; Lee, Sang Bae; Nguyen, Truong L.X. [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of)] [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Lee, Kyung-Hoon [Department of Anatomy, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of) [Department of Anatomy, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Um, Sung Hee [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of) [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Kim, Jihoe [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of)] [School of Biotechnology, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Ahn, Jee-Yin, E-mail: email@example.com [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of) [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of); Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746 (Korea, Republic of)
Endogenous n-3 Polyunsaturated Fatty Acids Delay Progression of Pancreatic Ductal Adenocarcinoma in Fat-1-p48Cre/+-LSL-KrasG12D/+ Mice12
Preclinical studies suggest that diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be beneficial for prevention of pancreatic cancer. Nutritional intervention studies are often complex, and there is no clear evidence, without potential confounding factors, on whether conversion of n-6 PUFAs to n-3 PUFAs in pancreatic tissues would provide protection. Experiments were designed using n-3 fatty acid desaturase (Fat-1) transgenic mice, which can convert n-6 PUFA to n-3 FAs endogenously, to determine the impact of n-3 PUFAs on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC). Six-weekold female p48Cre/+-LSL-KrasG12D/+ andcompoundFat-1-p48Cre/+-LSL-KrasG12D/+ mice were fed (AIN-76A) diets containing 10% safflower oil for 35 weeks. Pancreata were evaluated histopathologically for PanINs and PDAC. Results showed a dramatic reduction in incidence of PDAC (84%; P < .02) in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. Importantly, significant reductions of pancreatic ducts with carcinoma (90%; P < .0001) and PanIN 3 (?50%; P < .001) lesions were observed in the compound transgenic mice. The levels of n-3 PUFA were much higher (>85%; P < .05�0.01) in pancreas of compound transgenic mice than in those of p48Cre/+-LSL-KrasG12D/+ mice. Molecular analysis of the pancreas showed a significant down-regulation of proliferating cell nuclear antigen, cyclooxygenase-2, 5-lipoxygenase (5-LOX), 5-LOX-activating protein, Bcl-2, and cyclin D1 expression levels in Fat-1-p48Cre/+-LSL-KrasG12D/+ mice compared to p48Cre/+-LSL-KrasG12D/+ mice. These data highlight the promise of dietary n-3 FAs for chemoprevention of pancreatic cancer in high-risk individuals.
Mohammed, Altaf; Janakiram, Naveena B; Brewer, Misty; Duff, Ashley; Lightfoot, Stan; Brush, Richard S; Anderson, Robert E; Rao, Chinthalapally V
Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice.
Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor(�)) and the role of the phosphatidyl-inositol 3-kinase (PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48(Cre/+) -LSL-Kras(G12D/+) transgenic mice. Six-week-old male p48(Cre/+) -LSL-Kras(G12D/+) (20/group) mice were fed AIN-76A diets containing 0, 200 and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or reverse transcription-PCR methods. Control diet-fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35%, respectively (p < 0.0001). Similarly, significant suppression of PanIN-3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin-treated mice were ?68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p-ERK, RhoA, cyclin D1, survivin, Akt, pAKT, ?-catenin, cyclin E, cdK2 and caveolin-1. Also, atorvastatin-treated mice had shown dose-dependent suppression of inflammatory cytokines and a significant increase in tunnel-positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN-1 and -2 lesions to PanIN-3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high-risk pancreatic cancer patients. PMID:22287227
Mohammed, Altaf; Qian, Li; Janakiram, Naveena B; Lightfoot, Stan; Steele, Vernon E; Rao, Chinthalapally V
Retinoic acid resistance in NB4 APL cells is associated with lack of interferon alpha synthesis Stat1 and p48 induction.
In the t(15;17) acute promyelocytic leukaemia (APL), all trans-retinoic (RA) treatment induces maturation leading to clinically complete but not durable remission, as RA resistance develops in the treated patients as well as in vitro. RA and interferons (IFNs) are known inhibitors of proliferation in various cells including those from APL. In this report, we show that they can act cooperatively to inhibit growth and to induce differentiation of NB4 cells but not of two RA-resistant NB4 derived cell lines, NB4-R1 and NB4-R2. However, the resistant cell lines respond to IFN. In NB4 cells, RA increases the expression of Stat1, p48 and IRF-1, three transcription factors playing a central role in the IFN response and induces the synthesis and the secretion of IFN alpha. RA-induced IFN alpha seems to play a role in inhibition of NB4 cell growth but not in their differentiation. In the resistant cells, NB4-R1 and NB4-R2, both the induction of IFN and the increase of Statl and p48 expression by RA are completely blocked. In contrast, IRF-1 mRNA and protein expressions are induced in the three cell lines. This suggests that increase of IRF-1 expression is not sufficient for IFN induction. Our results identify some defects linked to RA-resistance in APL and support the hypothesis that RA-induced Stat1 expression and IFN secretion may be one of the mechanisms mediating growth inhibition by RA. PMID:10435617
Pelicano, L; Brumpt, C; Pitha, P M; Chelbi-Alix, M K
Pax: a murine multigene family of paired box-containing genes.
A murine multigene family has been identified that shares a conserved sequence motif, the paired box, with developmental control and tissue-specific genes of Drosophila. To date five murine paired box-containing genes (Pax genes) have been described and one, Pax-1, has been associated with the developmental mutant phenotype undulated. Here we describe the paired boxes of three novel Pax genes, Pax-4, Pax-5, and Pax-6. Comparison of the eight murine paired domains of the mouse, the five Drosophila paired domains, and the three human paired domains shows that they fall into six distinct classes: class I comprises Pox meso, Pax-1, and HuP48; class II paired, gooseberry-proximal, gooseberry-distal, Pax-3, Pax-7, HuP1, and HuP2; class III Pax-2, Pax-5, and Pax-8; class IV Pax-4; class V Pox neuro; and class VI Pax-6. Pax-1 and the human gene HuP48 have identical paired domains, as do Pax-3 and HuP2 as well as Pax-7 and HuP1, and are likely to represent homologous genes in mouse and man. Identical intron-exon structure and extensive sequence homology of their paired boxes suggest that several Pax genes represent paralogs. The chromosomal location of all novel Pax genes and of Pax-3 and Pax-7 has been determined and reveals that they are not clustered. PMID:1685142
Walther, C; Guenet, J L; Simon, D; Deutsch, U; Jostes, B; Goulding, M D; Plachov, D; Balling, R; Gruss, P
Conservation of the paired domain in metazoans and its structure in three isolated human genes.
Sequences homologous to the paired domain of Drosophila melanogaster have been conserved in species as distantly related as nematodes, sea urchins, or man. In particular, paired domains of three human genes, HuP1, HuP2 and HuP48, have been isolated and sequenced. Together with four Drosophila paired domains, they fall into two separate paired domain classes named according to their Drosophila members, paired--gooseberry and P29 class. The P29 class includes the mouse Pax 1 and the human HuP48 gene which are nearly identical in their sequenced portions and hence might be true homologues. In addition to the paired domain, the two human genes HuP1 and HuP2 share the highly conserved octapeptide HSIAGILG with the two gooseberry genes of Drosophila. Possible functions of the paired domain are discussed in the light of a predicted helix-turn-helix structure in its carboxy-terminal portion. PMID:2501086
Burri, M; Tromvoukis, Y; Bopp, D; Frigerio, G; Noll, M
National Technical Information Service (NTIS)
The invention provides strategies, methods, vectors, reagents, and systems for production of synthetic genes, production of libraries of such genes, and manipulation and characterization of the genes and corresponding encoded polypeptides. In one aspect, ...
D. Sand K. G. Patel R. C. Reid S. J. Kodunal
This book contains 13 chapters. Some of the titles are: Gene Transfer and Expression of Mammalian Cell Receptors; Mapping Endocrine Genes with Sorted Human Chromosomes; Structure, Function, Hormonal Regulation of Steroidogenic Enzyme Genes; Molecular Analysis of Steroid Hormone Action Using the Human Metallothionein Genes as a Model.
Lau, Y.F.
Gene therapy is defined as the treatment of disease by transfer of genetic material into cells. This review will explore methods available for gene transfer as well as current and potential applications for craniofacial regeneration, with emphasis on future development and design. Though non-viral gene delivery methods are limited by low gene transfer efficiency, they benefit from relative safety, low immunogenicity, ease of manufacture, and lack of DNA insert size limitation. In contrast, viral vectors are nature�s gene delivery machines that can be optimized to allow for tissue-specific targeting, site-specific chromosomal integration, and efficient long-term infection of dividing and non-dividing cells. In contrast to traditional replacement gene therapy, craniofacial regeneration seeks to use genetic vectors as supplemental building blocks for tissue growth and repair. Synergistic combination of viral gene therapy with craniofacial tissue engineering will significantly enhance our ability to repair and replace tissues in vivo.
Scheller, E.L.; Krebsbach, P.H.
NSDL National Science Digital Library
This module will examine the "Language" of genes and illustrate how basic statistical methods can be applied to the problem of gene prediction. The merger of computational sciences with biology, and the challenges facing BioinFormatics, will also be explored through the use of analysis tools available at the National Center for Biotechnology InFormation (NCBI).
Daniels, Chuck
This fifth edition book encompasses a wide range of topics covering 1,272 pages. The book is arranged into nine parts with a total of 36 chapters. These nine parts include Introduction; DNA as a Store of Information; Translation; Constructing Cells; Control of Prokaryotypic Gene Expression; Perpetuation of DNA; Organization of the Eukaryotypic Genome; Eukaryotypic Transcription and RNA Processing; The Dynamic Genome; and Genes in Development.
Lewin, B.
NSDL National Science Digital Library
Teachers' Domain presents this interactive, adapted from the University of Nebraska's Library of Crop Technologies, with reading material and animations to help students learn the basics of gene cloning. Following an introduction, the lesson is divided two parts: Making a Recombinant Plasmid and Bacteria Transformation. On the site, visitors will also find a supplemental background essay, discussion questions, and standards alignment from Teachers' Domain.
ERIC Educational Resources Information Center
A major problem for developmental science is understanding how the cognitive and emotional networks important in carrying out mental processes can be related to individual differences. The last five years have seen major advances in establishing links between alleles of specific genes and the neural networks underlying aspects of attention. These�
Posner, Michael I.; Rothbart, Mary K.; Sheese, Brad E.
ERIC Educational Resources Information Center
Genetic technologies may soon help fill some of the most important needs of humanity from food to energy to health care. The research of major designer genes companies and reasons why the initial mad rush for biotechnology has slowed are reviewed. (SR)
Miller, Judith; Miller, Mark
Analysis of Gene-Gene Interactions
The goal of this unit is to introduce gene-gene interactions (epistasis) as a significant complicating factor in the search for disease susceptibility genes. This unit begins with an overview of gene-gene interactions and why they are likely to be common. Then, it reviews several statistical and computational methods for detecting and characterizing genes with effects that are dependent on other genes. The focus of this unit is genetic association studies of discrete and quantitative traits because most of the methods for detecting gene-gene interactions have been developed specifically for these study designs.
Gilbert-Diamond, Diane; Moore, Jason H.
NSDL National Science Digital Library
In this activity, learners explore how genetic switches function and the role of genetic switches in the process of evolution. To make these concepts less abstract and more understandable, learners first view a series of video clips and animations from the HHMI DVD (or online) "Evolution: Constant Change and Common Threads." Then, learners construct a model of a gene switch using craft materials or FridgiGears (magnetic gears). This activity can be done as a demonstration, a student inquiry activity, or a combination of the two.
Colvard, Mary
Gene - Gene Interactions Among MCP Genes Polymorphisms in Asthma
Purpose Monocyte chemoattractant proteins (MCPs) are important cytokines that involved in cellular activation and releasing of inflammatoy mediators by basophils and eosinophils in allergic disease. Some MCP gene variants implicate in asthma and monoclonal antibody for MCP-3 blocks allergic inflammations in the patients with asthma. Detection of interactions between gene and environment or between genes for complex disease such as asthma is important. We searched for an evidence of genetic effect of single nucleotide polymorphisms (SNPs) of MCP genes as well as gene - gene interactions involved in asthma. Methods Four hundreds asthmatics and four hundreds normal controls were enrolled. Asthma was defined as a positive bronchodilator response or positive methacholine provocation test with compatible clinical symptoms. Seven MCP gene SNPs (2 SNPs in MCP-1, 1 in MCP-2, and 4 in MCP-3) were included. Association analyses between SNP and asthma, and the tests for gene - gene interaction were performed. Results Strong linkage disequilibria were found among 7 MCP gene polymorphisms. There was no SNP that showed a significant association with asthma among 7 SNPs of 3 MCP genes. No haplotype was associated with asthma, either. The combination of MCP1-2518G>A, MCP2+46A>C, and MCP3+563C>T was the best predictive model for asthma as compared to the control in tests for gene - gene interaction. The MCP1-2518G>A and MCP2+46A>C was the second best predictive combination and this had the highest synergistic interaction effect on the subject's status than any other combination of polymorphisms. Complete linkages were not associated with the gene - gene interactions models. Conclusions MCP gene polymorphisms probably interact with each other; thus, these findings may help in developing a possible genetic marker to predict asthma.
Lee, June-Hyuk
NSDL National Science Digital Library
Benjamin Lewin provides this detailed educational site as the online (and continuously updated) version of the printed resource, GENES. Designed as a pilot project "for building an online site that will develop into a general resource for the life sciences, including molecular biology, cell biology, development, immunology, and neurobiology, at levels varying from introductory to advanced," this impressive site is intended to be useful to students at the undergraduate level (or above). First-time users must register (access is free, "at least temporarily") to gain access to chapters; registered users may conduct searches, build references, write notes, highlight specified information, or browse the full resource. Future plans include "better (and faster) searches on the text, searches on figures, identification of new material and recently added references, printing by chapter or by section, more animations, on line tests and problem sets." Content is detailed, well illustrated, and thorough; this looks to be an exceptional resource.
Gene expression microarray technologies provide the simultaneous measurements of a large number of genes. Typical analyses of such data focus on the individual genes, but recent work has demonstrated that evaluating changes in expression across predefined sets of genes often increases statistical power and produces more robust results. We introduce a new methodology for identifying gene sets that are differentially
Babak Shahbaba; Robert Tibshirani; Catherine M. Shachaf; Sylvia K. Plevritis
Chromatin loops, gene positioning, and gene expression
Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the ?- and ?-globin gene loci, the antigen receptor loci, the imprinted H19�Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.
Holwerda, Sjoerd; de Laat, Wouter
... mutation may only have dystopia canthorum. How Do Genes Work? Genes are a road map for the synthesis of ... lung, etc. Every child inherits half of its genes from one parent and half from the other ...
Gene conversion in steroid 21-hydroxylase genes.
The steroid 21-hydroxylase gene, CYP21B, encodes cytochrome P450c21, which mediates 21-hydroxylation. The gene is located about 30 kb downstream from pseudogene CYP21A. The CYP21A gene is homologous to the CYP21B gene but contains some mutations, including a C----T change which leads a termination codon, TAG, in the eighth exon. We found the same change in a mutant CYP21B gene isolated from a patient with 21-hydroxylase deficiency. Furthermore, a reciprocal change--i.e., a T----C change in the eighth exon of the CYP21A gene--was observed in the Japanese population and was associated with the two HLA haplotypes, HLA-B44-DRw13 and HLA-Bw46-DRw8. These changes may be considered the result of gene conversion-like events. Images Figure 1 Figure 3 Figure 5 Figure 6
Urabe, K; Kimura, A; Harada, F; Iwanaga, T; Sasazuki, T
Gene conversion in steroid 21-hydroxylase genes.
The steroid 21-hydroxylase gene, CYP21B, encodes cytochrome P450c21, which mediates 21-hydroxylation. The gene is located about 30 kb downstream from pseudogene CYP21A. The CYP21A gene is homologous to the CYP21B gene but contains some mutations, including a C----T change which leads a termination codon, TAG, in the eighth exon. We found the same change in a mutant CYP21B gene isolated from a patient with 21-hydroxylase deficiency. Furthermore, a reciprocal change--i.e., a T----C change in the eighth exon of the CYP21A gene--was observed in the Japanese population and was associated with the two HLA haplotypes, HLA-B44-DRw13 and HLA-Bw46-DRw8. These changes may be considered the result of gene conversion-like events. PMID:1971153
Urabe, K; Kimura, A; Harada, F; Iwanaga, T; Sasazuki, T
ERIC Educational Resources Information Center
This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic�
National Institutes of Health, 2005
Clustering gene expression patterns
Recent advances in biotechnology allow researchers to measure expression levels for thousands of genes simultaneously, across different conditions and over time. Analysis of data produced by such experiments offers potential insight into gene function and regulatory mechanisms. A key step in the analysis of gene expression data is the detection of groups of genes that manifest similar expression patterns. The
Amir Ben-Dor; Zohar Yakhinit; Zohar Yakhini
Gene targeting: The classical approach Central to an understanding of the in vivo function of genes is their analysis by mutation, that is, inactivation or modification of a gene by mutation and the study of the consequences of the mutation in the mutant organism. In mammals, before gene targeting, this approach was limited to the rare spontaneous mutations reflected in
Klaus Rajewsky; Hua Gu; Ralf K�hn; Ulrich A. K. Betz; Werner M�ller; J�rgen Roes; Frieder Schwenk
Gene�environment interdependence
The modern understanding of genetic influences, of environmental effects, of mental disorder, and of heritabilities is noted. The practical utility of finding susceptibility genes with a very small effect is questioned. The empirical findings and implications of developmental perturbations, epigenetics, gene�environment correlations and interactions are then discussed. It is noted that the genes involved in gene�environment interactions may be concerned
Michael Rutter
Gene expression microarray technologies provide the simultaneous measurements\\u000aof a large number of genes. Typical analyses of such data focus on the\\u000aindividual genes, but recent work has demonstrated that evaluating changes in\\u000aexpression across predefined sets of genes often increases statistical power\\u000aand produces more robust results. We introduce a new methodology for\\u000aidentifying gene sets that are differentially
Babak Shahbaba; Robert Tibshirani; Catherine M. Shachaf; Sylvia K. Plevritis
Gene therapy is an emerging field in medical and pharmaceutical sciences because of its potential in treating chronic diseases like cancer, viral infections, myocardial infarctions, and genetic disorders. Application of gene therapy is limited because of lack of suitable methods for proper introduction of genes into cells and therefore, this is an area of interest for most of the researchers. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several nonviral and viral gene transfer methods have been developed. Even though the viral agents have a high transferring efficiency, they are difficult to handle due to their toxicity. To overcome the safety problems of the viral counterpart, several nonviral in vitro and in vivo gene delivery systems are developed. Out of these, the most promising and latest systems include polymer-based nonviral gene carriers, dendrimers, and physical means like electroporation, microinjection, etc., Shunning of possible immunogenicity and toxicity, and the feasibility of repeated administration are some of the merits of nonviral gene delivery systems over viral gene delivery. An ideal nonviral gene carrying system should possess all these merits without any compromise to its gene transferring efficiency. The viral gene delivery systems include lytic and nonlytic vectors for drug delivery. Inspite of its toxicity they are still preferred because of their long term expression, stability, and integrity. This review explores the recent developments and relevancy of the novel gene delivery systems in gene therapy.
Manjila, Steffy B; Baby, Jomon N; Bijin, Elambilan N; Constantine, Icey; Pramod, Kannissery; Valsalakumari, Janardhanan
Background Analyses of speciation genes � genes that contribute to the cessation of gene flow between populations � can offer clues regarding the ecological settings, evolutionary forces and molecular mechanisms that drive the divergence of populations and species. This review discusses the identities and attributes of genes that contribute to reproductive isolation (RI) in plants, compares them with animal speciation genes and investigates what these genes can tell us about speciation. Scope Forty-one candidate speciation genes were identified in the plant literature. Of these, seven contributed to pre-pollination RI, one to post-pollination, prezygotic RI, eight to hybrid inviability, and 25 to hybrid sterility. Genes, gene families and genetic pathways that were frequently found to underlie the evolution of RI in different plant groups include the anthocyanin pathway and its regulators (pollinator isolation), S RNase-SI genes (unilateral incompatibility), disease resistance genes (hybrid necrosis), chimeric mitochondrial genes (cytoplasmic male sterility), and pentatricopeptide repeat family genes (cytoplasmic male sterility). Conclusions The most surprising conclusion from this review is that identities of genes underlying both prezygotic and postzygotic RI are often predictable in a broad sense from the phenotype of the reproductive barrier. Regulatory changes (both cis and trans) dominate the evolution of pre-pollination RI in plants, whereas a mix of regulatory mutations and changes in protein-coding genes underlie intrinsic postzygotic barriers. Also, loss-of-function mutations and copy number variation frequently contribute to RI. Although direct evidence of positive selection on speciation genes is surprisingly scarce in plants, analyses of gene family evolution, along with theoretical considerations, imply an important role for diversifying selection and genetic conflict in the evolution of RI. Unlike in animals, however, most candidate speciation genes in plants exhibit intraspecific polymorphism, consistent with an important role for stochastic forces and/or balancing selection in development of RI in plants.
Rieseberg, Loren H.; Blackman, Benjamin K.
\\u000a Gene therapy has a potential for effective therapeutic intervention in rheumatoid arthritis (RA). Proof of concept has been\\u000a demonstrated in animal models, either through local gene delivery to the joint space or through systemic gene delivery for\\u000a immune intervention. This chapter reviews how certain clinical applications of gene therapy would be beneficial for RA patients\\u000a and discusses the roadblocks that
Florence Apparailly; Paul Peter Tak; Christian Jorgensen
NASA Astrophysics Data System (ADS)
Gene therapy is proving likely to be a viable alternative to conventional therapies in coronary artery disease and heart failure. Phase 1 clinical trials indicate high levels of safety and clinical benefits with gene therapy using angiogenic growth factors in myocardial ischaemia. Although gene therapy for heart failure is still at the pre-clinical stage, experimental data indicate that therapeutic angiogenesis using short-term gene expression may elicit functional improvement in affected individuals.
Isner, Jeffrey M.
Cyanobacterial signature genes
A comparison of 8 cyanobacterial genomes reveals that there are 181 shared genes that do not have obvious orthologs in other\\u000a bacteria. These signature genes define aspects of the genotype that are uniquely cyanobacterial. Approximately 25% of these\\u000a genes have been associated with some function. These signature genes may or may not be involved in photosynthesis but likely\\u000a they will
Kirt A. Martin; Janet L. Siefert; Sailaja Yerrapragada; Yue Lu; Thomas Z. McNeill; Pedro A. Moreno; George M. Weinstock; William R. Widger; George E. Fox
Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identi- fied several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider
M. J. Owen; N. Craddock; M. C. O'Donovan
Family, twin, and adoption studies have documented a strong genetic basis for ADHD\\/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD\\/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which
J. M Swanson; Pamela Flodman; James Kennedy; M. Anne Spence; Robert Moyzis; Sabrina Schuck; Michael Murias; Joan Moriarity; Cathy Barr; Moyra Smith; Michael Posner
ERIC Educational Resources Information Center
Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called "generalist genes". This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading�
Haworth, Claire M. A.; Meaburn, Emma L.; Harlaar, Nicole; Plomin, Robert
Some genes produce RNAs that are functional instead of encoding proteins. Noncoding RNA genes are surprisingly numerous. Recently, active research areas include small nucleolar RNAs, antisense riboregulator RNAs, and RNAs involved in X-dosage compensation. Genome sequences and new algorithms have begun to make systematic computational screens for noncoding RNA genes possible.
Sean R. Eddy
Cloning Human Chromosome 17 Genes: Candidate Genes for BRCA1.
National Technical Information Service (NTIS)
Our research interest is focused on the identification of genes from chromosome 17. The isolation of genes transcribed from chromosome 17 will provide candidates for the proposed sporadic breast cancer genes and genes for other human disorders.The ability...
C. Lee
Cloning Human Chromosome 17 Genes: Candidate Genes for BRCA1.
National Technical Information Service (NTIS)
Our research interest is focused on the identification of genes from chromosome 17. The isolation of genes transcribed from chromosome 17 will provide candidates for the proposed sporadic breast cancer genes and genes for other human disorders. The abilit...
C. C. Lee
Gene Gateway: Exploring Genes and Genetic Disorders
NSDL National Science Digital Library
This collection of guides and tutorials is intended to help users take advantage of of online data sources from the Human Genome Project for learning about genetic disorders, genes, and proteins. Resources include the Gene Gateway Workbook, a downloadable tutorial consisting of activities with screenshots and instructions, that helps new users locate and use genetic-disorder and bioinformatics resources on the web. There are also resources for learning about genes and the proteins they encode; tips, tutorials, and terminology for using selected resources in the Genome Database Guide; a guide to nontechnical resources on genetic disorder descriptions and treatments; a human genome landmarks poster; and others.
Pax1, a member of the paired box-containing class of developmental control genes, is mapped to human chromosome 20p11.2 by in situ hybridization (ISH and FISH).
Pax-1, a member of a murine multigene family, belongs to the paired box-containing class of developmental control genes first identified in Drosophila. The Pax-1 gene encodes a sequence-specific DNA-binding protein with transcriptional activating properties and has been found to be mutated in the autosomal recessive mutation undulated (un) on mouse chromosome 2 with vertebral anomalies along the entire rostrocaudal axis. By radioactive in situ hybridization (ISH) using a fragment from the murine Pax-1 paired box that is almost identical to the respective sequences from the cognate human gene HuP48 and fluorescence in situ hybridization (FISH) using a complete mouse Pax-1 cDNA, we have assigned the human homologue of murine Pax-1, the PAX1 locus, to chromosome 20p. The map position of PAX1 after FISH (FL-pter value of 0.34 +/- 0.04) corresponds to band p11.2. These results confirm the exceptional homology between human chromosome 20 and the distal segment of mouse chromosome 2, extending from bands F to G, and add PAX1 to the group of genes on 20p like PTPA, PRNP, SCG1, BMP2A, which are located in proximity on both chromosomes. PMID:1358810
Schnittger, S; Rao, V V; Deutsch, U; Gruss, P; Balling, R; Hansmann, I
Phosphinothricin-resistance gene
US Patent & Trademark Office Database
Phosphinothricin (PTC) selection of bacteria which are not fungus-like yields PTC-resistant selectants. The DNA fragment which carries the resistance gene is obtained from the complete DNA of these selectants by constructing a gene bank and screening for chemical modification of PTC. The resistance gene can be localized to a fragment which is 2 kb in size, and selection for PTC resistance. This gene is suitable for producing PTC-resistant plants and propagation material thereof, and as a resistance marker as well. Microorganisms which contain this PTC-resistance gene can be used in sewage treatment plants.
Understanding Cancer Series: Gene Testing
... Dictionary Search for Clinical Trials NCI Publications Espa�ol Gene Testing Slide Number and Title Genes in the News DNA Chemical Bases in DNA DNA Molecules Gene Subunits DNA->RNA->Protein Different Genes - Different Functions ...
Essential Bacillus subtilis genes
To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among ?4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from bacteria with small genomes. Unexpectedly, most genes involved in the Embden�Meyerhof�Parnas pathway are essential. Identification of unknown and unexpected essential genes opens research avenues to better understanding of processes that sustain bacterial life.
Kobayashi, K.; Ehrlich, S. D.; Albertini, A.; Amati, G.; Andersen, K. K.; Arnaud, M.; Asai, K.; Ashikaga, S.; Aymerich, S.; Bessieres, P.; Boland, F.; Brignell, S. C.; Bron, S.; Bunai, K.; Chapuis, J.; Christiansen, L. C.; Danchin, A.; Debarbouille, M.; Dervyn, E.; Deuerling, E.; Devine, K.; Devine, S. K.; Dreesen, O.; Errington, J.; Fillinger, S.; Foster, S. J.; Fujita, Y.; Galizzi, A.; Gardan, R.; Eschevins, C.; Fukushima, T.; Haga, K.; Harwood, C. R.; Hecker, M.; Hosoya, D.; Hullo, M. F.; Kakeshita, H.; Karamata, D.; Kasahara, Y.; Kawamura, F.; Koga, K.; Koski, P.; Kuwana, R.; Imamura, D.; Ishimaru, M.; Ishikawa, S.; Ishio, I.; Le Coq, D.; Masson, A.; Mauel, C.; Meima, R.; Mellado, R. P.; Moir, A.; Moriya, S.; Nagakawa, E.; Nanamiya, H.; Nakai, S.; Nygaard, P.; Ogura, M.; Ohanan, T.; O'Reilly, M.; O'Rourke, M.; Pragai, Z.; Pooley, H. M.; Rapoport, G.; Rawlins, J. P.; Rivas, L. A.; Rivolta, C.; Sadaie, A.; Sadaie, Y.; Sarvas, M.; Sato, T.; Saxild, H. H.; Scanlan, E.; Schumann, W.; Seegers, J. F. M. L.; Sekiguchi, J.; Sekowska, A.; Seror, S. J.; Simon, M.; Stragier, P.; Studer, R.; Takamatsu, H.; Tanaka, T.; Takeuchi, M.; Thomaides, H. B.; Vagner, V.; van Dijl, J. M.; Watabe, K.; Wipat, A.; Yamamoto, H.; Yamamoto, M.; Yamamoto, Y.; Yamane, K.; Yata, K.; Yoshida, K.; Yoshikawa, H.; Zuber, U.; Ogasawara, N.
Parkinson's Disease: Gene Therapies
With the recent development of effective gene delivery systems, gene therapy for the central nervous system is finding novel applications. Here, we review existing viral vectors and discuss gene therapy strategies that have been proposed for Parkinson�s disease. To date, most of the clinical trials were based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. Initial trials used genes to relieve the major motor symptoms caused by nigrostriatal degeneration. Although these new genetic approaches still need to prove more effective than existing symptomatic treatments, there is a need for disease-modifying strategies. The investigation of the genetic factors implicated in Parkinson�s disease is providing precious insights in disease pathology that, combined with innovative gene delivery systems, will hopefully offer novel opportunities for gene therapy interventions to slow down, or even halt disease progression.
Coune, Philippe G.; Schneider, Bernard L.; Aebischer, Patrick
Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size-regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution.
Myoadenylate deaminase deficiency caused by alternative splicing due to a novel intronic mutation in the AMPD1 gene.
We have examined two Caucasian brothers with myoadenylate deaminase (AMPD) deficiency who presented with exercise intolerance and muscle cramps. Allele-specific PCR amplification assays demonstrated that the common Q12X (C34T) and P48L (C143T) mutations were not found within their AMPD1 genes. Further analysis revealed that both brothers were compound heterozygotes for a previously reported K287I (A860T) mutation in exon 7 and a novel deletion within intron 2 (IVS2-(4-7)delCTTT). The intronic deletion appears to affect the splicing machinery since characterization of AMPD1 mRNA from skeletal muscle of one brother identified multiple alternatively spliced transcripts resulting in multiple deletions in exon 3, the complete deletion of either exon 3 or exons 3 and 4, and the activation of a cryptic splice site that resulted in an insertion at the 5' end of exon 4. The predominant transcript contains a 51 base deletion at the 5' end of exon 3 that is predicted to produce a functional form of AMPD containing a 17-amino acid residue deletion within its N-terminal region. Analysis of 137 Caucasian normal control patients determined that the K287I mutation is relatively frequent (5.1% carrier frequency), whereas the IVS2-(4-7)delCTTT mutation is rare and not present in 274 chromosomes. PMID:16040263
Isackson, Paul J; Bujnicki, Heather; Harding, Cary O; Vladutiu, Georgirene D
NSDL National Science Digital Library
Today you will learn about the parts of DNA and what DNA, genes and chromosomes are. Today you will learn what DNA, genes and chromosomes are and the parts of the DNA molecule. Look at all of the websites, take whatever notes you need to. At the end of the assignment, be able to describle DNA, the parts of DNA, genes and chromosomes. Covers Biology Core Curriculum, ...
Fomby, Mrs.
Arthritis is among the leading causes of disability in the developed world. There remains no cure for this disease and the current treatments are only modestly effective at slowing the disease's progression and providing symptomatic relief. The clinical effectiveness of current treatment regimens has been limited by short half-lives of the drugs and the requirement for repeated systemic administration. Utilizing gene transfer approaches for the treatment of arthritis may overcome some of the obstacles associated with current treatment strategies. The present review examines recent developments in gene therapy for arthritis. Delivery strategies, gene transfer vectors, candidate genes, and safety are also discussed.
Traister, Russell S.
Genes Involved in Atherosclerosis
Atherosclerosis is a multifactorial disease that involves several genes and proteins. The purpose of this article is to focus on the arterial wall and to review lipoprotein receptors, growth factors, cytokines, chemokines, matrix metalloproteinases, adhesion molecules, and apoptosis genes and their involvement in atherogenesis.
Johanna Laukkanen; Seppo Yl�-Herttuala
NSDL National Science Digital Library
The Institute for Genomic Resources (TIGR) placed online the Tomato Gene Index (version 1.2) in 1999. The index is searchable by nucleotide or protein sequence, identifier (TC, ET, EST, GB), tissue, or gene product name. Note that this resource is available free of charge "only to researchers at non-profit institutions using it for non-commercial purposes."
The release of the sequence of the human genome in early 2000 generated enormous excitement with the promise of rapid identification of the gene products responsible for cellular function. What has become apparent is that knowledge of the DNA sequence of the gene that is involved in a particular metabolic process is insufficient to predict its function, expression and activity.
Gene Expression Mural: Visualizing Gene Expression Databases
The Gene Expression Mural is a tool designed for managing the vast amount of information produced by the rapidly growing field of Bioinformatics. The advantages of this tool are that it not only provides an overview of many experiments for an entire genome, but also promotes discovery with its zooming and navigation capabilities. A \\
Mathew Clement; Margaret Ellis; Josh Steele; Yuying Tian; Chris North
GeneEd: Genetics, Education, Discovery
NSDL National Science Digital Library
The GeneEd website was created by the National Library of Medicine (NLM), the National Human Genome Research Institute (NHGRI), and the National Institutes of Health (NIH) as a helpful resource for the teaching and learning of genetics. On the site, visitors can find labs and experiments, fact sheets, and teacher resources on topics including DNA forensics, genetic conditions, evolution, and biostatistics. First-time visitors will want to start their journey by looking over the Topics tab at the top of the page. There are 40 different thematic areas here consisting of articles, video clips, webcasts, and links to additional quality resources vetted by the GeneEd web team. The Labs & Experiments section includes virtual labs that explore the genetics of different organisms as well as links to resources provided by the Howard Hughes Medical Institute and Cold Spring Harbor Laboratory. Young people may also wish to take a look at the Careers in Genetics section as it features interviews with scientists that will inspire and delight.
In its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane�bound autophagosome and delivered to the lysosome for degradation. This pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type I interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. Most of these links have emerged from studies in which genes encoding molecules involved in autophagy are inactivated in immune effector cells. However, it is not yet known whether all of the critical functions of such genes in immunity represent �classical autophagy� or possible as-yet-undefined autophagolysosome-independent functions of these genes. This review summarizes phenotypes that result from the inactivation of autophagy genes in the immune system and discusses the pleiotropic functions of autophagy genes in immunity.
Virgin, Herbert W; Levine, Beth
A central focus of postgenomic research will be to understand how cellular phenomena arise from the connectivity of genes and proteins. This connectivity generates molecular network diagrams that resemble complex electrical circuits, and a systematic understanding will require the development of a mathematical framework for describing the circuitry. From an engineering perspective, the natural path towards such a framework is the construction and analysis of the underlying submodules that constitute the network. Recent experimental advances in both sequencing and genetic engineering have made this approach feasible through the design and implementation of synthetic gene networks amenable to mathematical modelling and quantitative analysis. These developments have signalled the emergence of a gene circuit discipline, which provides a framework for predicting and evaluating the dynamics of cellular processes. Synthetic gene networks will also lead to new logical forms of cellular control, which could have important applications in functional genomics, nanotechnology, and gene and cell therapy. PMID:12432407
Hasty, Jeff; McMillen, David; Collins, J J
The retinoblastoma gene Rb was the first tumor suppressor gene cloned, and it is well known as a negative regulator of the cell cycle through its ability to bind the transcription factor E2Fand repress transcription of genes required for S phase. Although over 100 other proteins have been reported to interact with Rb, in most cases these interactions are much less well characterized. Therefore, this review will primarily focus on Rb and E2F interactions. In addition to cell cycle regulation, studies of Rb and E2Fproteins in animal models have revealed important roles for these proteins in apoptosis and differentiation. Recent screens of Rb/E2Ftarget genes have identified new targets in all these areas. In addition, the mechanisms determining how different subsets of target genes are regulated under different conditions have only begun to be addressed and offer exciting possibilities for future research.
Du, W; Pogoriler, J
The ultimate goal of gene therapy is the replacement of a defective gene sequence with a corrected version to eliminate disease for the lifetime of the patient. This challenging task is not yet accomplished, however significant progress is evident. An initial spate of clinical trials attempting the treatment of haemophilia with gene transfer primarily resulted in the demonstration of good safety profiles, but without efficacy. Subsequent reengineering of vector plasmids and delivery systems resulted in markedly improved outcomes in animal models of the disease. The most recent clinical trial for the treatment of haemophilia B with gene transfer showed transient achievement of efficacy in the highest dose cohort tested, but also exposed a previously hidden barrier to the future success of these treatments. The progress and problems of gene therapies for haemorrhagic disorders will be discussed. This review will concentrate on approaches in or near clinical application.
Murphy, Samuel L; High, Katherine A
Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey
4. AERIAL VIEW OF GENE WASH RESERVOIR AND GENE CAMP LOOKING SOUTHWEST. DAM AND SPILLWAY VISIBLE IN BOTTOM OF PHOTO. - Gene Wash Reservoir & Dam, 2 miles west of Parker Dam, Parker Dam, San Bernardino County, CA
Gene�gene effects on central processing of aversive stimuli
Emotional reactivity and regulation are fundamental to human behavior. As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene�gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli. These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of
M N Smolka; M B�hler; G Schumann; S Klein; X-Z Hu; M Moayer; A Zimmer; J Wrase; H Flor; K Mann; D F Braus; D Goldman; A Heinz
Characterization of beta-R1, a gene that is selectively induced by interferon beta (IFN-beta) compared with IFN-alpha.
We report preliminary characterization of a gene designated beta-R1, which is selectively expressed in response to interferon beta (IFN-beta) compared with IFN-alpha. In human astrocytoma cells, beta-R1 was induced to an equivalent extent by 10 IU/mL IFN-beta or 2500 IU/mL IFN-alpha2. To address the mechanism of this differential response, we analyzed induction of the beta-R1 gene in fibrosarcoma cells and derivative mutant cells lacking components required for signaling by type I IFNs. beta-R1 was readily induced by IFN-beta in the parental 2fTGH cell line, but not by recombinant IFN-alpha2, IFN-alpha Con1, or a mixture of IFN-alpha subtypes. IFN-alpha8 induced beta-R1 weakly. beta-R1 was not induced by IFN-beta in mutant cell lines U2A, U3A, U4A, and U6A, which lack, respectively, p48, STAT1, JAK1, and STAT2. U5A cells, which lack the Ifnar 2.2 component of the IFN-alpha and -beta receptor, also failed to express beta-R1. U1A cells are partially responsive to IFN-beta and IFN-alpha8 but lacked beta-R1 expression, indicating that TYK2 protein is essential for induction of this gene. Taken together, these results suggest that the expression of beta-R1 in response to type I IFN requires IFN-stimulated gene factor 3 plus an additional component, which is more efficiently formed on induction by IFN-beta compared with IFN-alpha. PMID:8798467
Rani, M R; Foster, G R; Leung, S; Leaman, D; Stark, G R; Ransohoff, R M
There have been tremendous advances in our understanding of cancer from the application of molecular biology over the past decade. The disease is caused by a series of defects in the genes that accelerate growth--oncogenes--and those that slow down cellular turnover--tumour suppressor genes. The proteins they encode provide a promising hunting ground in which to design and test new anticancer drugs. Several treatment strategies are now under clinical trial entailing direct gene transfer. These include the use of gene marking to detect minimal residual disease, the production of novel cancer vaccines by the insertion of genes which uncloak cancer cells so making them visible to the host's immune system, the isolation and coupling of cancer specific molecular switches upstream of drug activating genes, and the correction of aberrant oncogenes or tumour suppressor genes. The issues in these approaches are likely to have a profound impact on the management of cancer patients as we enter the next century. Images p1221-a
Sikora, K.
Launched in October 2009, the CARTaGENE project is the largest prospective longitudinal cohort of Qu�bec. CARTaGENE's distinguishing features are that it is a quantitative prospective cohort that has deeply phenotyped 20,000 individuals aged 40-69, the age most individuals will develop chronic disease. 37,000 individuals will be enrolled by 2014. It is an open-access infrastructure enabling researchers to investigate the genetic, environmental, and lifestyle determinants of disease in the French Canadian population. CARTaGENE has collected whole blood for DNA from 30,000 individuals.
... Francisco, Dr. Wilson Liao is using new genetic sequencing technology to find rare "trigger genes" that may ... and therefore never developed the disease. Working with DNA samples from a large family that includes many ...
How is RNA Polymerase II (RNAP) regulated at poised loci in embryonic stem cells? Recent work provides new insights into Ring1-mediated transcriptional control of this important subset of developmental regulatory genes. PMID:18059356
Spektor, Tanya M; Rice, Judd C
NSDL National Science Digital Library
This interactive activity, adapted from the Dolan DNA Learning Center, illustrates how Gregor Mendel used pure-bred yellow and green peas to show that some genes are dominant and others are recessive.
Foundation, Wgbh E.
... as a major cause of cancer. This knowledge led to some of the most effective early screening ... gene toxicity in human health and disease and led to new treatments for cancer. NIH-funded research ...
Eucaryotic gene expression requires chromatin-remodel- ing activities. We show by time-course studies that trans- criptional induction of the yeast glucose-regulated SUC2 gene is rapid and shows a striking biphasic pattern, the first phase of which is partly mediated by the general stress transcription factors Msn2p\\/Msn4p. The SWI\\/SNF ATP-dependent chromatin-remodeling complex associates with the promoter in a similar biphasic manner and
Fuqiang Geng; Brehon C Laurent
Background: Genome comparisons have revealed major lateral gene transfer between the three primary kingdoms of life - Bacteria, Archaea, and Eukarya. Another important evolutionary phenomenon involves the evolutionary mobility of protein domains that form versatile multidomain architectures. We were interested in investigating the possibility of a combination of these phenomena, with an invading gene merging with a pre-existing gene in the recipient genome. Results: Complete genomes of fifteen bacteria, four archaea and one eukaryote were searched for interkingdom gene fusions (IKFs); that is, genes coding for proteins that apparently consist of domains originating from different primary kingdoms. Phylogenetic analysis supported 37 cases of IKF, each of which includes a 'native' domain and a horizontally acquired 'alien' domain. IKFs could have evolved via lateral transfer of a gene coding for the alien domain (or a larger protein containing this domain) followed by recombination with a native gene. For several IKFs, this scenario is supported by the presence of a gene coding for a second, stand-alone version of the alien domain in the recipient genome. Among the genomes investigated, the greatest number of IKFs has been detected in Mycobacterium tuberculosis, where they are almost always accompanied by a stand-alone alien domain. For most of the IKF cases detected in other genomes, the stand-alone counterpart is missing. Conclusions: The results of comparative genome analysis show that IKF formation is a real, but relatively rare, evolutionary phenomenon. We hypothesize that IKFs are formed primarily via the proposed two-stage mechanism, but other than in the Actinomycetes, in which IKF generation seems to be an active, ongoing process, most of the stand-alone intermediates have been eliminated, perhaps because of functional redundancy.
Wolf, Yuri I; Kondrashov, Alexey S; Koonin, Eugene V
GeneCards Version 3: the human gene integrator
GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73 000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards� unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene�s functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org
Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron
Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes
We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets.
Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie
Gene discovery and gene function assignment in filamentous fungi
Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant
Lisbeth Hamer; Kiichi Adachi; Maria V. Montenegro-Chamorro; Matthew M. Tanzer; Sanjoy K. Mahanty; Clive Lo; Rex W. Tarpey; Amy R. Skalchunes; Ryan W. Heiniger; Sheryl A. Frank; Blaise A. Darveaux; David J. Lampe; Ted M. Slater; Lakshman Ramamurthy; Todd M. Dezwaan; Grant H. Nelson; Jeffrey R. Shuster; Jeffrey Woessner; John E. Hamer
Positive Darwinian Selection after Gene Duplication in Primate Ribonuclease Genes
Evolutionary mechanisms of origins of new gene function have been a subject of long-standing debate. Here we report a convincing case in which positive Darwinian selection operated at the molecular level during the evolution of novel function by gene duplication. The genes for eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) in primates belong to the ribonuclease gene family, and
Jianzhi Zhang; Helene F. Rosenberg; Masatoshi Nei
Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey
5. OVERHEAD VIEW OF GENE CAMP LOOKING SOUTH. GENE PUMP PLANT IS AT CENTER WITH ADMINISTRATIVE COMPLEX IN FOREGROUND AND RESIDENTIAL AREA BEYOND PLANT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA
Classification of genes based on gene expression analysis
Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.
Angelova, M., E-mail: email@example.com; Myers, C., E-mail: email@example.com; Faith, J., E-mail: firstname.lastname@example.com [Northumbria University (United Kingdom)
Classification of genes based on gene expression analysis
NASA Astrophysics Data System (ADS)
Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.
Angelova, M.; Myers, C.; Faith, J.
Stochastic Gene Expression Model Base Gene Regulatory Networks
NASA Astrophysics Data System (ADS)
Gene regulatory networks consist of a number of genes and their interactions which regulate expressions of the genes. Along with the development of gene regulatory network studies, computer simulations have become a valuable tool to evaluate complex relationships between genes. Due to the stochastic nature of gene expressions, various stochastic approaches have attracted increasing interest. In this study, we build gene regulatory networks based on a stochastic gene expression model with delicate assumptions such as transcription, translation, DNA-protein, protein-protein associations and time delay for protein activation. Two simple in-silico gene regulatory network models are constructed and monitored their expression profiles reflecting the inhibition and activation of the gene regulations.
Kim, Haseong; Gelenbe, Erol
GeneCards Version 3: the human gene integrator.
GeneCards (www.genecards.org) is a comprehensive, authoritative compendium of annotative information about human genes, widely used for nearly 15 years. Its gene-centric content is automatically mined and integrated from over 80 digital sources, resulting in a web-based deep-linked card for each of >73,000 human gene entries, encompassing the following categories: protein coding, pseudogene, RNA gene, genetic locus, cluster and uncategorized. We now introduce GeneCards Version 3, featuring a speedy and sophisticated search engine and a revamped, technologically enabling infrastructure, catering to the expanding needs of biomedical researchers. A key focus is on gene-set analyses, which leverage GeneCards' unique wealth of combinatorial annotations. These include the GeneALaCart batch query facility, which tabulates user-selected annotations for multiple genes and GeneDecks, which identifies similar genes with shared annotations, and finds set-shared annotations by descriptor enrichment analysis. Such set-centric features address a host of applications, including microarray data analysis, cross-database annotation mapping and gene-disorder associations for drug targeting. We highlight the new Version 3 database architecture, its multi-faceted search engine, and its semi-automated quality assurance system. Data enhancements include an expanded visualization of gene expression patterns in normal and cancer tissues, an integrated alternative splicing pattern display, and augmented multi-source SNPs and pathways sections. GeneCards now provides direct links to gene-related research reagents such as antibodies, recombinant proteins, DNA clones and inhibitory RNAs and features gene-related drugs and compounds lists. We also portray the GeneCards Inferred Functionality Score annotation landscape tool for scoring a gene's functional information status. Finally, we delineate examples of applications and collaborations that have benefited from the GeneCards suite. Database URL: www.genecards.org. PMID:20689021
Safran, Marilyn; Dalah, Irina; Alexander, Justin; Rosen, Naomi; Iny Stein, Tsippi; Shmoish, Michael; Nativ, Noam; Bahir, Iris; Doniger, Tirza; Krug, Hagit; Sirota-Madi, Alexandra; Olender, Tsviya; Golan, Yaron; Stelzer, Gil; Harel, Arye; Lancet, Doron
Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern-day gene and then to reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework that can be used to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. PMID:23915718
Capra, John A; Stolzer, Maureen; Durand, Dannie; Pollard, Katherine S
FunGene: the functional gene pipeline and repository.
Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes. PMID:24101916
Fish, Jordan A; Chai, Benli; Wang, Qiong; Sun, Yanni; Brown, C Titus; Tiedje, James M; Cole, James R
Eukaryotic Genes Involved in Adult Lifespan Regulation.
National Technical Information Service (NTIS)
The present invention relates to regulation of adult lifespan in eukaryotes. More particularly, the present invention is directed to methods of assaying for genes, gene products, and genes in pathways controlled by such genes and gene products, using RNAi...
A. Dillin A. L. A. Hsu C. Kenyon D. Garigan J. Apfeld
Integrated Analysis of Gene Expression and Gene Copy Number for Gene Shaving Based on ICA Approach
Microarray gene expression and array CGH (aCGH) are two genomic approaches, which are widely used for biomedical discovery. While microarray gene expression analysis provides functional information, the aCGH analysis provides structural variations of genome using gene copy number analysis. The integration of this complementary information is challenging. We proposed a method, named as �gene shaving�, to identify subsets of the
Yu-Ping Wang
Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions
Motivation: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interac- tion). Detecting and
Lance W. Hahn; Marylyn D. Ritchie; Jason H. Moore
Characterizing gene family evolution
Gene families are widely used in comparative genomics, molecular evolution, and in systematics. However, they are constructed in different manners, their data analyzed and interpreted differently, with different underlying assumptions, leading to sometimes divergent conclusions. In systematics, concepts like monophyly and the dichotomy between homoplasy and homology have been central to the analysis of phylogenies. We critique the traditional use of such concepts as applied to gene families and give examples of incorrect inferences they may lead to. Operational definitions that have emerged within functional genomics are contrasted with the common formal definitions derived from systematics. Lastly, we question the utility of layers of homology and the meaning of homology at the character state level in the context of sequence evolution. From this, we move forward to present an idealized strategy for characterizing gene family evolution for both systematic and functional purposes, including recent methodological improvements.
Liberles, David A.
We provide a comprehensive list of all known forms of X-linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes. The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators. 74 refs., 2 figs., 5 tabs.
Neri, G.; Chiurazzi, P. [Universita Cattolica del Sacro Cuore, Rome (Italy); Arena, J.F.; Lubs, H.A. [Univ. of Miami School of Medicine, FL (United States)
NSDL National Science Digital Library
This site comes from the BBC's "Gene Stories...The Basics of Being," a Web feature that explores in great depth the field of genetics and how it relates to our everyday lives. In Genes and History, visitors can "find out how science can help solve historical riddles that have long perplexed historians, and how history can offer cautionary tales about the promise of science." The site also includes some interactive features like How Viking Are You?, a fun way to find out if Viking blood runs through your veins.
Phospholipid - Driven gene regulation
Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.
Musille, Paul M.; Kohn, Jeffrey A.; Ortlund, Eric A.
Genes2FANs: connecting genes through functional association networks
Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs), researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI) network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user�s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our finding that disease genes in many cancers are mostly connected through PPIs whereas other complex diseases, such as autism and type-2 diabetes, are mostly connected through FANs without PPIs, can guide better strategies for disease gene discovery. Genes2FANs is available at: http://actin.pharm.mssm.edu/genes2FANs.
Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T cells target and destroy insulin-secreting ?-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T cells to prevent islet destruction (prophylactic) or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date and promising novel techniques for the maintenance of euglycemia in the treatment of T1D.
Wong, Mary S; Hawthorne, Wayne J
Engineering prokaryotic gene circuits
Engineering of synthetic gene circuits is a rapidly growing discipline, currently dominated by prokaryotic transcription networks, which can be easily rearranged or rewired to give different output behaviours. In this review, we examine both a rational and a combinatorial design of such networks and discuss progress on using in vitro evolution techniques to obtain functional systems. Moving beyond pure transcription networks, more and more networks are being implemented at the level of RNA, taking advantage of mechanisms of translational control and aptamer�small molecule complex formation. Unlike gene expression systems, metabolic components are generally not as interconnectable in any combination, and so engineering of metabolic circuits is a particularly challenging field. Nonetheless, metabolic engineering has immense potential to provide useful biosynthesis tools for biotechnology applications. Finally, although prokaryotes are mostly studied as single cell systems, cell�cell communication networks are now being developed that result in spatial pattern formation in multicellular prokaryote colonies. This represents a crossover with multicellular organisms, showing that prokaryotic systems have the potential to tackle questions traditionally associated with developmental biology. Overall, the current advances in synthetic gene synthesis, ultra-high-throughput DNA sequencing and computation are synergizing to drive synthetic gene network design at an unprecedented pace.
Michalodimitrakis, Konstantinos; Isalan, Mark
Exploring Genes & Genetic Disorders
NSDL National Science Digital Library
More and more excellent data continues to be produced by the Human Genome Project, and a number of government organizations have created top-notch educational resources based on this information. The Gene Gateway website was originally produced as a companion to the Human Genome Landmarks poster and has evolved into a "collection of guides and tutorials designed to help students and other novice users get started with some of the resources that make these data available to the public." Here visitors are introduced to various Internet tools that anyone can use to investigate "genetic disorders, chromosomes, genome maps, genes, sequence data, genetic variants, and molecular structures." Visitors can download the Gene Gateway workbook, which contains five activities, complete with screenshots and step-by-step instructions "designed to introduce new users to genetic disorder and bioinformatics resources on the Web". Moving down the homepage, visitors can look into sections such as "Bioinformatics Tools", the "Genetic Disorder Guide", and an outstanding "Chromosome Viewer". The viewer provides a great backdrop for those seeking to understand the physical makeup of human chromosomes. Also, visitors can order a free copy of the wall poster "Human Genome Landmarks: Selected Genes, Traits, and Disorders".
ERIC Educational Resources Information Center
Could a mutation in a single gene be the evolutionary lynchpin supporting the development of human language? A rare mutation in the molecule known as FOXP2 discovered in a human family seemed to suggest so, and its sequence phylogeny reinforced a Chomskian view that language emerged wholesale in humans. Spurred by this discovery, research in�
White, Stephanie A.
Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting ( #24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on
M. Ian Phillips
Our ability to genetically manipulate the mouse has had a great impact on medical research over the last few decades. Mouse genetics has developed into a powerful tool for dissecting the genetic causes of human disease and identifying potential targets for pharmaceutical intervention. With the recent sequencing of the human and mouse genomes, a large number of novel genes have
A. Abuin; G. Hansen; B. Zambrowicz
Ultrasound mediated gene transfection
NASA Astrophysics Data System (ADS)
Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.
Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.
GeneTrail--advanced gene set enrichment analysis
We present a comprehensive and efficient gene set analysis tool, called �GeneTrail� that offers a rich functionality and is easy to use. Our web-based application facilitates the statistical evaluation of high-throughput genomic or proteomic data sets with respect to enrichment of functional categories. GeneTrail covers a wide variety of biological categories and pathways, among others KEGG, TRANSPATH, TRANSFAC, and GO. Our web server provides two common statistical approaches, �Over-Representation Analysis� (ORA) comparing a reference set of genes to a test set, and �Gene Set Enrichment Analysis� (GSEA) scoring sorted lists of genes. Besides other newly developed features, GeneTrail's statistics module includes a novel dynamic-programming algorithm that improves the P-value computation of GSEA methods considerably. GeneTrail is freely accessible at http://genetrail.bioinf.uni-sb.de
Backes, Christina; Keller, Andreas; Kuentzer, Jan; Kneissl, Benny; Comtesse, Nicole; Elnakady, Yasser A.; Muller, Rolf; Meese, Eckart; Lenhof, Hans-Peter
Evolution of teleostean hatching enzyme genes and their paralogous genes
We isolated genes for hatching enzymes and their paralogs having two cysteine residues at their N-terminal regions in addition to four cysteines conserved in all the astacin family proteases. Genes for such six-cysteine-containing astacin proteases (C6AST) were searched out in the medaka genome database. Five genes for MC6AST1 to 5 were found in addition to embryo-specific hatching enzyme genes. RT-PCR
Mari Kawaguchi; Shigeki Yasumasu; Junya Hiroi; Kiyoshi Naruse; Masayuki Inoue; Ichiro Iuchi
Identification of Genes and Gene Products Necessary for Bacterial Bioluminescence
Expression of luminescence in Escherichia coli was recently achieved by cloning genes from the marine bacterium Vibrio fischeri. One DNA fragment on a hybrid plasmid encoded regulatory functions and enzymatic activities necessary for light production. We report the results of a genetic analysis to identify the luminescence genes (lux) that reside on this recombinant plasmid. lux gene mutations were generated
Joanne Engebrecht; Michael Silverman
The choice of a dose-response model used for extrapolation can be influenced by knowledge of mechanism of action. We have already showed that arsenic affects methylation of the human p53 gene promoter. Evidence that genes other than the p53 tumor suppressor gene are affected woul...
Proto-genes and de novo gene birth
Novel protein-coding genes can arise either through re-organization of pre-existing genes or de novo1,2. Processes involving re-organization of pre-existing genes, notably following gene duplication, have been extensively described1,2. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or �non-genic� sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions1,3-6. Here, we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes4 generated by widespread translational activity in non-genic sequences. Testing this model at genome-scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events appear to provide adaptive potential7, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non-genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation.
Carvunis, Anne-Ruxandra; Rolland, Thomas; Wapinski, Ilan; Calderwood, Michael A.; Yildirim, Muhammed A.; Simonis, Nicolas; Charloteaux, Benoit; Hidalgo, Cesar A.; Barbette, Justin; Santhanam, Balaji; Brar, Gloria A.; Weissman, Jonathan S.; Regev, Aviv; Thierry-Mieg, Nicolas; Cusick, Michael E.; Vidal, Marc
Interactive Fly: Maternally transcribed genes
NSDL National Science Digital Library
The maternally transcribed genes section of the award-winning and comprehensive site: Interactive fly. It thoroughly discusses genes, tissues, biochemical paths, and developmental processes in the fruit fly, Drosophila.
PhD Thomas B Brody (NIH Laboratory of Neurochemistry)
Using Genes to Guide Prescriptions
... role in how your body responds to medicines. Credit: Stock image. Your genes determine the color of ... of them, and genes might make the difference. Credit: Stock image. For people who have had a ...
Interactive Fly: Genes involved in Malpighian Tubules
NSDL National Science Digital Library
A list and description of Drosophila genes involved in malpigian tubule formation, highlighting transcription factors, ATPase genes, and surface protein genes. A subset of the Interactive Fly collection.
PhD Thomas B Brody (NIH Laboratory of Neurochemistry)
Hematopoietic Stem Cell Gene Therapy
Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic\\u000a disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified\\u000a cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some\\u000a of the seminal
David W. Emery; Tamon Nishino; Ken Murata; Michalis Fragkos; George Stamatoyannopoulos
The Human Gene Mutation Database
NSDL National Science Digital Library
The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.
The Human Gene Mutation Database
NSDL National Science Digital Library
The Human Gene Mutation Database from the Institute of Medical Genetics at Cardiff provides practical information for researchers, physicians, and genetic counselors. The database is currently undergoing some reorganization, but information can be searched by "disease, gene name, or gene symbol." Search results are well organized and easy to navigate, linking directly to results from external Web databases without requiring that the user perform additional searches. Frequent users may also appreciate the listing of genes recently added to the database.
\\u000a The connexin genes code for a family of proteins that form intercellular gap junction channels. There are 21 connexin genes\\u000a in the human genome and 20 in the mouse genome. Most connexin genes contain the protein coding region in a single exon. Variations\\u000a in promoter usage and splicing of 5�-untranslated exons contribute to regulation of connexin expression. Connexin gene promoters
Eric C. Beyer; Viviana M. Berthoud
Regulatory Protein Coordinating Gene Expression
NSDL National Science Digital Library
The action of the glucocorticoid receptor is illustrated. On the left is shown a series of genes, each of which has various gene activator proteins bound to its regulatory region. However, these bound proteins are not sufficient on their own to activate transcription efficiently. On the right is shown the effects of adding an additional gene regulatory protein
BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts;Bruce REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Dennis Bray N:Bray;Dennis REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Alexander Johnson N:Johnson;Alexander REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Julian Lewis N:Lewis;Julian REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Martin Raff N:Raff;Martin REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Keith Roberts N:Roberts;Keith REV:2005-04-16 END:VCARD
Gene regulation in physiological stress
A range of new tools in molecular biology are now available to allow the comparative biochemist to explore animal responses to environmental stress at multiple levels. In particular, new techniques of gene discovery, such as cDNA array screening, allow broad assessment of the responses of thousands of genes to a stress. This approach frequently identifies genes (and their associated metabolic
Kenneth B. Storey
Homologous Recombination Based Gene Therapy
Background\\/Aims: Most of the current expression vector based gene therapy protocols fail to achieve clinically significant transgene expression required for treating genetic diseases. Homologous recombination, initially considered to be of limited use for gene therapy because of its low frequency in mammalian cells, has recently emerged as a potential strategy for developing gene therapy. Methods: Six recent studies of homologous
Li-Wen Lai; Yeong-Hau H. Lien
Male Germ Cell Gene Expression
Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is develop- mentally regulated and stage specific. Some of these transcripts are product of genes that are male germ cell-specific homologs of genes expressed in somatic cells, while some are expressed from unique genes unlike any
Prospects for Human Gene Therapy
Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application
W. French Anderson
Inducible Gene Targeting in Mice
A method of gene targeting that allows the inducible inactivation of a target gene in mice is presented. The method uses an interferon-responsive promoter to control the expression of Cre recombinase. Here, Cre was used to delete a segment of the DNA polymerase beta gene flanked by loxP recombinase recognition sites. Deletion was complete in liver and nearly complete in
Ralf Kuhn; Frieder Schwenk; Michel Aguet; Klaus Rajewsky
Generalist Genes and Learning Disabilities
The authors reviewed recent quantitative genetic research on learning disabilities that led to the conclusion that genetic diagnoses differ from traditional diagnoses in that the effects of relevant genes are largely general rather than specific. This research suggests that most genes associated with common learning disabilities�language impairment, reading disability, and mathematics disability�are generalists in 3 ways. First, genes that affect
Robert Plomin; Yulia Kovas
The Merck Gene Index project (MGIP) fills an important niche in the Human Genome Project by directly identifying genes through sequences of their transcripts and placing in the public domain a set of EST sequences and associated clones for the uniquely expressed human genes. The MGIP promotes the unrestricted exchange of human genomic data, and facilitates progress in biomedical research
Alan R. Williamson
Models of variance components and their intraclass correlational equivalences are developed for genes falling into various categories of subdivisions within a population. Estimable functions are elaborated demonstrating that intraclass correlations can be estimated only relative to that for the least related genes in the informational system. The effects of different types of subdivisions�and of ignoring them�on the parameters are demonstrated. Small sample estimators are formulated for all of the parameters by three different methods, including both a weighted and an unweighted method of analysis of the variation among subpopulations. How estimators change with assumptions about the parameters is illustrated. Various tests of hypotheses are outlined in ?2 and F-test terminology. Discussed are factors which may affect the correlations and the manner in which their effects are manifest, hopefully in clarification of some of the misconceptions that have arisen in this connection.
Cockerham, C. Clark
NSDL National Science Digital Library
This Web site, offered through Johns Hopkins University School of Medicine and Johns Hopkins Health System, aims to "provide a hub for the integration of information on Myc target genes, the role of Myc in human cancers, and proteins that interact with the Myc transcription factors." Users will find a well-organized collection of resources relating to Myc, such as an extensive set of links to PubMed articles, related databases, and some original data. The Web site's introduction provides a very readable explanation of Myc gene function and its role in tumor formation. Researchers working with Myc are encouraged to submit data to the site, which also offers a Myc-related listserve for convenient email updates.
ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.
Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Helio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael
Basic Sciences - Gene Regulation
Currently, Dr. Levens's research is focusing on the transcriptional regulation of c-myc and the elucidation of the roles of conformation and topology-selective, sequence-specific DNA binding transcription factors. The c-myc gene employs multiple cis-elements, upstream and downstream of its promoters, P1 and P2. The goal is to illuminate the mechanisms through which the input of multiple factors sets the expression level of this critical proto-oncogene.
\\u000a The diagnosis of a child with a single gene disorder can take on different meanings for different families. It is not uncommon\\u000a for some families to arrive at a pediatric genetics clinic after months or years of searching for an underlying reason for\\u000a their child�s symptoms. The fact that, through genetic testing, clinicians can put a name to the collection
Tricia See; Cynthia J. Tifft
In most species�from cyanobacteria to humans�endogenous clocks have evolved that drive 24-h rhythms of behavior and physiology.\\u000a In mammals, these circadian rhythms are regulated by a hierarchical network of cellular oscillators controlled by a set of\\u000a clock genes organized in a system of interlocked transcriptional feedback loops. One of the most prominent outputs of the\\u000a circadian system is the synchronization
Dominic Landgraf; Anton Shostak; Henrik Oster
NSDL National Science Digital Library
In this exploration, we'll take a look at how DNA stores information and how scientists identify what particular genes do. DNA is a very, very long molecule. To find out what a particular piece is for, a person (most often a scientist) must search -- or rather hunt-- for the genetic meaning. At the end, we examine how you can use the DNA code yourself.
Nickle, Todd
Gene delivery to bone is useful both as an experimental tool and as a potential therapeutic strategy. Among its advantages over protein delivery are the potential for directed, sustained and regulated expression of authentically processed, nascent proteins. Although no clinical trials have been initiated, there is a substantial pre-clinical literature documenting the successful transfer of genes to bone, and their intraosseous expression. Recombinant vectors derived from adenovirus, retrovirus and lentivirus, as well as non-viral vectors, have been used for this purpose. Both ex vivo and in vivo strategies, including gene-activated matrices, have been explored. Ex vivo delivery has often employed mesenchymal stem cells (MSCs), partly because of their ability to differentiate into osteoblasts. MSCs also have the potential to home to bone after systemic administration, which could serve as a useful way to deliver transgenes in a disseminated fashion for the treatment of diseases affecting the whole skeleton, such as osteoporosis or osteogenesis imperfecta. Local delivery of osteogenic transgenes, particularly those encoding bone morphogenetic proteins, has shown great promise in a number of applications where it is necessary to regenerate bone. These include healing large segmental defects in long bones and the cranium, as well as spinal fusion and treating avascular necrosis.
Evans, C. H.
Design of polyketide synthase genes
US Patent & Trademark Office Database
Methods for the computational analysis of polyketides and the computer-assisted design of PKS genes are facilitated by representing the structure of a polyketide and/or a PKS gene that encodes the PKS that produces the polyketide by alphanumeric symbols that facilitates computer assisted analysis. A database of polyketides and corresponding PKS genes that can be rapidly searched and information extracted for a variety of applications, including the design and specification of PKS genes via the recombining of modules or portions of modules or sets of modules from already known and available PKS genes.
Gene-Gene, Gene-Environment & Multiple Interactions in Colorectal Cancer
This review comprehensively evaluates the influence of gene-gene, gene-environment and multiple interactions on the risk of colorectal cancer (CRC). Methods of studying these interactions and their limitations have been discussed herein. There is a need to develop biomarkers of exposure and of risk that are sensitive, specific, present in the pathway of the disease, and that have been clinically tested
Same Genes May Influence Reading, Math Skills
... Preidt Wednesday, July 9, 2014 Related MedlinePlus Pages Children's Health Genes and Gene Therapy WEDNESDAY, July 9, 2014 ( ... HealthDay . All rights reserved. More Health News on: Children's Health Genes and Gene Therapy Recent Health News Page ...
Horizontal gene transfer in choanoflagellates.
Horizontal gene transfer (HGT), also known as lateral gene transfer, results in the rapid acquisition of genes from another organism. HGT has long been known to be a driving force in speciation in prokaryotes, and there is evidence for HGT from symbiotic and infectious bacteria to metazoans, as well as from protists to bacteria. Recently, it has become clear that as many as a 1,000 genes in the genome of the choanoflagellate Monosiga brevicollis may have been acquired by HGT. Interestingly, these genes reportedly come from algae, bacteria, and other choanoflagellate prey. Some of these genes appear to have allowed an ancestral choanoflagellate to exploit nutrient-poor environments and were not passed on to metazoan descendents. However, some of these genes are also found in animal genomes, suggesting that HGT into a common ancestor of choanozoans and animals may have contributed to metazoan evolution. PMID:22997182
Tucker, Richard P
The Gene Wiki: community intelligence applied to human gene annotation.
Annotating the function of all human genes is a critical, yet formidable, challenge. Current gene annotation efforts focus on centralized curation resources, but it is increasingly clear that this approach does not scale with the rapid growth of the biomedical literature. The Gene Wiki utilizes an alternative and complementary model based on the principle of community intelligence. Directly integrated within the online encyclopedia, Wikipedia, the goal of this effort is to build a gene-specific review article for every gene in the human genome, where each article is collaboratively written, continuously updated and community reviewed. Previously, we described the creation of Gene Wiki 'stubs' for approximately 9000 human genes. Here, we describe ongoing systematic improvements to these articles to increase their utility. Moreover, we retrospectively examine the community usage and improvement of the Gene Wiki, providing evidence of a critical mass of users and editors. Gene Wiki articles are freely accessible within the Wikipedia web site, and additional links and information are available at http://en.wikipedia.org/wiki/Portal:Gene_Wiki. PMID:19755503
Huss, Jon W; Lindenbaum, Pierre; Martone, Michael; Roberts, Donabel; Pizarro, Angel; Valafar, Faramarz; Hogenesch, John B; Su, Andrew I
From gene expression to gene regulatory networks in Arabidopsis thaliana
Background The elucidation of networks from a compendium of gene expression data is one of the goals of systems biology and can be a valuable source of new hypotheses for experimental researchers. For Arabidopsis, there exist several thousand microarrays which form a valuable resource from which to learn. Results A novel Bayesian network-based algorithm to infer gene regulatory networks from gene expression data is introduced and applied to learn parts of the transcriptomic network in Arabidopsis thaliana from a large number (thousands) of separate microarray experiments. Starting from an initial set of genes of interest, a network is grown by iterative addition to the model of the gene, from another defined set of genes, which gives the 'best' learned network structure. The gene set for iterative growth can be as large as the entire genome. A number of networks are inferred and analysed; these show (i) an agreement with the current literature on the circadian clock network, (ii) the ability to model other networks, and (iii) that the learned network hypotheses can suggest new roles for poorly characterized genes, through addition of relevant genes from an unconstrained list of over 15,000 possible genes. To demonstrate the latter point, the method is used to suggest that particular GATA transcription factors are regulators of photosynthetic genes. Additionally, the performance in recovering a known network from different amounts of synthetically generated data is evaluated. Conclusion Our results show that plausible regulatory networks can be learned from such gene expression data alone. This work demonstrates that network hypotheses can be generated from existing gene expression data for use by experimental biologists.
Needham, Chris J; Manfield, Iain W; Bulpitt, Andrew J; Gilmartin, Philip M; Westhead, David R
Gene Circuit Analysis of the Terminal Gap Gene huckebein
The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.
Ashyraliyev, Maksat; Siggens, Ken; Janssens, Hilde; Blom, Joke; Akam, Michael; Jaeger, Johannes
Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.
The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects. PMID:17024427
Motsinger, Alison A; Brassat, David; Caillier, Stacy J; Erlich, Henry A; Walker, Karen; Steiner, Lori L; Barcellos, Lisa F; Pericak-Vance, Margaret A; Schmidt, Silke; Gregory, Simon; Hauser, Stephen L; Haines, Jonathan L; Oksenberg, Jorge R; Ritchie, Marylyn D
Gene delivery and gene therapy of prostate cancer.
Surgery, radiation or hormonal therapy are not adequate to control prostate cancer. Clearly, other novel treatment approaches, such as gene therapy, for advanced/recurrent disease are desperately needed to achieve long-term local control and particularly to develop effective systemic therapy for metastatic prostate cancer. In the last decade, significant progress in gene therapy for the treatment of localised prostate cancer has been demonstrated. A broad range of different gene therapy approaches, including cytolytic, immunological and corrective gene therapy, have been successfully applied for prostate cancer treatment in animal models, with translation into early clinical trials. In addition, a wide variety of viral and nonbiological gene delivery systems are available for basic and clinical research. Gene therapy approaches that have been developed for the treatment of prostate cancer are summarised. PMID:16370939
Kaliberov, Sergey A; Buchsbaum, Donald J
Gene therapy for ocular diseases
The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.
Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao
Gene transfer in experimental medicine.
Gene transfer technology has many potential applications in medicine. Phase I and phase II gene-based clinical trials have been conducted for the treatment of cancer, monogenic disorders, some neurodegenerative illnesses, cardiopathies and infectious diseases. A phase I gene therapy clinical trial has recently been approved for the treatment of Parkinson's disease, while preclinical studies are in progress to develop gene-based interventions for the treatment of Alzheimer's disease and Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and diabetes type 1 and type 2. A number of gene transfer models have been generated for gene therapy and genetic immunization programs. Vector design is addressing several pressing issues in the matter of gene delivery improvement, stabilization of transgene expression and safety. This is necessary in order to achieve efficient gene-based therapeutic interventions. Indeed, considerable progress has been reported in the field of vector design, which has produced some encouraging results in clinical trials and preclinical studies. However, vector design should be further developed to allow for the successful application of gene transfer technology in therapy. This review summarizes the latest achievements and controversies in clinical trials and preclinical studies in the field of gene therapy. PMID:12942157
Romano, Gaetano
Statistics for approximate gene clusters
Background Genes occurring co-localized in multiple genomes can be strong indicators for either functional constraints on the genome organization or remnant ancestral gene order. The computational detection of these patterns, which are usually referred to as gene clusters, has become increasingly sensitive over the past decade. The most powerful approaches allow for various types of imperfect cluster conservation: Cluster locations may be internally rearranged. The individual cluster locations may contain only a subset of the cluster genes and may be disrupted by uninvolved genes. Moreover cluster locations may not at all occur in some or even most of the studied genomes. The detection of such low quality clusters increases the risk of mistaking faint patterns that occur merely by chance for genuine findings. Therefore, it is crucial to estimate the significance of computational gene cluster predictions and discriminate between true conservation and coincidental clustering. Results In this paper, we present an efficient and accurate approach to estimate the significance of gene cluster predictions under the approximate common intervals model. Given a single gene cluster prediction, we calculate the probability to observe it with the same or a higher degree of conservation under the null hypothesis of random gene order, and add a correction factor to account for multiple testing. Our approach considers all parameters that define the quality of gene cluster conservation: the number of genomes in which the cluster occurs, the number of involved genes, the degree of conservation in the different genomes, as well as the frequency of the clustered genes within each genome. We apply our approach to evaluate gene cluster predictions in a large set of well annotated genomes.
A 2.5-Mb transcript map of a tumor-suppressing subchromosomal transferable fragment from 11p15.5, and isolation and sequence analysis of three novel genes.
11p15.5 is an important tumor-suppressor gene region, showing loss of heterozygosity in Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. We previously mapped directly by genetic complementation a subtransferable fragment (STF) harboring an embryonal tumor-suppressor gene and spanning about 2.5 Mb. We have now mapped the centromeric end of this STF between D11S988 and D11S12 and its telomeric end between D11S1318 and TH. We have isolated a complete contig of PAC, P1, BAC, and cosmid genomic clones spanning the entire 2.5-Mb region defined by this STF, as well as more than 200 exons from these genomic clones using exon trapping. We have isolated genes in this region by directly screening DNA libraries as well as by database searching for ESTs. Nine of these genes have been reported previously by us and by others. However, the initial mapping of most of those genes was based on FISH or somatic cell hybrid analysis, and here we precisely define their physical location. These genes include RRM1, GOK (D11S4896E), Nup98, CARS, hNAP2 (NAP1L4), p57KIP2 (CDKN1C), KVLQT1 (KCNA9), TAPA-1, and ASCL2. In addition, we have identified several novel genes in this region, three of which, termed TSSC1, TSSC2, and TSSC3, are reported here. TSSC1 shows homology to Rb-associated protein p48 and chromatin assembly factor CAF1, and it is located between GOK and Nup98. TSSC2 is homologous to Caenorhabditis elegans beta-mannosyl transferase, and it lies between Nup98 and CARS. TSSC3 shows homology to mouse TDAG51, which is implicated in FasL-mediated apoptosis, and it is located between hNAP2 and p57KIP2. Thus, these genes may play a role in malignancies that involve this region. PMID:9403053
Hu, R J; Lee, M P; Connors, T D; Johnson, L A; Burn, T C; Su, K; Landes, G M; Feinberg, A P
Frequent gene conversion between human red and green opsin genes
To study the evolution of human X-linked red and green opsin genes, genomic sequences in large regions of the two genes were\\u000a compared. The divergences in introns 3, 4, and 5 and the 3? flanking sequence of the two genes are significantly lower than\\u000a those in exons 4 and 5. The homogenization mechanism of introns and the 3? flanking sequence
Zhongming Zhao; David Hewett-Emmett; Wen-Hsiung Li
GeneMark.hmm: new solutions for gene finding.
The number of completely sequenced bacterial genomes has been growing fast. There are computer methods available for finding genes but yet there is a need for more accurate algorithms. The GeneMark. hmm algorithm presented here was designed to improve the gene prediction quality in terms of finding exact gene boundaries. The idea was to embed the GeneMark models into naturally derived hidden Markov model framework with gene boundaries modeled as transitions between hidden states. We also used the specially derived ribosome binding site pattern to refine predictions of translation initiation codons. The algorithm was evaluated on several test sets including 10 complete bacterial genomes. It was shown that the new algorithm is significantly more accurate than GeneMark in exact gene prediction. Interestingly, the high gene finding accuracy was observed even in the case when Markov models of order zero, one and two were used. We present the analysis of false positive and false negative predictions with the caution that these categories are not precisely defined if the public database annotation is used as a control.
Lukashin, A V; Borodovsky, M
Identification of additional genes that influence baculovirus late gene expression.
We were unable to confirm transient late gene expression using constructs of 18 genes that had been reported to support Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) late gene expression when transfected into Spodoptera frugiperda cells [Lu, A., and Miller, L. K. (1995). J. Virol. 69, 975-982]. Three genes (orf66, orf68, and orf41) were included, all or in part, in the constructs used in that study, but they had not been independently tested. Therefore we investigated these and neighboring orfs for their influence on late gene expression. We found that orf41 was required for late gene expression and that sequences within orf45 appeared to be required for the expression of orf41. Although orf66 and orf68 did not appear to affect late gene expression, orf69 stimulated expression. orf69 was found to have high homology to recent entries in GenBank from a variety of organisms. In addition, it was found that orf121, which was shown to be involved in early gene expression, and the viral homolog of pcna did not influence late gene expression. PMID:10049816
Li, L; Harwood, S H; Rohrmann, G F
A current list of all known forms of X-linked mental retardation (XLMR) and a slightly revised classification are presented. The number of known disorders has not increased because 6 disorders have been combined based on new molecular data or on clinical grounds and only 6 newly described XLMR disorders have been reported. Of the current 105 XLMR disorders, 34 have been mapped, and 18 disorders and 1 non-specific XLMR (FRAXE) have been cloned. The number of families with nonspecific XLMR with a LOD score of {ge}2.0 has more than doubled, with 42 (including FRAXE) now being known. A summary of the localization of presumed nonspecific mental retardation (MR) genes from well-studied X-chromosomal translocations and deletions is also included. Only 10-12 nonoverlapping loci are required to explain all localizations of non-specific MR from both approaches. These new trends mark the beginning of a significantly improved understanding of the role of genes on the X chromosome in producing MR. Continued close collaboration between clinical and molecular investigators will be required to complete the process. 105 refs., 2 figs., 6 tabs.
Lubs, H.A.; Tranebjaerg, L. [Univ. Hospital of Tromso (Norway)] [Univ. Hospital of Tromso (Norway); Arena, J.F. [Univ. of Miami School of Medicine, FL (United States)] [and others] [Univ. of Miami School of Medicine, FL (United States); and others
Loricrin is the major protein component of the cornified cell envelope of terminally differentiated mammalian epidermal (stratum corneum) cells. Using a specific human cDNA clone, we have isolated and characterized the human loricrin gene. We show that it has a very simple structure of a single intron of 1188 base pairs (bp) in the 5'-untranslated region; there are no introns in coding sequences. By use of rodent-human somatic cell hybrids, followed by in situ hybridization with a biotin-labeled genomic DNA clone, the single-copy gene maps to chromosome location 1q21. Polymerase chain reaction analyses of genomic DNAs from different individuals show that human loricrin consists of two allelic size variants, due to sequence variations in its second glycine loop domain, and these variants segregate in the human population by normal Mendelian mechanisms. Furthermore, there are multiple sequence variants within these two size class alleles due to various deletions of 12 bp (4 amino acids) in the major loop of this glycine loop domain. By use of a specific loricrin antibody, we show by immunogold electron microscopy that loricrin initially appears in the granular layer of human epidermis and forms composite keratohyalin granules with profilaggrin, but localizes to the cell periphery (cell envelope) of fully differentiated stratum corneum cells. PMID:1355480
Yoneda, K; Hohl, D; McBride, O W; Wang, M; Cehrs, K U; Idler, W W; Steinert, P M
Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level.�Stow, L. R., Jacobs, M. E., Wingo, C. S., Cain, B. D. Endothelin-1 gene regulation.
Stow, Lisa R.; Jacobs, Mollie E.; Wingo, Charles S.; Cain, Brian D.
Introns are integral elements of eukaryotic genomes that perform various important functions and actively participate in gene evolution. We review six distinct roles of spliceosomal introns: (1) sources of non-coding RNA; (2) carriers of transcription regulatory elements; (3) actors in alternative and trans-splicing; (4) enhancers of meiotic crossing over within coding sequences; (5) substrates for exon shuffling; and (6) signals for mRNA export from the nucleus and nonsense-mediated decay. We consider transposable capacities of introns and the current state of the long-lasting debate on the 'early-or-late' origin of introns. Cumulative data on known types of contemporary exon shuffling and the estimation of the size of the underlying exon universe are also discussed. We argue that the processes central to introns-early (exon shuffling) and introns-late (intron insertion) theories are entirely compatible. Each has provided insight: the latter through elucidating the transposon capabilities of introns, and the former through understanding the importance of introns in genomic recombination leading to gene rearrangements and evolution. PMID:12868603
Fedorova, Larisa; Fedorov, Alexei
Gene therapy for psychiatric disorders.
Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. PMID:23268195
Gelfand, Yaroslav; Kaplitt, Michael G
Evolutionary biclustering of gene expressions
With the advent of microarray technology it has been possible to measure thousands of expression values of genes in a single experiment. Biclustering or simultaneous clustering of both genes and conditions is challenging particularly for the analysis of high-dimensional gene expression data in information retrieval, knowledge discovery, and data mining. The objective here is to find sub-matrices, i.e., maximal subgroups
Haider Banka; Sushmita Mitra
Combinatorial Approaches to Gene Recognition
Recognition of genes via exon assembly approaches leads naturally to the use of dynamic programming. We consider the general graph-theoretical formulation of the exon assembly problem and analyze in detail some specific variants: multicriterial optimization in the case of non-linear gene-scoring functions; context-dependent schemes for scoring exons and related procedures for exon filtering; and highly specific recognition of arbitrary gene
Mikhail A. Roytberg; Tatiana V. Astakhova; Mikhail S. Gelfand
AMIGene: Annotation of MIcrobial Genes
AMIGene (Annotation of MIcrobial Genes) is an application for automatically identifying the most likely coding sequences (CDSs) in a large contig or a complete bacterial genome sequence. The first step in AMIGene is dedicated to the construction of Markov models that fit the input genomic data (i.e. the gene model), followed by the combination of well-known gene-finding methods and an
St�phanie Bocs; St�phane Cruveiller; David Vallenet; Gr�gory Nuel; Claudine M�digue
Understanding Cancer Series: Gene Testing
Lydia Schindler Donna Kerrigan, M.S. Jeanne Kelly Brian Hollen Illustrates what genes are, explains how mutations occur and are identified within genes, and discusses the benefits and limitations of gene testing for cancer and other disorders. These PowerPoint slides are not locked files. You can mix and match slides from different tutorials as you prepare your own lectures. In the Notes section, you will find explanations of the graphics.
\\u000a Gene therapy shows great potential to assist numerous patients with inadequate relief of inflammatory or neuropathic pain,\\u000a or intractable pain associated with advanced cancer. A brief overview is provided of the methods of gene therapy and of preclinical\\u000a findings in animal models of prolonged inflammatory, neuropathic and cancer pain. Preclinical findings demonstrate no efficacy\\u000a of gene therapy on basal thermal
William R. Lariviere; Doris K. Cope
Gene and Genome Parameters of Mammalian Liver Circadian Genes (LCGs)
The mammalian circadian system controls various physiology processes and behavior responses by regulating thousands of circadian genes with rhythmic expressions. In this study, we redefined circadian-regulated genes based on published results in the mouse liver and compared them with other gene groups defined relative to circadian regulations, especially the non-circadian-regulated genes expressed in liver at multiple molecular levels from gene position to protein expression based on integrative analyses of different datasets from the literature. Based on the intra-tissue analysis, the liver circadian genes or LCGs show unique features when compared to other gene groups. First, LCGs in general have less neighboring genes and larger in both genomic and 3?-UTR lengths but shorter in CDS (coding sequence) lengths. Second, LCGs have higher mRNA and protein abundance, higher temporal expression variations, and shorter mRNA half-life. Third, more than 60% of LCGs form major co-expression clusters centered in four temporal windows: dawn, day, dusk, and night. In addition, larger and smaller LCGs are found mainly expressed in the day and night temporal windows, respectively, and we believe that LCGs are well-partitioned into the gene expression regulatory network that takes advantage of gene size, expression constraint, and chromosomal architecture. Based on inter-tissue analysis, more than half of LCGs are ubiquitously expressed in multiple tissues but only show rhythmical expression in one or limited number of tissues. LCGs show at least three-fold lower expression variations across the temporal windows than those among different tissues, and this observation suggests that temporal expression variations regulated by the circadian system is relatively subtle as compared with the tissue expression variations formed during development. Taken together, we suggest that the circadian system selects gene parameters in a cost effective way to improve tissue-specific functions by adapting temporal variations from the environment over evolutionary time scales.
Wu, Gang; Zhu, Jiang; He, Fuhong; Wang, Weiwei; Hu, Songnian; Yu, Jun
SYNOPSIS Both advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.
Vachani, Anil; Moon, Edmund; Wakeam, Elliot; Haas, Andrew R.; Sterman, Daniel H.; Albelda, Steven M.
Importance of Combinatorial Gene Control
NSDL National Science Digital Library
A hypothetical scheme illustrating how combinations of a few gene regulatory proteins can generate many different cell types during development. In this simple scheme a "decision" to make a new gene regulatory protein (shown as a numbered circle) is made after each cell division. Repetition of this simple rule enables eight cell types (A through H) to be created using only three different regulatory proteins. Each of these hypothetical cell types would then express different genes, as dictated by the combination of gene regulatory proteins that are present within it.
BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts;Bruce REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Dennis Bray N:Bray;Dennis REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Alexander Johnson N:Johnson;Alexander REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Julian Lewis N:Lewis;Julian REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Martin Raff N:Raff;Martin REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Keith Roberts N:Roberts;Keith REV:2005-04-16 END:VCARD
It is the regulation of gene expression that determines phenotype and cellular response. Several families of proteins control gene expression in cells and influence the pathogenesis of multiple organ failure, the acute phase response, atherosclerosis, and graft-vs-host disease. Understanding the basics of the regulation of gene transcription will allow the knowledgeable surgeon to target gene expression as a therapeutic modality in multiple diseases. We examine nuclear factor kappa B as an example of a transcription factor that is involved in multiple surgical diseases and has pharmacological inhibitors available to knowledgeable surgeons. PMID:9637469
Shames, B D; Selzman, C H; Meng, X; Meldrum, D R; Cain, B S; Harken, A H
Selector Genes, Polymorphisms, and Evolution
NSDL National Science Digital Library
Access to the article is free, however registration and sign-in are required. Evolution has been thought to act on small changes in the characteristics of organisms coded by genes called realizator genes. D. Tautz explains how a new result in this issue of Science by Gibson and Hogness (p. 200) shows that this may not always be true. A small phenotypic variation in Drosophila (sensitivity to ether), apparent only under environmental stress, turns out to be coded by a polymorphism in a selector gene, Ultrabithorax, a member of a class of genes that specifies whole body parts and anatomical regions.
Diethard Tautz (Zoologisches Institut der Universit�¤t M�¼nchen;)
Fuzzy measures on the Gene Ontology for gene product similarity.
One of the most important objects in bioinformatics is a gene product (protein or RNA). For many gene products, functional information is summarized in a set of Gene Ontology (GO) annotations. For these genes, it is reasonable to include similarity measures based on the terms found in the GO or other taxonomy. In this paper, we introduce several novel measures for computing the similarity of two gene products annotated with GO terms. The fuzzy measure similarity (FMS) has the advantage that it takes into consideration the context of both complete sets of annotation terms when computing the similarity between two gene products. When the two gene products are not annotated by common taxonomy terms, we propose a method that avoids a zero similarity result. To account for the variations in the annotation reliability, we propose a similarity measure based on the Choquet integral. These similarity measures provide extra tools for the biologist in search of functional information for gene products. The initial testing on a group of 194 sequences representing three proteins families shows a higher correlation of the FMS and Choquet similarities to the BLAST sequence similarities than the traditional similarity measures such as pairwise average or pairwise maximum. PMID:17048464
Popescu, Mihail; Keller, James M; Mitchell, Joyce A
Gene structure conservation aids similarity based gene prediction
One of the primary tasks in deciphering the func- tional contents of a newly sequenced genome is the identification of its protein coding genes. Existing computational methods for gene prediction include ab initio methods which use the DNA sequence itself as the only source of information, comparative methods using multiple genomic sequences, and similarity based methods which employ the cDNA
Irmtraud M. Meyer; Richard Durbin
Targeted gene alteration in Caenorhabditis elegans by gene conversion
Now that some genomes have been completely sequenced, the ability to direct specific mutations into genomes is particularly desirable. Here we present a method to create mutations in the Caenorhabditis elegans genome efficiently through transgene-directed, transposon-mediated gene conversion. Engineered deletions targeted into two genes show that the frequency of obtaining the desired mutation was higher using this approach than using
Peter L Barrett; John T Fleming; Verena G�bel
Antigen receptor gene rearrangement.
Two specialized forms of site-directed double-strand (ds) DNA breakage and rejoining are part of the physiologic program of lymphocytes. One is recombination of the V, D and J gene sequences, termed V(D)J recombination, occurring during early B- and T-cell development, and the other is class-switch recombination occurring exclusively in mature B cells. For V(D)J recombination significant progress has been made recently elucidating the biochemistry of the reaction. In particular our understanding of how DNA ds breaks are both generated and rejoined has increased. For class-switch recombination no definitive information is known about the nucleases required for making the ds breaks, but recent evidence suggests that the joining phase shares activities also required for V(D)J recombination and general DNA ds break repair. PMID:9602306
Grawunder, U; West, R B; Lieber, M R
Heart failure is a chronic progressive disorder where frequent and recurrent hospitalizations are associated with high mortality and morbidity. The incidence and the prevalence of this disease will increase with the increase in the number of the aging population of the United States. Understanding the molecular pathology and pathophysiology of this disease will uncover novel targets and therapies that can restore the function or attenuate the damage of malfunctioning cardiomyocytes by gene therapy that becomes an interesting and a promising field for the treatment of heart failure as well as other diseases in the future. Of equal importance is developing vectors and delivery methods that can efficiently transduce the majority of the cardiomyocytes, that can offer a long term expression and that can escape the host immune response. Recombinant adeno-associated virus vectors have the potential to become a promising novel therapeutic vehicles for molecular medicine in the future.
Chaanine, Antoine H.; Kalman, Jill; Hajjar, Roger J.
Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental, or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable.
Kohrman, David C.; Raphael, Yehoash
NSDL National Science Digital Library
Through this concluding lesson and its associated activity, students experience one valuable and often overlooked skill of successful scientists and engineers�communicating your work and ideas. They explore the importance of scientific communication, including the basic, essential elements of communicating new information to the public and pitfalls to avoid. In the associated activity, student groups create posters depicting their solutions to the unit's challenge question�accurate, efficient methods for detecting cancer-causing genes using optical biosensors�which includes providing a specific example with relevant equations. Students are also individually assessed on their understanding of refraction via a short quiz. This lesson and its associated activity conclude the unit and serve as the culminating Go Public phase of the Legacy Cycle, providing unit review and summative assessment.
Vu Bioengineering Ret Program
Information-theoretic gene-gene and gene-environment interaction analysis of quantitative traits
BACKGROUND: The purpose of this research was to develop a novel information theoretic method and an efficient algorithm for analyzing the gene-gene (GGI) and gene-environmental interactions (GEI) associated with quantitative traits (QT). The method is built on two information-theoretic metrics, the k-way interaction information (KWII) and phenotype-associated information (PAI). The PAI is a novel information theoretic metric that is obtained
Pritam Chanda; Lara Sucheston; Song Liu; Aidong Zhang; Murali Ramanathan
Uncovering trends in gene naming
We take stock of current genetic nomenclature and attempt to organize strange and notable gene names. We categorize, for instance, those that involve a naming system transferred from another context (for example, Pavlov�s dogs). We hope this analysis provides clues to better steer gene naming in the future.
Seringhaus, Michael R; Cayting, Philip D; Gerstein, Mark B
The Meaning of Gene Positioning
There is no doubt that genomes are organized nonrandomly in the nucleus of higher eukaryotes. But what is the functional relevance of this nonrandomness? In this Essay, we explore the biological meaning of spatial gene positioning by examining the functional link between the activity of a gene and its radial position in the nucleus.
Takizawa, Takumi; Meaburn, Karen J.; Misteli, Tom
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.
The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders.
Kaufmann, Kerstin B; Buning, Hildegard; Galy, Anne; Schambach, Axel; Grez, Manuel
Adeno-associated viral (AAV) vector is attracting significant interest for use in gene therapy for genetic diseases, because of its unique and advantageous characteristics, compared to other currently available viral vectors. Eight natural serotypes of AAV have been identified, of which AAV serotype 2 is the one best characterized and most widely used in current gene delivery studies. The application of
Gene Therapy for Liver Disease
With major advances in biomedical science over the last 2 decades, the possibility of treating human disease at a genetic level has become a tantalizing possibility. As a result, a growing number of investigators are focusing on the development of techniques to deliver therapeutic genes into cells. The liver has been a model organ in the development of this gene
Timothy J. Davern II; Bruce F. Scharschmidt
Gene targeting in Physcomitrella patens
Gene-targeting efficiency in the land plant Physcomitrella patens (Bryophyta) can only be compared with that observed in Saccharomyces cerevisiae. Sequencing programs and microbiological molecular genetic approaches are now being developed to unravel the precise function of plant genes. Physcomitrella patens, as the new �green yeast�, might well become a major tool for functional genomic studies of multicellular eukaryotes.
Didier G Schaefer
Multifunctional nanorods for gene delivery
NASA Astrophysics Data System (ADS)
The goal of gene therapy is to introduce foreign genes into somatic cells to supplement defective genes or provide additional biological functions, and can be achieved using either viral or synthetic non-viral delivery systems. Compared with viral vectors, synthetic gene-delivery systems, such as liposomes and polymers, offer several advantages including ease of production and reduced risk of cytotoxicity and immunogenicity, but their use has been limited by the relatively low transfection efficiency. This problem mainly stems from the difficulty in controlling their properties at the nanoscale. Synthetic inorganic gene carriers have received limited attention in the gene-therapy community, the only notable example being gold nanoparticles with surface-immobilized DNA applied to intradermal genetic immunization by particle bombardment. Here we present a non-viral gene-delivery system based on multisegment bimetallic nanorods that can simultaneously bind compacted DNA plasmids and targeting ligands in a spatially defined manner. This approach allows precise control of composition, size and multifunctionality of the gene-delivery system. Transfection experiments performed in vitro and in vivo provide promising results that suggest potential in genetic vaccination applications.
Salem, Aliasger K.; Searson, Peter C.; Leong, Kam W.
The ability to express transgenes selectively within the lung will greatly facilitate the development of gene therapy for a variety of human diseases. We have demonstrated that aerosol administration of a chloramphenicol acetyltransferase (CAT) expression plasmid complexed to cationic liposomes produces high-level, lung-specific CAT gene expression in mice in vivo. Significant levels of CAT activity are seen in the lungs
Roscoe Stribling; Elisa Brunette; Denny Liggitt; Karin Gaensler; Robert Debs
US Patent & Trademark Office Database
A mammal is provided, in which the LKB1 gene can be deleted phase-specifically and tissue-specifically. These mammals are highly useful as tools to reveal the onset mechanism for diseases caused by LKB1 gene deficiency, such as Peutz-Jeghers syndrome and cancers, as well as to develop therapeutic agents, methods, and so on for the diseases.
In this article we examine the effects of the emergence of a new replicator, memes, on the evolution of a pre-existing replicator, genes. Using a version of the NKCS model we examine the effects of increasing the rate of meme evolution in relation to the rate of gene evolution, for various degrees of interdependence between the two replicators. That is, the effects of memes' (suggested) more rapid rate of evolution in comparison to that of genes is investigated using a tunable model of coevolution. It is found that, for almost any degree of interdependence between the two replicators, as the rate of meme evolution increases, a phase transition-like dynamic occurs under which memes have a significantly detrimental effect on the evolution of genes, quickly resulting in the cessation of effective gene evolution. Conversely, the memes experience a sharp increase in benefit from increasing their rate of evolution. We then examine the effects of enabling genes to reduce the percentage of gene-detrimental evolutionary steps taken by memes. Here a critical region emerges as the comparative rate of meme evolution increases, such that if genes cannot effectively select memes a high percentage of the time, they suffer from meme evolution as if they had almost no selective capability. PMID:11224917
Bull, L; Holland, O; Blackmore, S
Expression divergence between duplicate genes
A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be
Wen-Hsiung Li; Jing Yang; Xun Gu
Molecular Clock and Gene Function
Molecular phylogenies based on the molecular clock require the comparison of orthologous genes. Orthologous and paralogous genes usually have very different evolutionary fates. In general, orthologs keep the same functions in species, whereas, particularly over a long time span, paralogs diverge functionally and may become pseudogenes or get lost. In eukaryotic genomes, because of the degree of redundancy of genetic
Cecilia Saccone; Corrado Caggese; Anna Maria D�Erchia; Cecilia Lanave; Marta Oliva; Graziano Pesole
Control of expression of silk protein genes
At least three silk genes are specifically expressed in the posterior, and five other genes in middle, silk glands. The products of genes active in PSG include fibroin, L-chain fibroin and P25 protein. PSG genes as well as the Ser-1 gene, differing in structure, exhibit a striking degree of homology of their 5? flanking sequences. This suggests the presence of
Krystyna Grzelak
PAGE: Parametric Analysis of Gene Set Enrichment
Background: Gene set enrichment analysis (GSEA) is a microarray data analysis method that uses predefined gene sets and ranks of genes to identify significant biological changes in microarray data sets. GSEA is especially useful when gene expression changes in a given microarray data set is minimal or moderate. Results: We developed a modified gene set enrichment analysis method based on
Seon-young Kim; David J. Volsky
Discovering Connected Patterns in Gene Expression Arrays
Clustering methods have been extensively used for gene expression data analysis to detect groups of related genes. The clusters provide useful information to analyze gene function, gene regulation and cellular patterns. Most existing clustering algorithms, though, discover only coherent gene expression patterns, and do not handle connected patterns. Coherent and connected patterns correspond to globular and arbitrary shaped clusters, respectively,
Noha A. Yousri; Mohamed A. Ismail; Mohamed S. Kamel
The evolution of disease resistance genes
Several common themes have shaped the evolution of plant disease resistance genes. These include duplication events of progenitor resistance genes and further expansion to create clustered gene families. Variation can arise from both intragenic and intergenic recombination and gene conversion. Recombination has also been implicated in the generation of novel resistance specificities. Resistance gene clusters appear to evolve more rapidly
Todd E. Richter; Pamela C. Ronald
New colon cancer gene discovered
A new gene has been discovered, by genetic linkage studies, that predisposes to colon cancer. The gene was discovered by linkage to a microsatellite marker on human chromosome 2. The microsatellite DNA shows a high degree of variation in colon cancers, varying in length from tumor to tumor. The gene may act by destabilizing the genome. Different groups looking at different satellite markers saw thousands of microsatellite instabilities throughout the genome, raising the possibility that the DNA as a whole is not being copied correctly, apparently due to a gene mutation that causes wholesale errors during DNA replication. Researchers hope to use the gene as a screening tool for screening individuals susceptible to colon cancer.
Marx, J.
Systems Biophysics of Gene Expression
Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and�extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific�protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses.
Vilar, Jose M.G.; Saiz, Leonor
Nuclear Neighborhoods and Gene Expression
Summary The eukaryotic nucleus is a highly compartmentalized and dynamic environment. Chromosome territories are arranged non-randomly within the nucleus and numerous studies have indicated that a gene�s position in the nucleus can impact its transcriptional activity. Here, we focus on recent advances in our understanding of the influence of specific nuclear neighborhoods on gene expression or repression. Nuclear neighborhoods associated with transcriptional repression include the inner nuclear membrane/nuclear lamina and peri-nucleolar chromatin, whereas neighborhoods surrounding the nuclear pore complex, PML nuclear bodies, and nuclear speckles seem to be transcriptionally permissive. While nuclear position appears to play an important role in gene expression, it is likely to be only one piece of a flexible puzzle that incorporates numerous parameters. We are still at a very early, yet exciting stage in our journey toward deciphering the mechanism(s) that govern the permissiveness of gene expression/repression within different nuclear neighborhoods.
Zhao, Rui; Bodnar, Megan S.; Spector, David L.
NCBI completed the transition of its main genome annotation database from Locuslink to Entrez Gene in Spring 2005. However, to this date few parsers exist for the Entrez Gene annotation file. Owing to the widespread use of Locuslink and the popularity of Perl programming language in bioinformatics, a publicly available high performance Entrez Gene parser in Perl is urgently needed. We present four such parsers that were developed using several parsing approaches (Parse::RecDescent, Parse::Yapp, Perl-byacc and Perl 5 regular expressions) and provide the first in-depth comparison of these sophisticated Perl tools. Our fastest parser processes the entire human Entrez Gene annotation file in under 12 min on one Intel Xeon 2.4 GHz CPU and can be of help to the bioinformatics community during and after the transition from Locuslink to Entrez Gene. PMID:15879451
Liu, Mingyi; Grigoriev, Andrei
Delivery systems for gene therapy
The structure of DNA was unraveled by Watson and Crick in 1953, and two decades later Arber, Nathans and Smith discovered DNA restriction enzymes, which led to the rapid growth in the field of recombinant DNA technology. From expressing cloned genes in bacteria to expressing foreign DNA in transgenic animals, DNA is now slated to be used as a therapeutic agent to replace defective genes in patients suffering from genetic disorders or to kill tumor cells in cancer patients. Gene therapy provides modern medicine with new perspectives that were unthinkable two decades ago. Progress in molecular biology and especially, molecular medicine is now changing the basics of clinical medicine. A variety of viral and non-viral possibilities are available for basic and clinical research. This review summarizes the delivery routes and methods for gene transfer used in gene therapy.
Mali, Shrikant
Gene therapy in cystic fibrosis.
The principal cause of morbidity and mortality in cystic fibrosis (CF) is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Since the cloning of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for CF. Early studies using viral vectors carrying a healthy CFTR plasmid highlighted the difficulties with overcoming the body's host defences. This article reviews the work on gene therapy in CF to date and describes the ongoing work of the UK CF Gene Therapy Consortium in investigating the potential of gene therapy as a treatment for patients with CF. PMID:24464978
Armstrong, David K; Cunningham, Steve; Davies, Jane C; Alton, Eric W F W
Phylogenetic analysis of gene expression.
Phylogenetic analyses of gene expression have great potential for addressing a wide range of questions. These analyses will, for example, identify genes that have evolutionary shifts in expression that are correlated with evolutionary changes in morphological, physiological, and developmental characters of interest. This will provide entirely new opportunities to identify genes related to particular phenotypes. There are, however, 3 key challenges that must be addressed for such studies to realize their potential. First, data on gene expression must be measured from multiple species, some of which may be field-collected, and parameterized in such a way that they can be compared across species. Second, it will be necessary to develop comparative phylogenetic methods suitable for large multidimensional datasets. In most phylogenetic comparative studies to date, the number n of independent observations (independent contrasts) has been greater than the number p of variables (characters). The behavior of comparative methods for these classic problems is now well understood under a wide variety of conditions. In studies of gene expression, and in studies based on other high-throughput tools, the number n of samples is dwarfed by the number p of variables. The estimated covariance matrices will be singular, complicating their analysis and interpretation, and prone to spurious results. Third, new approaches are needed to investigate the expression of the many genes whose phylogenies are not congruent with species phylogenies due to gene loss, gene duplication, and incomplete lineage sorting. Here we outline general considerations of project design for phylogenetic analyses of gene expression and suggest solutions to these three categories of challenges. These topics are relevant to high-throughput phenotypic data well beyond gene expression. PMID:23748631
Dunn, Casey W; Luo, Xi; Wu, Zhijin
Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations
Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene�gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results.
Yaari, Gur; Bolen, Christopher R.; Thakar, Juilee; Kleinstein, Steven H.
Reference Gene Screening for Analyzing Gene Expression Across Goat Tissue
Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken.
Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai
Imprinted genes and regulation of gene expression by epigenetic inheritance.
Six new imprinted genes have recently been identified by association with established imprinted regions, in systematic screens or by serendipity. This brings the total to seventeen imprinted genes, which display a wide variety of functions. Some imprinted genes have been shown to be both physically and mechanistically linked within domains that are under the control of an imprinting centre. Others may apparently undergo imprinting independently. Methylation is clearly required for maintenance of mono-allelic expression while chromatin structure and non-coding RNAs may also play a role. PMID:8743885
John, R M; Surani, M A
GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes
We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.
Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.
Genes, Economics, and Happiness *
We explore the influence of genetic variation on subjective well-being by employing a twin design and genetic association study. In a nationally-representative twin sample, we first show that about 33% of the variation in life satisfaction is explained by genetic variation. Although previous studies have shown that baseline happiness is significantly heritable, little research has considered molecular genetic associations with subjective well-being. We study the relationship between a functional polymorphism on the serotonin transporter gene (5-HTTLPR) and life satisfaction. We initially find that individuals with the longer, transcriptionally more efficient variant of this genotype report greater life satisfaction (n=2,545, p=0.012). However, our replication attempts on independent samples produce mixed results indicating that more work needs to be done to better understand the relationship between this genotype and subjective well-being. This work has implications for how economists think about the determinants of utility, and the extent to which exogenous shocks might affect individual well-being.
De Neve, Jan-Emmanuel; Christakis, Nicholas A.; Fowler, James H.; Frey, Bruno S.
NSDL National Science Digital Library
The Dolan DNA Learning Center at Cold Spring Harbor, NY has created this fantastic website to explore neuroscience, and it is focused on cognitive disorders, cognitive processes, and research approaches. There are many activities on the site, and each is broken down into six categories of analysis, "Genes", "Biochemicals", "Cells", "Brain Anatomy", "Cognition", and "Environment". Thus, clicking on "Bipolar Disorder" under the "Disorders" tab at the top of the page, will take the visitor to a "subway line" at the top of the page. There are several "stops" on the line, and each allows the visitor to learn about the key areas of bipolar disorder research. Scrolling over the stops opens up a small window with a blurb about the content to view. The blurb also shows whether the content is a video, an application, animation, etc. Visitors wishing to see all the research available, should click on the network map, which is the screen behind the smaller "subway line" page. The "Teacher Feature", under the "Targeted Content" tab, and next to the small model of the brain, offers lessons on such topics as autism, memory, and ethical decision-making. "Teacher Pages," "Student Worksheets", and "Test Items" are offered in PDF form.
Environment, genes, and cancer
In January, comedian George Burns turned 100 years old. In recent appearances in the media, he still seems sharp as a tack, and is still seen smoking his trademark cigars. Others of us, however, were never very funny, and would die of cancer at age 60 if we continuously smoked cigars or cigarettes. Burns presents a common but perplexing paradox; some people are able to tolerate at least moderate exposure to toxins such as cigarette smoke with little adverse affect, while others develop cancer, emphysema, or heart disease. New studies support the idea that there is an interaction between genes and the environment, and that this interaction may be an important determinant of cancer risk. To understand such risks, it is essential to look at both an individual`s genetic makeup and environmental exposures. Such studies require the collaboration of molecular epidemiologists and molecular biologists. At the NIEHS, Jack A. Taylor, a lead clinical investigator in the Epidemiology Branch, and Douglas A. Bell, an investigator with the Genetic Risk Group of the Laboratory of Biochemical Risk Analysis, have worked together and with other scientists to uncover new information in this area.
Manuel, J.
Longevity Gene May Boost Brain Power
... Friday, May 9, 2014 Longevity gene may boost brain power NIH-funded researchers discover the gene may ... of a longevity gene, called KLOTHO, have improved brain skills such as thinking, learning and memory regardless ...
Your Genes May Help Pick Your Friends
New Gene 'Atlas' Maps Human DNA Activity
IGF-Regulated Genes in Prostate Cancer.
National Technical Information Service (NTIS)
We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression, and include metastasis-regulating genes that could const...
C. T. Roberts
Gene function prediction with gene interaction networks: a context graph kernel approach
Predicting gene functions is a challenge for biologists in the postgenomic era. Interactions among genes and their products compose networks that can be used to infer gene functions. Most previous studies adopt a linkage assumption, i.e., they assume that gene interactions indicate functional similarities between connected genes. In this study, we propose to use a gene's context graph, i.e., the
Xin Li; Hsinchun Chen; Jiexun Li; Zhu Zhang
Selection of housekeeping genes for gene expression studies in human reticulocytes using real-time PCR
BACKGROUND: Control genes, which are often referred to as housekeeping genes, are frequently used to normalise mRNA levels between different samples. However, the expression level of these genes may vary among tissues or cells and may change under certain circumstances. Thus, the selection of housekeeping genes is critical for gene expression studies. To address this issue, 7 candidate housekeeping genes
Nicholas Silver; Steve Best; Jie Jiang; Swee Lay Thein
in silico analysis resistance gene, tomato genome, SNPs, multiplex Plant disease resistance genes (R-Genes) are an important class of genes from which a subset are well characterized at the molecular level. These genes play a key role in the recognition of the products of avirulence (Avr) genes from pathogens and in the activation of plant defence responses. In the Solanaceae
NASA Astrophysics Data System (ADS)
DNA microarray (``gene chip'') technology has enabled a rapid accumulation of gene-expression data for model organisms such as S. cerevisiae and C. elegans, as well as for H. sapiens, raising the issue of how best to extract information about the gene regulatory networks of these organisms from this data. While basic clustering algorithms have been successful at finding genes that are coregulated for a small, specific set of experimental conditions, these algorithms are less effective when applied to large, varied data sets. One of the major challenges in analyzing the data is the diversity in both size and signal strength of the various transcriptional modules, i.e. sets of coregulated genes along with the sets of conditions for which the genes are strongly coregulated. One method that has proven successful at identifying large and/or strong modules is the Iterative Signature Algorithm (ISA) [1]. A modified version of the ISA algorithm, the Progressive Iterative Signature Algorithm (PISA), is also able to identify smaller, weaker modules by sequentially eliminating transcriptional modules as they are identified. Applying these algorithms to a large set of yeast gene expression data illustrates the strengths and weaknesses of each approach. [1] Bergmann, S., Ihmels, J., and Barkai, N., Phys. Rev. E 67, 031902 (2002).
Kloster, Morten
Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation, erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes� genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes� genotyping and gene doping possibilities, including their development and detection techniques.
Kaliszewski, P.; Majorczyk, E.; Zembron-Lacny, A.
The Gene Resource Locator: gene locus maps for transcriptome analysis
Since the advent of the draft human genome sequence there has been growing interest in transcriptome analysis based on genomic data. The Gene Resource Locator (GRL) assembles gene maps that include information on gene-expression patterns, cis-elements in regulatory regions and alternatively spliced transcripts. The database was constructed using customized software, and currently contains 2.2 million alignments (exon�intron structures). The alignments have been annotated and integrated into a system that encompasses approximately 90 000 EST loci sharing common exons, 8091 alternatively spliced transcript groups, 10 801 expression-profile groups, 8066 candidate regulatory regions in full-length cDNAs, and 1 million SNP loci. We have used Flash technology to build a dynamic web viewer that facilitates browsing through the millions of alignments. All of the information is available through the World Wide Web at the Gene Resource Locator web site (http://grl.gi.k.u-tokyo.ac.jp).
Honkura, Toshihiko; Ogasawara, Jun; Yamada, Tomoyuki; Morishita, Shinichi
The DNA sequences encoding component C of methyl coenzyme M reductase (mcr genes) in Methanothermus fervidus, Methanobacterium thermoautotrophicum, Methanococcus vannielii, and Methanosarcina barkeri have been published. omparisons of transcription initiation and termination site...
GeneTRACE-reconstruction of gene content of ancestral species.
While current computational methods allow the reconstruction of individual ancestral protein sequences, reconstruction of complete gene content of ancestral species is not yet an established task. In this paper, we describe GENETRACE, an efficient linear-time algorithm that allows the reconstruction of evolutionary history of individual protein families as well as the complete gene content of ancestral species. The performance of the method was validated with a simulated evolution program called SimulEv. Our results indicate that given a set of correct phylogenetic profiles and a correct species tree, ancestral gene content can be reconstructed with sensitivity and selectivity of more than 90%. SimulEv simulations were also used to evaluate performance of the reconstruction of gene content-based phylogenetic trees, suggesting that these trees may be accurate at the terminal branches but suffer from long branch attraction near the root of the tree. PMID:12874054
Kunin, Victor; Ouzounis, Christos A
Regulation of Primary Response Genes
Primary response genes (PRGs) are a set of genes that are induced in response to both cell-extrinsic and cell-intrinsic signals and do not require de novo protein synthesis for their expression. These 'first responders' in the waves of transcription of signal responsive genes play pivotal roles in a wide rage of biological responses, including neuronal survival and plasticity, cardiac stress response, innate and adaptive immune responses, glucose metabolism and oncogeneic transformation. Here we bring together recent advances and our current understanding of the signal-induced transcriptional and epigenetic regulation of PRGs.
Fowler, Trent; Sen, Ranjan; Roy, Ananda L
Genomics screens for metastasis genes
Metastasis is responsible for most cancer mortality. The process of metastasis is complex, requiring the coordinated expression and fine regulation of many genes in multiple pathways in both the tumor and host tissues. Identification and characterization of the genetic programs that regulate metastasis is critical to understanding the metastatic process and discovering molecular targets for the prevention and treatment of metastasis. Genomic approaches and functional genomic analyses can systemically discover metastasis genes. In this review, we summarize the genetic tools and methods that have been used to identify and characterize the genes that play critical roles in metastasis.
Yan, Jinchun; Huang, Qihong
Prospects for human gene therapy.
Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application in humans should result in at least partial correction of a number of genetic disorders. However, the safety of the procedures must still be established by further animal studies before human clinical trials would be ethical. PMID:6093246
Anderson, W F
This unit describes generation of and gene transfer to several commonly used airway models. Isolation and transduction of primary airway epithelial cells are first described. Next, the preparation of polarized airway epithelial monolayers is outlined. Transduction of these polarized cells is also described. Methods are presented for generation of tracheal xenografts as well as both ex vivo and in vivo gene transfer to these xenografts. Finally, a method for in vivo gene delivery to the lungs of rodents is included. Methods for evaluating transgene expression are given in the support protocols.
Keiser, Nicholas W.; Engelhardt, John F.
Cationic liposomes for gene delivery.
Cationic liposome-DNA complexes (lipoplexes) constitute a potentially viable alternative to viral vectors for the delivery of therapeutic genes. This review will focus on various parameters governing lipoplex biological activity, from their mode of formation to in vivo behaviour. Particular emphasis is given to the mechanism of interaction of lipoplexes with cells, in an attempt to dissect the different barriers that need to be surpassed for efficient gene expression to occur. Aspects related to new trends in the formulation of lipid-based gene delivery systems aiming at overcoming some of their limitations will be covered. Finally, examples illustrating the potential of cationic liposomes in clinical applications will be provided. PMID:16296751
Sim�es, S�rgio; Filipe, Ana; Faneca, Henrique; Mano, Miguel; Penacho, Nuno; D�zg�nes, Nejat; de Lima, Maria Pedroso
FYN Kinase Gene: Another Glutamatergic Gene Associated with Bipolar Disorder?
Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and
Aleksandra Szczepankiewicz; Janusz K. Rybakowski; Maria Skibinska; Monika Dmitrzak-Weglarz; Anna Leszczynska-Rodziewicz; Monika Wilkosc; Joanna Hauser
THE REX GENE OF BACTERIOPHAGE h IS REALLY TWO GENES
Complementation tests among previously isolated rex- mutants of bacterio- phage A reveal that the mutants comprise two complementation groups, desig- nate,d rexA and rexB. Because rexB- mutants complement prm- mutants, but rexA- mutants do not, it appears that the rexA gene is coordinately controlled with the cI (repressor) gene under the direction of the PW promoter, but that some other
Gene-gene interaction filtering with ensemble of filters
Background Complex diseases are commonly caused by multiple genes and their interactions with each other. Genome-wide association (GWA) studies provide us the opportunity to capture those disease associated genes and gene-gene interactions through panels of SNP markers. However, a proper filtering procedure is critical to reduce the search space prior to the computationally intensive gene-gene interaction identification step. In this study, we show that two commonly used SNP-SNP interaction filtering algorithms, ReliefF and tuned ReliefF (TuRF), are sensitive to the order of the samples in the dataset, giving rise to unstable and suboptimal results. However, we observe that the �unstable� results from multiple runs of these algorithms can provide valuable information about the dataset. We therefore hypothesize that aggregating results from multiple runs of the algorithm may improve the filtering performance. Results We propose a simple and effective ensemble approach in which the results from multiple runs of an unstable filter are aggregated based on the general theory of ensemble learning. The ensemble versions of the ReliefF and TuRF algorithms, referred to as ReliefF-E and TuRF-E, are robust to sample order dependency and enable a more informative investigation of data characteristics. Using simulated and real datasets, we demonstrate that both the ensemble of ReliefF and the ensemble of TuRF can generate a much more stable SNP ranking than the original algorithms. Furthermore, the ensemble of TuRF achieved the highest success rate in comparison to many state-of-the-art algorithms as well as traditional ?2-test and odds ratio methods in terms of retaining gene-gene interactions.
Antivirulence genes: insights into pathogen evolution through gene loss.
The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation--a "fine-tuning" process--for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens. PMID:23045475
Bliven, Kimberly A; Maurelli, Anthony T
Gene discovery and gene function assignment in filamentous fungi.
Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens. PMID:11296265
Hamer, L; Adachi, K; Montenegro-Chamorro, M V; Tanzer, M M; Mahanty, S K; Lo, C; Tarpey, R W; Skalchunes, A R; Heiniger, R W; Frank, S A; Darveaux, B A; Lampe, D J; Slater, T M; Ramamurthy, L; DeZwaan, T M; Nelson, G H; Shuster, J R; Woessner, J; Hamer, J E
Gene discovery and gene function assignment in filamentous fungi
Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.
Hamer, Lisbeth; Adachi, Kiichi; Montenegro-Chamorro, Maria V.; Tanzer, Matthew M.; Mahanty, Sanjoy K.; Lo, Clive; Tarpey, Rex W.; Skalchunes, Amy R.; Heiniger, Ryan W.; Frank, Sheryl A.; Darveaux, Blaise A.; Lampe, David J.; Slater, Ted M.; Ramamurthy, Lakshman; DeZwaan, Todd M.; Nelson, Grant H.; Shuster, Jeffrey R.; Woessner, Jeffrey; Hamer, John E.
Microarray analysis of genes and gene functions in disc degeneration
The aim of the present study was to screen differentially expressed genes (DEGs) in human degenerative intervertebral discs (IVDs), and to perform functional analysis on these DEGs. The gene expression profile was downloaded from the Gene Expression Omnibus database (GSE34095)and included six human IVD samples: three degenerative and three non-degenerative. The DEGs between the normal and disease samples were identified using R packages. The online software WebGestalt was used to perform the functional analysis of the DEGs, followed by Osprey software to search for interactions between the DEGs. The Database for Annotation, Visualization and Integrated Discovery was utilized to annotate the DEGs in the interaction network and then the DEGs were uploaded to the Connectivity Map database to search for small molecules. In addition, the active binding sites for the hub genes in the network were obtained, based on the Universal Protein database. By comparing the gene expression profiles of the non-degenerative and degenerative IVDs, the DEGs between the samples were identified. The DEGs were significantly associated with transforming growth factor ? and the extracellular matrix. Matrix metalloproteinase 2 (MMP2) was identified as the hub gene of the interaction network of DEGs. In addition, MMP2 was found to be upregulated in degenerative IVDs. The screened small molecules and the active binding sites of MMP2 may facilitate the development of methods to inhibit overexpression of MMP2.
Gene Therapy for Parkinson's Disease
Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.
Denyer, Rachel; Douglas, Michael R.
Gene regulatory networks for development
The genomic program for development operates primarily by the regulated expression of genes encoding transcription factors and components of cell signaling pathways. This program is executed by cis-regulatory DNAs (e.g., enhancers and silencers) that control gene expression. The regulatory inputs and functional outputs of developmental control genes constitute network-like architectures. In this PNAS Special Feature are assembled papers on developmental gene regulatory networks governing the formation of various tissues and organs in nematodes, flies, sea urchins, frogs, and mammals. Here, we survey salient points of these networks, by using as reference those governing specification of the endomesoderm in sea urchin embryos and dorsal�ventral patterning in the Drosophila embryo.
Levine, Michael; Davidson, Eric H.
Autophagy Genes as Tumor Suppressors
Autophagy, originally described as a universal lysosome-dependent bulk degradation of cytoplasmic components upon nutrient deprivation, has since been shown to influence diverse aspects of homeostasis and is implicated in a wide variety of pathological conditions, including cancer. The list of autophagy-related (Atg) genes associated with the initiation and progression of human cancer as well as with responses to cancer therapy continues to grow as these genes are being discovered. However, whether Atg genes work through their expected mechanisms of autophagy regulation and/or through as-yet-undefined functions in the development of cancer remains to be further clarified. Here we review recent advances in the knowledge of the molecular basis of autophagy genes and their biological outputs during tumor development. A better understanding of the mechanistic link between cellular autophagy and tumor growth control may ultimately better human cancer treatments.
Liang, Chengyu; Jung, Jae U.
Gene Therapy for Heart Failure
Congestive heart failure accounts for half a million deaths per year in the US. Despite its place among the leading causes of morbidity, pharmcalogical and mechanic remedies have been able to slow the progression of the disease, today�s science has yet to provide a cure and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) along with the start of more recent phase 1 trials opens a new era for gene therapy for the treatment of heart failure.
Tilemann, Lisa; Ishikawa, Kiyotake; Weber, Thomas; Hajjar, Roger J.
Gene discovery in Triatoma infestans
Background Triatoma infestans is the most relevant vector of Chagas disease in the southern cone of South America. Since its genome has not yet been studied, sequencing of Expressed Sequence Tags (ESTs) is one of the most powerful tools for efficiently identifying large numbers of expressed genes in this insect vector. Results In this work, we generated 826 ESTs, resulting in an increase of 47% in the number of ESTs available for T. infestans. These ESTs were assembled in 471 unique sequences, 151 of which represent 136 new genes for the Reduviidae family. Conclusions Among the putative new genes for the Reduviidae family, we identified and described an interesting subset of genes involved in development and reproduction, which constitute potential targets for insecticide development.
Vibrio Fischeri Symbiosis Gene Regulation.
National Technical Information Service (NTIS)
The goals of this project were to investigate the molecular mechanisms controlling luminescence gene expression of the symbiotic bioluminescent bacterium Vibrio fischeri; and to identify and investigate the regulation of other symbiosis functions in this ...
P. V. Dunlap
Prospects for Human Gene Therapy.
National Technical Information Service (NTIS)
In this taped lecture Dr. Anderson reviews the currently most promising means for using gene therapy in managing various disease states. He outlines a technique by which genetically modified calls can be used in a specific cancer chemotherapy protocol, an...
Gene Cloning, Transfection, and Mutagenesis
\\u000a Mutagenesis is a change or alteration in the DNA sequences of a gene. Mutagenic events may occur spontaneously within the\\u000a genome of an organism and many times do not lead to functional consequences or an altered phenotype. However, at times a change\\u000a in the coding sequence of a gene manifests itself as a dysfunctional phenotypic trait or predisposes an individual
Ellen C. Breen; Jason X.-J. Yuan
Monoallelic gene expression in mammals
Three systems of monoallelic gene expression in mammals are known, namely, X-chromosome inactivation, imprinting, and allelic\\u000a exclusion. In all three systems, monoallelic expression is regulated epigenetically and is frequently directed by long non-coding\\u000a RNAs (ncRNAs). This review briefs all three systems of monoallelic gene expression in mammals focusing on chromatin modifications,\\u000a spatial chromosome organization in the nucleus, and the functioning
Irina S. Zakharova; Alexander I. Shevchenko; Suren M. Zakian
Arthritis gene therapy's first death
In July 2007 a subject died while enrolled in an arthritis gene therapy trial. The study was placed on clinical hold while the circumstances surrounding this tragedy were investigated. Early in December 2007 the Food and Drug Administration removed the clinical hold, allowing the study to resume with minor changes to the protocol. In the present article we collate the information we were able to obtain about this clinical trial and discuss it in the wider context of arthritis gene therapy.
Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D
More options for gene editing.
Engineering precise genetic changes in a genome is powerful way to study gene function, and several recent papers describe new applications of gene-editing tools. Working with researchers at Sangamo BioSciences, Howard Hughes Medical Institute investigator Barbara Meyer and her colleagues at the University of California, Berkeley, described the first systems for making targeted genomic modifications in the roundworm Caenorhabditis elegans, a valuable model organism (Wood et al., 2011). PMID:21985000
Baker, Monya
Double-stranded RNA (dsRNA) has recently been shown to trigger sequence-specific gene silencing in a wide variety of organisms, including nematodes, plants, trypanosomes, fruit flies and planaria; meanwhile an as yet uncharacterized RNA trigger has been shown to induce DNA methylation in several different plant systems. In addition to providing a surprisingly effective set of tools to interfere selectively with gene
Andrew Fire
Gene Therapy for Erectile Dysfunction
Our current understanding of the underlying mechanisms of erectile dysfunction suggests that gene therapy will become a therapeutic\\u000a treatment in the near future. Over the past decade, erectile dysfunction has been ameliorated in animal models using viral-and\\u000a plasmid-based vectors. Genes that stimulate smooth muscle cell relaxation, such as neuronal, inducible, and endothelial nitric\\u000a oxide synthase, or that inhibit smooth muscle
Thomas R. Magee; Jacob Rajfer; Nestor F. Gonzalez-Cadavid
Methylated genes in breast cancer
Background Hundreds of hypermethylated genes have been described in breast cancer, yet the nature and contribution of these genes in their methylated state to overall risk and prognosis is under-characterized in non-sporadic breast cancers. We therefore compared associations of DNA methylation with tumor stage, hormone/growth receptor status and clinical outcomes in a familial breast cancer cohort. Because few previous methylation studies have considered the oncogenic or tumor suppressor properties of their gene sets, this functional status was included as part of our correlative analysis. Results We found methylation of oncogenes was associated with better prognostic indicators, whereas tumor suppressor gene methylation was associated with a more severe phenotype in women that were either HER2+ or lymph node positive at diagnosis, and/or tended to recur or develop distant metastases. For example, the methylation of the tumor suppressor gene APC was strongly associated with a specific subset of tumors that were both ER+ and HER2+, while methylation of the TWIST oncogene was associated with breast cancers that did not metastasize. Methods This was a retrospective, hospital-based study of n = 99 archival breast tumors derived from women with a germline genetic BRCA1 or BRCA2 mutation and/or familial breast cancer history. DNA methylation was quantified from formalin fixed, paraffin embedded tumors using the established protocol of quantitative multiplex-methylation specific PCR (QM-MSP). Non-parametric statistics were used to analyze candidate gene methylation in association with clinical outcomes. Conclusion We report several novel, positive associations between percent methylation of the APC, RASSF1A, TWIST, ER?, CDH1 and Cyclin D2 genes and key variables such as tumor stage, hormone and growth receptor status, and a history of recurrent or metastatic disease. Our data suggest the potential utility of parsing gene methylation by functional status and breast tumor subtype.
Vang, Russell; Blackford, Amanda; Fackler, Mary Jo
Transgenic Arabidopsis Gene Expression System
NASA Technical Reports Server (NTRS)
The Transgenic Arabidopsis Gene Expression System (TAGES) investigation is one in a pair of investigations that use the Advanced Biological Research System (ABRS) facility. TAGES uses Arabidopsis thaliana, thale cress, with sensor promoter-reporter gene constructs that render the plants as biomonitors (an organism used to determine the quality of the surrounding environment) of their environment using real-time nondestructive Green Fluorescent Protein (GFP) imagery and traditional postflight analyses.
Ferl, Robert; Paul, Anna-Lisa
Hydrogels for Lentiviral Gene Delivery
Introduction Gene delivery from hydrogel biomaterials provides a fundamental tool for a variety of clinical applications including regenerative medicine, gene therapy for inherited disorders and drug delivery. The high water content and mild gelation conditions of hydrogels support their use for gene delivery by preserving activity of lentiviral vectors and acting to shield vectors from any host immune response. Areas Covered Strategies to control lentiviral entrapment within and retention/release from hydrogels are reviewed. We discuss the ability of hydrogel design parameters to control the transgene expression profile and the capacity of hydrogels to protect vectors from (and even modulate) the host immune response. Expert Opinion Delivery of genetic vectors from scaffolds provides a unique opportunity to capitalize on the potential synergy between the biomaterial design for cell processes and gene delivery. Hydrogel properties can be tuned to directly control the events that determine the tissue response to controlled gene delivery, which include the extent of cell infiltration, preservation of vector activity and vector retention. While some design parameters have been identified, numerous opportunities for investigation are available in order to develop a complete model relating the biomaterial properties and host response to gene delivery.
Seidlits, Stephanie K.; Gower, R. Michael; Shepard, Jaclyn A.; Shea, Lonnie D.
DNA methylation and gene expression.
A large body of evidence demonstrates that DNA methylation plays a role in gene regulation in animal cells. Not only is there a correlation between gene transcription and undermethylation, but also transfection experiments clearly show that the presence of methyl moieties inhibits gene expression in vivo. Furthermore, gene activation can be induced by treatment of cells with 5-azacytidine, a potent demethylating agent. Methylation appears to influence gene expression by affecting the interactions with DNA of both chromatin proteins and specific transcription factors. Although methylation patterns are very stable in somatic cells, the early embryo is characterized by large alterations in DNA modification. New methodologies are now becoming available for studying methylation at this stage and in the germ line. During development, tissue-specific genes undergo demethylation in their tissue of expression. In tissue culture cells this process is highly specific and appears to involve an active mechanism which takes place in the absence of DNA replication. The X chromosome undergoes inactivation during development; this is accompanied by de novo methylation, which appears necessary to stably maintain its silent state. As opposed to the programmed changes in DNA methylation which occur in vivo, immortalized tissue culture cells demonstrate alterations in DNA modification which take place over a long time scale and which appear to be the result of selective pressures present during the growth of these cells in culture. PMID:1943996
Razin, A; Cedar, H
Homologous Gene Replacement in Physarum
The protist Physarum polycephalum is useful for analysis of several aspects of cellular and developmental biology. To expand the opportunities for experimental analysis of this organism, we have developed a method for gene replacement. We transformed Physarum amoebae with plasmid DNA carrying a mutant allele, ardD?1, of the ardD actin gene; ardD?1 mutates the critical carboxy-terminal region of the gene product. Because ardD is not expressed in the amoeba, replacement of ardD(+) with ardD?1 should not be lethal for this cell type. Transformants were obtained only when linear plasmid DNA was used. Most transformants carried one copy of ardD?1 in addition to ardD(+), but in two (5%), ardD(+) was replaced by a single copy of ardD?1. This is the first example of homologous gene replacement in Physarum. ardD?1 was stably maintained in the genome through growth, development and meiosis. We found no effect of ardD?1 on viability, growth, or development of any of the various cell types of Physarum. Thus, the carboxy-terminal region of the ardD product appears not to perform a unique essential role in growth or development. Nevertheless, this method for homologous gene replacement can be applied to analyze the function of any cloned gene.
Burland, T. G.; Pallotta, D.
Book Review: Plant Gene Expression
NSDL National Science Digital Library
Whereas many important biological discoveries have been made using plants, subsequent progress in some areas of plant research has fallen behind that in other organisms for which funding and in vitro assays are more readily available. Gene expression is one such field in which importance continues to grow because many potential plant biotechnology–based solutions to global problems depend on regulating the expression of specific genes. Previous limitations to exploring gene expression in plants have been partially mitigated by recent advances in genomics, genetics, and transformation techniques. The book Regulation of Gene Expression in Plants: The Role of Transcript Structure and Processing, edited by Carole L. Bassett, summarizes our current understanding of plant gene expression, with an emphasis on transcriptional and posttranscriptional regulation. The topics covered in six chapters include differences in messenger RNA (mRNA) structure caused by variations in transcription start and polyadenylation sites, alternative splicing, regulation by small RNAs, and mRNA transport and degradation. The chapters vary in depth, quality, and the degree to which the emphasis is placed on plants rather than eukaryotes in general. However, this slim volume is a useful review of gene expression in plants. The question of whether or not all differences in mRNA structure have functional importance remains open.
Alan Rose (University of California Davis;Molecular and Cellular Biology REV)
Gene therapy in status epilepticus.
Gene therapy in human disease has expanded rapidly in recent years with the development of safer and more effective viral vectors, and presents a novel approach to the treatment of epilepsy. Studies in animals models have demonstrated that overexpression of inhibitory peptides can modify seizure threshold, prevent the development of epilepsy, and modify established epilepsy. More recently there has been a flurry of studies using optogenetics in which light-activated channels expressed in neurons can transiently change neuronal excitability on exposure to light, thereby enabling the development of closed loop systems to detect and stop seizure activity. The treatment of status epilepticus presents its own challenges. Because of both the delay in gene expression following transfection and also the necessity of using focal transfection, there are a limited number of situations in which gene therapy can be used in status epilepticus. One such condition is epilepsia partialis continua (EPC). We have used gene therapy in a model of EPC and have shown that we can "cure" the condition. Recent evidence suggesting that gene therapy targeting subcortical regions can modify generalized or more diffuse epilepsies, indicates that the range of situations in status epilepticus in which gene therapy could be used will expand. PMID:24001071
Walker, Matthew C; Schorge, Stephanie; Kullmann, Dimitri M; Wykes, Robert C; Heeroma, Joost H; Mantoan, Laura
Shared gene expression in distinct neurons expressing common selector genes
Expression of the mec-3/unc-86 selector gene complex induces the differentiation of the touch receptor neurons (TRNs) of Caenorhabditis elegans. These genes are also expressed in another set of embryonically derived mechanosensory neurons, the FLP neurons, but these cells do not share obvious TRN traits or proteins. We have identified ?300 genes in each cell type that are up-regulated at least threefold using DNA microarrays. Twenty-three percent of these genes are up-regulated in both cells. Surprisingly, some of the common genes had previously been identified as TRN-specific. Although the FLP neurons contain low amounts of the mRNAs for these TRN genes, they do not have detectable proteins. These results suggest that transcription control is relatively inexact but that these apparent errors of transcription are tolerated and do not alter cell fate. Previous studies showed that loss of the EGL-44 and EGL-46 transcription factors cause the FLP neurons to acquire TRN-like traits. Here, we show that similar changes occur (e.g., the expression of both the TRN mRNAs and proteins) when the FLP neurons ectopically express the auxiliary transcription factor ALR-1 (Aristaless related), which ensures, but does not direct, TRN differentiation. Thus, the FLP neurons can acquire a TRN-like fate but use multiple levels of regulation to ensure they do not. Our data indicate that expression of common master regulators in different cell types can result in inappropriate expression of effector genes. This misexpression makes these cells vulnerable to influences that could cause them to acquire alternative fates.
Topalidou, Irini; Chalfie, Martin
Combining Hierarchical and Associative Gene Ontology Relations with Textual Evidence in Estimating Gene and Gene Product Similarity
Gene and gene product similarity is a fundamental diagnostic measure in analyzing biological data and constructing predictive models for functional genomics. With the rising influence of the Gene Ontology, two complementary approaches have emerged where the similarity between two genes or gene products is obtained by comparing Gene Ontology (GO) annotations associated with the genes or gene products. One approach captures GO-based similarity in terms of hierarchical relations within each gene subontology. The other approach identifies GO-based similarity in terms of associative relations across the three gene subontologies. We propose a novel methodology where the two approaches can be merged with ensuing benefits in coverage and accuracy, and demonstrate that further improvements can be obtained by integrating textual evidence extracted from relevant biomedical literature.
Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Riensche, Roderick M.; Beagley, Nathaniel; Baddeley, Bob L.; Tratz, Stephen C.; Gregory, Michelle L.
Use of Gene Replacement Transformation to Elucidate Gene Function in the Qa Gene Cluster of Neurospora Crassa
Gene replacement by transformation, employing selective genetic recombination techniques, has been used to delete or disrupt the qa-x, qa-y and qa-1S genes of the qa gene cluster of Neurospora crassa. The growth characteristics of the strain carrying the deletion of the qa-y gene support earlier evidence that this gene encodes a quinic acid permease. The strain containing the deletion of the qa-1S gene (?qa-1S) was examined with respect to quinic acid induction and carbon catabolite repression. The ?qa-1S strain exhibits constitutive expression of the qa genes supporting earlier evidence that the qa-1S gene codes for a repressor. Several of the qa genes continued to be expressed at high levels even in the presence of glucose in the ?qa-1S strain, which indicates that transcription of these genes is not being affected directly by a repressor molecule in the presence of glucose.
Case, M. E.; Geever, R. F.; Asch, D. K.
Aphids acquired symbiotic genes via lateral gene transfer
Background Aphids possess bacteriocytes, which are cells specifically differentiated to harbour the obligate mutualist Buchnera aphidicola (?-Proteobacteria). Buchnera has lost many of the genes that appear to be essential for bacterial life. From the bacteriocyte of the pea aphid Acyrthosiphon pisum, we previously identified two clusters of expressed sequence tags that display similarity only to bacterial genes. Southern blot analysis demonstrated that they are encoded in the aphid genome. In this study, in order to assess the possibility of lateral gene transfer, we determined the full-length sequences of these transcripts, and performed detailed structural and phylogenetic analyses. We further examined their expression levels in the bacteriocyte using real-time quantitative RT-PCR. Results Sequence similarity searches demonstrated that these fully sequenced transcripts are significantly similar to the bacterial genes ldcA (product, LD-carboxypeptidase) and rlpA (product, rare lipoprotein A), respectively. Buchnera lacks these genes, whereas many other bacteria, including Escherichia coli, a close relative of Buchnera, possess both ldcA and rlpA. Molecular phylogenetic analysis clearly demonstrated that the aphid ldcA was derived from a rickettsial bacterium closely related to the extant Wolbachia spp. (?-Proteobacteria, Rickettsiales), which are intracellular symbionts of various lineages of arthropods. The evolutionary origin of rlpA was not fully resolved, but it was clearly demonstrated that its double-? ?-barrel domain is of bacterial origin. Real-time quantitative RT-PCR demonstrated that ldcA and rlpA are expressed 11.6 and 154-fold higher in the bacteriocyte than in the whole body, respectively. LdcA is an enzyme required for recycling murein (peptidoglycan), which is a component of the bacterial cell wall. As Buchnera possesses a cell wall composed of murein but lacks ldcA, a high level of expression of the aphid ldcA in the bacteriocyte may be essential to maintain Buchnera. Although the function of RlpA is not well known, conspicuous up-regulation of the aphid rlpA in the bacteriocyte implies that this gene is also essential for Buchnera. Conclusion In this study, we obtained several lines of evidence indicating that aphids acquired genes from bacteria via lateral gene transfer and that these genes are used to maintain the obligately mutualistic bacterium, Buchnera.
Nikoh, Naruo; Nakabachi, Atsushi
The biology of novel animal genes: Mouse APEX gene knockout
This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.
MacInnes, M.; Altherr, M.R.; Ludwig, D. [Los Alamos National Lab., NM (United States); Pedersen, R.; Mold, C. [Univ. of California, San Francisco, CA (United States)
Newer Gene Editing Technologies toward HIV Gene Therapy
Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called �Berlin patient� who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.
Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata
Restricted parameter space models for testing gene-gene interaction
There is a growing recognition that interactions (gene-gene and gene-environment) can play an important role in common disease etiology. The development of cost-effective genotyping technologies has made genome-wide association studies the preferred tool for searching for loci affecting disease risk. These studies are characterized by a large number of investigated SNPs, and efficient statistical methods are even more important than in classical association studies that are done with a small number of markers. In this paper we propose a novel gene-gene interaction test that is more powerful than classical methods. The increase in power is due to the fact that the proposed method incorporates reasonable constraints in the parameter space. The test for both association and interaction is based on a likelihood ratio statistic that has a chi-bar-squared distribution asymptotically. We also discuss the definitions used for �no interaction� and argue that tests for pure interaction are useful in genome-wide studies, especially when using two stage strategies where the analyses in the second stage are done on pairs of loci for which at least one is associated with the trait.
Song, Minsun; Nicolae, Dan L.
Fetal muscle gene therapy/gene delivery in large animals.
Gene delivery to the fetal muscles is a potential strategy for the early treatment of muscular dystrophies. In utero muscle gene therapy can also be used to treat other genetic disorders such as hemophilia, where the missing clotting proteins may be secreted from the treated muscle. In the past few years, studies in small animal models have raised the hopes that a phenotypic cure can be obtained after fetal application of gene therapy. Studies of efficacy and safety in large animals are, however, essential before clinical application can be considered in the human fetus. For this reason, the development of clinically applicable strategies for the delivery of gene therapy to the fetal muscles is of prime importance. In this chapter, we describe the protocols for in utero ultrasound-guided gene delivery to the ovine fetal muscle in early gestation. In particular, procedures to inject skeletal muscle groups such as the thigh and thoracic musculature and targeting the diaphragm in the fetus are described in detail. PMID:21194032
Abi-Nader, Khalil N; David, Anna L
Molecular Evolution of Human Visual Pigment Genes
By comparing the published DNA sequences for (a) the genes encoding the human visual color pigments (red, green, and blue) with (b) the genes encoding human, bovine, and Drosophila rhodopsins, a phylogenetic tree for the mammalian pigment genes has been constructed. This evolutionary tree shows that the common ancestor of the visual color pigment genes diverged first from that of
Shozo Yokoyama; Ruth Yokoyama
Polymers for gene delivery across length scales
A number of human diseases stem from defective genes. One approach to treating such diseases is to replace, or override, the defective genes with normal genes, an approach called 'gene therapy'. However, the introduction of correctly functioning DNA into cells is a non-trivial matter, and cells must be coaxed to internalize, and then use, the DNA in the desired manner.
David Putnam
Environmentally Induced Gene Silencing in Breast Cancer.
National Technical Information Service (NTIS)
The main goal of the study was to test the hypothesis that a reduction in gene expression could induce gene silencing (i.e. relatively stable loss of gene expression) in breast cells. Silencing of a variety of tumor suppressor genes plays a major role in ...
M. Turker
Common Genes Implicated in Autism Study
... Preidt Monday, July 21, 2014 Related MedlinePlus Pages Autism Genes and Gene Therapy SUNDAY, July 20, 2014 (HealthDay News) -- Most of ... HealthDay . All rights reserved. More Health News on: Autism Genes and Gene Therapy Recent Health News Page last updated on 21 ...
Comparative Gene Prediction in Human and Mouse
The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level
Genis Parra; Pankaj Agarwal; Josep F. Abril; Thomas Wiehe; James W. Fickett; Roderic Guigo
Markov process modelling of gene regulation
This paper discusses the mathematical modelling of gene regulation with emphasis on the bottom-up modelling of genetic componentry rather than the reverse-engineering of networks from gene expression data. Reflecting the stochastic nature of gene regulation, the chemical master equation is used as a tool to study Markovian models of networks of gene states between which probabilistic transitions occur. These states
Hilary S. Booth; Conrad J. Burden; Markus Hegland; Lucia Santoso
Evolution by gene duplication: an update
The importance of gene duplication in supplying raw genetic material to biological evolution has been recognized since the 1930s. Recent genomic sequence data provide substantial evidence for the abundance of duplicated genes in all organisms surveyed. But how do newly duplicated genes survive and acquire novel functions, and what role does gene duplication play in the evolution of genomes and
Jianzhi Zhang
Analysis of Microarray Gene Expression Data
Microarrays provide the biological research community with tremendously rich, sensitive and detailed information on gene expression profiles. Gene expression profiling and gene expression patterns have been found useful for solving a wide variety of important biological and biomedical problems, including the study of metabolic pathways, inference of the functions of unknown genes, diagnosis of diseased states, as well as facilitating
Tuan D. Pham; Christine Wells; Denis I. Crane
Accessory Gene Regulator Locus of Staphylococcus intermedius
The accessory gene regulator (agr) locus, a candidate system for the regulation of the production of virulence factors in Staphylococcus intermedius, has been characterized. Using PCR-based genome walking, we have obtained the first complete sequence (3,436 bp) of the accessory gene regulator (agr) gene in this organism. Sequence analysis of the agr gene has identified five open reading frames (ORFs),
Julia M. L. Sung; Peter D. Chantler; David H. Lloyd
Gene Therapy of Brain and Endocrine Tumors
Gene therapy of cancer has become a major interest of medical research since more than 60% of the ongoing gene therapy protocols today involve cancer patients. To increase the therapeutic index of cancer gene therapy, targeting strategies have been developed to ensure that the expression of therapeutic genes is restricted exclusively to the tissue of interest. An attractive approach lies
Giorgio Pal�; Roberta Bonaguro; Elisa Gnatta; Elisa Franchin; Luisa Barzon
Tissue engineering via local gene delivery
The first goal of this review is to describe a local plasmid gene transfer technology known as the gene activated matrix (GAM). GAM was the first gene therapy designed specifically for tissue engineering applications, and the mechanism of action of plasmid gene transfer is closely tied to the normal sequence of events associated with wound healing. The normal sequence of
Jeffrey Bonadio
Locating Multiple Gene Duplications through Reconciled Trees
We introduce the first exact and efficient algorithm for Guig� o et al.'s problem that, given a collection of rooted, binary gene trees and a rooted, binary species tree, determines a minimum number of locations for gene duplication events from the gene trees on the species tree. We examined the performance of our algorithm using a set of 85 gene
J. Gordon Burleigh; Mukul S. Bansal; Andr� Wehe; Oliver Eulenstein
EMF Genes Regulate Arabidopsis Inflorescence Development
Mutations in EMBRYONlC FLOWER (EMF) genes EMFl and EMf2 abolish rosette development, and the mutants pro- duce either a much reduced inflorescence or a transformed flower. These mutant characteristics suggest a repressive effect of EMF activities on reproductive development. To investigate the role of EMf genes in regulating reproductive development, we studied the relationship between EMf genes and the genes
Lingjing Chen; Jin-Chen Cheng; Linda Castle; Renee Sung
From circadian clock gene expression to pathologies
In most organisms, circadian rhythms are generated by a molecular clockwork involving so-called clock genes. These circadian clock genes participate in regulatory feedback loops, in which proteins regulate their own expression. The outcome is that ribonucleic acids (RNAs) and proteins produced from many of these genes oscillate with a circadian rhythm. Here, we describe the regulation of clock genes and
Elaine Waddington Lamont; Francine O. James; Diane B. Boivin; Nicolas Cermakian
Genes and Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since first candidate gene studies were published 20 years ago, nearly 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. The studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, if appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called CNTN3 which is located on chromosome 3p12.3. Two follow-up studies, however, could not replicate the association. Two other SNPs, which are located on chromosome 9p21 and 9q33 were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense RNA that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute to AAA pathogenesis.
Hinterseher, Irene; Tromp, Gerard; Kuivaniemi, Helena
The aristaless (Arx) gene: one gene for many "interneuronopathies".
The ARX (Aristaless-related (X-linked) homeobox) gene is not only present in arthropods and their ancestors, but also in vertebrates including humans (ARX orthologs). The gene is composed of 5 coding exons and it is expressed predominantly in foetal and adult brain and skeletal muscle. In this review we report on our experience and review the existing literature on the genotype and phenotype heterogeneity associated with ARX abnormalities in humans ranging from severe neuronal migration defects (e.g., lissencephaly), to mild forms of X-linked mental retardation without apparent brain abnormalities. The ARX-related disorders are reviewed focusing on their clinical features and on the role of the ARX gene. It has yet to be established whether the molecular defect alone could cause a given cerebral abnormality and/or malformation or an additional or related molecular or environmental event could contribute to a given phenotype in molecularly. PMID:20036914
Ruggieri, Martino; Pavone, Piero; Scapagnini, Giovanni; Romeo, Loriana; Lombardo, Ilaria; Li Volti, Giovanni; Corsello, Giovanni; Pavone, Lorenzo
Learning or inferring networks of genomic regulation specific to a cellular state, such as a subtype of tumor, can yield insight above and beyond that resulting from network learning-techniques which do not acknowledge the adaptive nature of the cellular system. In this study we show that Cellular Context Mining, which is based on a mathematical model of contextual genomic regulation, produces gene regulatory networks (GRNs) from steady-state expression microarray data which are specific to the varying cellular contexts hidden in the data; we show that these GRNs not only model gene interactions, but that they are also readily annotated with context-specific genomic information. We propose that these context-specific GRNs provide advantages over other techniques, such as clustering and Bayesian networks, when applied to gene expression data of cancer patients.
Sen, Ina; Verdicchio, Michael P.; Jung, Sungwon; Trevino, Robert; Bittner, Michael; Kim, Seungchan
Advancement and prospects of tumor gene therapy
Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell� and T cell�based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy.
Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin
Activities of Human Gene Nomenclature Committee
The objective of this project, shared between NIH and DOE, has been and remains to enable the medical genetics communities to use common names for genes that are discovered by different gene hunting groups, in different species. This effort provides consistent gene nomenclature and approved gene symbols to the community at large. This contributes to a uniform and consistent understanding of genomes, particularly the human as well as functional genomics based on comparisons between homologous genes in related species (human and mice).
Combination of Gene Therapy with Radiation
To date tremendous progress has been made in the field of cancer gene therapy. Strategies have been explored for achieving\\u000a therapeutic benefit using various genes and several clinical trials for cancer gene therapy have been carried out demonstrating\\u000a that gene therapy is well tolerated. However, in most cases the efficacy of gene transfer has been very limited. As an alternative,
Anupama Munshi; Raymond E. Meyn
Update on acquired tetracycline resistance genes
This mini-review summarizes the changes in the field of bacterial acquired tetracycline resistance (tet) and oxytetracycline (otr) genes identified since the last major review in 2001. Thirty-eight acquired tetracycline resistant (Tcr) genes are known of which nine are new and include five genes coding for energy-dependent efflux proteins, two genes coding for ribosomal protection proteins, and two genes coding for
Marilyn C. Roberts
Gene Therapy for Pituitary Tumors
Pituitary tumors are the most common primary intracranial neoplasms. Although most pituitary tumors are considered typically benign, others can cause severe and progressive disease. The principal aims of pituitary tumor treatment are the elimination or reduction of the tumor mass, normalization of hormone secretion and preservation of remaining pituitary function. In spite of major advances in the therapy of pituitary tumors, for some of the most difficult tumors, current therapies that include medical, surgical and radiotherapeutic methods are often unsatisfactory and there is a need to develop new treatment strategies. Gene therapy, which uses nucleic acids as drugs, has emerged as an attractive therapeutic option for the treatment of pituitary tumors that do not respond to classical treatment strategies if the patients become intolerant to the therapy. The development of animal models for pituitary tumors and hormone hypersecretion has proven to be critical for the implementation of novel treatment strategies and gene therapy approaches. Preclinical trials using several gene therapy approaches for the treatment of anterior pituitary diseases have been successfully implemented. Several issues need to be addressed before clinical implementation becomes a reality, including the development of more effective and safer viral vectors, uncovering novel therapeutic targets and development of targeted expression of therapeutic transgenes. With the development of efficient gene delivery vectors allowing long-term transgene expression with minimal toxicity, gene therapy will become one of the most promising approaches for treating pituitary adenomas.
Seilicovich, Adriana; Pisera, Daniel; Sciascia, Sandra A.; Candolfi, Marianela; Puntel, Mariana; Xiong, Weidong; Jaita, Gabriela; Castro, Maria G.
Ontogeny of erythroid gene expression
Erythroid ontogeny is characterized by overlapping waves of primitive and definitive erythroid lineages that share many morphologic features during terminal maturation but have marked differences in cell size and globin expression. In the present study, we compared global gene expression in primitive, fetal definitive, and adult definitive erythroid cells at morphologically equivalent stages of maturation purified from embryonic, fetal, and adult mice. Surprisingly, most transcriptional complexity in erythroid precursors is already present by the proerythroblast stage. Transcript levels are markedly modulated during terminal erythroid maturation, but housekeeping genes are not preferentially lost. Although primitive and definitive erythroid lineages share a large set of nonhousekeeping genes, annotation of lineage-restricted genes shows that alternate gene usage occurs within shared functional categories, as exemplified by the selective expression of aquaporins 3 and 8 in primitive erythroblasts and aquaporins 1 and 9 in adult definitive erythroblasts. Consistent with the known functions of Aqp3 and Aqp8 as H2O2 transporters, primitive, but not definitive, erythroblasts preferentially accumulate reactive oxygen species after exogenous H2O2 exposure. We have created a user-friendly Web site (http://www.cbil.upenn.edu/ErythronDB) to make these global expression data readily accessible and amenable to complex search strategies by the scientific community.
Kingsley, Paul D.; Greenfest-Allen, Emily; Frame, Jenna M.; Bushnell, Timothy P.; Malik, Jeffrey; McGrath, Kathleen E.; Stoeckert, Christian J.
Metazoan Gene Families from Metazome
Metazome is a joint project of the Department of Energy's Joint Genome Institute and the Center for Integrative Genomics to facilitate comparative genomic studies amongst metazoans. Clusters of orthologous and paralogous genes that represent the modern descendents of ancestral gene sets are constructed at key phylogenetic nodes. These clusters allow easy access to clade specific orthology/paralogy relationships as well as clade specific genes and gene expansions. As of version 2.0.4, Metazome provides access to twenty-four sequenced and annotated metazoan genomes, clustered at nine evolutionarily significant nodes. Where possible, each gene has been annotated with PFAM, KOG, KEGG, and PANTHER assignments, and publicly available annotations from RefSeq, UniProt, Ensembl, and JGI are hyper-linked and searchable. The included organisms (by common name) are: Human, Mouse, Rat, Dog, Opossum, Chicken, Frog, Stickleback, Medaka, Fugu pufferfish; Zebrafish, Seasquirt - savignyi, Seasquirt - intestinalis, Amphioxus, Sea Urchin, Fruitfly, Mosquite, Yellow Fever Mosquito, Silkworm, Red Flour Beetle, Worm, Briggsae Worm, Owl limpet (snail), and Sea anemone. [Copied from Metazome Overview at http://www.metazome.net/Metazome_info.php
Melatonin receptor genes in vertebrates.
Melatonin receptors are members of the G protein-coupled receptor (GPCR) family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A) and MT2 (or Mel1b or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C), has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor. PMID:23712359
Li, Di Yan; Smith, David Glenn; Hardeland, R�diger; Yang, Ming Yao; Xu, Huai Liang; Zhang, Long; Yin, Hua Dong; Zhu, Qing
Improved Algorithms for Finding Gene Teams and Constructing Gene Team Trees
A gene team is a set of genes that appear in two or more species, possibly in a different order yet with the distance between adjacent genes in the team for each chromosome always no more than a certain threshold ? . A gene team tree is a succinct way to represent all gene teams for every possible value of
Biing-Feng Wang; Chien-Hsin Lin
Gene expression studies in prostate cancer tissue: which reference gene should be selected for normalization?
Using quantitative reverse transcription�polymerase chain reaction (RT-PCR), reference genes are utilized as endogenous controls for relative quantification of target genes in gene profiling studies. The suitability of housekeeping genes for that purpose in prostate cancer tissue has not been sufficiently investigated so far. The objective of this study was to select from a panel of 16 potential candidate reference genes
Falk Ohl; Monika Jung; Chuanliang Xu; Carsten Stephan; Anja Rabien; Mick Burkhardt; Andreas Nitsche; Glen Kristiansen; Stefan A. Loening; Aleksandar Radoni?; Klaus Jung
GOToolBox: functional analysis of gene datasets based on Gene Ontology
We have developed methods and tools based on the Gene Ontology (GO) resource allowing the identification of statistically over- or under-represented terms in a gene dataset; the clustering of functionally related genes within a set; and the retrieval of genes sharing annotations with a query gene. GO annotations can also be constrained to a slim hierarchy or a given level
David Martin; Christine Brun; Elisabeth Remy; Pierre Mouren; Denis Thieffry; Bernard Jacq
Graph Kernel-Based Learning for Gene Function Prediction from Gene Interaction Network
Prediction of gene functions is a major challenge to biologists in the post-genomic era. Interactions between genes and their products compose networks and can be used to infer gene functions. Most previous studies used heuristic approaches based on either local or global information of gene interaction networks to assign unknown gene functions. In this study, we propose a graph kernel-based
Xin Li; Zhu Zhang; Hsinchun Chen; Jiexun Li
Graph Kernel-Based Learning for Gene Function Prediction from Gene Interaction Network
Prediction of gene functions is a major challenge to biol- ogists in the post-genomic era. Interactions between genes and their products compose networks and can be used to infer gene functions. Most previous studies used heuris- tic approaches based on either local or global informa- tion of gene interaction networks to assign unknown gene functions. In this study, we propose
Xin Li; Zhu Zhang; Hsinchun Chen; Jiexun Li
GeneMANIA Prediction Server 2013 Update
GeneMANIA (http://www.genemania.org) is a flexible user-friendly web interface for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA extends the list with functionally similar genes that it identifies using available genomics and proteomics data. GeneMANIA also reports weights that indicate the predictive value of each selected data set for the query. GeneMANIA can also be used in a function prediction setting: given a query gene, GeneMANIA finds a small set of genes that are most likely to share function with that gene based on their interactions with it. Enriched Gene Ontology categories among this set can sometimes point to the function of the gene. Seven organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus, Homo sapiens, Rattus norvegicus and Saccharomyces cerevisiae), and hundreds of data sets have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze.
Zuberi, Khalid; Franz, Max; Rodriguez, Harold; Montojo, Jason; Lopes, Christian Tannus; Bader, Gary D.; Morris, Quaid
Gene expression throughout a vertebrate's embryogenesis
Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (> 200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation) the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development.
Nonviral gene therapy targeting cardiovascular system.
The goal of gene therapy is either to introduce a therapeutic gene into or replace a defective gene in an individual's cells and tissues. Gene therapy has been urged as a potential method to induce therapeutic angiogenesis in ischemic myocardium and peripheral tissues after extensive investigation in recent preclinical and clinical studies. A successful gene therapy mainly relies on the development of the gene delivery vector. Developments in viral and nonviral vector technology including cell-based gene transfer will further improve transgene delivery and expression efficiency. Nonviral approaches as alternative gene delivery vehicles to viral vectors have received significant attention. Recently, a simple and safe approach of gene delivery into target cells using naked DNA has been improved by combining several techniques. Among the physical approaches, ultrasonic microbubble gene delivery, with its high safety profile, low costs, and repeatable applicability, can increase the permeability of cell membrane to macromolecules such as plasmid DNA by its bioeffects and can provide as a feasible tool in gene delivery. On the other hand, among the promising areas for gene therapy in acquired diseases, ischemic cardiovascular diseases have been widely studied. As a result, gene therapy using advanced technology may play an important role in this regard. The aims of this review focus on understanding the cellular and in vivo barriers in gene transfer and provide an overview of currently used chemical vectors and physical tools that are applied in nonviral cardiovascular gene transfer. PMID:22821991
Su, Cheng-Huang; Wu, Yih-Jer; Wang, Hsueh-Hsiao; Yeh, Hung-I
Gene-gene and gene-environment interactions in ulcerative colitis.
Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P�=�3.26E-05). Explained UC variance increased from 37 to 42�% after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions. PMID:24241240
Wang, Ming-Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M Ilyas; Rebert, Nancy; Duerr, Richard H; Achkar, Jean-Paul
Gene Expression Studies in Mosquitoes
Research on gene expression in mosquitoes is motivated by both basic and applied interests. Studies of genes involved in hematophagy, reproduction, olfaction, and immune responses reveal an exquisite confluence of biological adaptations that result in these highly-successful life forms. The requirement of female mosquitoes for a bloodmeal for propagation has been exploited by a wide diversity of viral, protozoan and metazoan pathogens as part of their life cycles. Identifying genes involved in host-seeking, blood feeding and digestion, reproduction, insecticide resistance and susceptibility/refractoriness to pathogen development is expected to provide the bases for the development of novel methods to control mosquito-borne diseases. Advances in mosquito transgenesis technologies, the availability of whole genome sequence information, mass sequencing and analyses of transcriptomes and RNAi techniques will assist development of these tools as well as deepen the understanding of the underlying genetic components for biological phenomena characteristic of these insect species.
Chen, Xlao-Guang; Mathur, Geetika; James, Anthony A.
Gene therapy in Parkinson's disease.
Gene therapy in Parkinson's disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinson's disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinson's disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinson's disease. PMID:15322915
Eberhardt, O; Schulz, J B
Epigenetic manipulation of gene expression
Cell biologists have been afforded extraordinary new opportunities for experimentation by the emergence of powerful technologies that allow the selective manipulation of gene expression. Currently, RNA interference is very much in the limelight; however, significant progress has also been made with two other approaches. Thus, antisense oligonucleotide technology is undergoing a resurgence as a result of improvements in the chemistry of these molecules, whereas designed transcription factors offer a powerful and increasingly convenient strategy for either up- or down-regulation of targeted genes. This mini-review will highlight some of the key features of these three approaches to gene regulation, as well as provide pragmatic guidance concerning their use in cell biological experimentation based on our direct experience with each of these technologies. The approaches discussed here are being intensely pursued in terms of possible therapeutic applications. However, we will restrict our comments primarily to the cell culture situation, only briefly alluding to fundamental differences between utilization in animals versus cells.
Juliano, Rudy L.; Dixit, Vidula R.; Kang, Hyunmin; Kim, Tai Young; Miyamoto, Yuko; Xu, Dong
Transients in chloroplast gene transcription
Transcriptional regulation of chloroplast genes is demonstrated by Quantitative Polymerase Chain Reaction (qPCR). These genes encode apoproteins of the reaction centres of photosystem I and photosystem II. Their transcription is regulated by changes in wavelength of light selectively absorbed by photosystem I and photosystem II, and therefore by the redox state of an electron carrier located between the two photosystems. Chloroplast transcriptional redox regulation is shown to have greater amplitude, and the kinetics of transcriptional changes are more complex, than suggested by previous experiments using only DNA probes in Northern blot experiments. Redox effects on chloroplast transcription appear to be superimposed on an endogenous rhythm of mRNA abundance. The functional significance of these transients in chloroplast gene transcription is discussed.
Puthiyaveetil, Sujith [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom); Allen, John F. [School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS (United Kingdom)], E-mail: firstname.lastname@example.com
Gene encoding plant asparagine synthetase
The identification and cloning of the gene(s) for plant asparagine synthetase (AS), an important enzyme involved in the formation of asparagine, a major nitrogen transport compound of higher plants is described. Expression vectors constructed with the AS coding sequence may be utilized to produce plant AS; to engineer herbicide resistant plants, salt/drought tolerant plants or pathogen resistant plants; as a dominant selectable marker; or to select for novel herbicides or compounds useful as agents that synchronize plant cells in culture. The promoter for plant AS, which directs high levels of gene expression and is induced in an organ specific manner and by darkness, is also described. The AS promoter may be used to direct the expression of heterologous coding sequences in appropriate hosts.
Coruzzi, Gloria M. (New York, NY); Tsai, Fong-Ying (New York, NY)
Human height genes and cancer.
Body development requires the ability to control cell proliferation and metabolism, together with selective 'invasive' cell migration for organogenesis. These requirements are shared with cancer. Human height-associated loci have been recently identified by genome-wide SNP-association studies. Strikingly, most of the more than 100 genes found associated to height appear linked to neoplastic growth, and impose a higher risk for cancer. Height-associated genes drive the HH/PTCH and BMP/TGF? pathways, with p53, c-Myc, ER?, HNF4A and SMADs as central network nodes. Genetic analysis of body-size-affecting diseases and evidence from genetically-modified animals support this model. The finding that cancer is deeply linked to normal, body-plan master genes may profoundly affect current paradigms on tumor development. PMID:23428607
Tripaldi, Romina; Stuppia, Liborio; Alberti, Saverio
Cardiac arrest is the leading cause of death in the United States and other developed countries. Ventricular tachyarrhythmias are the most prominent cause of cardiac arrest, and patients with structural heart disease are at increased risk for these abnormal heart rhythms. Drug and device therapy have important limitations that make them inadequate to meet this challenge. We and others have proposed development of arrhythmia gene therapy as an alternative to current treatment methods. In this review, I discuss the basic mechanisms of ventricular arrhythmias and summarize the literature on the use of gene therapy for ventricular tachyarrhythmias.
Donahue, J. Kevin
Leukemogenesis: More Than Mutant Genes
Acute leukemias are characterized by recurring chromosomal aberrations and gene mutations which are critical to disease pathogenesis. It is now evident that epigenetic modifications including DNA methylation and histone modifications contribute significantly to the leukemogenic phenotype. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukemias, and their key role in the transcriptional regulation of tumor suppressor genes and oncogenes. The genetic heterogeneity of acute leukemias poses therapeutic challenges, but pharmacologic agents that target components of the epigenetic machinery hold promise as a part of the therapeutic arsenal for this group of diseases.
Chen, Jianjun; Odenike, Olatoyosi; Rowley, Janet D.
Gene therapy in clinical medicine
Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application.
Selkirk, S
NASA Astrophysics Data System (ADS)
Using data from gene expression databases on various organisms and tissues, including yeast, nematodes, human normal and cancer tissues, and embryonic stem cells, we found that the abundances of expressed genes exhibit a power-law distribution with an exponent close to -1; i.e., they obey Zipf�s law. Furthermore, by simulations of a simple model with an intracellular reaction network, we found that Zipf�s law of chemical abundance is a universal feature of cells where such a network optimizes the efficiency and faithfulness of self-reproduction. These findings provide novel insights into the nature of the organization of reaction dynamics in living cells.
Furusawa, Chikara; Kaneko, Kunihiko
GenePRIMP: Improving Microbial Gene Prediction Quality
Amrita Pati of the DOE Joint Genome Institute's Genome Biology group talks about a computational pipeline that evaluates the accuracy of gene models in genomes and metagenomes at different stages of finishing at the "Sequencing, Finishing, Analysis in the Future" meeting in Santa Fe, NM
Pati, Amrita [DOE Joint Genome Institute's Genome Biology group
Machine Learning for Detecting Gene-Gene Interactions
Complex interactions among genes and environmental factors are known to play a role in common human disease aetiology. There is a growing body of evidence to suggest that complex interactions are �the norm� and, rather than amounting to a small perturbation to classical Mendelian genetics, interactions may be the predominant effect. Traditional statistical methods are not well suited for detecting such interactions, especially when the data are high dimensional (many attributes or independent variables) or when interactions occur between more than two polymorphisms. In this review, we discuss machine-learning models and algorithms for identifying and characterising susceptibility genes in common, complex, multifactorial human diseases. We focus on the following machine-learning methods that have been used to detect gene-gene interactions: neural networks, cellular automata, random forests, and multifactor dimensionality reduction. We conclude with some ideas about how these methods and others can be integrated into a comprehensive and flexible framework for data mining and knowledge discovery in human genetics.
McKinney, Brett A.; Reif, David M.; Ritchie, Marylyn D.; Moore, Jason H.
Many ribosomal protein genes are cancer genes in zebrafish
We have generated several hundred lines of zebrafish (Danio rerio), each heterozygous for a recessive embryonic lethal mutation. Since many tumor suppressor genes are recessive lethals, we screened our colony for lines that display early mortality and\\/or gross evidence of tumors. We identified 12 lines with elevated cancer incidence. Fish from these lines develop malignant peripheral nerve sheath tumors, and
Adam Amsterdam; Kirsten C. Sadler; Kevin Lai; Sarah Farrington; Roderick T. Bronson; Jacqueline A. Lees; Nancy Hopkins
Gene-Environment Interaction in Yeast Gene Expression
The effects of genetic variants on phenotypic traits often depend on environmental and physiological conditions, but such gene�environment interactions are poorly understood. Recently developed approaches that treat transcript abundances of thousands of genes as quantitative traits offer the opportunity to broadly characterize the architecture of gene�environment interactions. We examined the genetic and molecular basis of variation in gene expression between two yeast strains (BY and RM) grown in two different conditions (glucose and ethanol as carbon sources). We observed that most transcripts vary by strain and condition, with 2,996, 3,448, and 2,037 transcripts showing significant strain, condition, and strain�condition interaction effects, respectively. We expression profiled over 100 segregants derived from a cross between BY and RM in both growth conditions, and identified 1,555 linkages for 1,382 transcripts that show significant gene�environment interaction. At the locus level, local linkages, which usually correspond to polymorphisms in cis-regulatory elements, tend to be more stable across conditions, such that they are more likely to show the same effect or the same direction of effect across conditions. Distant linkages, which usually correspond to polymorphisms influencing trans-acting factors, are more condition-dependent, and often show effects in different directions in the two conditions. We characterized a locus that influences expression of many growth-related transcripts, and showed that the majority of the variation is explained by polymorphism in the gene IRA2. The RM allele of IRA2 appears to inhibit Ras/PKA signaling more strongly than the BY allele, and has undergone a change in selective pressure. Our results provide a broad overview of the genetic architecture of gene�environment interactions, as well as a detailed molecular example, and lead to key insights into how the effects of different classes of regulatory variants are modulated by the environment. These observations will guide the design of studies aimed at understanding the genetic basis of complex traits.
Smith, Erin N; Kruglyak, Leonid
Computational disease gene identification: a concert of methods prioritizes type 2 diabetes and obesity candidate genes.
Genome-wide experimental methods to identify disease genes, such as linkage analysis and association studies, generate increasingly large candidate gene sets for which comprehensive empirical analysis is impractical. Computational methods employ data from a variety of sources to identify the most likely candidate disease genes from these gene sets. Here, we review seven independent computational disease gene prioritization methods, and then apply them in concert to the analysis of 9556 positional candidate genes for type 2 diabetes (T2D) and the related trait obesity. We generate and analyse a list of nine primary candidate genes for T2D genes and five for obesity. Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases. PMID:16757574
Tiffin, Nicki; Adie, Euan; Turner, Frances; Brunner, Han G; van Driel, Marc A; Oti, Martin; Lopez-Bigas, Nuria; Ouzounis, Christos; Perez-Iratxeta, Carolina; Andrade-Navarro, Miguel A; Adeyemo, Adebowale; Patti, Mary Elizabeth; Semple, Colin A M; Hide, Winston
Amplification of kinetic oscillations in gene expression
NASA Astrophysics Data System (ADS)
Because of the feedbacks between the DNA transcription and mRNA translation, the gene expression in cells may exhibit bistability and oscillations. The deterministic and stochastic calculations presented illustrate how the bistable kinetics of expression of one gene in a cell can be influenced by the kinetic oscillations in the expression of another gene. Due to stability of the states of the bistable kinetics of gene 1 and the relatively small difference between the maximum and minimum protein amounts during the oscillations of gene 2, the induced oscillations of gene 1 are found to typically be related either to the low-or high-reactive state of this gene. The quality of the induced oscillations may be appreciably better than that of the inducing oscillations. This means that gene 1 can serve as an amplifier of the kinetic oscillations of gene 2.
Zhdanov, V. P.
Gene therapy on demand: site specific regulation of gene therapy.
Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, ?-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases. PMID:23566848
Jazwa, Agnieszka; Florczyk, Urszula; Jozkowicz, Alicja; Dulak, Jozef
Identification of 10 murine homeobox genes.
In Drosophila a number of genes important in establishing segmentation patterns and in determining segment identities have been shown to carry the homeobox sequence. Over 30 murine homeobox genes have been cloned, many on the basis of sequence homology to Drosophila prototypes. Here we report the cloning and sequencing of 10 new and 6 previously known homeobox genes by screening a murine genomic library with a 768-fold degenerate oligonucleotide corresponding to the most conserved 8-amino acid motif in the recognition helix of the homeodomain. Eight of these new homeobox genes have been chromosomally mapped. Four genes do not belong to any of the known homeobox gene clusters but instead map to new locations on chromosome 1 (single gene) and chromosome 5 (three genes). Sequence comparisons indicate that two of these are very closely related and represent a distinct new category of homeobox genes. The remaining four mapped genes reside in previously established murine homeobox gene clusters. Specifically, two map to the cluster HOX-1 on chromosome 6 and one each to HOX-3 and HOX-4 on chromosome 15 and 2, respectively. The ratio of newly identified homeobox genes to the previously characterized murine homeobox genes suggests that there remain several uncharacterized homeobox genes in the murine genome. Images
Singh, G; Kaur, S; Stock, J L; Jenkins, N A; Gilbert, D J; Copeland, N G; Potter, S S
Identifying disease feature genes based on cellular localized gene functional modules and regulation networks
Identifying disease-relevant genes and functional modules, based on gene expression profiles and gene functional knowledge,\\u000a is of high importance for studying disease mechanisms and subtyping disease phenotypes. Using gene categories of biological\\u000a process and cellular component in Gene Ontology, we propose an approach to selecting functional modules enriched with differentially\\u000a expressed genes, and identifying the feature functional modules of high
Min Zhang; Jing Zhu; Zheng Guo; Xia Li; Da Yang; Lei Wang; Shaoqi Rao
Rapid Concerted Evolution via Gene Conversion at the Drosophila hsp70 Genes
.�� We analyzed nucleotide variation in the hsp70 genes of Drosophila melanogaster (five genes) and D. simulans (four genes) to characterize the homogenizing and diversifying roles of gene conversion in their evolution. Gene conversion\\u000a within and between the 87A7 and 87C1 gene clusters homogenize the hsp70 coding regions; in both D. melanogaster and D. simulans, same-cluster paralogues are virtually identical,
Brian R. Bettencourt; Martin E. Feder
Evolution of the chicken Toll-like receptor gene family: A story of gene gain and gene loss
Background Toll-like receptors (TLRs) perform a vital role in disease resistance through their recognition of pathogen associated molecular patterns (PAMPs). Recent advances in genomics allow comparison of TLR genes within and between many species. This study takes advantage of the recently sequenced chicken genome to determine the complete chicken TLR repertoire and place it in context of vertebrate genomic evolution. Results The chicken TLR repertoire consists of ten genes. Phylogenetic analyses show that six of these genes have orthologs in mammals and fish, while one is only shared by fish and three appear to be unique to birds. Furthermore the phylogeny shows that TLR1-like genes arose independently in fish, birds and mammals from an ancestral gene also shared by TLR6 and TLR10. All other TLRs were already present prior to the divergence of major vertebrate lineages 550 Mya (million years ago) and have since been lost in certain lineages. Phylogenetic analysis shows the absence of TLRs 8 and 9 in chicken to be the result of gene loss. The notable exception to the tendency of gene loss in TLR evolution is found in chicken TLRs 1 and 2, each of which underwent gene duplication about 147 and 65 Mya, respectively. Conclusion Comparative phylogenetic analysis of vertebrate TLR genes provides insight into their patterns and processes of gene evolution, with examples of both gene gain and gene loss. In addition, these comparisons clarify the nomenclature of TLR genes in vertebrates.
Temperley, Nicholas D; Berlin, Sofia; Paton, Ian R; Griffin, Darren K; Burt, David W
The mammalian RPS6 gene, homolog of the Drosophila air8 tumor suppressor gene: is it an oncosuppressor gene?
The mammalian gene encoding the S6 ribosomal protein is the homolog of the Drosophila air8 tumor suppressor gene. We assigned the rat Rps6 gene to chromosome 5q22-33. The rat 5q22-33 chromosome region, previously shown to bear a malignant transformation suppressor gene, is homologous to the human 9p2l region, frequently deleted in various kinds of cancers and also containing at least one tumor suppressor (oncosuppressor) gene. To test the possibility that the Rps6 gene could be an oncosuppressor gene in mammals, we analysed its sequence and expression in normal and malignantly transformed cells. In mouse hepatoma cells (BWTG3), the Rps6 gene is hemizygously deleted but the remaining copy shows no sequence anomaly in the coding region, indicating that Rps6 is not oncosuppressor and that another gene acting as an oncosuppressor is located in its vicinity. In human tumor cells, the RPS6 gene is retained in cells showing deletion of the near-by gene, IFNB. Our results do not support the possibility that the RPS6 gene acts as an oncosuppressor gene in mammalian cells. PMID:8600571
Lecomte, F; Champagne, B; Dasnoy, J F; Szpirer, J; Szpirer, C
Gene therapy and its implications in Periodontics
Gene therapy is a field of Biomedicine. With the advent of gene therapy in dentistry, significant progress has been made in the control of periodontal diseases and reconstruction of dento-alveolar apparatus. Implementation in periodontics include: -As a mode of tissue engineering with three approaches: cell, protein-based and gene delivery approach. -Genetic approach to Biofilm Antibiotic Resistance. Future strategies of gene therapy in preventing periodontal diseases: -Enhances host defense mechanism against infection by transfecting host cells with an antimicrobial peptide protein-encoding gene. -Periodontal vaccination. Gene therapy is one of the recent entrants and its applications in the field of periodontics are reviewed in general here.
Mahale, Swapna; Dani, Nitin; Ansari, Shumaila S.; Kale, Triveni
Gene transfer: anything goes in plant mitochondria
Parasitic plants and their hosts have proven remarkably adept at exchanging fragments of mitochondrial DNA. Two recent studies provide important mechanistic insights into the pattern, process and consequences of horizontal gene transfer, demonstrating that genes can be transferred in large chunks and that gene conversion between foreign and native genes leads to intragenic mosaicism. A model involving duplicative horizontal gene transfer and differential gene conversion is proposed as a hitherto unrecognized source of genetic diversity. See research article: http://www.biomedcentral.com/1741-7007/8/150
GenePRIMP: a gene prediction improvement pipeline for prokaryotic genomes.
We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies. PMID:20436475
Pati, Amrita; Ivanova, Natalia N; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D; Lykidis, Athanasios; Kyrpides, Nikos C
Ancient genes of Saccharomyces cerevisiae.
Amber is a plant resin mainly produced by coniferous trees that, after entrapping a variety of living beings, was subjected to a process of fossilization until it turned into yellowish, translucent stones. It is also one of the best sources of ancient DNA on which to perform studies on evolution. Here a method for the sterilization of amber that allows reliable ancient DNA extraction with no actual DNA contamination is described. Working with insects taken from amber, it was possible to amplify the ATP9, PGU1 and rRNA18S ancient genes of Saccharomyces cerevisiae corresponding to samples from the Miocene and Oligocene. After comparison of the current genes with their ancient (up to 35-40 million years) counterparts it was concluded that essential genes such as rRNA18S are highly conserved and that even normal 'house-keeping' genes, such as PGU1, are strikingly conserved along the millions of years that S. cerevisiae has evolved. PMID:15256564
Veiga-Crespo, P; Poza, M; Prieto-Alcedo, M; Villa, T G
To survive in host cells, intracellular pathogens or symbiotic bacteria require protective mechanisms to overcome the oxidative stress generated by phagocytic activities of the host. By genomic library tagging, we cloned a dps (stands for DNA-binding protein from starved cells) gene of the symbiotic \\
Seong Tae Yun; Sue-Yun Hwang; Choong-Ill Chun; Tae In Ahn
National Technical Information Service (NTIS)
The invention relates to a newly identified tumor suppressor gene, designated DOS (for Deleted in Osteosarcoma and alternatively referred to herein as DOCK 3) which has been cloned from human and mouse cells. The DOS nucleic acid and protein molecules and...
A. McClatchey C. Paulding D. Haber V. Yajnik
DNA Methylation and Gene Function
In most higher organisms, DNA is modified after synthesis by the enzymatic conversion of many cytosine residues to 5-methylcytosine. For several years, control of gene activity by DNA methylation has been recognized as a logically attractive possibility, but experimental support has proved elusive. However, there is now reason to believe, from recent studies, that DNA methylation is a key element
Aharon Razin; Arthur D. Riggs
Orthopedic Gene Therapy in 2008
Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic
Christopher H Evans; Steven C Ghivizzani; Paul D Robbins
Gene therapy for pancreatitis pain.
Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replication defective Herpes (HSV-1, DPE) viral vector construct encoding the human preproenkephalin gene (HSV-Enk), used as a molecular therapy for alleviation of pancreatitis pain, is reviewed here. The characteristics of the gene therapy treatment for inflammation and pain-related behavior in two alcoholic pancreatitis animal models is described. Significant analgesia and protection of pancreatic tissue was provided for the duration of the transgene expression (approximately 4-6 weeks). These studies establish a basis for use of HSV-based gene therapy for chronic visceral pain. Targeted enkephalin gene therapy approaches are providing clear promise for pain control. As innovative means of significantly reducing pancreatic inflammation and preserving tissue architecture, they may extend their clinical usefulness for pancreatitis and pancreatic cancer pain patients. PMID:19262610
Westlund, K N
Ethics of Gene Therapy Debated.
ERIC Educational Resources Information Center
Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)
Borman, Stu
If benign cystic teratomas (dermoid cysts) of the ovary arise from a germ cell that has undergone meiosis, they should be missing genes which are present in the person. Three independently segregating allelic isozymes in 11 benign cystic teratomas of the human female ovary were compared with normal tissue of the same case. Dermoid cysts from persons heterozygous for these
David Linder
Gene Expression in Trypanosomatid Parasites
The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa.
Martinez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C.; Florencio-Martinez, Luis E.; Manning-Cela, Rebeca G.; Figueroa-Angulo, Elisa E.
Gene expression in trypanosomatid parasites.
The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa. PMID:20169133
Mart�nez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C; Florencio-Mart�nez, Luis E; Manning-Cela, Rebeca G; Figueroa-Angulo, Elisa E
Circadian gene variants in cancer.
Abstract Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment. PMID:24901356
Kettner, Nicole M; Katchy, Chinenye A; Fu, Loning
Genes and Syndromic Hearing Loss.
ERIC Educational Resources Information Center
This article provides a description of the human genome and patterns of inheritance and discusses genes that are associated with some of the syndromes for which hearing loss is a common finding, including: Waardenburg, Stickler, Jervell and Lange-Neilsen, Usher, Alport, mitochondrial encephalomyopathy, and sensorineural hearing loss. (Contains�
Keats, Bronya J. B.
ACTH resistance: genes and mechanisms.
ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses. PMID:23392095
Meimaridou, E; Hughes, C R; Kowalczyk, J; Chan, L F; Clark, A J L; Metherell, L A
The Caenorhabditis chemoreceptor gene families
BACKGROUND: Chemoreceptor proteins mediate the first step in the transduction of environmental chemical stimuli, defining the breadth of detection and conferring stimulus specificity. Animal genomes contain families of genes encoding chemoreceptors that mediate taste, olfaction, and pheromone responses. The size and diversity of these families reflect the biology of chemoperception in specific species. RESULTS: Based on manual curation and sequence
James H Thomas; Hugh M Robertson
Molecular biology of epilepsy genes.
Multifactorial inheritance is the most important model accounting for the genetic behavior of the common epilepsies. Important to this model is the concept that many cumulative or synergistic risk genes ultimately lead to a threshold effect. Sophisticated molecular testing indicates that the common epilepsies are very polygenic without evidence of any single gene having even a mild-to-modest risk effect. However, enrichment of copy number variants in cohorts of individuals with epilepsy indicates that certain structural changes in the genome can confer significant risk for epilepsy. The mechanisms whereby copy number variants confer this effect are not yet known. The study of epilepsy due to single gene defects however has helped clarify certain seizure mechanisms. For example, discoveries using animal models of SCN1A or ARX mutations implicate a predominant role for interneurons due to disturbed GABAergic function. It is hoped that future genetic and neurobiological studies will provide better insight into how multiple genes contribute to the common epilepsies. PMID:22178301
Williams, Charles A; Battaglia, Agatino
Gene-Culture Coevolutionary Games
ERIC Educational Resources Information Center
Gene-culture interactions have largely been modelled employing population genetic-type models. Moreover, in the most notable application to date, the "interactive" modes have been one way rather than bidirectional. This paper suggests using game theoretic, fully interactive models. Employing the logic utilized in population ecology for coevolution�
Blute, Marion
Molecular Genetics: Proteins and Genes
NSDL National Science Digital Library
In this chapter, the authors focus conceptually on the connection between genotype and phenotype, specifically the role of genes and proteins in that connection. They also consider the importance of proteins to the work of cells and the impact of proteins
Tweed, Susan K.
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.
MGC: a metagenomic gene caller
Background Computational gene finding algorithms have proven their robustness in identifying genes in complete genomes. However, metagenomic sequencing has presented new challenges due to the incomplete and fragmented nature of the data. During the last few years, attempts have been made to extract complete and incomplete open reading frames (ORFs) directly from short reads and identify the coding ORFs, bypassing other challenging tasks such as the assembly of the metagenome. Results In this paper we introduce a metagenomics gene caller (MGC) which is an improvement over the state-of-the-art prediction algorithm Orphelia. Orphelia uses a two-stage machine learning approach and computes a model that classifies extracted ORFs from fragmented sequences. We hypothesise and demonstrate evidence that sequences need separate models based on their local GC-content in order to avoid the noise introduced to a single model computed with sequences from the entire GC spectrum. We have also added two amino-acid features based on the benefit of amino-acid usage shown in our previous research. Our algorithm is able to predict genes and translation initiation sites (TIS) more accurately than Orphelia which uses a single model. Conclusions Learning separate models for several pre-defined GC-content regions as opposed to a single model approach improves the performance of the neural network as demonstrated by the experimental results presented in this paper. The inclusion of amino-acid usage features also helps improve the overall accuracy of our algorithm. MGC's improvement sets the ground for further investigation into the use of GC-content to separate data for training models in machine learning based gene finders.
Vascular gene expression: a hypothesis
The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a �primitive� vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.
Martinez-Navarro, Angelica C.; Galvan-Gordillo, Santiago V.; Xoconostle-Cazares, Beatriz; Ruiz-Medrano, Roberto
Small genes/gene-products in Escherichia coli K-12.
Forty-two protein spots of observed M(r) 6-15 kDa were resolved by two-dimensional gel electrophoresis, stained by Coomassie blue and subjected to Edman microsequencing. All of the proteins could be related back to their encoding open reading frames, thereby vindicating the bioinformatic tools currently utilised in their identification. However, only 14/42 gene-products were expressed as annotated. Translation was confirmed for 14 open reading frames with no attributed function (EcoGene Y-entries), while N-terminal sequence allowed the start codon to be accurately annotated for the genes yigF, yccU, yqiC, ynfD, and yeeX. The methionine start codon was cleaved in 11 gene-products (AtpE, Hns, RpoZ, RplL, CspC, YccJ, YggX, YjgF, HimA, InfA, RpsQ) and a further five showed loss of a signal peptide (PspE, HdeB, HdeA, YnfD, YkfE). Internal (Tig, AtpA, TufA) and N-terminal fragmentation (CspD, RpsF, AtcU) of much larger proteins was also detected, which may have resulted from physiological or translational processes. M(r) and pI isoforms were detected respectively for PtsH and GatB, each being phosphoproteins, as well as RplY which manifested differences with respect to predicted M(r) and pI. In addition, YjgF was shown to belong to a small gene family of unknown function with ancient conserved regions across procaryotes and eucaryotes. YgiN was revealed to have a paralogue and orthologues in Bacillus subtilis, Synechocystis sp., Mycobacterium tuberculosis, Neisseria gonorrhoea, and Rhodococcus erythropolis. Orthologues are also reported for YihD, YccU and YeeX. Of the 14 Y-genes, only YkfE possessed no detectable orthologues. These results highlight the need to complement genomic analysis with detailed proteomics in order to gain a better understanding of cellular molecular biology, while the confirmation of the open reading frame start codon using Edman degradation protein microsequencing has yet to be superseded by recent advances in mass spectrometry. PMID:9868784
Wasinger, V C; Humphery-Smith, I
Simultaneous Identification of Duplications and Lateral Gene Transfers
The incongruency between a gene tree and a corresponding species tree can be attributed to evolutionary events such as gene duplication and gene loss. This paper describes a combinatorial model where so-called DTL-scenarios are used to explain the differences between a gene tree and a corresponding species tree taking into account gene duplications, gene losses, and lateral gene transfers (also
Ali Tofigh; Michael T. Hallett; Jens Lagergren
Homeobox genes in normal hematopoiesis and leukemogenesis.
Homeobox genes are broadly classified into two subclasses: HOX and non-HOX homeobox genes. A number of genes in both classes are expressed in a variety of hematopoietic cells. Two major categories of evidence implying the involvement of these genes in normal hematopoiesis have been demonstrated. First, the expression pattern of the homeobox genes in hematopoietic cells is lineage- and differentiation-stage specific. Second, enforced and suppressed expression of various homeobox genes cause defects in the hematopoietic cells of specific lineages. The reduction in myeloid, erythroid and B cell progenitors is found in mice with a disrupted HOXA9 gene. The thymuses of HOXB3-overexpressed marrow recipients contain a markedly decreased number of CD4/CD8 double-positive T cells. These examples suggest that the proper level of expression and timely down-regulation of some homeobox genes are necessary for normal hematopoiesis. Homeobox genes are also implicated in human and mouse leukemias. In human leukemias, a HOX gene (HOXA9) and two non-HOX homeobox genes (PBX1 and HOX11) are involved in chromosomal translocations. In mouse leukemias, provirus integrations cause aberrant expression of several HOX and non-HOX genes. Currently available information will be discussed separately on HOX and non-HOX genes, in normal and leukemic hematopoiesis, respectively. PMID:9885434
Chiba, S
Nucleotide sequence of Klebsiella pneumoniae lac genes.
The nucleotide sequences of the Klebsiella pneumoniae lacI and lacZ genes and part of the lacY gene were determined, and these genes were located and oriented relative to one another. The K. pneumoniae lac operon is divergent in that the lacI and lacZ genes are oriented head to head, and complementary strands are transcribed. Besides base substitutions, the lacZ genes of K. pneumoniae and Escherichia coli have suffered short distance shifts of reading frame caused by additions or deletions or both during evolutionary divergence from a common ancestral gene. Relative to corresponding E. coli sequences, the nucleotide sequences of the lacZ and lacY genes are 61 and 67% conserved, and the lacI genes are 49% conserved. A comparison of both nucleotide and amino acid sequences revealed that the K. pneumoniae and E. coli lacI genes and lac repressor proteins each are related to the galR gene and gal repressor of E. coli to about the same extent. In terms of evolutionary relationships, the divergence of the forerunner of the galR gene from an ancestral lac repressor gene preceded separation and differentiation of the K. pneumoniae and E. coli lac repressor genes.
Buvinger, W E; Riley, M
Thesaurus-based disambiguation of gene symbols
Background Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. Results We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols), not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. Conclusion The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.
Schijvenaars, Bob JA; Mons, Barend; Weeber, Marc; Schuemie, Martijn J; van Mulligen, Erik M; Wain, Hester M; Kors, Jan A
Wistar Institute study finds multiple 'siblings' from every gene: Alternate gene reading leads to alternate gene products:
A genome-wide survey by researchers at The Wistar Institute shows how our cells create alternate versions of mRNA transcripts by altering how they "read" DNA. Many genes are associated with multiple gene promoters, the researchers say, which is the predominant way multiple variants of a given gene, for example, can be made with the same genetic instructions.
Gene Therapy Progress and Prospects: cancer gene therapy using tumour suppressor genes
Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit
IA McNeish; SJ Bell; NR Lemoine
Bayesian Mixture Modeling of Gene-Environment and Gene-Gene Interactions
With the advent of rapid and relatively cheap genotyping technologies there is now the opportunity to attempt to identify gene-environment and gene-gene interactions when the number of genes and environmental factors is potentially large. Unfortunately the dimensionality of the parameter space leads to a computational explosion in the number of possible interactions that may be investigated. The full model that includes all interactions and main effects can be unstable, with wide confidence intervals arising from the large number of estimated parameters. We describe a hierarchical mixture model that allows all interactions to be investigated simultaneously, but assumes the effects come from a mixture prior with two components, one that reflects small null effects and the second for epidemiologically significant effects. Effects from the former are effectively set to zero, hence increasing the power for the detection of real signals. The prior framework is very flexible, which allows substantive information to be incorporated into the analysis. We illustrate the methods first using simulation, and then on data from a case-control study of lung cancer in Central and Eastern Europe.
Wakefield, Jon; De Vocht, Frank; Hung, Rayjean J.
A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies.
Widespread multifactor interactions present a significant challenge in determining risk factors of complex diseases. Several combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, have emerged as a promising tool for better detecting gene-gene (G x G) and gene-environment (G x E) interactions. We recently developed a general combinatorial approach, namely the generalized multifactor dimensionality reduction (GMDR) method, which can entertain both qualitative and quantitative phenotypes and allows for both discrete and continuous covariates to detect G x G and G x E interactions in a sample of unrelated individuals. In this article, we report the development of an algorithm that can be used to study G x G and G x E interactions for family-based designs, called pedigree-based GMDR (PGMDR). Compared to the available method, our proposed method has several major improvements, including allowing for covariate adjustments and being applicable to arbitrary phenotypes, arbitrary pedigree structures, and arbitrary patterns of missing marker genotypes. Our Monte Carlo simulations provide evidence that the PGMDR method is superior in performance to identify epistatic loci compared to the MDR-pedigree disequilibrium test (PDT). Finally, we applied our proposed approach to a genetic data set on tobacco dependence and found a significant interaction between two taste receptor genes (i.e., TAS2R16 and TAS2R38) in affecting nicotine dependence. PMID:18834969
Lou, Xiang-Yang; Chen, Guo-Bo; Yan, Lei; Ma, Jennie Z; Mangold, Jamie E; Zhu, Jun; Elston, Robert C; Li, Ming D
Small genes\\/gene-products in Escherichia coli K-12
Forty-two protein spots of observed Mr 6�15 kDa were resolved by two-dimensional gel electrophoresis, stained by Coomassie blue and subjected to Edman microsequencing. All of the proteins could be related back to their encoding open reading frames, thereby vindicating the bioinformatic tools currently utilised in their identification. However, only 14\\/42 gene-products were expressed as annotated. Translation was confirmed for 14
Valerie C Wasinger; Ian Humphery-Smith
Gene conversions may obscure actin gene family relationships.
Phylogenetic hypotheses of muscle actin evolution are significantly different when a sea urchin is used as a representative echinoderm than when a sea star is used. While sea urchin muscle actins support an echinoderm-chordate sister relationship, sea star sequences suggest that echinoderm muscle actins are convergent with chordate muscle actins. Our results suggest that gene conversion in the sea star muscle actin may be responsible for these discordant results. PMID:10684350
White, M E; Crother, B I
Identification of genes responsive to PFOS using gene expression profiling
Perfluorooctane sulfonic acid (PFOS) is widely distributed in the environment including in the tissues of wildlife and humans, however, its mechanism of action remains unclear. Here, the Affymetrix rat genome U34A genechip was used to identify alterations in gene expression due to PFOS exposure. Rat hepatoma cells were treated with PFOS at 2�50mg\\/L (4�100?M) for 96h. Sprague-Dawley rats were orally
Wenyue Hu; Paul D. Jones; Trine Celius; John P. Giesy
Interactive Fly: Early Zygotic Gene Expression Images
NSDL National Science Digital Library
In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.
PhD Thomas B Brody (NIH Laboratory of Neurochemistry)
Towards integrative gene functional similarity measurement
Background In Gene Ontology, the "Molecular Function" (MF) categorization is a widely used knowledge framework for gene function comparison and prediction. Its structure and annotation provide a convenient way to compare gene functional similarities at the molecular level. The existing gene similarity measures, however, solely rely on one or few aspects of MF without utilizing all the rich information available including structure, annotation, common terms, lowest common parents. Results We introduce a rank-based gene semantic similarity measure called InteGO by synergistically integrating the state-of-the-art gene-to-gene similarity measures. By integrating three GO based seed measures, InteGO significantly improves the performance by about two-fold in all the three species studied (yeast, Arabidopsis and human). Conclusions InteGO is a systematic and novel method to study gene functional associations. The software and description are available at http://www.msu.edu/~jinchen/InteGO.
PAX Genes in Cancer; Friends or Foes?
PAX genes have been shown to be critically required for the development of specific tissues and organs during embryogenesis. In addition, PAX genes are expressed in a handful of adult tissues where they are thought to play important roles, usually different from those in embryogenesis. A common theme in adult tissues is a requirement for PAX gene expression in adult stem cell maintenance or tissue regeneration. The connections between adult stem cell PAX gene expression and cancer are intriguing, and the literature is replete with examples of PAX gene expression in either situation. Here we systematically review the literature and present an overview of postnatal PAX gene expression in normal and cancerous tissue. We discuss the potential link between PAX gene expression in adult tissue and cancer. In addition, we discuss whether persistent PAX gene expression in cancer is favorable or unfavorable.
Li, Caiyun G.; Eccles, Michael R.
Human fibroblast interferon gene lacks introns
A recombinant ? bacteriophage isolated from a human genome library contains the gene for fibroblast interferon (IFN-?1). The DNA sequence of this gene is identical to the sequence of its mRNA and is devoid of introns.
Lawn, Richard M.; Adelman, John; Franke, Arthur E.; Houck, Catherine M.; Gross, Mitchell; Najarian, Richard; Goeddel, David V.
Potato Genes for Resistance to Late Blight.
National Technical Information Service (NTIS)
Resistance genes and their encoded proteins from the wild potato, Solanum bulbocastanum, are disclosed. The genes and proteins are useful for conferring disease resistance to plants, particularly solanaceous species such as potato and tomato. In particula...
J. Jiang J. Song J. P. Helgeson S. Austin-Phillips S. K. Naess
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- ...
Physical Characterization of Clostridium Botulinum Neurotoxin Genes.
National Technical Information Service (NTIS)
DNA fragments encompassing the neurotoxin genes of Clostridium botulinum types B and E have been cloned and their entire nucleotide sequences determined. Similarly, recombinant clones carrying all but the extreme 51 end of the type F gene have been obtain...
N. P. Minton
Diacylglycerol Acyltransferase Genes, Proteins, and Uses Thereof.
National Technical Information Service (NTIS)
The present invention relates to diacylglycerol acyltransferase genes and proteins, and methods of their use. In particular, the invention describes genes and proteins that exhibit both long-chain acyltransferase and acetyltransferase activity. The presen...
A. Milcamps D. A. Pan M. R. Pollard
IGF-Regulated Genes in Prostate Cancer.
National Technical Information Service (NTIS)
We hypothesize that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression, and include metastasis-regulating genensthat could consti...
C. Roberts
Gene-gene interactions in breast cancer susceptibility.
There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 � 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 � 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393
Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D Gareth; Donnelly, Peter; Easton, Douglas F; Stratton, Michael R; Rahman, Nazneen
Polymer Design for Nonviral Gene Delivery
Gene therapy continues to hold promise in treating a variety of inherited and acquired diseases. The great majority of gene\\u000a therapy trials rely on viral vectors for gene transduction because of their high efficiency. Viruses remain the vectors of\\u000a choice in achieving high efficiency of gene transfer in vivo. Viral vectors, however, pose safety concerns unlikely to abate\\u000a in the
Kam W. Leong
Evolutionary Dynamics of Overlapped Genes in Salmonella
Presence of overlapping genes (OGs) is a common phenomenon in bacterial genomes. Most frequently, overlapping genes share coding regions with as few as one nucleotide to as many as thousands of nucleotides. Overlapping genes are often co-regulated, transcriptionally and translationally. Overlapping genes are also subject to the whims of evolution, as the gene overlap is known to be disrupted in some species/strains and participating genes are sometimes lost in independent lineages. Therefore, a better understanding of evolutionary patterns and rates of the disruption of overlapping genes is an important component of genome structure and evolution of gene function. In this study, we investigate the fate of ancestrally overlapping genes in complete genomes from 15 contemporary strains of Salmonella species. We find that the fates of overlapping genes inside and outside operons are distinctly different. A larger fraction of overlapping genes inside operons conserves their overlap as compared to gene pairs outside of the operons (average 0.89 vs. 0.83 per genome). However, when overlapping genes in the operons separate, one partner is lost more frequently than in those separated genes outside of operons (average 0.02 vs. 0.01 per genome). We also investigate the fate of a pan set of overlapping genes at the present and ancestral nodes over a phylogenetic tree based on genome sequence data, respectively. We propose that co-regulation plays important roles on the fates of genes. Furthermore, a vast majority of disruptions occurred prior to the common ancestor of all 15 Salmonella strains, which enables us to obtain an estimate of disruptions between Salmonella and E. coli.
Luo, Yingqin; Battistuzzi, Fabia; Lin, Kui
Evolution of Exceptionally Large Genes in Prokaryotes
Analysis of bacterial genomic sequences revealed an average bacterial gene size of approximately 1 kb. However, genes with\\u000a a size >10�kb were also noted. This study investigates the prevalence, possible function, and origin of exceptionally large-size\\u000a genes (ELSGs; >10�kb) in prokaryotes. Forty-two ELSGs (0.03%) were identified after searching more than 170,000 genes in 46\\u000a bacterial and 11 archaeal species. These
Min-Chieh Kuo; Li-Fang Chou; Hwan-You Chang
The HUGO Gene Nomenclature Database, 2006 updates
The HUGO Gene Nomenclature Committee (HGNC) aims to give every human gene a unique and ideally meaningful name and symbol. The HGNC database, previously known as Genew, contains over 22000 public records with approved human gene nomen- clature and associated information. The database has undergone major improvements throughout the last year, is publicly available for online searching at http:\\/\\/www.gene.ucl.ac.uk\\/cgi-bin\\/nomenclature\\/ searchgenes.pl
Tina A. Eyre; Fabrice Ducluzeau; Tam P. Sneddon; Sue Povey; Elspeth A. Bruford; Michael J. Lush
Polycystic kidney disease - where gene dosage counts
Gene dosage effects have emerged as playing a central role in the pathogenesis of polycystic kidney disease. Yet, how gene dosage can ultimately have an impact on the formation of kidney cysts remains unknown. In this commentary we review the evidence for the role of gene dosage effects versus the �2-hit� mutation model in polycystic kidney disease (PKD), and also discuss how gene networks may potentially make intertwined contributions to PKD.
Stayner, Cherie A.
Identifying Antimicrobial Resistance Genes with DNA Microarrays
We developed and tested a glass-based microarray suitable for detecting multiple tetracycline (tet) resistance genes. Microarray probes for 17 tet genes, the -lactamase blaTEM-1 gene, and a 16S ribosomal DNA gene (Escherichia coli) were generated from known controls by PCR. The resulting products (ca. 550 bp) were applied as spots onto epoxy-silane-derivatized, Teflon-masked slides by using a robotic spotter. DNA
Douglas R. Call; Marlene K. Bakko; Melissa J. Krug; Marilyn C. Roberts
Plant nitrogen regulatory P-PII genes
The present invention generally relates to plant nitrogen regulatory PII gene (hereinafter P-PII gene), a gene involved in regulating plant nitrogen metabolism. The invention provides P-PII nucleotide sequences, expression constructs comprising said nucleotide sequences, and host cells and plants having said constructs and, optionally expressing the P-PII gene from said constructs. The invention also provides substantially pure P-PII proteins. The P-PII nucleotide sequences and constructs of the
Coruzzi, Gloria M. (New York, NY); Lam, Hon-Ming (Hong Kong, HK); Hsieh, Ming-Hsiun (Woodside, NY)
Serotonergic genes and suicide: a systematic review.
Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5-HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene-environment interactions. PMID:23742855
Antypa, Niki; Serretti, Alessandro; Rujescu, Dan
ETS gene fusions in prostate cancer
Chromosomal rearrangements that result in high level expression of ETS gene family members are common events in human prostate cancer. Most frequently, the androgen-activated gene TMPRSS2 is found fused to the ERG gene. Fusions involving ETV1, ETV4 and ETV5 occur less frequently but exhibit greater variability in fusion structure with 12 unique 5? fusion partners identified so far. ETS gene
Colin S. Cooper; Jeremy P. Clark
Regulation of the genes involved in nitrification.
OAK-B135 This project focuses on the characterization of the regulation of the genes involved in nitrification in the bacterium Nitrosomonas europaea. The key genes in the nitrification pathway, amo and hao, are present in multiple copies in the genome. The promoters for these genes were identified and characterized. It was shown that there were some differences in the transcriptional regulation of the copies of these genes.
Arp, D.J.; Sayavedra-Soto, L.A.
NSDL National Science Digital Library
As a result of the human genome project, we now know largely where our genes are, and what structure they have. The search to uncover each gene's function, on the other hand, is only in its infancy. Functional genomics is an area of research dedicated to studying what protein is produced by a gene, and what happens in the body when it is activated. Understanding gene function is the next major hurdle in genomic research, which holds the key to developing revolutionary therapeutics.
Fungal avirulence genes: structure and possible functions.
Avirulence (Avr) genes exist in many fungi that share a gene-for-gene relationship with their host plant. They represent unique genetic determinants that prevent fungi from causing disease on plants that possess matching resistance (R) genes. Interaction between elicitors (primary or secondary products of Avr genes) and host receptors in resistant plants causes induction of various defense responses often involving a hypersensitive response. Avr genes have been successfully isolated by reverse genetics and positional cloning. Five cultivar-specific Avr genes (Avr4, Avr9, and Ecp2 from Cladosporium fulvum; nip1 from Rhynchosporium secalis; and Avr2-YAMO from Magnaporthe grisea) and three species-specific Avr genes (PWL1 and PWL2 from M. grisea and inf1 from Phytophthora infestans) have been cloned. Isolation of additional Avr genes from these fungi, but also from other fungi such as Uromyces vignae, Melampsora lini, Phytophthora sojae, and Leptosphaeria maculans, is in progress. Molecular analyses of nonfunctional Avr gene alleles show that these originate from deletions or mutations in the open reading frame or the promoter sequence of an Avr gene. Although intrinsic biological functions of most Avr gene products are still unknown, recent studies have shown that two Avr genes, nip1 and Ecp2, encode products that are important pathogenicity factors. All fungal Avr genes cloned so far have been demonstrated or predicted to encode extracellular proteins. Current studies focus on unraveling the mechanisms of perception of avirulence factors by plant receptors. The exploitation of Avr genes and the matching R genes in engineered resistance is also discussed. PMID:9756710
Laug�, R; De Wit, P J
Gene Therapy for Chronic Granulomatous Disease
Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory
W. Scott Goebel; Mary C. Dinauer
Basics on Genes and Genetic Disorders
The Basics on Genes and Genetic Disorders KidsHealth > Teens > Body > Health Basics > The Basics on Genes and Genetic Disorders Print A A A Text Size What's in ... repair" the gene change. Back Continue What Are Genetic Disorders? Researchers have identified more than 4,000 ...
Mining gene expression databases for association rules
Motivation: Global gene expression profiling, both at the transcript level and at the protein level, can be a valuable tool in the understanding of genes, biological networks, and cellular states. As larger and larger gene expression data sets become available, data mining techniques can be applied to identify patterns of interest in the data. As- sociation rules, used widely in
Chad Creighton; Samir Hanash
Recurrent gene fusions in prostate cancer
The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours. Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of haematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5? genomic
Chandan Kumar-Sinha; Scott A. Tomlins; Arul M. Chinnaiyan
Comparative Gene Prediction in Human and Mouse
The completion of the sequencing of the mouse genome promises to help predict human genes with greater accuracy. While current ab initio gene prediction programs are remarkably sensitive (i.e., they predict at least a fragment of most genes), their specificity is often low, predicting a large number of false-positive genes in the human genome. Sequence conservation at the protein level with the mouse genome can help eliminate some of those false positives. Here we describe SGP2, a gene prediction program that combines ab initio gene prediction with TBLASTX searches between two genome sequences to provide both sensitive and specific gene predictions. The accuracy of SGP2 when used to predict genes by comparing the human and mouse genomes is assessed on a number of data sets, including single-gene data sets, the highly curated human chromosome 22 predictions, and entire genome predictions from ENSEMBL. Results indicate that SGP2 outperforms purely ab initio gene prediction methods. Results also indicate that SGP2 works about as well with 3x shotgun data as it does with fully assembled genomes. SGP2 provides a high enough specificity that its predictions can be experimentally verified at a reasonable cost. SGP2 was used to generate a complete set of gene predictions on both the human and mouse by comparing the genomes of these two species. Our results suggest that another few thousand human and mouse genes currently not in ENSEMBL are worth verifying experimentally.
Parra, Genis; Agarwal, Pankaj; Abril, Josep F.; Wiehe, Thomas; Fickett, James W.; Guigo, Roderic
Dynamic modeling of gene expression data
We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by
Neal S. Holter; Amos Maritan; Marek Cieplak; Nina V. Fedoroff; Jayanth R. Banavar
Recent Patents Relating to Tumor Suppressor Genes
Researchers in the field of tumor suppressor genes are actively attempting to discover new tumor suppressor genes and\\/or characterize known tumor suppressor genes with the intention of treating and diagnosing cancers. A number of recent patents and patent applications have been published that discuss some of these discoveries. Some of the patents and patent applications discuss newly discovered tumor suppressor
Jason J. Derry; Yijan E. Chang
Environmental and Behavioral Influences on Gene Activity
The central dogma of molecular biology holds that �information� flows from the genes to the structure of the proteins that the genes bring about through the formula DNA ? RNA ? protein. In this view, a set of master genes activates the DNA necessary to produce the appropriate proteins that the organism needs during development. In contrast to this view,
Gilbert Gottlieb
Evolution of Mitochondrial Gene Orders in Echinoderms
A comprehensive analysis of the mitochondrial gene orders of all previously pub- lished and two novel Antedon mediterranea (Crinoidea) and Ophiura albida (Ophi- uroidea) complete echinoderm mitochondrial genomes shows that all major types of rearrangement operations are necessary to explain the evolution of mitochondrial genomes. In addition to protein coding genes we include all tRNA genes as well as the
Marleen Perseke; Guido Fritzsch; Kai Ramsch; Matthias Bernt; Daniel Merkle; Martin Middendorf; Detlef Bernhard; Peter F. Stadler; Martin Schlegel
Gene therapy for childhood immunological diseases
Gene therapy using autologous hematopoietic stem cells (HSC) that are corrected with the normal gene may have a beneficial effect on blood cell production or function, without the immunologic complications of allogeneic HSC transplantation. Childhood immunological diseases are highly favorable candidates for responses to gene therapy using HSC. Hemoglobinopathies, lysosomal and metabolic disorders and defects of hematopoietic stem and progenitor
D B Kohn
Uses of antimicrobial genes from microbial genome
We describe a method for mining microbial genomes to discover antimicrobial genes and proteins having broad spectrum of activity. Also described are antimicrobial genes and their expression products from various microbial genomes that were found using this method. The products of such genes can be used as antimicrobial agents or as tools for molecular biology.
Sorek, Rotem; Rubin, Edward M.
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
Sarajli?, Anida; Janji?, Vuk; Stojkovi?, Neda; Radak, Djordje; Pr�ulj, Nata�a
Gene prioritization through genomic data fusion
The identification of genes involved in health and disease remains a challenge. We describe a bioinformatics approach, together with a freely accessible, interactive and flexible software termed Endeavour, to prioritize candidate genes underlying biological processes or diseases, based on their similarity to known genes involved in these phenomena. Unlike previous approaches, ours generates distinct prioritizations for multiple heterogeneous data sources,
Diether Lambrechts; Sunit Maity; Peter Van Loo; Bert Coessens; Frederik De Smet; Leon-Charles Tranchevent; Bart De Moor; Peter Marynen; Bassem Hassan; Peter Carmeliet; Yves Moreau; Stein Aerts
Rough Overlapping Biclustering of Gene Expression Data
A great number of biclustering algorithms have been proposed for analyzing gene expression data. Many of them assume to find exclusive biclusters whose subsets of genes are co-regulated under subsets of conditions without intersection. This is not consistent with a general understanding of biological processes that many genes participate in multiple different processes. Therefore nonexclusive biclustering algorithms are required. In
Ruizhi Wang; Duoqian Miao; Gang Li; Hongyun Zhang
Jumping Genes: The Transposable DNAs of Bacteria.
ERIC Educational Resources Information Center
Transposons are transposable elements that carry genes for antibiotic resistance. Provides background information on the structure and organization of these "jumping genes" in bacteria. Also describes the use of transposons in tagging genes and lists pertinent references and resource materials. (DH)
Berg, Claire M.; Berg, Douglas E.
The evolutionary demography of duplicate genes
Although gene duplication has generally been viewed as a necessary source of material for the origin of evolu- tionary novelties, the rates of origin, loss, and preservation of gene duplicates are not well understood. Applying steady-state demographic techniques to the age distributions of duplicate genes censused in seven completely sequenced genomes, we estimate the average rate of duplication of a
Michael Lynch; John S. Conery
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.
Stojkovic, Neda; Radak, Djordje; Przulj, Natasa
Sample size for gene expression microarray experiments
Motivation: Microarray experiments often involve hundreds or thou- sands of genes. In a typical experiment, only a fraction of genes are expected to be differentially expressed; in addition, the measured intensities among different genes may be correlated. Depending on the experimental objectives, sample size calculations can be based on one of the three specified measures: sensitivity, true discovery and accuracy
Chen-an Tsai; Sue-jane Wang; Dung-tsa Chen; James J. Chen
Gene therapy for the regeneration of bone
Gene transfer technologies offer the prospect of enhancing bone regeneration by delivering osteogenic gene products locally to osseous defects. In most cases the gene product will be a protein, which will be synthesized endogenously within and around the lesion in a sustained fashion. It will have undergone authentic post-translational processing and lack the alterations that occur when recombinant proteins are
Christopher Evans
Discovery of Tumor Suppressor Gene Function.
ERIC Educational Resources Information Center
This is an update of a 1991 review on tumor suppressor genes written at a time when understanding of how the genes work was limited. A recent major breakthrough in the understanding of the function of tumor suppressor genes is discussed. (LZ)
Oppenheimer, Steven B.
Human gene therapy and imaging: cardiology
This review discusses the basics of cardiovascular gene therapy, the results of recent human clinical trials, and the rapid progress in imaging techniques in cardiology. Improved understanding of the molecular and genetic basis of coronary heart disease has made gene therapy a potential new alternative for the treatment of cardiovascular diseases. Experimental studies have established the proof-of-principle that gene transfer
Joseph C. Wu; Seppo Yla-Herttuala
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kyoto Encyclopedia of Genes and Genomes (KEGG) is a knowledge base for systematic analysis of gene functions in terms of the networks of genes and molecules. The major component of KEGG is the PATHWAY database that consists of graphical dia- grams of biochemical pathways including most of the known metabolic pathways and some of the known regulatory pathways. The pathway
Hiroyuki Ogata; Susumu Goto; Kazushige Sato; Wataru Fujibuchi; Hidemasa Bono; Minoru Kanehisa
IGF-Regulated Genes in Prostate Cancer.
National Technical Information Service (NTIS)
We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression. IGF-I receptor target genes may include metastasis-promo...
C. T. Roberts
Muscle Gene Therapy for Hemophilia
Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia.
Sabatino, Denise E.; Arruda, Valder R.
Gene Therapy for Primary Immunodeficiencies
Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.
Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby
Ikaros gene expression and leukemia.
The Ikaros (Ik) protein, or LyF1, was initially described as a protein binding to regulatory sequences of a number of genes expressed in murine lymphoid cells. Ikaros is a critical regulator of normal hematopoietic stem cell differentiation, as evidenced by dramatic defects in the lymphoid compartments, in homozygous animals with gene inactivation. Because differential splicing produces multiple isoforms with potentially different functions, Ikaros provides a unique model to study how post-transcriptional mechanisms may be involved in neoplastic processes. Indeed, several groups including ours have underlined evidences that expression of different Ikaros isoforms vary among different types of leukemias. The predominance of short isoforms in certain subsets is intriguing. Here, additional observations reinforced the hypothesis that Ikaros expression may be deregulated in human leukemias. Whether this is a cause or a consequence of the leukemic process remains speculative. Other human diseases however, provide examples of abnormal post-transcriptional regulations that have been further characterized. PMID:11908734
Tonnelle, C�cile; Calmels, Boris; Maroc, Christine; Gabert, Jean; Chabannon, Christian
Nickel and epigenetic gene silencing.
Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing. PMID:24705264
Sun, Hong; Shamy, Magdy; Costa, Max
Nickel and Epigenetic Gene Silencing
Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.
Sun, Hong; Shamy, Magdy; Costa, Max
RGST - Rat Gene Symbol Tracker, a database for defining official rat gene symbols
BACKGROUND: The names of genes are central in describing their function and relationship. However, gene symbols are often a subject of controversy. In addition, the discovery of mammalian genes is now so rapid that a proper use of gene symbol nomenclature rules tends to be overlooked. This is currently the situation in the rat and there is a need for
Greta Petersen; Fredrik St�hl
Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma
In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the so-called bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC)
Shigeki Kuriyama; Toshiya Nakatani; Kazuhiro Masui; Takemi Sakamoto; Kentarou Tominaga; Masahide Yoshikawa; Hiroshi Fukui; Kazuhiro Ikenaka; Tadasu Tsujii
Reranking candidate gene models with cross-species comparison for improved gene prediction
Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc). Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models.
Liu, Qian; Crammer, Koby; Pereira, Fernando CN; Roos, David S
The Homeobox Gene Caudal Regulates Constitutive Local Expression of Antimicrobial Peptide Genes in Drosophila Epithelia
In Drosophila melanogaster, although the NF-B transcription factors play a pivotal role in the inducible expression of innate immune genes, such as antimicrobial peptide genes, the exact regulatory mechanism of the tissue-specific constitutive expression of these genes in barrier epithelia is largely unknown. Here, we show that the Drosophila homeobox gene product Caudal functions as the innate immune transcription modulator
Ji-Hwan Ryu; Ki-Bum Nam; Chun-Taek Oh; Hyuck-Jin Nam; Sung-Hee Kim; Joo-Heon Yoon; Je-Kyeong Seong; Mi-Ae Yoo; In-Hwan Jang; Paul T. Brey; Won-Jae Lee
Detection of gene orthology from gene co-expression and protein interaction networks
BACKGROUND: Ortholog detection methods present a powerful approach for finding genes that participate in similar biological processes across different organisms, extending our understanding of interactions between genes across different pathways, and understanding the evolution of gene families. RESULTS: We exploit features derived from the alignment of protein-protein interaction networks and gene-coexpression networks to reconstruct KEGG orthologs for Drosophila melanogaster, Saccharomyces
Fadi Towfic; Susan VanderPlas; Casey A. Oliver; Oliver Couture; Christopher K. Tuggle; M. Heather West Greenlee; Vasant Honavar
Expression of a truncated tomato polygalacturonase gene inhibits expression of the endogenous gene in transgenic plants
Tomato plants were transformed with a chimaeric polygalacturonase (PG) gene, designed to produce a truncated PG transcript constitutively. In these plants expression of the endogenous PG gene was inhibited during ripening, resulting in a substantial reduction in PG mRNA and enzyme accumulation. This inhibition was comparable to that achieved previously using antisense genes. The expression of the truncated gene in
C. J. S. Smith; C. F. Watson; C. R. Bird; J. Ray; W. Schuch; D. Grierson
Associating Genes with Gene Ontology Codes Using a Maximum Entropy Analysis of Biomedical Literature
Functional characterizations of thousands of gene products from many species are described in the published literature. These discussions are extremely valuable for characterizing the functions not only of these gene products, but also of their homologs in other organisms. The Gene Ontology (GO) is an effort to create a controlled terminology for labeling gene functions in a more precise, reliable,
Soumya Raychaudhuri; Jeffrey T. Chang; Patrick D. Sutphin; Russ B. Altman
Active plant defense, also known as gene-for-gene resistance, is triggered when a plant resistance (R) gene recognizes the intrusion of a specific insect pest or pathogen. Activation of plant defense includes an array of physiological and transcriptional reprogramming. During the past decade, a large number of plant R genes that confer resistance to diverse group of pathogens have been cloned
Evaluating reference genes to normalize gene expression in human epileptogenic brain tissues
Several reference genes have been used to quantify gene expression in human epilepsy surgery tissue. However, their reliability has not been validated in detail, although this is crucial in interpreting epilepsy-related changes of gene expression. We evaluated 12 potential reference genes in neocortical tissues resected from patients with temporal lobe epilepsy (TLE) with either few or many seizures (n=6 each)
Stephan Wierschke; Sylvain Gigout; Peter Horn; Thomas-Nicolas Lehmann; Christoph Dehnicke; Anja U. Br�uer; Rudolf A. Deisz
Identification and validation of suitable endogenous reference genes for gene expression studies in human peripheral blood
BACKGROUND: Gene expression studies require appropriate normalization methods. One such method uses stably expressed reference genes. Since suitable reference genes appear to be unique for each tissue, we have identified an optimal set of the most stably expressed genes in human blood that can be used for normalization. METHODS: Whole-genome Affymetrix Human 2.0 Plus arrays were examined from 526 samples
Boryana S Stamova; Michelle Apperson; Wynn L Walker; Yingfang Tian; Huichun Xu; Peter Adamczy; Xinhua Zhan; Da-Zhi Liu; Bradley P Ander; Isaac H Liao; Jeffrey P Gregg; Renee J Turner; Glen Jickling; Lisa Lit; Frank R Sharp
Reference genes for normalising gene expression data in collagenase-induced rat intracerebral haemorrhage
BACKGROUND: The mechanisms of brain injury following intracerebral haemorrhage (ICH) are incompletely understood. Gene expression studies using quantitative real-time RT-PCR following ICH have increased our understanding of these mechanisms, however the inconsistent results observed may be related to inappropriate reference gene selection. Reference genes should be stably expressed across different experimental conditions, however, transcript levels of common reference genes have
Naomi L Cook; Timothy J Kleinig; Corinna van den Heuvel; Robert Vink
Reconstruction of Ancestral Gene Order Following Large Scale Genome Duplication and Gene Loss
Gene order evolves through gross chromosomal rearrangements, small scale inversions and transpo- sitions, gene duplication, and gene loss. Much research has been done on the calculation of edit distance and on sorting algorithms under a variety of rearrangement models in which the genome may be repre- sented as conserved segments with permuted order and orientation. However, gene loss within otherwise
Jun Huan; Jan F. Prins; Wei Wang; Todd J. Vision
Ranking differentially expressed genes from Affymetrix gene expression data: methods with reproducibility, sensitivity, and specificity
BACKGROUND: To identify differentially expressed genes (DEGs) from microarray data, users of the Affymetrix GeneChip system need to select both a preprocessing algorithm to obtain expression-level measurements and a way of ranking genes to obtain the most plausible candidates. We recently recommended suitable combinations of a preprocessing algorithm and gene ranking method that can be used to identify DEGs with
Koji Kadota; Yuji Nakai; Kentaro Shimizu
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expres- sion databases
Ron Edgar; Michael Domrachev; Alex E. Lash
Gene teams: a new formalization of gene clusters for comparative genomics
This paper describes an efficient algorithm based on a new concept called gene team for detecting conserved gene clusters among an arbitrary number of chromosomes. Within the clusters, neither the order of the genes nor their orientation need be conserved. In addition, insertion of foreign genes within the clusters are permitted to a user-defined extent. This algorithm has been implemented
Nicolas Luc; Jean-loup Risler; Anne Bergeron; Mathieu Raffinot
Indexing TNF-? gene expression using a gene-targeted reporter cell line
BACKGROUND: Current cell-based drug screening technologies utilize randomly integrated reporter genes to index transcriptional activity of an endogenous gene of interest. In this context, reporter expression is controlled by known genetic elements that may only partially capture gene regulation and by unknown features of chromatin specific to the integration site. As an alternative technology, we applied highly efficient gene-targeting with
Ziying Yan; Diana Lei-Butters; John F Engelhardt; Gregory H Leno
Reshaping of global gene expression networks and sex-biased gene expression by integration of a young gene
New genes originate frequently across diverse taxa. Given that genetic networks are typically comprised of robust, co-evolved interactions, the emergence of new genes raises an intriguing question: how do new genes interact with pre-existing genes? Here, we show that a recently originated gene rapidly evolved new gene networks and impacted sex-biased gene expression in Drosophila. This 4�6 million-year-old factor, named Zeus for its role in male fecundity, originated through retroposition of a highly conserved housekeeping gene, Caf40. Zeus acquired male reproductive organ expression patterns and phenotypes. Comparative expression profiling of mutants and closely related species revealed that Zeus has recruited a new set of downstream genes, and shaped the evolution of gene expression in germline. Comparative ChIP-chip revealed that the genomic binding profile of Zeus diverged rapidly from Caf40. These data demonstrate, for the first time, how a new gene quickly evolved novel networks governing essential biological processes at the genomic level.
Chen, Sidi; Ni, Xiaochun; Krinsky, Benjamin H; Zhang, Yong E; Vibranovski, Maria D; White, Kevin P; Long, Manyuan
Gene expression in diabetic nephropathy
Diabetic nephropathy (DN) is a common complication of diabetes types 1 and 2. One of the hallmarks of DN is the development\\u000a of mesangial expansion, which occurs through accumulation of extracellular matrix (ECM) components. Altered local gene expression\\u000a of humoral factors (eg, transforming growth factor-�, connective tissue growth factor, and platelet-derived growth factor) can lead to increased\\u000a production of ECM
Daniela Hohenadel; Fokko J. van der Woude
PPAR?, the ultimate thrifty gene
\\u000a \\u000a Abstract\\u000a \\u000a �� The peroxisome proliferator-activated receptor gamma (PPAR?) quickly evolved over the last decade from a new orphan receptor to one of the best characterized nuclear receptors. This\\u000a fast pace in PPAR? research was triggered by two main discoveries. Firstly, that PPAR? was shown to have a key role in adipogenesis and be a master controller of the �thrifty gene
J. Auwerx
Active Gene Sequences are Undermethylated
The degree of methylation of active regions of the chromosome has been investigated by several techniques. DNase I (deoxyribonuclease I, EC 188.8.131.52) was used to introduce nicks in the active regions of the nucleus and thereby specifically label these areas. By using the methylation-specific restriction enzymes Hpa II and Hha I it could be shown that active genes are more
Tally Naveh-Many; Howard Cedar
Method for determining gene knockouts
A method for determining candidates for gene deletions and additions using a model of a metabolic network associated with an organism, the model includes a plurality of metabolic reactions defining metabolite relationships, the method includes selecting a bioengineering objective for the organism, selecting at least one cellular objective, forming an optimization problem that couples the at least one cellular objective with the bioengineering objective, and solving the optimization problem to yield at least one candidate.
Maranas, Costa D; Burgard, Anthony R; Pharkya, Priti
Gene expression in Chromobacterium violaceum
The repertoire of 4,431 open reading frames (ORFs), eight rRNA operons and 98 tRNA genes of Chromobacterium viola- ceum must be expressed in a regulated manner for successful adapta- tion to a wide variety of environmental conditions. To accomplish this feat, the organism relies on protein machineries involved in transcription, RNA processing and translation. Analysis of the C. violaceum genome
Rosane Silva; J�lia R. Araripe; Edson Rondinelli; Tur�n P. �rm�nyi
Transgenic plants with cyanobacterial genes
Over the years, cyanobacteria have been regarded as ideal model systems for studying fundamental biochemical processes like\\u000a oxygenic photosynthesis and carbon and nitrogen assimilation. Additionally, they have been used as human foods, sources for\\u000a vitamins, proteins, fine chemicals, and bioactive compounds. Aiming to increase plant productivity as well as nutritional\\u000a values, cyanobacterial genes involved in carbon metabolism, fatty acid biosynthesis,
Youn-Il Park; Sang-Bong Choi; Jang R. Liu
Chromosomal destabilization during gene amplification.
Acentric extrachromosomal elements, such as submicroscopic autonomously replicating circular molecules (episomes) and double minute chromosomes, are common early, and in some cases initial, intermediates of gene amplification in many drug-resistant and tumor cell lines. In order to gain a more complete understanding of the amplification process, we investigated the molecular mechanisms by which such extrachromosomal elements are generated and we traced the fate of these amplification intermediates over time. The model system consists of a Chinese hamster cell line (L46) created by gene transfer in which the initial amplification product was shown previously to be an unstable extrachromosomal element containing an inverted duplication spanning more than 160 kilobases (J. C. Ruiz and G. M. Wahl, Mol. Cell. Biol. 8:4302-4313, 1988). In this study, we show that these molecules were formed by a process involving chromosomal deletion. Fluorescence in situ hybridization was performed at multiple time points on cells with amplified sequences. These studies reveal that the extrachromosomal molecules rapidly integrate into chromosomes, often near or at telomeres, and once integrated, the amplified sequences are themselves unstable. These data provide a molecular and cytogenetic chronology for gene amplification in this model system; an early event involves deletion to generate extrachromosomal elements, and subsequent integration of these elements precipitates a cascade of chromosome instability. Images
Ruiz, J C; Wahl, G M
Liver Damage using Suicide Genes
Liver regeneration from the facultative hepatic stem cells, the oval cells, takes place in situations in which liver regeneration from pre-existing hepatocytes is prevented. Different models have been used to stimulate oval cell response. Many of them involve the use of carcinogenic agents with or without partial hepatectomy. In this study we show that adenovirus-mediated gene transfer of the suicide gene thymidine kinase followed by ganciclovir administration caused hepatotoxicity of variable intensity. Rats with moderate elevation in serum transaminases recovered normal liver architecture few weeks after adenovirus injection. In contrast, rats with severe liver damage exhibited a marked and persisting activation of oval cells accompanied by ductular hyperplasia. In some rats, such lesion eventually evolved to cholangiofibrosis and in one rat to cholangiocarcinoma. Deposition of fibronectin and increased number of hepatic stellate cells were found in association with oval cells and cholangiofibrotic lesions. Hepatocyte growth factor was hyperexpressed in the livers with intense oval cell response or ductular proliferation, suggesting a participation of this factor in those lesions. In summary, our data demonstrate activation of oval cell response after gene transfer of thymidine kinase followed by ganciclovir administration. These findings indicate that high doses of this therapy causes liver damage together with an impairment in hepatocellular regeneration.
Bustos, Matilde; Sangro, Bruno; Alzuguren, Pilar; Gil, Ana Gloria; Ruiz, Juan; Beraza, Naiara; Qian, Chen; Garcia-Pardo, Angeles; Prieto, Jesus
Collaborative computing for gene mapping
The authors are investigating mechanisms for utilizing advances in high performance computing and alignment algorithm development which will allow the analysis of newly acquired sequence data in real time and eliminate the global alignments problems associated with existing datasets. The presence of repetitive DNA sequences in the human genome complicates the process of homology comparisons. Three approaches have been used to address this problem. Two of the approaches involve elimination of the repetitive elements either by removing the repetitive element from the query or scoring words due to the repetitive elements poorly or not at all during the alignment process. The approach involves identification of the repetitive element in the query by comparison to a known repeat set prior to comparison to the large database. Any homologies returned which are contained within a previously identified repeat are ignored unless the homology exceeds set quality parameters. The homologies which extend outside the bounds of the repetitive element are reported. Using this approach the repeat is not eliminated from larger homologous units which may exist, and is returned as part of the overall homology result. The method the authors utilize in the laboratory for gene mapping is fluorescent in situ hybridization (FISH). This approach involves labelling a gene segment with a fluorescent molecule and then mixing the labeled gene segment (probe) with chromosomes.
Gatewood, J.M.
The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrangements. We report here the detection and analysis of 118 duplications in the DMD gene of DMD/BMD patients. In an unselected patient series the duplication frequency was 7%. In patients already screened for deletions and point mutations, duplications were detected in 87% of cases. There were four complex, noncontiguous rearrangements, with two also involving a partial triplication. In one of the few cases where RNA was analyzed, a seemingly contiguous duplication turned out to be a duplication/deletion case generating a transcript with an unexpected single-exon deletion and an initially undetected duplication. These findings indicate that for clinical diagnosis, duplications should be treated with special care, and without further analysis the reading frame rule should not be applied. As with deletions, duplications occur nonrandomly but with a dramatically different distribution. Duplication frequency is highest near the 5' end of the gene, with a duplication of exon 2 being the single most common duplication identified. Analysis of the extent of 11 exon 2 duplications revealed two intron 2 recombination hotspots. Sequencing four of the breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining. There appear to be fundamental differences therefore in the origin of deletions and duplications in the DMD gene. PMID:16917894
White, S J; Aartsma-Rus, A; Flanigan, K M; Weiss, R B; Kneppers, A L J; Lalic, T; Janson, A A M; Ginjaar, H B; Breuning, M H; den Dunnen, J T
Noise in eukaryotic gene expression
NASA Astrophysics Data System (ADS)
Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.
Blake, William J.; K�rn, Mads; Cantor, Charles R.; Collins, J. J.
Integrating Ontological Knowledge and Textual Evidence in Estimating Gene and Gene Product Similarity
With the rising influence of the Gene On-tology, new approaches have emerged where the similarity between genes or gene products is obtained by comparing Gene Ontology code annotations associ-ated with them. So far, these approaches have solely relied on the knowledge en-coded in the Gene Ontology and the gene annotations associated with the Gene On-tology database. The goal of this paper is to demonstrate that improvements to these approaches can be obtained by integrating textual evidence extracted from relevant biomedical literature.
Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Tratz, Stephen C.; Gregory, Michelle L.
Gene-for-gene interactions of five cloned avirulence genes from Xanthomonas campestris pv. malvacearum with specific resistance genes in cotton.
A total DNA clone bank of a strain of Xanthomonas campestris pv. malvacearum (Xcm) was constructed in the cosmid vector pSa747 and transfected into Escherichia coli. The Xcm strain carries at least nine identifiable avirulence (A) genes. Clones in E. coli were mated individually into a recombination-proficient Xcm isolate carrying no known A genes. Screening was for incompatibility on congenic cotton host lines that differ by single specific resistance (R) genes. Ten different cosmid clones conferring race-specific avirulence were recovered. In most cases, the same A gene clone was recovered independently several times. Using the congenic host lines and the merodiploid transconjugant pathogen strains, five of the A genes were shown to specifically interact, gene-for-gene, with individual R genes in the congenic cotton lines. Some A/R gene interactions appeared qualitatively different from others, suggesting that the physiological mechanism(s) of gene-for-gene specified incompatibility may be unique to the interactive gene pair. All A genes appeared to be chromosomally determined, three were found linked on a single 32-kilobase clone, and the rest were spaced more than 31 kilobases apart. Colinearity of the cosmid inserts with the Xcm recipient (carrying no known A genes) chromosome was demonstrated in two of the three tested. This and other evidence suggests that at least some A genes in bacteria may have the equivalent of virulence (a) alleles. The genetics of race specificity in this phytopathogenic bacterium appeared in all respects to be identical to that found in phytopathogenic fungi. PMID:16593751
Gabriel, D W; Burges, A; Lazo, G R
DEFOG: Discrete Enrichment of Functionally Organized Genes�
High-throughput biological experiments commonly result in a list of genes or proteins of interest. In order to understand the observed changes of the genes and to generate new hypotheses, one needs to understand the functions and roles of the genes and how those functions relate to the experimental conditions. Typically, statistical tests are performed in order to detect enriched Gene Ontology categories or Pathways, i.e. the categories are observed in the genes of interest more often than is expected by chance. Depending on the number of genes and the complexity and quantity of functions in which they are involved, such an analysis can easily result in hundreds of enriched terms. To this end we developed DEFOG, a web-based application that facilitates the functional analysis of gene sets by hierarchically organizing the genes into functionally related modules. Our computational pipeline utilizes three powerful tools to achieve this goal: (1) GeneMANIA creates a functional consensus network of the genes of interest based on gene-list-specific data fusion of hundreds of genomic networks from publicly available sources; (2) Transitivity Clustering organizes those genes into a clear hierarchy of functionally related groups, and (3) Ontologizer performs a Gene Ontology enrichment analysis on the resulting gene clusters. DEFOG integrates this computational pipeline within an easy-to-use web interface, thus allowing for a novel visual analysis of gene sets that aids in the discovery of potentially important biological mechanisms and facilitates the creation of new hypotheses. DEFOG is available at http://www.mooneygroup.org/defog.
Wittkop, Tobias; Berman, Ari E.; Fleisch, K. Mathew; Mooney, Sean D.
Heart Specific Genes Revealed by EST Sampling
Background Cardio-vascular diseases are the first cause of death worldwide, particularly in the developed countries; the identification of genes specifically expressed in the cardiac muscle is thus of major biomedical interest. In this study, we performed a comprehensive analysis of the expression profiles to identify genes over-expressed in the human adult heart using the public Expressed Sequence Tags (ESTs) database. The initial set of genes expressed in the heart was constructed by clustering and assembling ESTs from human adult heart cDNA libraries. Expression profiles were then generated for each of these genes by counting their cognate ESTs in all libraries. Differential expression was assessed by applying to these profiles a previously published statistical procedure. Results We identified 35 "cardiac specific" genes significantly over-expressed in the heart, some of them exhibiting significant co-expressions. Some genes had clear functional association with the heart, and others had no previously recognized cardiac function. Of the 35 genes, 32 were mapped back onto the human genome sequence. According to OMIM, 5 genes were previously known as heart disease genes and one gene was located in the locus of a bleeding disorder. The analysis of the core promoter regions of our collection of "cardiac specific" genes provides the first list of putative regulatory elements associated with differential gene expression in the heart. Conclusion This study shows that ESTs are still a powerful tool to identify differentially expressed genes: we presented a list of genes specifically expressed in the human heart, one of them being a candidate for a bleeding disorder. In addition, we provided the first set of putative regulatory elements, the combination of which appears correlated with heart-specific gene expression.
Comparative Genomic Analysis of Soybean Flowering Genes
Flowering is an important agronomic trait that determines crop yield. Soybean is a major oilseed legume crop used for human and animal feed. Legumes have unique vegetative and floral complexities. Our understanding of the molecular basis of flower initiation and development in legumes is limited. Here, we address this by using a computational approach to examine flowering regulatory genes in the soybean genome in comparison to the most studied model plant, Arabidopsis. For this comparison, a genome-wide analysis of orthologue groups was performed, followed by an in silico gene expression analysis of the identified soybean flowering genes. Phylogenetic analyses of the gene families highlighted the evolutionary relationships among these candidates. Our study identified key flowering genes in soybean and indicates that the vernalisation and the ambient-temperature pathways seem to be the most variant in soybean. A comparison of the orthologue groups containing flowering genes indicated that, on average, each Arabidopsis flowering gene has 2-3 orthologous copies in soybean. Our analysis highlighted that the CDF3, VRN1, SVP, AP3 and PIF3 genes are paralogue-rich genes in soybean. Furthermore, the genome mapping of the soybean flowering genes showed that these genes are scattered randomly across the genome. A paralogue comparison indicated that the soybean genes comprising the largest orthologue group are clustered in a 1.4 Mb region on chromosome 16 of soybean. Furthermore, a comparison with the undomesticated soybean (Glycine soja) revealed that there are hundreds of SNPs that are associated with putative soybean flowering genes and that there are structural variants that may affect the genes of the light-signalling and ambient-temperature pathways in soybean. Our study provides a framework for the soybean flowering pathway and insights into the relationship and evolution of flowering genes between a short-day soybean and the long-day plant, Arabidopsis.
Jung, Chol-Hee; Wong, Chui E.; Singh, Mohan B.; Bhalla, Prem L.
Review: the dominant flocculation genes of Saccharomyces cerevisiae constitute a new subtelomeric gene family.
The quality of brewing strains is, in large part, determined by their flocculation properties. By classical genetics, several dominant, semidominant and recessive flocculation genes have been recognized. Recent results of experiments to localize the flocculation genes FLO5 and FLO8, combined with the in silicio analysis of the available sequence data of the yeast genome, have revealed that the flocculation genes belong to a family which comprises at least four genes and three pseudogenes. All members of this gene family are located near the end of chromosomes, just like the SUC, MEL and MAL genes, which are also important for good quality baking or brewing strains. Transcription of the flocculation genes is repressed by several regulatory genes. In addition, a number of genes have been found which cause cell aggregation upon disruption or overexpression in an as yet unknown manner. In total, 33 genes have been reported that are involved in flocculation or cell aggregation. PMID:7502576
Teunissen, A W; Steensma, H Y
A Review for Detecting Gene-Gene Interactions Using Machine Learning Methods in Genetic Epidemiology
Recently, the greatest statistical computational challenge in genetic epidemiology is to identify and characterize the genes that interact with other genes and environment factors that bring the effect on complex multifactorial disease. These gene-gene interactions are also denoted as epitasis in which this phenomenon cannot be solved by traditional statistical method due to the high dimensionality of the data and the occurrence of multiple polymorphism. Hence, there are several machine learning methods to solve such problems by identifying such susceptibility gene which are neural networks (NNs), support vector machine (SVM), and random forests (RFs) in such common and multifactorial disease. This paper gives an overview on machine learning methods, describing the methodology of each machine learning methods and its application in detecting gene-gene and gene-environment interactions. Lastly, this paper discussed each machine learning method and presents the strengths and weaknesses of each machine learning method in detecting gene-gene interactions in complex human disease.
Koo, Ching Lee; Liew, Mei Jing; Mohamad, Mohd Saberi
Phoenix rising: gene therapy makes a comeback.
Despite the first application of gene therapy in 1990, gene therapy has until recently failed to meet the huge expectations set forth by researchers, clinicians, and patients, thus dampening enthusiasm for an imminent cure for many life-threatening genetic diseases. Nonetheless, in recent years we have witnessed a strong comeback for gene therapy, with clinical successes in young and adult subjects suffering from inherited forms of blindness or from X-linked severe combined immunodeficiency disease. In this review, various gene therapy vectors progressing into clinical development and pivotal advances in gene therapy trials will be discussed. PMID:22623503
Limberis, Maria P
Gene doping is the newest threat to the spirit of fair play in sports. Its concept stemmed out from legitimate gene therapy trials, but anti-doping authorities fear that they now may be facing a form of doping that is virtually undetectable and extremely appealing to athletes. This paper presents studies that generated mouse models with outstanding physical performance, by manipulating genes such as insulin-like growth factor 1 (IGF-1) or phosphoenolpyruvate carboxykinase (PEPCK), which are likely to be targeted for gene doping. The potential transition from super mice to super athletes will also be discussed, in addition to possible strategies for detection of gene doping. PMID:19272337
Azzazy, Hassan M E; Mansour, Mai M H; Christenson, Robert H
Translational considerations for CNS gene therapy.
Gene transfer is being rigorously evaluated in the laboratory in the preparation for the development of clinical therapies. Many CNS diseases, which have proved more challenging to treat than peripheral disorders, are prime candidates for gene therapy. However, there are numerous considerations in the development of gene therapy, including delivery, maintenance of expression, transgene level regulation, toxicity of the viral vector system and safety of the gene product. The authors review these issues and discuss various approaches used in preclinical studies. Alzheimer's and Parkinson's disease are employed as models, in which much research has already been performed, to address disease-specific questions about gene therapy approaches. PMID:17309323
Ryan, Deborah A; Federoff, Howard J
The murine Pax family consists of nine genes containing a highly conserved sequence, the paired box. The expression of these genes is temporally and spatially restricted during development. Evidence gathered indicates that Pax genes are involved in the regionalization of the nervous system and in important inductive events leading to the formation of various organs. The demonstration that mutations in Pax-1, Pax-3 and Pax-6 are linked with various murine mutants (undulated, splotch and small eye) and human diseases (Waardenburg syndrome and aniridia) confirms the importance of these genes as essential morphoregulators. Recent observations also indicate that inappropriate expression of these genes can lead to the appearance of cancer. PMID:7938171
Tremblay, P; Gruss, P
Social regulation of human gene expression
Relationships between genes and social behavior have historically been construed as a one-way street, with genes in control. Recent analyses have challenged this view by discovering broad alterations in the expression of human genes as a function of differing socio-environmental conditions. The emerging field of social genomics has begun to identity the types of genes subject to social regulation, the biological signaling pathways mediating those effects, and the genetic polymorphisms that moderate socio-environmental influences on human gene expression.
Cole, Steve W.
Hematopoietic Stem Cell Expansion and Gene Therapy
Hematopoietic stem cell (HSC) gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions, immunodeficiencies including HIV/AIDS, and other genetic disorders like lysosomal storage diseases, among others. In this review, we discuss the successes, side effects, and limitations of current gene therapy protocols. In addition, we describe the opportunities presented by implementing ex vivo expansion of gene-modified HSCs, as well as summarize the most promising ex vivo expansion techniques currently available. We conclude by discussing how some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy.
Watts, Korashon Lynn; Adair, Jennifer; Kiem, Hans-Peter
Thermostable cellulase from a thermomonospora gene
The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity.
Wilson, David B. (Ithaca, NY); Walker, Larry P. (Ithaca, NY); Zhang, Sheng (Ithaca, NY)
Thermostable cellulase from a thermomonospora gene
The invention relates to a gene isolated from Thermomonospora fusca, wherein the gene encodes a thermostable cellulase. Disclosed is the nucleotide sequence of the T. fusca gene; and nucleic acid molecules comprising the gene, or a fragment of the gene, that can be used to recombinantly express the cellulase or a catalytically active polypeptide thereof, respectively. The isolated and purified recombinant cellulase or catalytically active polypeptide may be used to hydrolyze substrate either by itself; or in combination with other cellulases, with the resultant combination having unexpected hydrolytic activity. 3 figs.
Wilson, D.B.; Walker, L.P.; Zhang, S.
Gene and protein structure of the mate recognition protein gene family in Brachionus manjavacas (Rotifera)
The mate recognition protein (MRP) gene is a member of a family of extracellular matrix protein genes, called MRP Motif Repeat\\u000a (MMR) genes, with no known homologs. Two sets of MMR genes, designated MMR-A and MMR-B, were found in Brachionus manjavacas. MMR-B has previously been shown to encode the MRP in the Brachionus plicatilis species complex. MMR family genes share
Kristin E. Gribble; Terry Snell; David B. Mark Welch
Selection of reliable reference genes for gene expression studies in peach using real-time PCR
BACKGROUND: RT-qPCR is a preferred method for rapid and reliable quantification of gene expression studies. Appropriate application of RT-qPCR in such studies requires the use of reference gene(s) as an internal control to normalize mRNA levels between different samples for an exact comparison of gene expression level. However, recent studies have shown that no single reference gene is universal for
Zhaoguo Tong; Zhihong Gao; Fei Wang; Jun Zhou; Zhen Zhang
Gene and genome duplications: the impact of dosage-sensitivity on the fate of nuclear genes
Whole genome duplications (WGDs) followed by diploidization, which includes gene loss, have been an important recurrent process\\u000a in the evolution of higher eukaryotes. Gene retention is biased to specific functional gene categories during diploidization.\\u000a Dosage-sensitive genes, which include transcription factors, are significantly over-retained following WGDs. By contrast,\\u000a these same functional gene categories exhibit lower retention rates following smaller scale duplications
Patrick P. Edger; J. Chris Pires
Reconstruction of a Functional Human Gene Network, with an Application for Prioritizing Positional Candidate Genes
Most common genetic disorders have a complex inheritance and may result from variants in many genes, each contributing only weak effects to the disease. Pinpointing these disease genes within the myriad of susceptibility loci identified in linkage studies is difficult because these loci may contain hundreds of genes. However, in any disorder, most of the disease genes will be involved in only a few different molecular pathways. If we know something about the relationships between the genes, we can assess whether some genes (which may reside in different loci) functionally interact with each other, indicating a joint basis for the disease etiology. There are various repositories of information on pathway relationships. To consolidate this information, we developed a functional human gene network that integrates information on genes and the functional relationships between genes, based on data from the Kyoto Encyclopedia of Genes and Genomes, the Biomolecular Interaction Network Database, Reactome, the Human Protein Reference Database, the Gene Ontology database, predicted protein-protein interactions, human yeast two-hybrid interactions, and microarray coexpressions. We applied this network to interrelate positional candidate genes from different disease loci and then tested 96 heritable disorders for which the Online Mendelian Inheritance in Man database reported at least three disease genes. Artificial susceptibility loci, each containing 100 genes, were constructed around each disease gene, and we used the network to rank these genes on the basis of their functional interactions. By following up the top five genes per artificial locus, we were able to detect at least one known disease gene in 54% of the loci studied, representing a 2.8-fold increase over random selection. This suggests that our method can significantly reduce the cost and effort of pinpointing true disease genes in analyses of disorders for which numerous loci have been reported but for which most of the genes are unknown.
Franke, Lude; Bakel, Harm van; Fokkens, Like; de Jong, Edwin D.; Egmont-Petersen, Michael; Wijmenga, Cisca
Cloning of Tumor Suppressor Genes in Breast Cancer.
National Technical Information Service (NTIS)
Breast cancer arises through the accumulation of genetic alterations that affect two classes of genes, ongogenes and tumor suppressor genes. These genes must be identified for several reasons. Characterization of the genes that drive carcinogenesis will f...
M. Hamaguchi
Cheaper 'Gene Panel' Screening May Reveal Cancer Risks
... 14, 2014 Related MedlinePlus Pages Cancer Genes and Gene Therapy Women's Health MONDAY, April 14, 2014 (HealthDay News) -- ... reserved. More Health News on: Cancer Genes and Gene Therapy Women's Health Recent Health News Page last updated ...
Scientists Study Gene Clues from 115-Year-Old Woman
... April 23, 2014 Related MedlinePlus Page Genes and Gene Therapy WEDNESDAY, April 23, 2014 (HealthDay News) -- More than ... rights reserved. More Health News on: Genes and Gene Therapy Recent Health News Page last updated on 24 ...
The sea urchin histone gene complement.
The only eukaryotic mRNAs that are not polyadenylated are the replication-dependent histone mRNAs in metazoans. The sea urchin genome contains two sets of histone genes that encode non-polyadenylated mRNAs. One of these sets is a tandemly repeated gene cluster with a 5.6-kb repeat unit containing one copy of each of the five alpha-histone genes and is present as a single large cluster which spans over 1 Mb. There is a second set of genes, consisting of 39 genes, containing two histone H1 genes, 34 genes encoding core histone proteins (H2a, H2b, H3 and H4) and three genes expressed only in the testis. Unlike vertebrates where these genes are clustered, the sea urchin late histone genes, expressed in embryos, larvae and adults, are dispersed throughout the genome. There are also genes encoding polyadenylated histone mRNAs, which encode histone variants, including all variants found in other metazoans, as well as a unique set of five cleavage stage histone proteins expressed in oocytes. The cleavage stage histone H1 is the orthologue of an oocyte-specific histone H1 protein found in vertebrates. PMID:17078943
Marzluff, William F; Sakallah, Sameer; Kelkar, Hemant
Gene recognition via spliced sequence alignment.
Gene recognition is one of the most important problems in computational molecular biology. Previous attempts to solve this problem were based on statistics, and applications of combinatorial methods for gene recognition were almost unexplored. Recent advances in large-scale cDNA sequencing open a way toward a new approach to gene recognition that uses previously sequenced genes as a clue for recognition of newly sequenced genes. This paper describes a spliced alignment algorithm and software tool that explores all possible exon assemblies in polynomial time and finds the multiexon structure with the best fit to a related protein. Unlike other existing methods, the algorithm successfully recognizes genes even in the case of short exons or exons with unusual codon usage; we also report correct assemblies for genes with more than 10 exons. On a test sample of human genes with known mammalian relatives, the average correlation between the predicted and actual proteins was 99%. The algorithm correctly reconstructed 87% of genes and the rare discrepancies between the predicted and real exon-intron structures were caused either by short (less than 5 amino acids) initial/terminal exons or by alternative splicing. Moreover, the algorithm predicts human genes reasonably well when the homologous protein is nonvertebrate or even prokaryotic. The surprisingly good performance of the method was confirmed by extensive simulations: in particular, with target proteins at 160 accepted point mutations (PAM) (25% similarity), the correlation between the predicted and actual genes was still as high as 95%.
Gelfand, M S; Mironov, A A; Pevzner, P A
Biomarker Discovery Using Statistically Significant Gene Sets
Abstract Analysis of large gene expression data sets in the presence and absence of a phenotype can lead to the selection of a group of genes serving as biomarkers jointly predicting the phenotype. Among gene selection methods, filter methods derived from ranked individual genes have been widely used in existing products for diagnosis and prognosis. Univariate filter approaches selecting genes individually, although computationally efficient, often ignore gene interactions inherent in the biological data. On the other hand, multivariate approaches selecting gene subsets are known to have a higher risk of selecting spurious gene subsets due to the overfitting of the vast number of gene subsets evaluated. Here we propose a framework of statistical significance tests for multivariate feature selection that can reduce the risk of selecting spurious gene subsets. Using three existing data sets, we show that our proposed approach is an essential step to identify such a gene set that is generated by a significant interaction of its members, even improving classification performance when compared to established approaches. This technique can be applied for the discovery of robust biomarkers for medical diagnosis.
Kim, Hoon; Watkinson, John
Biomarker discovery using statistically significant gene sets.
Analysis of large gene expression data sets in the presence and absence of a phenotype can lead to the selection of a group of genes serving as biomarkers jointly predicting the phenotype. Among gene selection methods, filter methods derived from ranked individual genes have been widely used in existing products for diagnosis and prognosis. Univariate filter approaches selecting genes individually, although computationally efficient, often ignore gene interactions inherent in the biological data. On the other hand, multivariate approaches selecting gene subsets are known to have a higher risk of selecting spurious gene subsets due to the overfitting of the vast number of gene subsets evaluated. Here we propose a framework of statistical significance tests for multivariate feature selection that can reduce the risk of selecting spurious gene subsets. Using three existing data sets, we show that our proposed approach is an essential step to identify such a gene set that is generated by a significant interaction of its members, even improving classification performance when compared to established approaches. This technique can be applied for the discovery of robust biomarkers for medical diagnosis. PMID:21457009
Kim, Hoon; Watkinson, John; Anastassiou, Dimitris
HOX GENES: Seductive Science, Mysterious Mechanisms
HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21.2, 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.
Lappin, Terrence RJ; Grier, David G; Thompson, Alexander; Halliday, Henry L
Integrating Various Resources for Gene Name Normalization
The recognition and normalization of gene mentions in biomedical literature are crucial steps in biomedical text mining. We present a system for extracting gene names from biomedical literature and normalizing them to gene identifiers in databases. The system consists of four major components: gene name recognition, entity mapping, disambiguation and filtering. The first component is a gene name recognizer based on dictionary matching and semi-supervised learning, which utilizes the co-occurrence information of a large amount of unlabeled MEDLINE abstracts to enhance feature representation of gene named entities. In the stage of entity mapping, we combine the strategies of exact match and approximate match to establish linkage between gene names in the context and the EntrezGene database. For the gene names that map to more than one database identifiers, we develop a disambiguation method based on semantic similarity derived from the Gene Ontology and MEDLINE abstracts. To remove the noise produced in the previous steps, we design a filtering method based on the confidence scores in the dictionary used for NER. The system is able to adjust the trade-off between precision and recall based on the result of filtering. It achieves an F-measure of 83% (precision: 82.5% recall: 83.5%) on BioCreative II Gene Normalization (GN) dataset, which is comparable to the current state-of-the-art.
Hu, Yuncui; Li, Yanpeng; Lin, Hongfei; Yang, Zhihao; Cheng, Liangxi
Apolipoprotein gene involved in lipid metabolism
Methods and materials for studying the effects of a newly identified human gene, APOAV, and the corresponding mouse gene apoAV. The sequences of the genes are given, and transgenic animals which either contain the gene or have the endogenous gene knocked out are described. In addition, single nucleotide polymorphisms (SNPs) in the gene are described and characterized. It is demonstrated that certain SNPs are associated with diseases involving lipids and triglycerides and other metabolic diseases. These SNPs may be used alone or with SNPs from other genes to study individual risk factors. Methods for intervention in lipid diseases, including the screening of drugs to treat lipid-related or diabetic diseases are also disclosed.
Rubin, Edward (Berkeley, CA) [Berkeley, CA; Pennacchio, Len A. (Sebastopol, CA) [Sebastopol, CA
Identification of horizontal gene transfer and recombination of PsaA gene in streptococcus mitis group.
Pneumococcal surface adhesin A (psaA) gene is universally confirmed as one of the Streptococcus pneumoniae adhesion genes, but it is disputed whether the psaA gene is a Streptococcus pneumoniae species-specific gene. In the present study, the presence of the psaA gene in 34 streptococcus mitis group isolates was identified by the PCR approach and a comparison of sequencing PCR products (Streptococcus pneumoniae R6 as the control strain). Also, the evolutionary scenarios of these psaA genes in these streptococcus mitis group isolates were analyzed by a phylogenetic tree based on the housekeeping genes (sodA and rnpB) and psaA genes. As a result, a high degree of conservation of open reading frame sequences in all six Streptococcus pneumoniae strains (100% similarity) and in the other species of the streptococcus mitis group (92.6-100% similarity) was revealed. Further genetics research based on housekeeping genes and psaA gene phylogenies showed that the psaA gene was of vertical inheritance only in Streptococcus pneumoniae; however, high-frequency horizontal psaA gene transfer and recombination occurred in the other species of the streptococcus mitis group. These findings confirmed that the psaA gene was not a Streptococcus pneumoniae species-specific gene, and high-frequency HGT and recombination events may explain the presence of the psaA gene in the other species of the streptococcus mitis group. PMID:20536729
Zhang, Qiao; Ma, Qianli; Su, Dan; Li, Qi; Yao, Wei; Wang, Changzheng
GeneTack database: genes with frameshifts in prokaryotic genomes and eukaryotic mRNA sequences.
Database annotations of prokaryotic genomes and eukaryotic mRNA sequences pay relatively low attention to frame transitions that disrupt protein-coding genes. Frame transitions (frameshifts) could be caused by sequencing errors or indel mutations inside protein-coding regions. Other observed frameshifts are related to recoding events (that evolved to control expression of some genes). Earlier, we have developed an algorithm and software program GeneTack for ab initio frameshift finding in intronless genes. Here, we describe a database (freely available at http://topaz.gatech.edu/GeneTack/db.html) containing genes with frameshifts (fs-genes) predicted by GeneTack. The database includes 206?991 fs-genes from 1106 complete prokaryotic genomes and 45?295 frameshifts predicted in mRNA sequences from 100 eukaryotic genomes. The whole set of fs-genes was grouped into clusters based on sequence similarity between fs-proteins (conceptually translated fs-genes), conservation of the frameshift position and frameshift direction (-1, +1). The fs-genes can be retrieved by similarity search to a given query sequence via a web interface, by fs-gene cluster browsing, etc. Clusters of fs-genes are characterized with respect to their likely origin, such as pseudogenization, phase variation, etc. The largest clusters contain fs-genes with programed frameshifts (related to recoding events). PMID:23161689
Antonov, Ivan; Baranov, Pavel; Borodovsky, Mark
Novel methods to identify biologically relevant genes for leukemia and prostate cancer from gene expression profiles
Background High-throughput microarray experiments now permit researchers to screen thousands of genes simultaneously and determine the different expression levels of genes in normal or cancerous tissues. In this paper, we address the challenge of selecting a relevant and manageable subset of genes from a large microarray dataset. Currently, most gene selection methods focus on identifying a set of genes that can further improve classification accuracy. Few or none of these small sets of genes, however, are biologically relevant (i.e. supported by medical evidence). To deal with this critical issue, we propose two novel methods that can identify biologically relevant genes concerning cancers. Results In this paper, we propose two novel techniques, entitled random forest gene selection (RFGS) and support vector sampling technique (SVST). Compared with results from six other methods developed in this paper, we demonstrate experimentally that RFGS and SVST can identify more biologically relevant genes in patients with leukemia or prostate cancer. Among the top 25 genes selected using SVST method, 15 genes were biologically relevant genes in patients with leukemia and 13 genes were biologically relevant genes in patients with prostate cancer. Meanwhile, the RFGS method, while less effective than SVST, still identified an average of 9 biologically relevant genes in both leukemia and prostate cancers. In contrast to traditional statistical methods, which only identify less than 8 genes in patients with leukemia and less than 8 genes in patients with prostate cancer, our methods yield significantly better results. Conclusions Our proposed SVST and RFGS methods are novel approaches that can identify a greater number of biologically relevant genes. These methods have been successfully applied to both leukemia and prostate cancers. Research in the fields of biology and medicine should benefit from the identification of biologically relevant genes by confirming recent discoveries in cancer research or suggesting new avenues for exploration.
An Arabidopsis gene network based on the graphical Gaussian model
We describe a gene network for the Arabidopsis thaliana transcriptome based on a modified graphical Gaussian model (GGM). Through partial correlation (pcor), GGM infers coregulation patterns between gene pairs conditional on the behavior of other genes. Regularized GGM calculated pcor between gene pairs among approximately 2000 input genes at a time. Regularized GGM coupled with iterative random samplings of genes
Shisong Ma; Qingqiu Gong; Hans J. Bohnert
Cancer is now known as a disease of genomic alterations. Mutational analysis and genomics profiling in recent years have advanced the field of lung cancer genetics/genomics significantly. It is becoming more accepted now that the identification of genomic alterations in lung cancer can impact therapeutics, especially when the alterations represent �oncogenic drivers� in the processes of tumorigenesis and progression. In this review, we will highlight the key driver oncogenic gene mutations and fusions identified in lung cancer. The review will summarize and report the available demographic and clinicopathological data as well as molecular details behind various lung cancer gene alterations in the context of race. We hope to shed some light into the disparities in the incidence of various genetic mutations among lung cancer patients of different racial backgrounds. As molecularly targeted therapy continues to advance in lung cancer, racial differences in specific genetic/genomic alterations can have an important impact in the choices of therapeutics and in our understanding of the drug sensitivity/resistance profile. The most relevant genes in lung cancer described in this review include the following: EGFR, KRAS, MET, LKB1, BRAF, PIK3CA, ALK, RET, and ROS1. Commonly identified genetic/genomic alterations such as missense or nonsense mutations, small insertions or deletions, alternative splicing, and chromosomal fusion rearrangements were discussed. Relevance in current targeted therapeutic drugs was mentioned when appropriate. We also highlighted various targeted therapeutics that are currently under clinical development, such as the MET inhibitors and antibodies. With the advent of next-generation sequencing, the landscape of genomic alterations in lung cancer is expected to be much transformed and detailed in upcoming years. These genomic landscape differences in the context of racial disparities should be emphasized both in tumorigenesis and in drug sensitivity/resistance. It is hoped that such effort will help to diminish racial disparities in lung cancer outcome in the future.
El-Telbany, Ahmed
Random forests-based differential analysis of gene sets for gene expression data.
In DNA microarray studies, gene-set analysis (GSA) has become the focus of gene expression data analysis. GSA utilizes the gene expression profiles of functionally related gene sets in Gene Ontology (GO) categories or priori-defined biological classes to assess the significance of gene sets associated with clinical outcomes or phenotypes. Many statistical approaches have been proposed to determine whether such functionally related gene sets express differentially (enrichment and/or deletion) in variations of phenotypes. However, little attention has been given to the discriminatory power of gene sets and classification of patients. In this study, we propose a method of gene set analysis, in which gene sets are used to develop classifications of patients based on the Random Forest (RF) algorithm. The corresponding empirical p-value of an observed out-of-bag (OOB) error rate of the classifier is introduced to identify differentially expressed gene sets using an adequate resampling method. In addition, we discuss the impacts and correlations of genes within each gene set based on the measures of variable importance in the RF algorithm. Significant classifications are reported and visualized together with the underlying gene sets and their contribution to the phenotypes of interest. Numerical studies using both synthesized data and a series of publicly available gene expression data sets are conducted to evaluate the performance of the proposed methods. Compared with other hypothesis testing approaches, our proposed methods are reliable and successful in identifying enriched gene sets and in discovering the contributions of genes within a gene set. The classification results of identified gene sets can provide an valuable alternative to gene set testing to reveal the unknown, biologically relevant classes of samples or patients. In summary, our proposed method allows one to simultaneously assess the discriminatory ability of gene sets and the importance of gen