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Sample records for genome-wide renal gene

  1. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice

    PubMed Central

    Alkaissi, Hammoudi; Ekstrand, Jimmy; Jawad, Aksa; Nielsen, Jesper Bo; Havarinasab, Said; Soderkvist, Peter; Hultman, Per

    2016-01-01

    Background: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg. A.SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S. Objectives: We aimed to find candidate genes associated with regulation of renal Hg concentrations. Methods: A.SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with microsatellites was conducted on 84 F2 mice for genome-wide scanning with ion pair reverse-phase high-performance liquid chromatography (IP RP HPLC). Quantitative trait loci (QTL) were established. Denaturing HPLC was used to detect single nucleotide polymorphisms for haplotyping and fine mapping in 184 and 32 F2 mice, respectively. Candidate genes (Pprc1, Btrc and Nfkb2) verified by fine mapping and QTL were further investigated by real-time polymerase chain reaction. Genes enhanced by Pprc1 (Nrf1 and Nrf2) were included for gene expression analysis. Results: Renal Hg concentrations differed significantly between A.SW and B10.S mice and between males and females within each strain. QTL analysis showed a peak logarithm of odds ratio score 5.78 on chromosome 19 (p = 0.002). Haplotype and fine mapping associated the Hg accumulation with Pprc1, which encodes PGC-1-related coactivator (PRC), a coactivator for proteins involved in detoxification. Pprc1 and two genes coactivated by Pprc1 (Nrf1 and Nrf2) had significantly lower gene expression in the A.SW strain than in the B10.S strain. Conclusions: This study supports Pprc1 as a key regulator for renal Hg excretion. Citation: Alkaissi H, Ekstrand J, Jawad A, Nielsen JB, Havarinasab S, Soderkvist P

  2. Genome-wide analysis of differentially expressed genes and splicing isoforms in clear cell renal cell carcinoma.

    PubMed

    Valletti, Alessio; Gigante, Margherita; Palumbo, Orazio; Carella, Massimo; Divella, Chiara; Sbisà, Elisabetta; Tullo, Apollonia; Picardi, Ernesto; D'Erchia, Anna Maria; Battaglia, Michele; Gesualdo, Loreto; Pesole, Graziano; Ranieri, Elena

    2013-01-01

    Clear cell renal cell carcinoma (ccRCC) is the most common malignant renal epithelial tumor and also the most deadly. To identify molecular changes occurring in ccRCC, in the present study we performed a genome wide analysis of its entire complement of mRNAs. Gene and exon-level analyses were carried out by means of the Affymetrix Exon Array platform. To achieve a reliable detection of differentially expressed cassette exons we implemented a novel methodology that considered contiguous combinations of exon triplets and candidate differentially expressed cassette exons were identified when the expression level was significantly different only in the central exon of the triplet. More detailed analyses were performed for selected genes using quantitative RT-PCR and confocal laser scanning microscopy. Our analysis detected over 2,000 differentially expressed genes, and about 250 genes alternatively spliced and showed differential inclusion of specific cassette exons comparing tumor and non-tumoral tissues. We demonstrated the presence in ccRCC of an altered expression of the PTP4A3, LAMA4, KCNJ1 and TCF21 genes (at both transcript and protein level). Furthermore, we confirmed, at the mRNA level, the involvement of CAV2 and SFRP genes that have previously been identified. At exon level, among potential candidates we validated a differentially included cassette exon in DAB2 gene with a significant increase of DAB2 p96 splice variant as compared to the p67 isoform. Based on the results obtained, and their robustness according to both statistical analysis and literature surveys, we believe that a combination of gene/isoform expression signature may remarkably contribute, after suitable validation, to a more effective and reliable definition of molecular biomarkers for ccRCC early diagnosis, prognosis and prediction of therapeutic response. PMID:24194935

  3. Genome-wide analysis of murine renal distal convoluted tubular cells for the target genes of mineralocorticoid receptor

    SciTech Connect

    Ueda, Kohei; Fujiki, Katsunori; Shirahige, Katsuhiko; Gomez-Sanchez, Celso E.; Fujita, Toshiro; Nangaku, Masaomi; Nagase, Miki

    2014-02-28

    Highlights: • We define a target gene of MR as that with MR-binding to the adjacent region of DNA. • We use ChIP-seq analysis in combination with microarray. • We, for the first time, explore the genome-wide binding profile of MR. • We reveal 5 genes as the direct target genes of MR in the renal epithelial cell-line. - Abstract: Background and objective: Mineralocorticoid receptor (MR) is a member of nuclear receptor family proteins and contributes to fluid homeostasis in the kidney. Although aldosterone-MR pathway induces several gene expressions in the kidney, it is often unclear whether the gene expressions are accompanied by direct regulations of MR through its binding to the regulatory region of each gene. The purpose of this study is to identify the direct target genes of MR in a murine distal convoluted tubular epithelial cell-line (mDCT). Methods: We analyzed the DNA samples of mDCT cells overexpressing 3xFLAG-hMR after treatment with 10{sup −7} M aldosterone for 1 h by chromatin immunoprecipitation with deep-sequence (ChIP-seq) and mRNA of the cell-line with treatment of 10{sup −7} M aldosterone for 3 h by microarray. Results: 3xFLAG-hMR overexpressed in mDCT cells accumulated in the nucleus in response to 10{sup −9} M aldosterone. Twenty-five genes were indicated as the candidate target genes of MR by ChIP-seq and microarray analyses. Five genes, Sgk1, Fkbp5, Rasl12, Tns1 and Tsc22d3 (Gilz), were validated as the direct target genes of MR by quantitative RT-qPCR and ChIP-qPCR. MR binding regions adjacent to Ctgf and Serpine1 were also validated. Conclusions: We, for the first time, captured the genome-wide distribution of MR in mDCT cells and, furthermore, identified five MR target genes in the cell-line. These results will contribute to further studies on the mechanisms of kidney diseases.

  4. Gene Fusion: A Genome Wide Survey

    NASA Technical Reports Server (NTRS)

    Liang, Ping; Riley, Monica

    2001-01-01

    As a well known fact, organisms form larger and complex multimodular (composite or chimeric) and mostly multi-functional proteins through gene fusion of two or more individual genes which have independent evolution histories and functions. We call each of these components a module. The existence of multimodular proteins may improves the efficiency in gene regulation and in cellular functions, and thus may give the host organism advantages in adaptation to environments. Analysis of all gene fusions in present-day organisms should allow us to examine the patterns of gene fusion in context with cellular functions, to trace back the evolution processes from the ancient smaller and uni-functional proteins to the present-day larger and complex multi-functional proteins, and to estimate the minimal number of ancestor proteins that existed in the last common ancestor for all life on earth. Although many multimodular proteins have been experimentally known, identification of gene fusion events systematically at genome scale had not been possible until recently when large number of completed genome sequences have been becoming available. In addition, technical difficulties for such analysis also exist due to the complexity of this biological and evolutionary process. We report from this study a new strategy to computationally identify multimodular proteins using completed genome sequences and the results surveyed from 22 organisms with the data from over 40 organisms to be presented during the meeting. Additional information is contained in the original extended abstract.

  5. Genome-wide copy number variation analysis of a Branchio-Oto-Renal syndrome cohort identifies a recombination hotspot and implicates new candidate genes

    PubMed Central

    Brophy, Patrick D.; Alasti, Fatemeh; Darbro, Benjamin W.; Clarke, Jason; Nishimura, Carla; Cobb, Bryan; Smith, Richard J.; Manak, J. Robert

    2013-01-01

    Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies, hearing loss and renal dysmorphology. Although haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients. In this study, we used high-resolution array-based comparative genomic hybridization (aCGH) on 32 BOR probands negative for coding-sequence and splice-site mutations in known BOR-causing genes to identify potential disease-causing genomic rearrangements. Of the >1,000 rare and novel copy number variants (CNVs) we identified, four were heterozygous deletions of EYA1 and several downstream genes that had nearly identical breakpoints associated with retroviral sequence blocks, suggesting that non-allelic homologous recombination seeded by this recombination hotspot is important in the pathogenesis of BOR. A different heterozygous deletion removing the last exon of EYA1 was identified in an additional proband. Thus in total 5 probands (14%) had deletions of all or part of EYA1. Using a novel disease-gene prioritization strategy that includes network analysis of genes associated with other deletions suggests that SHARPIN (Sipl1), FGF3 and the HOXA gene cluster may contribute to the pathogenesis of BOR. PMID:23851940

  6. Genome-wide characterization of maize miRNA genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in plant growth and development. We conducted a genome-wide survey of maize miRNA genes, characterizing their structure, expression, and evolution. Computational approaches based on homology and secondary structure modeling ident...

  7. Genome-Wide Detection and Analysis of Multifunctional Genes

    PubMed Central

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-01-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  8. Genome-Wide Detection and Analysis of Multifunctional Genes.

    PubMed

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-10-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms--H. sapiens, D. melanogaster, and S. cerevisiae--and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  9. Genome-wide gene-based association study.

    PubMed

    Yang, Hsin-Chou; Liang, Yu-Jen; Chung, Chia-Min; Chen, Jia-Wei; Pan, Wen-Harn

    2009-01-01

    Genome-wide association studies, which analyzes hundreds of thousands of single-nucleotide polymorphisms to identify disease susceptibility genes, are challenging because the work involves intensive computation and complex modeling. We propose a two-stage genome-wide association scanning procedure, consisting of a single-locus association scan for the first stage and a gene-based association scan for the second stage. Marginal effects of single-nucleotide polymorphisms are examined by using the exact Armitage trend test or logistic regression, and gene effects are examined by using a p-value combination method. Compared with some existing single-locus and multilocus methods, the proposed method has the following merits: 1) convenient for definition of biologically meaningful regions, 2) powerful for detection of minor-effect genes, 3) helpful for alleviation of a multiple-testing problem, and 4) convenient for result interpretation. The method was applied to study Genetic Analysis Workshop 16 Problem 1 rheumatoid arthritis data, and strong association signals were found. The results show that the human major histocompatibility complex region is the most important genomic region associated with rheumatoid arthritis. Moreover, previously reported genes including PTPN22, C5, and IL2RB were confirmed; novel genes including HLA-DRA, BTNL2, C6orf10, NOTCH4, TAP2, and TNXB were identified by our analysis. PMID:20018002

  10. Genome-Wide Architecture of Disease Resistance Genes in Lettuce.

    PubMed

    Christopoulou, Marilena; Wo, Sebastian Reyes-Chin; Kozik, Alex; McHale, Leah K; Truco, Maria-Jose; Wroblewski, Tadeusz; Michelmore, Richard W

    2015-12-01

    Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes. PMID:26449254

  11. Identification of Neural Outgrowth Genes using Genome-Wide RNAi

    PubMed Central

    Sepp, Katharine J.; Hong, Pengyu; Lizarraga, Sofia B.; Liu, Judy S.; Mejia, Luis A.; Walsh, Christopher A.; Perrimon, Norbert

    2008-01-01

    While genetic screens have identified many genes essential for neurite outgrowth, they have been limited in their ability to identify neural genes that also have earlier critical roles in the gastrula, or neural genes for which maternally contributed RNA compensates for gene mutations in the zygote. To address this, we developed methods to screen the Drosophila genome using RNA-interference (RNAi) on primary neural cells and present the results of the first full-genome RNAi screen in neurons. We used live-cell imaging and quantitative image analysis to characterize the morphological phenotypes of fluorescently labelled primary neurons and glia in response to RNAi-mediated gene knockdown. From the full genome screen, we focused our analysis on 104 evolutionarily conserved genes that when downregulated by RNAi, have morphological defects such as reduced axon extension, excessive branching, loss of fasciculation, and blebbing. To assist in the phenotypic analysis of the large data sets, we generated image analysis algorithms that could assess the statistical significance of the mutant phenotypes. The algorithms were essential for the analysis of the thousands of images generated by the screening process and will become a valuable tool for future genome-wide screens in primary neurons. Our analysis revealed unexpected, essential roles in neurite outgrowth for genes representing a wide range of functional categories including signalling molecules, enzymes, channels, receptors, and cytoskeletal proteins. We also found that genes known to be involved in protein and vesicle trafficking showed similar RNAi phenotypes. We confirmed phenotypes of the protein trafficking genes Sec61alpha and Ran GTPase using Drosophila embryo and mouse embryonic cerebral cortical neurons, respectively. Collectively, our results showed that RNAi phenotypes in primary neural culture can parallel in vivo phenotypes, and the screening technique can be used to identify many new genes that have

  12. Genome-Wide Architecture of Disease Resistance Genes in Lettuce

    PubMed Central

    Christopoulou, Marilena; Wo, Sebastian Reyes-Chin; Kozik, Alex; McHale, Leah K.; Truco, Maria-Jose; Wroblewski, Tadeusz; Michelmore, Richard W.

    2015-01-01

    Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes. PMID:26449254

  13. Identification of a set of genes associated with response to interleukin-2 and interferon-α combination therapy for renal cell carcinoma through genome-wide gene expression profiling

    PubMed Central

    MIZUMORI, OSAMU; ZEMBUTSU, HITOSHI; KATO, YOICHIRO; TSUNODA, TATSUHIKO; MIYA, FUYUKI; MORIZONO, TAKASHI; TSUKAMOTO, TAIJI; FUJIOKA, TOMOAKI; TOMITA, YOSHIHIKO; KITAMURA, TADAICHI; OZONO, SEIICHIRO; MIKI, TSUNEHARU; NAITO, SEIJI; AKAZA, HIDEYUKI; NAKAMURA, YUSUKE

    2010-01-01

    Interleukin (IL)-2 and interferon (IFN)-α combination therapy for metastatic renal cell carcinoma (RCC) improves the prognosis for a subset of patients, while some patients suffer from severe adverse drug reactions with little benefit. To establish a method to predict responses to this combination therapy (approximately 30% response rate), the gene expression profiles of primary RCCs were analyzed using an oligoDNA microarray consisting of 38,500 genes or ESTs, after enrichment of the cancer cell population by laser micro-beam microdissection. The analysis of 10 responders and 18 non-responders identified 24 genes that exhibited significant differential expression between the two groups. In addition, the patients whose tumors did not express HLA-DQA1 or HLA-DQB1 molecules demonstrated poor clinical response. Exclusion of patients with tumors lacking either of these two genes is likely to improve the response rate to IL-2 and IFN-α combination therapy from 30 to 67%, indicating that a simple pretreatment test provides useful information with which to subselect patients with renal cancer in order to improve the efficacy of this treatment and reduce unnecessary medical costs. PMID:22993625

  14. Meta-analysis of genome-wide linkage scans for renal function traits

    PubMed Central

    Rao, Madhumathi; Mottl, Amy K.; Cole, Shelley A.; Umans, Jason G.; Freedman, Barry I.; Bowden, Donald W.; Langefeld, Carl D.; Fox, Caroline S.; Yang, Qiong; Cupples, Adrienne; Iyengar, Sudha K.; Hunt, Steven C.

    2012-01-01

    Background. Several genome scans have explored the linkage of chronic kidney disease phenotypes to chromosomic regions with disparate results. Genome scan meta-analysis (GSMA) is a quantitative method to synthesize linkage results from independent studies and assess their concordance. Methods. We searched PubMed to identify genome linkage analyses of renal function traits in humans, such as estimated glomerular filtration rate (GFR), albuminuria, serum creatinine concentration and creatinine clearance. We contacted authors for numerical data and extracted information from individual studies. We applied the GSMA nonparametric approach to combine results across 14 linkage studies for GFR, 11 linkage studies for albumin creatinine ratio, 11 linkage studies for serum creatinine and 4 linkage studies for creatinine clearance. Results. No chromosomal region reached genome-wide statistical significance in the main analysis which included all scans under each phenotype; however, regions on Chromosomes 7, 10 and 16 reached suggestive significance for linkage to two or more phenotypes. Subgroup analyses by disease status or ethnicity did not yield additional information. Conclusions. While heterogeneity across populations, methodologies and study designs likely explain this lack of agreement, it is possible that linkage scan methodologies lack the resolution for investigating complex traits. Combining family-based linkage studies with genome-wide association studies may be a powerful approach to detect private mutations contributing to complex renal phenotypes. PMID:21622988

  15. Genome-wide prediction of imprinted murine genes

    PubMed Central

    Luedi, Philippe P.; Hartemink, Alexander J.; Jirtle, Randy L.

    2005-01-01

    Imprinted genes are epigenetically modified genes whose expression is determined according to their parent of origin. They are involved in embryonic development, and imprinting dysregulation is linked to cancer, obesity, diabetes, and behavioral disorders such as autism and bipolar disease. Herein, we train a statistical model based on DNA sequence characteristics that not only identifies potentially imprinted genes, but also predicts the parental allele from which they are expressed. Of 23,788 annotated autosomal mouse genes, our model identifies 600 (2.5%) to be potentially imprinted, 64% of which are predicted to exhibit maternal expression. These predictions allowed for the identification of putative candidate genes for complex conditions where parent-of-origin effects are involved, including Alzheimer disease, autism, bipolar disorder, diabetes, male sexual orientation, obesity, and schizophrenia. We observe that the number, type, and relative orientation of repeated elements flanking a gene are particularly important in predicting whether a gene is imprinted. PMID:15930497

  16. GENOME-WIDE IDENTIFICATION OF LONG NON-CODING RNAS IN RAT MODELS OF CARDIOVASCULAR AND RENAL DISEASE

    PubMed Central

    Gopalakrishnan, Kathirvel; Kumarasamy, Sivarajan; Mell, Blair; Joe, Bina

    2015-01-01

    Long noncoding RNAs (lncRNAs) are an emerging class of genomic regulatory molecules reported in various species. In the rat, which is one of the major mammalian model organisms, discovery of lncRNAs on a genome-wide scale is lagging. Renal LncRNA sequencing and lncRNA transcriptome analysis was conducted in three rat strains that are widely used in cardiovascular and renal research, the Dahl salt-sensitive (S) rat, the Spontaneously Hypertensive Rat (SHR) and the Dahl salt-resistant (R) rat. Through the RNA sequencing approach, 3,273 transcripts were identified as rat lncRNAs. A majority of lncRNAs were without predicted target genes. Differential expression of 273 and 749 lncRNAs was detected between S versus R and S versus SHR comparisons respectively. To couple the observed differential expression of lncRNAs with the status of mRNAs, an mRNA transcriptome analysis was conducted. Several cis mRNA genes were co-regulated with lncRNAs. Of these, the protein expression status of four target genes, Asb3, Chac2, Pex11b and Sp5, were differentially expressed between the relevant strain comparisons thereby suggesting that the differentially expressed lncRNAs associated with these genes are candidate genetic determinants of blood pressure. This study serves as a first-generation catalog of rat lncRNAs and illustrates the prioritization of lncRNAs as positional candidates for complex polygenic traits. PMID:25385761

  17. Genome-wide analysis of gestational gene-environment interactions in the developing kidney

    PubMed Central

    Yan, Lei; Yao, Xiao; Bachvarov, Dimcho; Saifudeen, Zubaida

    2014-01-01

    The G protein-coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2−/− embryos, but not their wild-type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2−/− mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2+/+ and Bdkrb2−/− embryos. The results reveal significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis reveal that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis shows that metanephric kidneys of salt-stressed Bdkrb2−/− have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2−/−;Pax2GFP+/tg mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene (Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2−/− mice. PMID:25005792

  18. A genome-wide association search for type 2 diabetes genes in African Americans.

    PubMed

    Palmer, Nicholette D; McDonough, Caitrin W; Hicks, Pamela J; Roh, Bong H; Wing, Maria R; An, S Sandy; Hester, Jessica M; Cooke, Jessica N; Bostrom, Meredith A; Rudock, Megan E; Talbert, Matthew E; Lewis, Joshua P; Ferrara, Assiamira; Lu, Lingyi; Ziegler, Julie T; Sale, Michele M; Divers, Jasmin; Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N; Ng, Maggie C Y; Langefeld, Carl D; Freedman, Barry I; Bowden, Donald W; Voight, Benjamin F; Scott, Laura J; Steinthorsdottir, Valgerdur; Morris, Andrew P; Dina, Christian; Welch, Ryan P; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S; Thorleifsson, Gudmar; McCulloch, Laura J; Ferreira, Teresa; Grallert, Harald; Amin, Najaf; Wu, Guanming; Willer, Cristen J; Raychaudhuri, Soumya; McCarroll, Steve A; Langenberg, Claudia; Hofmann, Oliver M; Dupuis, Josée; Qi, Lu; Segrè, Ayellet V; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L; Boström, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noël P; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn; Couper, David J; Crawford, Gabe; Doney, Alex S F; Elliott, Katherine S; Elliott, Amanda L; Erdos, Michael R; Fox, Caroline S; Franklin, Christopher S; Ganser, Martha; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon; Groves, Christopher J; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo; Jackson, Anne U; Johnson, Paul R V; Jørgensen, Torben; Kao, Wen H L; Klopp, Norman; Kong, Augustine; Kraft, Peter; Kuusisto, Johanna; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius; Lindgren, Cecilia M; Lyssenko, Valeriya; Marre, Michel; Meitinger, Thomas; Midthjell, Kristian; Morken, Mario A; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Payne, Felicity; Perry, John R B; Petersen, Ann-Kristin; Platou, Carl; Proença, Christine; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, N William; Robertson, Neil R; Rocheleau, Ghislain; Roden, Michael; Sampson, Michael J; Saxena, Richa; Shields, Beverley M; Shrader, Peter; Sigurdsson, Gunnar; Sparsø, Thomas; Strassburger, Klaus; Stringham, Heather M; Sun, Qi; Swift, Amy J; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Rob M; van Haeften, Timon W; van Herpt, Thijs; van Vliet-Ostaptchouk, Jana V; Walters, G Bragi; Weedon, Michael N; Wijmenga, Cisca; Witteman, Jacqueline; Bergman, Richard N; Cauchi, Stephane; Collins, Francis S; Gloyn, Anna L; Gyllensten, Ulf; Hansen, Torben; Hide, Winston A; Hitman, Graham A; Hofman, Albert; Hunter, David J; Hveem, Kristian; Laakso, Markku; Mohlke, Karen L; Morris, Andrew D; Palmer, Colin N A; Pramstaller, Peter P; Rudan, Igor; Sijbrands, Eric; Stein, Lincoln D; Tuomilehto, Jaakko; Uitterlinden, Andre; Walker, Mark; Wareham, Nicholas J; Watanabe, Richard M; Abecasis, Goncalo R; Boehm, Bernhard O; Campbell, Harry; Daly, Mark J; Hattersley, Andrew T; Hu, Frank B; Meigs, James B; Pankow, James S; Pedersen, Oluf; Wichmann, H-Erich; Barroso, Inês; Florez, Jose C; Frayling, Timothy M; Groop, Leif; Sladek, Rob; Thorsteinsdottir, Unnur; Wilson, James F; Illig, Thomas; Froguel, Philippe; van Duijn, Cornelia M; Stefansson, Kari; Altshuler, David; Boehnke, Michael; McCarthy, Mark I; Soranzo, Nicole; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Mägi, Reedik; Randall, Joshua; Johnson, Toby; Elliott, Paul; Rybin, Denis; Henneman, Peter; Dehghan, Abbas; Hottenga, Jouke Jan; Song, Kijoung; Goel, Anuj; Egan, Josephine M; Lajunen, Taina; Doney, Alex; Kanoni, Stavroula; Cavalcanti-Proença, Christine; Kumari, Meena; Timpson, Nicholas J; Zabena, Carina; Ingelsson, Erik; An, Ping; O'Connell, Jeffrey; Luan, Jian'an; Elliott, Amanda; McCarroll, Steven A; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ariyurek, Yavuz; Barter, Philip; Beilby, John P; Ben-Shlomo, Yoav; Bergmann, Sven; Bochud, Murielle; Bonnefond, Amélie; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Chen, Yii-Der Ida; Chines, Peter; Clarke, Robert; Coin, Lachlan J M; Cooper, Matthew N; Crisponi, Laura; Day, Ian N M; de Geus, Eco J C; Delplanque, Jerome; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Frants, Rune; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Grundy, Scott; Gwilliam, Rhian; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna-Liisa; Hayward, Caroline; Heath, Simon C; Hercberg, Serge; Hicks, Andrew A; Hillman, David R; Hingorani, Aroon D; Hui, Jennie; Hung, Joe; Jula, Antti; Kaakinen, Marika; Kaprio, Jaakko; Kesaniemi, Y Antero; Kivimaki, Mika; Knight, Beatrice; Koskinen, Seppo; Kovacs, Peter; Kyvik, Kirsten Ohm; Lathrop, G Mark; Lawlor, Debbie A; Le Bacquer, Olivier; Lecoeur, Cécile; Li, Yun; Mahley, Robert; Mangino, Massimo; Manning, Alisa K; Martínez-Larrad, María Teresa; McAteer, Jarred B; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D; Mukherjee, Sutapa; Naitza, Silvia; Neville, Matthew J; Oostra, Ben A; Orrù, Marco; Pakyz, Ruth; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F; Pedersen, Nancy L; Perola, Markus; Pfeiffer, Andreas F H; Pichler, Irene; Polasek, Ozren; Posthuma, Danielle; Potter, Simon C; Pouta, Anneli; Province, Michael A; Psaty, Bruce M; Rayner, Nigel W; Rice, Kenneth; Ripatti, Samuli; Rivadeneira, Fernando; Rolandsson, Olov; Sandbaek, Annelli; Sandhu, Manjinder; Sanna, Serena; Sayer, Avan Aihie; Scheet, Paul; Seedorf, Udo; Sharp, Stephen J; Shields, Beverley; Sijbrands, Eric J G; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L; Sovio, Ulla; Swift, Amy; Syddall, Holly; Syvänen, Ann-Christine; Tanaka, Toshiko; Tönjes, Anke; Uitterlinden, André G; van Dijk, Ko Willems; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Veronique; Vogelzangs, Nicole; Waeber, Gérard; Wagner, Peter J; Walley, Andrew; Ward, Kim L; Watkins, Hugh; Wild, Sarah H; Willemsen, Gonneke; Witteman, Jaqueline C M; Yarnell, John W G; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zhao, Jing Hua; Zillikens, M Carola; Borecki, Ingrid B; Loos, Ruth J F; Meneton, Pierre; Magnusson, Patrik K E; Nathan, David M; Williams, Gordon H; Silander, Kaisa; Salomaa, Veikko; Smith, George Davey; Bornstein, Stefan R; Schwarz, Peter; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R; Cooper, Cyrus; Dedoussis, George V; Serrano-Ríos, Manuel; Lind, Lars; Palmer, Lyle J; Franks, Paul W; Ebrahim, Shah; Marmot, Michael; Kao, W H Linda; Pramstaller, Peter Paul; Wright, Alan F; Stumvoll, Michael; Hamsten, Anders; Buchanan, Thomas A; Valle, Timo T; Rotter, Jerome I; Siscovick, David S; Penninx, Brenda W J H; Boomsma, Dorret I; Deloukas, Panos; Spector, Timothy D; Ferrucci, Luigi; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo; Jarvelin, Marjo-Riitta; Waterworth, Dawn M; Vollenweider, Peter; Peltonen, Leena; Mooser, Vincent; Sladek, Robert

    2012-01-01

    African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations. PMID:22238593

  19. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

    PubMed Central

    Palmer, Nicholette D.; McDonough, Caitrin W.; Hicks, Pamela J.; Roh, Bong H.; Wing, Maria R.; An, S. Sandy; Hester, Jessica M.; Cooke, Jessica N.; Bostrom, Meredith A.; Rudock, Megan E.; Talbert, Matthew E.; Lewis, Joshua P.; Ferrara, Assiamira; Lu, Lingyi; Ziegler, Julie T.; Sale, Michele M.; Divers, Jasmin; Shriner, Daniel; Adeyemo, Adebowale; Rotimi, Charles N.; Ng, Maggie C. Y.; Langefeld, Carl D.; Freedman, Barry I.; Bowden, Donald W.

    2012-01-01

    African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10−8). SNP rs7560163 (P = 7.0×10−9, OR (95% CI) = 0.75 (0.67–0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10−5) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations. PMID:22238593

  20. Genome-wide identification of Tribolium dorsoventral patterning genes.

    PubMed

    Stappert, Dominik; Frey, Nadine; von Levetzow, Cornelia; Roth, Siegfried

    2016-07-01

    The gene regulatory network controlling dorsoventral axis formation in insects has undergone drastic evolutionary changes. In Drosophila, a stable long-range gradient of Toll signalling specifies ventral cell fates and restricts BMP signalling to the dorsal half of the embryo. In Tribolium, however, Toll signalling is transient and only indirectly controls BMP signalling. In order to gain unbiased insights into the Tribolium network, we performed comparative transcriptome analyses of embryos with various dorsoventral pattering defects produced by parental RNAi for Toll and BMP signalling components. We also included embryos lacking the mesoderm (produced by Tc-twist RNAi) and characterized similarities and differences between Drosophila and Tribolium twist loss-of-function phenotypes. Using stringent conditions, we identified over 750 differentially expressed genes and analysed a subset with altered expression in more than one knockdown condition. We found new genes with localized expression and showed that conserved genes frequently possess earlier and stronger phenotypes than their Drosophila orthologues. For example, the leucine-rich repeat (LRR) protein Tartan, which has only a minor influence on nervous system development in Drosophila, is essential for early neurogenesis in Tribolium and the Tc-zinc-finger homeodomain protein 1 (Tc-zfh1), the orthologue of which plays a minor role in Drosophila muscle development, is essential for maintaining early Tc-twist expression, indicating an important function for mesoderm specification. PMID:27287803

  1. Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies

    PubMed Central

    Kottgen, Anna; Kao, Wen Hong L; Hwang, Shih-Jen; Boerwinkle, Eric; Yang, Qiong; Levy, Daniel; Benjamin, Emelia J; Larson, Martin G; Astor, Brad C; Coresh, Josef; Fox, Caroline S

    2008-01-01

    Background The Framingham Heart Study (FHS) recently obtained initial results from the first genome-wide association scan for renal traits. The study of 70,987 single nucleotide polymorphisms (SNPs) in 1,010 FHS participants provides a list of SNPs showing the strongest associations with renal traits which need to be verified in independent study samples. Methods Sixteen SNPs were selected for replication based on the most promising associations with chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), and serum cystatin C in FHS. These SNPs were genotyped in 15,747 participants of the Atherosclerosis in Communities (ARIC) Study and evaluated for association using multivariable adjusted regression analyses. Primary outcomes in ARIC were CKD and eGFR. Secondary prospective analyses were conducted for association with kidney disease progression using multivariable adjusted Cox proportional hazards regression. The definition of the outcomes, all covariates, and the use of an additive genetic model was consistent with the original analyses in FHS. Results The intronic SNP rs6495446 in the gene MTHFS was significantly associated with CKD among white ARIC participants at visit 4: the odds ratio per each C allele was 1.24 (95% CI 1.09–1.41, p = 0.001). Borderline significant associations of rs6495446 were observed with CKD at study visit 1 (p = 0.024), eGFR at study visits 1 (p = 0.073) and 4 (lower mean eGFR per C allele by 0.6 ml/min/1.73 m2, p = 0.043) and kidney disease progression (hazard ratio 1.13 per each C allele, 95% CI 1.00–1.26, p = 0.041). Another SNP, rs3779748 in EYA1, was significantly associated with CKD at ARIC visit 1 (odds ratio per each T allele 1.22, p = 0.01), but only with eGFR and cystatin C in FHS. Conclusion This genome-wide association study provides unbiased information implicating MTHFS as a candidate gene for kidney disease. Our findings highlight the importance of replication to identify common SNPs associated with

  2. Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data

    PubMed Central

    Liu, Zhi-Ping

    2015-01-01

    Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high-throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented. PMID:25937810

  3. Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

    PubMed Central

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M.; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M.; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U.; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G.; Mattheisen, Manuel; Nöthen, Markus M.

    2015-01-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10−12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region. PMID:25763902

  4. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population.

    PubMed

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene-environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10-8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  5. Genome-wide gene deletions in Streptococcus sanguinis by high throughput PCR.

    PubMed

    Ge, Xiuchun; Xu, Ping

    2012-01-01

    Transposon mutagenesis and single-gene deletion are two methods applied in genome-wide gene knockout in bacteria (1,2). Although transposon mutagenesis is less time consuming, less costly, and does not require completed genome information, there are two weaknesses in this method: (1) the possibility of a disparate mutants in the mixed mutant library that counter-selects mutants with decreased competition; and (2) the possibility of partial gene inactivation whereby genes do not entirely lose their function following the insertion of a transposon. Single-gene deletion analysis may compensate for the drawbacks associated with transposon mutagenesis. To improve the efficiency of genome-wide single gene deletion, we attempt to establish a high-throughput technique for genome-wide single gene deletion using Streptococcus sanguinis as a model organism. Each gene deletion construct in S. sanguinis genome is designed to comprise 1-kb upstream of the targeted gene, the aphA-3 gene, encoding kanamycin resistance protein, and 1-kb downstream of the targeted gene. Three sets of primers F1/R1, F2/R2, and F3/R3, respectively, are designed and synthesized in a 96-well plate format for PCR-amplifications of those three components of each deletion construct. Primers R1 and F3 contain 25-bp sequences that are complementary to regions of the aphA-3 gene at their 5' end. A large scale PCR amplification of the aphA-3 gene is performed once for creating all single-gene deletion constructs. The promoter of aphA-3 gene is initially excluded to minimize the potential polar effect of kanamycin cassette. To create the gene deletion constructs, high-throughput PCR amplification and purification are performed in a 96-well plate format. A linear recombinant PCR amplicon for each gene deletion will be made up through four PCR reactions using high-fidelity DNA polymerase. The initial exponential growth phase of S. sanguinis cultured in Todd Hewitt broth supplemented with 2.5% inactivated horse

  6. A Genome-Wide Map of AAV-Mediated Human Gene Targeting

    PubMed Central

    Deyle, David R.; Hansen, R. Scott; Cornea, Anda M.; Li, Li B.; Burt, Amber A.; Alexander, Ian E.; Sandstrom, Richard S.; Stamatoyannopoulos, John A.; Wei, Chia-Lin; Russell, David W.

    2014-01-01

    To determine which genomic features promote homologous recombination, we created a genome-wide map of gene targeting sites. An adeno-associated virus vector was used to target identical loci introduced as transcriptionally active retroviral vector proviruses. A comparison of ~2,000 targeted and untargeted sites showed that targeting occurred throughout the human genome and was not influenced by the presence of nearby CpG islands, sequence repeats, or DNase I hypersensitive sites. Targeted sites were preferentially found within transcription units, especially when the target loci were transcribed in the opposite orientation to their surrounding chromosomal genes. The impact of DNA replication was determined by mapping replication forks, which revealed a preference for recombination at target loci transcribed towards an incoming fork. Our results constitute the first genome-wide screen of gene targeting in mammalian cells, and they demonstrate a strong recombinogenic effect of colliding polymerases. PMID:25282150

  7. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population

    PubMed Central

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene–environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10−8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  8. Susceptibility Genes for Multiple Sclerosis Identified in a Gene-Based Genome-Wide Association Study

    PubMed Central

    Lin, Xiang; Deng, Fei-Yan; Lu, Xin

    2015-01-01

    Background and Purpose Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. The aim of this study was to identify more genes associated with MS. Methods Based on the publicly available data of the single-nucleotide polymorphism-based genome-wide association study (GWAS) from the database of Genotypes and Phenotypes, we conducted a powerful gene-based GWAS in an initial sample with 931 family trios, and a replication study sample with 978 cases and 883 controls. For interesting genes, gene expression in MS-related cells between MS cases and controls was examined by using publicly available datasets. Results A total of 58 genes was identified, including 20 "novel" genes significantly associated with MS (p<1.40×10-4). In the replication study, 44 of the 58 identified genes had been genotyped and 35 replicated the association. In the gene-expression study, 21 of the 58 identified genes exhibited differential expressions in MS-related cells. Thus, 15 novel genes were supported by replicated association and/or differential expression. In particular, four of the novel genes, those encoding myelin oligodendrocyte glycoprotein (MOG), coiled-coil alpha-helical rod protein 1 (CCHCR1), human leukocyte antigen complex group 22 (HCG22), and major histocompatibility complex, class II, DM alpha (HLA-DMA), were supported by the evidence of both. Conclusions The results of this study emphasize the high power of gene-based GWAS in detecting the susceptibility genes of MS. The novel genes identified herein may provide new insights into the molecular genetic mechanisms underlying MS. PMID:26320842

  9. Robust Gene-Gene Interaction Analysis in Genome Wide Association Studies.

    PubMed

    Kim, Yongkang; Park, Taesung

    2015-01-01

    Genome-wide association studies (GWAS) have successfully discovered hundreds of associations between genetic variants and complex traits. Most GWAS have focused on the identification of single variants. It has been shown that most of the variants that were discovered by GWAS could only partially explain disease heritability. The explanation for this missing heritability is generally believed to be gene-gene (GG) or gene-environment (GE) interactions and other structural variants. Generalized multifactor dimensionality reduction (GMDR) has been proven to be reasonably powerful in detecting GG and GE interactions; however, its performance has been found to decline when outlying quantitative traits are present. This paper proposes a robust GMDR estimation method (based on the L-estimator and M-estimator estimation methods) in an attempt to reduce the effects caused by outlying traits. A comparison of robust GMDR with the original MDR based on simulation studies showed the former method to outperform the latter. The performance of robust GMDR is illustrated through a real GWA example consisting of 8,577 samples from the Korean population using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) level as a phenotype. Robust GMDR identified the KCNH1 gene to have strong interaction effects with other genes on the function of insulin secretion. PMID:26267341

  10. Robust Gene-Gene Interaction Analysis in Genome Wide Association Studies

    PubMed Central

    Kim, Yongkang; Park, Taesung

    2015-01-01

    Genome-wide association studies (GWAS) have successfully discovered hundreds of associations between genetic variants and complex traits. Most GWAS have focused on the identification of single variants. It has been shown that most of the variants that were discovered by GWAS could only partially explain disease heritability. The explanation for this missing heritability is generally believed to be gene-gene (GG) or gene-environment (GE) interactions and other structural variants. Generalized multifactor dimensionality reduction (GMDR) has been proven to be reasonably powerful in detecting GG and GE interactions; however, its performance has been found to decline when outlying quantitative traits are present. This paper proposes a robust GMDR estimation method (based on the L-estimator and M-estimator estimation methods) in an attempt to reduce the effects caused by outlying traits. A comparison of robust GMDR with the original MDR based on simulation studies showed the former method to outperform the latter. The performance of robust GMDR is illustrated through a real GWA example consisting of 8,577 samples from the Korean population using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) level as a phenotype. Robust GMDR identified the KCNH1 gene to have strong interaction effects with other genes on the function of insulin secretion. PMID:26267341

  11. Genome-wide detection of gene extinction in early mammalian evolution.

    PubMed

    Kuraku, Shigehiro; Kuratani, Shigeru

    2011-01-01

    Detecting gene losses is a novel aspect of evolutionary genomics that has been made feasible by whole-genome sequencing. However, research to date has concentrated on elucidating evolutionary patterns of genomic components shared between species, rather than identifying disparities between genomes. In this study, we searched for gene losses in the lineage leading to eutherian mammals. First, as a pilot analysis, we selected five gene families (Wnt, Fgf, Tbx, TGFβ, and Frizzled) for molecular phylogenetic analyses, and identified mammalian lineage-specific losses of Wnt11b, Tbx6L/VegT/tbx16, Nodal-related, ADMP1, ADMP2, Sizzled, and Crescent. Second, automated genome-wide phylogenetic screening was implemented based on this pilot analysis. As a result, we detected 147 chicken genes without eutherian orthologs, which resulted from 141 gene loss events. Our inventory contained a group of regulatory genes governing early embryonic axis formation, such as Noggins, and multiple members of the opsin and prolactin-releasing hormone receptor ("PRLHR") gene families. Our findings highlight the potential of genome-wide gene phylogeny ("phylome") analysis in detecting possible rearrangement of gene networks and the importance of identifying losses of ancestral genomic components in analyzing the molecular basis underlying phenotypic evolution. PMID:22094861

  12. Gene-based and pathway-based genome-wide association study of alcohol dependence

    PubMed Central

    ZUO, Lingjun; ZHANG, Clarence K.; SAYWARD, Frederick G.; CHEUNG, Kei-Hoi; WANG, Kesheng; KRYSTAL, John H.; ZHAO, Hongyu; LUO, Xingguang

    2015-01-01

    Background The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aim Identify risk genes and risk gene pathways for alcohol dependence. Methods We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. Results We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the ‘cellextracellular matrix interactions’ pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the ‘Na+/Cl- dependent neurotransmitter transporters’ pathway and the ‘other glycan degradation’ pathway. Conclusion These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence. PMID:26120261

  13. Genome-wide signatures of male-mediated migration shaping the Indian gene pool.

    PubMed

    ArunKumar, GaneshPrasad; Tatarinova, Tatiana V; Duty, Jeff; Rollo, Debra; Syama, Adhikarla; Arun, Varatharajan Santhakumari; Kavitha, Valampuri John; Triska, Petr; Greenspan, Bennett; Wells, R Spencer; Pitchappan, Ramasamy

    2015-09-01

    Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India. PMID:25994871

  14. Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

    PubMed Central

    2012-01-01

    Background The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided. Results We performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions. Conclusions This first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis. The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319. PMID:22292898

  15. Analyse multiple disease subtypes and build associated gene networks using genome-wide expression profiles

    PubMed Central

    2015-01-01

    Background Despite the large increase of transcriptomic studies that look for gene signatures on diseases, there is still a need for integrative approaches that obtain separation of multiple pathological states providing robust selection of gene markers for each disease subtype and information about the possible links or relations between those genes. Results We present a network-oriented and data-driven bioinformatic approach that searches for association of genes and diseases based on the analysis of genome-wide expression data derived from microarrays or RNA-Seq studies. The approach aims to (i) identify gene sets associated to different pathological states analysed together; (ii) identify a minimum subset within these genes that unequivocally differentiates and classifies the compared disease subtypes; (iii) provide a measurement of the discriminant power of these genes and (iv) identify links between the genes that characterise each of the disease subtypes. This bioinformatic approach is implemented in an R package, named geNetClassifier, available as an open access tool in Bioconductor. To illustrate the performance of the tool, we applied it to two independent datasets: 250 samples from patients with four major leukemia subtypes analysed using expression arrays; another leukemia dataset analysed with RNA-Seq that includes a subtype also present in the previous set. The results show the selection of key deregulated genes recently reported in the literature and assigned to the leukemia subtypes studied. We also show, using these independent datasets, the selection of similar genes in a network built for the same disease subtype. Conclusions The construction of gene networks related to specific disease subtypes that include parameters such as gene-to-gene association, gene disease specificity and gene discriminant power can be very useful to draw gene-disease maps and to unravel the molecular features that characterize specific pathological states. The

  16. A genome-wide MeSH-based literature mining system predicts implicit gene-to-gene relationships and networks

    PubMed Central

    2013-01-01

    Background The large amount of literature in the post-genomics era enables the study of gene interactions and networks using all available articles published for a specific organism. MeSH is a controlled vocabulary of medical and scientific terms that is used by biomedical scientists to manually index articles in the PubMed literature database. We hypothesized that genome-wide gene-MeSH term associations from the PubMed literature database could be used to predict implicit gene-to-gene relationships and networks. While the gene-MeSH associations have been used to detect gene-gene interactions in some studies, different methods have not been well compared, and such a strategy has not been evaluated for a genome-wide literature analysis. Genome-wide literature mining of gene-to-gene interactions allows ranking of the best gene interactions and investigation of comprehensive biological networks at a genome level. Results The genome-wide GenoMesh literature mining algorithm was developed by sequentially generating a gene-article matrix, a normalized gene-MeSH term matrix, and a gene-gene matrix. The gene-gene matrix relies on the calculation of pairwise gene dissimilarities based on gene-MeSH relationships. An optimized dissimilarity score was identified from six well-studied functions based on a receiver operating characteristic (ROC) analysis. Based on the studies with well-studied Escherichia coli and less-studied Brucella spp., GenoMesh was found to accurately identify gene functions using weighted MeSH terms, predict gene-gene interactions not reported in the literature, and cluster all the genes studied from an organism using the MeSH-based gene-gene matrix. A web-based GenoMesh literature mining program is also available at: http://genomesh.hegroup.org. GenoMesh also predicts gene interactions and networks among genes associated with specific MeSH terms or user-selected gene lists. Conclusions The GenoMesh algorithm and web program provide the first genome-wide

  17. Chronic periodontitis genome-wide association studies: gene-centric and gene set enrichment analyses.

    PubMed

    Rhodin, K; Divaris, K; North, K E; Barros, S P; Moss, K; Beck, J D; Offenbacher, S

    2014-09-01

    Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP (n = 4,504) and periodontal pathogen colonization (n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach (i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP (NIN, p = 1.6 × 10(-7); ABHD12B, p = 3.6 × 10(-7); WHAMM, p = 1.7 × 10(-6); AP3B2, p = 2.2 × 10(-6)) and 2 with high periodontal pathogen colonization (red complex-KCNK1, p = 3.4 × 10(-7); Porphyromonas gingivalis-DAB2IP, p = 1.0 × 10(-6)). Top-ranked genes for moderate CP were HGD (p = 1.4 × 10(-5)), ZNF675 (p = 1.5 × 10(-5)), TNFRSF10C (p = 2.0 × 10(-5)), and EMR1 (p = 2.0 × 10(-5)). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism-based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP ("endoplasmic reticulum membrane," "cytochrome P450," "microsome," and "oxidation reduction") and moderate CP ("regulation of gene expression," "zinc ion binding," "BMP signaling pathway," and "ruffle"). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and new candidate genes and pathways

  18. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

    PubMed Central

    Rafnar, Thorunn; Vermeulen, Sita H.; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K.; Witjes, J. Alfred; Grotenhuis, Anne J.; Verhaegh, Gerald W.; Hulsbergen-van de Kaa, Christina A.; Besenbacher, Soren; Gudbjartsson, Daniel; Stacey, Simon N.; Gudmundsson, Julius; Johannsdottir, Hrefna; Bjarnason, Hjordis; Zanon, Carlo; Helgadottir, Hafdis; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Jonsson, Eirikur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Bishop, D. Timothy; Chung-Sak, Sei; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H.; Knowles, Margaret A.; de Verdier, Petra J.; Ryk, Charlotta; Lindblom, Annika; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Panadero, Angeles; Sanz-Velez, José I.; Sanchez, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D.; Hengstler, Jan G.; Selinski, Silvia; Gerullis, Holger; Ovsiannikov, Daniel; Khezri, Abdolaziz; Aminsharifi, Alireza; Malekzadeh, Mahyar; van den Berg, Leonard H.; Ophoff, Roel A.; Veldink, Jan H.; Zeegers, Maurice P.; Kellen, Eliane; Fostinelli, Jacopo; Andreoli, Daniele; Arici, Cecilia; Porru, Stefano; Buntinx, Frank; Ghaderi, Abbas; Golka, Klaus; Mayordomo, José I.; Matullo, Giuseppe; Kumar, Rajiv; Steineck, Gunnar; Kiltie, Anne E.; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; Kiemeney, Lambertus A.

    2011-01-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC. PMID:21750109

  19. Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations.

    PubMed

    Bendall, Matthew L; Stevens, Sarah Lr; Chan, Leong-Keat; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Froula, Jeff; Kang, Dongwan; Tringe, Susannah G; Bertilsson, Stefan; Moran, Mary A; Shade, Ashley; Newton, Ryan J; McMahon, Katherine D; Malmstrom, Rex R

    2016-07-01

    Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005-2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the 'ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment. PMID:26744812

  20. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

    PubMed Central

    Jahanshad, Neda; Rajagopalan, Priya; Hua, Xue; Hibar, Derrek P.; Nir, Talia M.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Medland, Sarah E.; Montgomery, Grant W.; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Thompson, Paul M.; Weiner, Michael; Aisen, Paul; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowski, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Liu, Enchi; Green, Robert C.; Montine, Tom; Petersen, Ronald; Aisen, Paul; Gamst, Anthony; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Beckett, Laurel; Harvey, Danielle; Gamst, Anthony; Donohue, Michael; Kornak, John; Jack, Clifford R.; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Jagust, William; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Morris, John; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Trojanowki, J.Q.; Shaw, Les; Lee, Virginia M.Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Saykin, Andrew J.; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Khachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Petersen, Ronald; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Coleman, R. Edward; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Lu, Po H.; Bartzokis, George; Silverman, Daniel H.S.; Graff-Radford, Neill R.; Parfitt, Francine; Johnson, Heather; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Herring, Scott; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Bwayo, Salome K.; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabeth; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick

    2013-01-01

    Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases. PMID:23471985

  1. Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations

    PubMed Central

    Bendall, Matthew L; Stevens, Sarah LR; Chan, Leong-Keat; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Froula, Jeff; Kang, Dongwan; Tringe, Susannah G; Bertilsson, Stefan; Moran, Mary A; Shade, Ashley; Newton, Ryan J; McMahon, Katherine D; Malmstrom, Rex R

    2016-01-01

    Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005–2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the ‘ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment. PMID:26744812

  2. Genome-wide association studies and gene expression profiles of rheumatoid arthritis

    PubMed Central

    Xiao, X.; Hao, J.; Wen, Y.; Wang, W.; Guo, X.

    2016-01-01

    Objectives The molecular mechanism of rheumatoid arthritis (RA) remains elusive. We conducted a protein-protein interaction network-based integrative analysis of genome-wide association studies (GWAS) and gene expression profiles of RA. Methods We first performed a dense search of RA-associated gene modules by integrating a large GWAS meta-analysis dataset (containing 5539 RA patients and 20 169 healthy controls), protein interaction network and gene expression profiles of RA synovium and peripheral blood mononuclear cells (PBMCs). Gene ontology (GO) enrichment analysis was conducted by DAVID. The protein association networks of gene modules were generated by STRING. Results For RA synovium, the top-ranked gene module is HLA-A, containing TAP2, HLA-A, HLA-C, TAPBP and LILRB1 genes. For RA PBMCs, the top-ranked gene module is GRB7, consisting of HLA-DRB5, HLA-DRA, GRB7, CD63 and KIT genes. Functional enrichment analysis identified three significant GO terms for RA synovium, including antigen processing and presentation of peptide antigen via major histocompatibility complex class I (false discovery rate (FDR) = 4.86 × 10 – 4), antigen processing and presentation of peptide antigen (FDR = 2.33 × 10 – 3) and eukaryotic translation initiation factor 4F complex (FDR = 2.52 × 10 – 2). Conclusion This study reported several RA-associated gene modules and their functional association networks. Cite this article: X. Xiao, J. Hao, Y. Wen, W. Wang, X. Guo, F. Zhang. Genome-wide association studies and gene expression profiles of rheumatoid arthritis: an analysis. Bone Joint Res 2016;5:314–319. DOI: 10.1302/2046-3758.57.2000502. PMID:27445359

  3. Genome-wide identification and functional analyses of calmodulin genes in Solanaceous species

    PubMed Central

    2013-01-01

    Background Calmodulin (CaM) is a major calcium sensor in all eukaryotes. It binds calcium and modulates the activity of a wide range of downstream proteins in response to calcium signals. However, little is known about the CaM gene family in Solanaceous species, including the economically important species, tomato (Solanum lycopersicum), and the gene silencing model plant, Nicotiana benthamiana. Moreover, the potential function of CaM in plant disease resistance remains largely unclear. Results We performed genome-wide identification of CaM gene families in Solanaceous species. Employing bioinformatics approaches, multiple full-length CaM genes were identified from tomato, N. benthamiana and potato (S. tuberosum) genomes, with tomato having 6 CaM genes, N. benthamiana having 7 CaM genes, and potato having 4 CaM genes. Sequence comparison analyses showed that three tomato genes, SlCaM3/4/5, two potato genes StCaM2/3, and two sets of N. benthamiana genes, NbCaM1/2/3/4 and NbCaM5/6, encode identical CaM proteins, yet the genes contain different intron/exon organization and are located on different chromosomes. Further sequence comparisons and gene structural and phylogenetic analyses reveal that Solanaceous species gained a new group of CaM genes during evolution. These new CaM genes are unusual in that they contain three introns in contrast to only a single intron typical of known CaM genes in plants. The tomato CaM (SlCaM) genes were found to be expressed in all organs. Prediction of cis-acting elements in 5' upstream sequences and expression analyses demonstrated that SlCaM genes have potential to be highly responsive to a variety of biotic and abiotic stimuli. Additionally, silencing of SlCaM2 and SlCaM6 altered expression of a set of signaling and defense-related genes and resulted in significantly lower resistance to Tobacco rattle virus and the oomycete pathogen, Pythium aphanidermatum. Conclusions The CaM gene families in the Solanaceous species tomato, N

  4. Genome-wide evidence for speciation with gene flow in Heliconius butterflies

    PubMed Central

    Martin, Simon H.; Dasmahapatra, Kanchon K.; Nadeau, Nicola J.; Salazar, Camilo; Walters, James R.; Simpson, Fraser; Blaxter, Mark; Manica, Andrea; Mallet, James; Jiggins, Chris D.

    2013-01-01

    Most speciation events probably occur gradually, without complete and immediate reproductive isolation, but the full extent of gene flow between diverging species has rarely been characterized on a genome-wide scale. Documenting the extent and timing of admixture between diverging species can clarify the role of geographic isolation in speciation. Here we use new methodology to quantify admixture at different stages of divergence in Heliconius butterflies, based on whole-genome sequences of 31 individuals. Comparisons between sympatric and allopatric populations of H. melpomene, H. cydno, and H. timareta revealed a genome-wide trend of increased shared variation in sympatry, indicative of pervasive interspecific gene flow. Up to 40% of 100-kb genomic windows clustered by geography rather than by species, demonstrating that a very substantial fraction of the genome has been shared between sympatric species. Analyses of genetic variation shared over different time intervals suggested that admixture between these species has continued since early in speciation. Alleles shared between species during recent time intervals displayed higher levels of linkage disequilibrium than those shared over longer time intervals, suggesting that this admixture took place at multiple points during divergence and is probably ongoing. The signal of admixture was significantly reduced around loci controlling divergent wing patterns, as well as throughout the Z chromosome, consistent with strong selection for Müllerian mimicry and with known Z-linked hybrid incompatibility. Overall these results show that species divergence can occur in the face of persistent and genome-wide admixture over long periods of time. PMID:24045163

  5. Genome-wide p63-regulated gene expression in differentiating epidermal keratinocytes

    PubMed Central

    Oti, Martin; Kouwenhoven, Evelyn N.; Zhou, Huiqing

    2015-01-01

    The transcription factor p63 is a key regulator in epidermal keratinocyte proliferation and differentiation. However, the role of p63 in gene regulation during these processes is not well understood. To investigate this, we recently generated genome-wide profiles of gene expression, p63 binding sites and active regulatory regions with the H3K27ac histone mark (Kouwenhoven et al., 2015). We showed that only a subset of p63 binding sites are active in keratinocytes, and that differentiation-associated gene expression dynamics correlate with the activity of p63 binding sites rather than with their occurrence per se. Here we describe in detail the generation and processing of the ChIP-seq and RNA-seq datasets used in this study. These data sets are deposited in the Gene Expression Omnibus (GEO) repository under the accession number GSE59827. PMID:26484246

  6. Genome-Wide Identification and Evolution of HECT Genes in Soybean

    PubMed Central

    Meng, Xianwen; Wang, Chen; Rahman, Siddiq Ur; Wang, Yaxu; Wang, Ailan; Tao, Shiheng

    2015-01-01

    Proteins containing domains homologous to the E6-associated protein (E6-AP) carboxyl terminus (HECT) are an important class of E3 ubiquitin ligases involved in the ubiquitin proteasome pathway. HECT-type E3s play crucial roles in plant growth and development. However, current understanding of plant HECT genes and their evolution is very limited. In this study, we performed a genome-wide analysis of the HECT domain-containing genes in soybean. Using high-quality genome sequences, we identified 19 soybean HECT genes. The predicted HECT genes were distributed unevenly across 15 of 20 chromosomes. Nineteen of these genes were inferred to be segmentally duplicated gene pairs, suggesting that in soybean, segmental duplications have made a significant contribution to the expansion of the HECT gene family. Phylogenetic analysis showed that these HECT genes can be divided into seven groups, among which gene structure and domain architecture was relatively well-conserved. The Ka/Ks ratios show that after the duplication events, duplicated HECT genes underwent purifying selection. Moreover, expression analysis reveals that 15 of the HECT genes in soybean are differentially expressed in 14 tissues, and are often highly expressed in the flowers and roots. In summary, this work provides useful information on which further functional studies of soybean HECT genes can be based. PMID:25894222

  7. Methods for Investigating Gene-Environment Interactions in Candidate Pathway and Genome-Wide Association Studies

    PubMed Central

    Thomas, Duncan

    2010-01-01

    Despite the considerable enthusiasm about the yield of novel and replicated discoveries of genetic associations from the new generation of genome-wide association studies (GWAS), the proportion of the heritability of most complex diseases that have been studied to date remains small. Some of this “dark matter” could be due to gene-environment (G×E) interactions or more complex pathways involving multiple genes and exposures. We review the basic epidemiologic study design and statistical analysis approaches to studying G×E interactions individually and then consider more comprehensive approaches to studying entire pathways or GWAS data. In addition to the usual issues in genetic association studies, particular care is needed in exposure assessment and very large sample sizes are required. Although hypothesis-driven pathway-based and “agnostic” GWAS approaches are generally viewed as opposite poles, we suggest that the two can be usefully married using hierarchical modeling strategies that exploit external pathway knowledge in mining genome-wide data. PMID:20070199

  8. Cytokine Gene Polymorphisms and Human Autoimmune Disease in the Era of Genome-Wide Association Studies

    PubMed Central

    2012-01-01

    Cytokine (receptor) genes have traditionally attracted great interest as plausible genetic risk factors for autoimmune disease. Since 2007, the implementation of genome-wide association studies has facilitated the robust identification of allelic variants in more than 35 cytokine loci as susceptibility factors for a wide variety of over 15 autoimmune disorders. In this review, we catalog the gene loci of interleukin, chemokine, and tumor necrosis factor receptor superfamily and ligands that have emerged as autoimmune risk factors. We examine recent progress made in the clarification of the functional mechanisms by which polymorphisms in the genes coding for interleukin-2 receptor alpha (IL2RA), IL7R, and IL23R may alter risk for autoimmune disease, and discuss opposite autoimmune risk alleles found, among others, at the IL10 locus. PMID:22191464

  9. High-resolution genome-wide scan of genes, gene-networks and cellular systems impacting the yeast ionome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To balance the demand for uptake of essential elements with their potential toxicity living cells have complex regulatory mechanisms. Here, we describe a genome-wide screen to identify genes that impact the elemental composition (‘ionome’) of yeast Saccharomyces cerevisiae. Using inductively coupled...

  10. Gene set analysis of genome-wide association studies: methodological issues and perspectives

    PubMed Central

    Wang, Lily; Jia, Peilin; Wolfinger, Russell D; Chen, Xi; Zhao, Zhongming

    2013-01-01

    Recent studies have demonstrated that gene set analysis, which tests disease association with genetic variants in a group of functionally related genes, is a promising approach for analyzing and interpreting genome-wide association studies (GWAS) data. These approaches aim to increase power by combining association signals from multiple genes in the same gene set. In addition, gene set analysis can also shed more light on the biological processes underlying complex diseases. However, current approaches for gene set analysis are still in an early stage of development in that analysis results are often prone to sources of bias, including gene set size and gene length, linkage disequilibrium patterns and the presence of overlapping genes. In this paper, we provide an in-depth review of the gene set analysis procedures, along with parameter choices and the particular methodology challenges at each stage. In addition to providing a survey of recently developed tools, we also classify the analysis methods into larger categories and discuss their strengths and limitations. In the last section, we outline several important areas for improving the analytical strategies in gene set analysis. PMID:21565265

  11. Genome-wide characterization of the ankyrin repeats gene family under salt stress in soybean.

    PubMed

    Zhang, Dayong; Wan, Qun; He, Xiaolan; Ning, Lihua; Huang, Yihong; Xu, Zhaolong; Liu, Jia; Shao, Hongbo

    2016-10-15

    Ankyrin repeats (ANK) gene family are common in diverse organisms and play important roles in cell growth, development and response to environmental stresses. Recently, genome-wide identification and evolutionary analyses of the ANK gene family have been carried out in Arabidopsis, rice and maize. However, little is known about the ANK genes in the whole soybean genome. In this study, we described the identification and structural characterization of 162ANK genes in soybean (GmANK). Then, comprehensive bioinformatics analyses of GmANK genes family were performed including gene locus, phylogenetic, domain composition analysis, chromosomal localization and expression profiling. Domain composition analyses showed that GmANK proteins formed eleven subfamilies in soybean. In sicilo expression analysis of these GmANK genes demonstrated that GmANK genes show a diverse/various expression pattern, suggesting that functional diversification of GmANK genes family. Based on digital gene expression profile (DGEP) data between cultivated soybean and wild type under salt treatment, some GmANKs related to salt/drought response were investigated. Moreover, the expression pattern and subcellular localization of GmANK6 were performed. The results will provide important clues to explore ANK genes expression and function in future studies in soybean. PMID:27335162

  12. Genome-wide analysis of chromatin packing in Arabidopsis thaliana at single-gene resolution

    PubMed Central

    Liu, Chang; Wang, Congmao; Wang, George; Becker, Claude; Zaidem, Maricris; Weigel, Detlef

    2016-01-01

    The three-dimensional packing of the genome plays an important role in regulating gene expression. We have used Hi-C, a genome-wide chromatin conformation capture (3C) method, to analyze Arabidopsis thaliana chromosomes dissected into subkilobase segments, which is required for gene-level resolution in this species with a gene-dense genome. We found that the repressive H3K27me3 histone mark is overrepresented in the promoter regions of genes that are in conformational linkage over long distances. In line with the globally dispersed distribution of RNA polymerase II in A. thaliana nuclear space, actively transcribed genes do not show a strong tendency to associate with each other. In general, there are often contacts between 5′ and 3′ ends of genes, forming local chromatin loops. Such self-loop structures of genes are more likely to occur in more highly expressed genes, although they can also be found in silent genes. Silent genes with local chromatin loops are highly enriched for the histone variant H3.3 at their 5′ and 3′ ends but depleted of repressive marks such as heterochromatic histone modifications and DNA methylation in flanking regions. Our results suggest that, different from animals, a major theme of genome folding in A. thaliana is the formation of structural units that correspond to gene bodies. PMID:27225844

  13. Genome-wide and candidate gene association study of cigarette smoking behaviors.

    PubMed

    Caporaso, Neil; Gu, Fangyi; Chatterjee, Nilanjan; Sheng-Chih, Jin; Yu, Kai; Yeager, Meredith; Chen, Constance; Jacobs, Kevin; Wheeler, William; Landi, Maria Teresa; Ziegler, Regina G; Hunter, David J; Chanock, Stephen; Hankinson, Susan; Kraft, Peter; Bergen, Andrew W

    2009-01-01

    The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, < or = 10 versus > 10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10(-7)) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10(-5) for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4x10(-5)), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up. PMID:19247474

  14. Genome-wide identification and analysis of the MADS-box gene family in sesame.

    PubMed

    Wei, Xin; Wang, Linhai; Yu, Jingyin; Zhang, Yanxin; Li, Donghua; Zhang, Xiurong

    2015-09-10

    MADS-box genes encode transcription factors that play crucial roles in plant growth and development. Sesame (Sesamum indicum L.) is an oil crop that contributes to the daily oil and protein requirements of almost half of the world's population; therefore, a genome-wide analysis of the MADS-box gene family is needed. Fifty-seven MADS-box genes were identified from 14 linkage groups of the sesame genome. Analysis of phylogenetic relationships with Arabidopsis thaliana, Utricularia gibba and Solanum lycopersicum MADS-box genes was performed. Sesame MADS-box genes were clustered into four groups: 28 MIKC(c)-type, 5 MIKC(⁎)-type, 14 Mα-type and 10 Mγ-type. Gene structure analysis revealed from 1 to 22 exons of sesame MADS-box genes. The number of exons in type II MADS-box genes greatly exceeded the number in type I genes. Motif distribution analysis of sesame MADS-box genes also indicated that type II MADS-box genes contained more motifs than type I genes. These results suggested that type II sesame MADS-box genes had more complex structures. By analyzing expression profiles of MADS-box genes in seven sesame transcriptomes, we determined that MIKC(C)-type MADS-box genes played significant roles in sesame flower and seed development. Although most MADS-box genes in the same clade showed similar expression features, some gene functions were diversified from the orthologous Arabidopsis genes. This research will contribute to uncovering the role of MADS-box genes in sesame development. PMID:25967387

  15. Genome-wide analysis suggests divergent evolution of lipid phosphotases/phosphotransferase genes in plants.

    PubMed

    Wang, Peng; Chen, Zhenxi; Kasimu, Rena; Chen, Yinhua; Zhang, Xiaoxiao; Gai, Jiangtao

    2016-08-01

    Genes of the LPPT (lipid phosphatase/phosphotransferase) family play important roles in lipid phosphorous transfer and triacylglycerol accumulation in plants. To provide overviews of the plant LPPT family and their overall relationships, here we carried out genome-wide identifications and analyses of plant LPPT family members. A total of 643 putative LPPT genes were identified from 48 sequenced plant genomes, among which 205 genes from 14 plants were chosen for further analyses. Plant LPPT genes belonged to three distinctive groups, namely the LPT (lipid phosphotransfease), LPP (lipid phosphatase), and pLPP (plastidic lipid phosphotransfease) groups. Genes of the LPT group could be further partitioned into three groups, two of which were only identified in terrestrial plants. Genes in the LPP and pLPP groups experienced duplications in early stages of plant evolution. Among 17 Zea mays LPPT genes, divergence of temporal-spatial expression patterns was revealed based on microarray data analysis. Peptide sequences of plant LPPT genes harbored different conserved motifs. A test of Branch Model versus One-ratio Model did not support significant selective pressures acting on different groups of LPPT genes, although quite different nonsynonymous evolutionary rates and selective pressures were observed. The complete picture of the plant LPPT family provided here should facilitate further investigations of plant LPPT genes and offer a better understanding of lipid biosynthesis in plants. PMID:27501416

  16. Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress.

    PubMed

    Li, Sisi; Papale, Ligia A; Zhang, Qi; Madrid, Andy; Chen, Li; Chopra, Pankaj; Keleş, Sündüz; Jin, Peng; Alisch, Reid S

    2016-02-01

    Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post-traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID:26598390

  17. A Genome-Wide Screen Indicates Correlation between Differentiation and Expression of Metabolism Related Genes

    PubMed Central

    Shende, Akhilesh; Singh, Anupama; Meena, Anil; Ghosal, Ritika; Ranganathan, Madhav; Bandyopadhyay, Amitabha

    2013-01-01

    Differentiated tissues may be considered as materials with distinct properties. The differentiation program of a given tissue ensures that it acquires material properties commensurate with its function. It may be hypothesized that some of these properties are acquired through production of tissue-specific metabolites synthesized by metabolic enzymes. To establish correlation between metabolism and organogenesis we have carried out a genome-wide expression study of metabolism related genes by RNA in-situ hybridization. 23% of the metabolism related genes studied are expressed in a tissue-restricted but not tissue-exclusive manner. We have conducted the screen on whole mount chicken (Gallus gallus) embryos from four distinct developmental stages to correlate dynamic changes in expression patterns of metabolic enzymes with spatio-temporally unique developmental events. Our data strongly suggests that unique combinations of metabolism related genes, and not specific metabolic pathways, are upregulated during differentiation. Further, expression of metabolism related genes in well established signaling centers that regulate different aspects of morphogenesis indicates developmental roles of some of the metabolism related genes. The database of tissue-restricted expression patterns of metabolism related genes, generated in this study, should serve as a resource for systematic identification of these genes with tissue-specific functions during development. Finally, comprehensive understanding of differentiation is not possible unless the downstream genes of a differentiation cascade are identified. We propose, metabolic enzymes constitute a significant portion of these downstream target genes. Thus our study should help elucidate different aspects of tissue differentiation. PMID:23717462

  18. Genome-Wide Identification and Characterization of WRKY Gene Family in Peanut

    PubMed Central

    Song, Hui; Wang, Pengfei; Lin, Jer-Young; Zhao, Chuanzhi; Bi, Yuping; Wang, Xingjun

    2016-01-01

    WRKY, an important transcription factor family, is widely distributed in the plant kingdom. Many reports focused on analysis of phylogenetic relationship and biological function of WRKY protein at the whole genome level in different plant species. However, little is known about WRKY proteins in the genome of Arachis species and their response to salicylic acid (SA) and jasmonic acid (JA) treatment. In this study, we identified 77 and 75 WRKY proteins from the two wild ancestral diploid genomes of cultivated tetraploid peanut, Arachis duranensis and Arachis ipaënsis, using bioinformatics approaches. Most peanut WRKY coding genes were located on A. duranensis chromosome A6 and A. ipaënsis chromosome B3, while the least number of WRKY genes was found in chromosome 9. The WRKY orthologous gene pairs in A. duranensis and A. ipaënsis chromosomes were highly syntenic. Our analysis indicated that segmental duplication events played a major role in AdWRKY and AiWRKY genes, and strong purifying selection was observed in gene duplication pairs. Furthermore, we translate the knowledge gained from the genome-wide analysis result of wild ancestral peanut to cultivated peanut to reveal that gene activities of specific cultivated peanut WRKY gene were changed due to SA and JA treatment. Peanut WRKY7, 8 and 13 genes were down-regulated, whereas WRKY1 and 12 genes were up-regulated with SA and JA treatment. These results could provide valuable information for peanut improvement. PMID:27200012

  19. Genome-wide identification and characterization of the Dof gene family in Medicago truncatula.

    PubMed

    Shu, Y J; Song, L L; Zhang, J; Liu, Y; Guo, C H

    2015-01-01

    The DNA-binding one zinc finger (Dof) family is a classic plant-specific zinc-finger transcription factor family, which is involved in many important processes, including seed maturation and germination, plant growth and development, and light responses. Investigation of the Medicago truncatula genome revealed 42 putative Dof genes, each of which holds one Dof domain. These genes were classified into four groups based on phylogenetic analysis, which are similar to the groups reported for Arabidopsis and rice. Based on genome duplication analysis, it was found that the MtDof genes were distributed on all chromosomes and had expanded through tandem gene duplication and segmental duplication events. Two main duplication regions were identified, one from tandem duplication and another from segmental duplication. By analyzing high-throughput sequencing data from M. truncatula, we found that most of the MtDof genes showed specific expression patterns in different tissues. According to cis-regulatory element analysis, these MtDof genes are regulated by different cis-acting motifs, which are important for the functional divergence of the MtDof genes in different processes. Thus, using genome-wide identification, evolution, and expression pattern analysis of the Dof genes in M. truncatula, our study provides valuable information for understanding the potential function of the Dof genes in regulating the growth and development of M. truncatula. PMID:26400295

  20. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples

    PubMed Central

    Gara, Sudheer Kumar; Wang, Yonghong; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Meltzer, Paul S.; Kebebew, Electron

    2015-01-01

    To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics. PMID:26446994

  1. Genome-wide temporal-spatial gene expression profiling of drought responsiveness in rice

    PubMed Central

    2011-01-01

    Background Rice is highly sensitive to drought, and the effect of drought may vary with the different genotypes and development stages. Genome-wide gene expression profiling was used as the initial point to dissect molecular genetic mechanism of this complex trait and provide valuable information for the improvement of drought tolerance in rice. Affymetrix rice genome array containing 48,564 japonica and 1,260 indica sequences was used to analyze the gene expression pattern of rice exposed to drought stress. The transcriptome from leaf, root, and young panicle at three developmental stages was comparatively analyzed combined with bioinformatics exploring drought stress related cis-elements. Results There were 5,284 genes detected to be differentially expressed under drought stress. Most of these genes were tissue- or stage-specific regulated by drought. The tissue-specific down-regulated genes showed distinct function categories as photosynthesis-related genes prevalent in leaf, and the genes involved in cell membrane biogenesis and cell wall modification over-presented in root and young panicle. In a drought environment, several genes, such as GA2ox, SAP15, and Chitinase III, were regulated in a reciprocal way in two tissues at the same development stage. A total of 261 transcription factor genes were detected to be differentially regulated by drought stress. Most of them were also regulated in a tissue- or stage-specific manner. A cis-element containing special CGCG box was identified to over-present in the upstream of 55 common induced genes, and it may be very important for rice plants responding to drought environment. Conclusions Genome-wide gene expression profiling revealed that most of the drought differentially expressed genes (DEGs) were under temporal and spatial regulation, suggesting a crosstalk between various development cues and environmental stimuli. The identification of the differentially regulated DEGs, including TF genes and unique candidate

  2. Genome-Wide Screening of Genes Regulated by DNA Methylation in Colon Cancer Development

    PubMed Central

    Galamb, Orsolya; Wichmann, Barna; Sipos, Ferenc; Péterfia, Bálint; Csabai, István; Kovalszky, Ilona; Semsey, Szabolcs; Tulassay, Zsolt; Molnár, Béla

    2012-01-01

    Tumorigenesis is accompanied by changes in the DNA methylation pattern. Our aim was to test a novel approach for identification of transcripts at whole transcript level which are regulated by DNA methylation. Our approach is based on comparison of data obtained from transcriptome profiling of primary human samples and in vitro cell culture models. Epithelial cells were collected by LCM from normal, adenoma, and tumorous colonic samples. Using gene expression analysis, we identified downregulated genes in the tumors compared to normal tissues. In parallel 3000 upregulated genes were determined in HT-29 colon adenocarcinoma cell culture model after DNA demethylation treatment. Of the 2533 transcripts showing reduced expression in the tumorous samples, 154 had increased expression as a result of DNA demethylation treatment. Approximately 2/3 of these genes had decreased expression already in the adenoma samples. Expression of five genes (GCG, NMES-1, LRMP, FAM161B and PTGDR), was validated using RT-PCR. PTGDR showed ambiguous results, therefore it was further studied to verify the extent of DNA methylation and its effect on the protein level. Results confirmed that our approach is suitable for genome-wide screening of genes which are regulated or inactivated by DNA methylation. Activity of these genes possibly interferes with tumor progression, therefore genes identified can be key factors in the formation and in the progression of the disease. PMID:23049694

  3. Genome-wide analysis reveals gene expression and metabolic network dynamics during embryo development in Arabidopsis.

    PubMed

    Xiang, Daoquan; Venglat, Prakash; Tibiche, Chabane; Yang, Hui; Risseeuw, Eddy; Cao, Yongguo; Babic, Vivijan; Cloutier, Mathieu; Keller, Wilf; Wang, Edwin; Selvaraj, Gopalan; Datla, Raju

    2011-05-01

    Embryogenesis is central to the life cycle of most plant species. Despite its importance, because of the difficulty associated with embryo isolation, global gene expression programs involved in plant embryogenesis, especially the early events following fertilization, are largely unknown. To address this gap, we have developed methods to isolate whole live Arabidopsis (Arabidopsis thaliana) embryos as young as zygote and performed genome-wide profiling of gene expression. These studies revealed insights into patterns of gene expression relating to: maternal and paternal contributions to zygote development, chromosomal level clustering of temporal expression in embryogenesis, and embryo-specific functions. Functional analysis of some of the modulated transcription factor encoding genes from our data sets confirmed that they are critical for embryogenesis. Furthermore, we constructed stage-specific metabolic networks mapped with differentially regulated genes by combining the microarray data with the available Kyoto Encyclopedia of Genes and Genomes metabolic data sets. Comparative analysis of these networks revealed the network-associated structural and topological features, pathway interactions, and gene expression with reference to the metabolic activities during embryogenesis. Together, these studies have generated comprehensive gene expression data sets for embryo development in Arabidopsis and may serve as an important foundational resource for other seed plants. PMID:21402797

  4. Computational Characterization of Osteoporosis Associated SNPs and Genes Identified by Genome-Wide Association Studies

    PubMed Central

    Wang, Ya; Wu, Guiju; Chen, Jie; Ye, Weiyuan; Yang, Jiancai; Huang, Qingyang

    2016-01-01

    Objectives Genome-wide association studies (GWASs) have revealed many SNPs and genes associated with osteoporosis. However, influence of these SNPs and genes on the predisposition to osteoporosis is not fully understood. We aimed to identify osteoporosis GWASs-associated SNPs potentially influencing the binding affinity of transcription factors and miRNAs, and reveal enrichment signaling pathway and “hub” genes of osteoporosis GWAS-associated genes. Methods We conducted multiple computational analyses to explore function and mechanisms of osteoporosis GWAS-associated SNPs and genes, including SNP conservation analysis and functional annotation (influence of SNPs on transcription factors and miRNA binding), gene ontology analysis, pathway analysis and protein-protein interaction analysis. Results Our results suggested that a number of SNPs potentially influence the binding affinity of transcription factors (NFATC2, MEF2C, SOX9, RUNX2, ESR2, FOXA1 and STAT3) and miRNAs. Osteoporosis GWASs-associated genes showed enrichment of Wnt signaling pathway, basal cell carcinoma and Hedgehog signaling pathway. Highly interconnected “hub” genes revealed by interaction network analysis are RUNX2, SP7, TNFRSF11B, LRP5, DKK1, ESR1 and SOST. Conclusions Our results provided the targets for further experimental assessment and further insight on osteoporosis pathophysiology. PMID:26930606

  5. Genome-wide characterization and comparative analysis of the MLO gene family in cotton.

    PubMed

    Wang, Xiaoyan; Ma, Qifeng; Dou, Lingling; Liu, Zhen; Peng, Renhai; Yu, Shuxun

    2016-06-01

    In plants, MLO (Mildew Locus O) gene encodes a plant-specific seven transmembrane (TM) domain protein involved in several cellular processes, including susceptibility to powdery mildew (PM). In this study, a genome-wide characterization of the MLO gene family in G. raimondii L., G. arboreum L. and G. hirsutum L. was performed. In total, 22, 17 and 38 homologous sequences were identified for each species, respectively. Gene organization, including chromosomal location, gene clustering and gene duplication, was investigated. Homologues related to PM susceptibility in upland cotton were inferred by phylogenetic relationships with functionally characterized MLO proteins. To conduct a comparative analysis between MLO candidate genes from G. raimondii L., G. arboreum L. and G. hirsutum L., orthologous relationships and conserved synteny blocks were constructed. The transcriptional variation of 38 GhMLO genes in response to exogenous application of salt, mannitol (Man), abscisic acid (ABA), ethylene (ETH), jasmonic acid (JA) and salicylic acid (SA) was monitored. Further studies should be conducted to elucidate the functions of MLO genes in PM susceptibility and phytohormone signalling pathways. PMID:26986931

  6. SYSTEMS BIOLOGY ANALYSES OF GENE EXPRESSION AND GENOME WIDE ASSOCIATION STUDY DATA IN OBSTRUCTIVE SLEEP APNEA

    PubMed Central

    LIU, YU; PATEL, SANJAY; NIBBE, ROD; MAXWELL, SEAN; CHOWDHURY, SALIM A.; KOYUTURK, MEHMET; ZHU, XIAOFENG; LARKIN, EMMA K.; BUXBAUM, SARAH G; PUNJABI, NARESH M.; GHARIB, SINA A.; REDLINE, SUSAN; CHANCE, MARK R.

    2015-01-01

    The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA. PMID:21121029

  7. A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

    PubMed Central

    Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M.; Himes, Blanca E.; Liu, Andy; Szefler, Stanley J.; Strunk, Robert; Castro, Mario; Hansel, Nadia N.; Diette, Gregory B.; Vonakis, Becky M.; Adkinson, N. Franklin; Avila, Lydiana; Soto-Quiros, Manuel; Barraza-Villareal, Albino; Lemanske, Robert F.; Solway, Julian; Krishnan, Jerry; White, Steven R.; Cheadle, Chris; Berger, Alan E.; Fan, Jinshui; Boorgula, Meher Preethi; Nicolae, Dan; Gilliland, Frank; Barnes, Kathleen; London, Stephanie J.; Martinez, Fernando; Ober, Carole; Celedón, Juan C.; Carey, Vincent J.; Weiss, Scott T.; Raby, Benjamin A.

    2014-01-01

    Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6,706 cis-acting expression-associated variants (eSNP) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNP were tested for association with asthma in 359 asthma cases and 846 controls from the Childhood Asthma Management Program, with verification using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE)-qPCR and Chromatin-Immunoprecipitation (ChIP)-PCR in lung derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNP demonstrated associations with asthma in both cohorts. We confirmed the previously-reported association of ORMDL3/GSDMB variants with asthma (combined p=2.9 × 108). Reproducible associations were also observed for eSNP in three additional genes: FADS2 (p=0.002), NAGA (p=0.0002), and F13A1 (p=0.0001). We subsequently demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatics, and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes, and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma. PMID:24934276

  8. Hypothesis-Driven Candidate Genes for Schizophrenia Compared to Genome-Wide Association Results

    PubMed Central

    Collins, Ann L.; Kim, Yunjung; Sklar, Pamela; O’Donovan, Michael C.; Sullivan, Patrick F.

    2014-01-01

    Background Candidate gene studies have been a key approach to the genetics of schizophrenia. Results of these studies have been confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised via comparison with the results of genome-wide association studies (GWAS). Methods We described the characteristics of hypothesis-driven candidate gene studies from SZGene, and used pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International Schizophrenia Consortium (ISC). Results SZGene contained 732 autosomal genes evaluated in 1,374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC had power of 89% to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p-values in hypothesis-driven candidate genes nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (schizophrenia as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes had no notable ISC results (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1, and SLC6A4). Conclusions We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature were enriched for common variation involved in the etiology of schizophrenia. Larger samples are required definitively to evaluate this conclusion. PMID:21854684

  9. Genome-wide analysis and expression profiling of the phospholipase D gene family in Gossypium arboreum.

    PubMed

    Tang, Kai; Dong, Chunjuan; Liu, Jinyuan

    2016-02-01

    The plant phospholipase D (PLD) plays versatile functions in multiple aspects of plant growth, development, and stress responses. However, until now, our knowledge concerning the PLD gene family members and their expression patterns in cotton has been limited. In this study, we performed for the first time the genome-wide analysis and expression profiling of PLD gene family in Gossypium arboretum, and finally, a total of 19 non-redundant PLD genes (GaPLDs) were identified. Based on the phylogenetic analysis, they were divided into six well-supported clades (α, β/γ, δ, ε, ζ and φ). Most of the GaPLD genes within the same clade showed the similar exon-intron organization and highly conserved motif structures. Additionally, the chromosomal distribution pattern revealed that GaPLD genes were unevenly distributed across 10 of the 13 cotton chromosomes. Segmental duplication is the major contributor to the expansion of GaPLD gene family and estimated to have occurred from 19.61 to 20.44 million years ago when a recent large-scale genome duplication occurred in cotton. Moreover, the expression profiling provides the functional divergence of GaPLD genes in cotton and provides some new light on the molecular mechanisms of GaPLDα1 and GaPLDδ2 in fiber development. PMID:26718354

  10. A Genome-Wide Regulatory Framework Identifies Maize Pericarp Color1 Controlled Genes[C][W

    PubMed Central

    Morohashi, Kengo; Casas, María Isabel; Ferreyra, Lorena Falcone; Mejía-Guerra, María Katherine; Pourcel, Lucille; Yilmaz, Alper; Feller, Antje; Carvalho, Bruna; Emiliani, Julia; Rodriguez, Eduardo; Pellegrinet, Silvina; McMullen, Michael; Casati, Paula; Grotewold, Erich

    2012-01-01

    Pericarp Color1 (P1) encodes an R2R3-MYB transcription factor responsible for the accumulation of insecticidal flavones in maize (Zea mays) silks and red phlobaphene pigments in pericarps and other floral tissues, which makes P1 an important visual marker. Using genome-wide expression analyses (RNA sequencing) in pericarps and silks of plants with contrasting P1 alleles combined with chromatin immunoprecipitation coupled with high-throughput sequencing, we show here that the regulatory functions of P1 are much broader than the activation of genes corresponding to enzymes in a branch of flavonoid biosynthesis. P1 modulates the expression of several thousand genes, and ∼1500 of them were identified as putative direct targets of P1. Among them, we identified F2H1, corresponding to a P450 enzyme that converts naringenin into 2-hydroxynaringenin, a key branch point in the P1-controlled pathway and the first step in the formation of insecticidal C-glycosyl flavones. Unexpectedly, the binding of P1 to gene regulatory regions can result in both gene activation and repression. Our results indicate that P1 is the major regulator for a set of genes involved in flavonoid biosynthesis and a minor modulator of the expression of a much larger gene set that includes genes involved in primary metabolism and production of other specialized compounds. PMID:22822204

  11. Genome-wide differential gene expression in immortalized DF-1 chicken embryo fibroblast cell line

    PubMed Central

    2011-01-01

    Background When compared to primary chicken embryo fibroblast (CEF) cells, the immortal DF-1 CEF line exhibits enhanced growth rates and susceptibility to oxidative stress. Although genes responsible for cell cycle regulation and antioxidant functions have been identified, the genome-wide transcription profile of immortal DF-1 CEF cells has not been previously reported. Global gene expression in primary CEF and DF-1 cells was performed using a 4X44K chicken oligo microarray. Results A total of 3876 differentially expressed genes were identified with a 2 fold level cutoff that included 1706 up-regulated and 2170 down-regulated genes in DF-1 cells. Network and functional analyses using Ingenuity Pathways Analysis (IPA, Ingenuity® Systems, http://www.ingenuity.com) revealed that 902 of 3876 differentially expressed genes were classified into a number of functional groups including cellular growth and proliferation, cell cycle, cellular movement, cancer, genetic disorders, and cell death. Also, the top 5 gene networks with intermolecular connections were identified. Bioinformatic analyses suggested that DF-1 cells were characterized by enhanced molecular mechanisms for cell cycle progression and proliferation, suppressing cell death pathways, altered cellular morphogenesis, and accelerated capacity for molecule transport. Key molecules for these functions include E2F1, BRCA1, SRC, CASP3, and the peroxidases. Conclusions The global gene expression profiles provide insight into the cellular mechanisms that regulate the unique characteristics observed in immortal DF-1 CEF cells. PMID:22111699

  12. Genome-Wide Analysis of the Cyclin Gene Family in Tomato

    PubMed Central

    Zhang, Tingyan; Wang, Xin; Lu, Yongen; Cai, Xiaofeng; Ye, Zhibiao; Zhang, Junhong

    2014-01-01

    Cyclins play important roles in cell division and cell expansion. They also interact with cyclin-dependent kinases to control cell cycle progression in plants. Our genome-wide analysis identified 52 expressed cyclin genes in tomato. Phylogenetic analysis of the deduced amino sequences of tomato and Arabidopsis cyclin genes divided them into 10 types, A-, B-, C-, D-, H-, L-, T-, U-, SDS- and J18. Pfam analysis indicated that most tomato cyclins contain a cyclin-N domain. C-, H- and J18 types only contain a cyclin-C domain, and U-type cyclins contain another potential cyclin domain. All of the cyclin genes are distributed throughout the tomato genome except for chromosome 8, and 30 of them were found to be segmentally duplicated; they are found on the duplicate segments of chromosome 1, 2, 3, 4, 5, 6, 10, 11 and 12, suggesting that tomato cyclin genes experienced a mass of segmental duplication. Quantitative real-time polymerase chain reaction analysis indicates that the expression patterns of tomato cyclin genes were significantly different in vegetative and reproductive stages. Transcription of most cyclin genes can be enhanced or repressed by exogenous application of gibberellin, which implies that gibberellin maybe a direct regulator of cyclin genes. The study presented here may be useful as a guide for further functional research on tomato cyclins. PMID:24366066

  13. Candidate Essential Genes in Burkholderia cenocepacia J2315 Identified by Genome-Wide TraDIS

    PubMed Central

    Wong, Yee-Chin; Abd El Ghany, Moataz; Naeem, Raeece; Lee, Kok-Wei; Tan, Yung-Chie; Pain, Arnab; Nathan, Sheila

    2016-01-01

    Burkholderia cenocepacia infection often leads to fatal cepacia syndrome in cystic fibrosis patients. However, antibiotic therapy rarely results in complete eradication of the pathogen due to its intrinsic resistance to many clinically available antibiotics. Recent attention has turned to the identification of essential genes as the proteins encoded by these genes may serve as potential targets for development of novel antimicrobials. In this study, we utilized TraDIS (Transposon Directed Insertion-site Sequencing) as a genome-wide screening tool to facilitate the identification of B. cenocepacia genes essential for its growth and viability. A transposon mutant pool consisting of approximately 500,000 mutants was successfully constructed, with more than 400,000 unique transposon insertion sites identified by computational analysis of TraDIS datasets. The saturated library allowed for the identification of 383 genes that were predicted to be essential in B. cenocepacia. We extended the application of TraDIS to identify conditionally essential genes required for in vitro growth and revealed an additional repertoire of 439 genes to be crucial for B. cenocepacia growth under nutrient-depleted conditions. The library of B. cenocepacia mutants can subsequently be subjected to various biologically related conditions to facilitate the discovery of genes involved in niche adaptation as well as pathogenicity and virulence. PMID:27597847

  14. Candidate Essential Genes in Burkholderia cenocepacia J2315 Identified by Genome-Wide TraDIS.

    PubMed

    Wong, Yee-Chin; Abd El Ghany, Moataz; Naeem, Raeece; Lee, Kok-Wei; Tan, Yung-Chie; Pain, Arnab; Nathan, Sheila

    2016-01-01

    Burkholderia cenocepacia infection often leads to fatal cepacia syndrome in cystic fibrosis patients. However, antibiotic therapy rarely results in complete eradication of the pathogen due to its intrinsic resistance to many clinically available antibiotics. Recent attention has turned to the identification of essential genes as the proteins encoded by these genes may serve as potential targets for development of novel antimicrobials. In this study, we utilized TraDIS (Transposon Directed Insertion-site Sequencing) as a genome-wide screening tool to facilitate the identification of B. cenocepacia genes essential for its growth and viability. A transposon mutant pool consisting of approximately 500,000 mutants was successfully constructed, with more than 400,000 unique transposon insertion sites identified by computational analysis of TraDIS datasets. The saturated library allowed for the identification of 383 genes that were predicted to be essential in B. cenocepacia. We extended the application of TraDIS to identify conditionally essential genes required for in vitro growth and revealed an additional repertoire of 439 genes to be crucial for B. cenocepacia growth under nutrient-depleted conditions. The library of B. cenocepacia mutants can subsequently be subjected to various biologically related conditions to facilitate the discovery of genes involved in niche adaptation as well as pathogenicity and virulence. PMID:27597847

  15. Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs.

    PubMed

    Steegenga, Wilma T; Boekschoten, Mark V; Lute, Carolien; Hooiveld, Guido J; de Groot, Philip J; Morris, Tiffany J; Teschendorff, Andrew E; Butcher, Lee M; Beck, Stephan; Müller, Michael

    2014-06-01

    Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression. PMID:24789080

  16. Genome-wide identification, evolutionary and expression analysis of the aspartic protease gene superfamily in grape

    PubMed Central

    2013-01-01

    Background Aspartic proteases (APs) are a large family of proteolytic enzymes found in almost all organisms. In plants, they are involved in many biological processes, such as senescence, stress responses, programmed cell death, and reproduction. Prior to the present study, no grape AP gene(s) had been reported, and their research on woody species was very limited. Results In this study, a total of 50 AP genes (VvAP) were identified in the grape genome, among which 30 contained the complete ASP domain. Synteny analysis within grape indicated that segmental and tandem duplication events contributed to the expansion of the grape AP family. Additional analysis between grape and Arabidopsis demonstrated that several grape AP genes were found in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the divergence of grape and Arabidopsis. Phylogenetic relationships of the 30 VvAPs with the complete ASP domain and their Arabidopsis orthologs, as well as their gene and protein features were analyzed and their cellular localization was predicted. Moreover, expression profiles of VvAP genes in six different tissues were determined, and their transcript abundance under various stresses and hormone treatments were measured. Twenty-seven VvAP genes were expressed in at least one of the six tissues examined; nineteen VvAPs responded to at least one abiotic stress, 12 VvAPs responded to powdery mildew infection, and most of the VvAPs responded to SA and ABA treatments. Furthermore, integrated synteny and phylogenetic analysis identified orthologous AP genes between grape and Arabidopsis, providing a unique starting point for investigating the function of grape AP genes. Conclusions The genome-wide identification, evolutionary and expression analyses of grape AP genes provide a framework for future analysis of AP genes in defining their roles during stress response. Integrated synteny and phylogenetic analyses provide novel insight into the

  17. Genome-Wide Identification, Characterization and Expression Analysis of the TCP Gene Family in Prunus mume

    PubMed Central

    Zhou, Yuzhen; Xu, Zongda; Zhao, Kai; Yang, Weiru; Cheng, Tangren; Wang, Jia; Zhang, Qixiang

    2016-01-01

    TCP proteins, belonging to a plant-specific transcription factors family, are known to have great functions in plant development, especially flower and leaf development. However, there is little information about this gene family in Prunus mume, which is widely cultivated in China as an ornamental and fruit tree. Here a genome-wide analysis of TCP genes was performed to explore their evolution in P. mume. Nineteen PmTCPs were identified and three of them contained putative miR319 target sites. Phylogenetic and comprehensive bioinformatics analyses of these genes revealed that different types of TCP genes had undergone different evolutionary processes and the genes in the same clade had similar chromosomal location, gene structure, and conserved domains. Expression analysis of these PmTCPs indicated that there were diverse expression patterns among different clades. Most TCP genes were predominantly expressed in flower, leaf, and stem, and showed high expression levels in the different stages of flower bud differentiation, especially in petal formation stage and gametophyte development. Genes in TCP-P subfamily had main roles in both flower development and gametophyte development. The CIN genes in double petal cultivars might have key roles in the formation of petal, while they were correlated with gametophyte development in the single petal cultivar. The CYC/TB1 type genes were highly detected in the formation of petal and pistil. The less-complex flower types of P. mume might result from the fact that there were only two CYC type genes present in P. mume and a lack of CYC2 genes to control the identity of flower types. These results lay the foundation for further study on the functions of TCP genes during flower development.

  18. Genome-wide identification of the expansin gene family in tobacco (Nicotiana tabacum).

    PubMed

    Ding, Anming; Marowa, Prince; Kong, Yingzhen

    2016-10-01

    Expansins are pH-dependent cell wall loosening proteins which form a large family in plants. They have been shown to be involved in various developmental processes and been implicated in enabling plants' ability to absorb nutrients from the soil as well as conferring biotic and abiotic stress resistances. It is therefore clear that they can be potential targets in genetic engineering for crop improvement. Tobacco (Nicotiana tabacum) is a major crop species as well as a model organism. Considering that only a few tobacco expansins have been studied, a genome-wide analysis of the tobacco expansin gene family is necessary. In this study, we identified 52 expansins in tobacco, which were classified into four subfamilies: 36 NtEXPAs, 6 NtEXPBs, 3 NtEXLAs and 7 NtEXLBs. Compared to other species, the NtEXLB subfamily size was relatively larger. Phylogenetic analysis showed that the 52 tobacco expansins were divided into 13 subgroups. Gene structure analysis revealed that genes within subfamilies/subgroups exhibited similar characteristics such as gene structure and protein motif arrangement. Whole-genome duplication and tandem duplication events may have played important roles in the expanding of tobacco expansins. Cis-Acting element analysis revealed that each expansin gene was regulated or several expansin genes were co-regulated by both internal and environmental factors. 35 of these genes were identified as being expressed according to a microarray analysis. In contrast to most NtEXPAs which had higher expression levels in young organs, NtEXLAs and NtEXLBs were preferentially expressed in mature or senescent tissues, suggesting that they might play different roles in different organs or at different developmental stages. As the first step towards genome-wide analysis of the tobacco expansin gene family, our work provides solid background information related to structure, evolution and expression as well as regulatory cis-acting elements of the tobacco expansins. This

  19. Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples

    PubMed Central

    Zeggini, Eleftheria; Weedon, Michael N.; Lindgren, Cecilia M.; Frayling, Timothy M.; Elliott, Katherine S.; Lango, Hana; Timpson, Nicholas J.; Perry, John R.B.; Rayner, Nigel W.; Freathy, Rachel M.; Barrett, Jeffrey C.; Shields, Beverley; Morris, Andrew P.; Ellard, Sian; Groves, Christopher J.; Harries, Lorna W.; Marchini, Jonathan L.; Owen, Katharine R.; Knight, Beatrice; Cardon, Lon R.; Walker, Mark; Hitman, Graham A.; Morris, Andrew D.; Doney, Alex S.F.; McCarthy, Mark I.; Hattersley, Andrew T.

    2013-01-01

    The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. PMID:17463249

  20. A genome-wide screen for genes affecting eisosomes reveals Nce102 function in sphingolipid signaling

    PubMed Central

    Fröhlich, Florian; Moreira, Karen; Aguilar, Pablo S.; Hubner, Nina C.; Mann, Matthias; Walter, Peter

    2009-01-01

    The protein and lipid composition of eukaryotic plasma membranes is highly dynamic and regulated according to need. The sphingolipid-responsive Pkh kinases are candidates for mediating parts of this regulation, as they affect a diverse set of plasma membrane functions, such as cortical actin patch organization, efficient endocytosis, and eisosome assembly. Eisosomes are large protein complexes underlying the plasma membrane and help to sort a group of membrane proteins into distinct domains. In this study, we identify Nce102 in a genome-wide screen for genes involved in eisosome organization and Pkh kinase signaling. Nce102 accumulates in membrane domains at eisosomes where Pkh kinases also localize. The relative abundance of Nce102 in these domains compared with the rest of the plasma membrane is dynamically regulated by sphingolipids. Furthermore, Nce102 inhibits Pkh kinase signaling and is required for plasma membrane organization. Therefore, Nce102 might act as a sensor of sphingolipids that regulates plasma membrane function. PMID:19564405

  1. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes

    PubMed Central

    Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P.; Keane, Thomas

    2016-01-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  2. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    PubMed

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  3. Genome-wide analyses for dissecting gene regulatory networks in the shoot apical meristem.

    PubMed

    Bustamante, Mariana; Matus, José Tomás; Riechmann, José Luis

    2016-04-01

    Shoot apical meristem activity is controlled by complex regulatory networks in which components such as transcription factors, miRNAs, small peptides, hormones, enzymes and epigenetic marks all participate. Many key genes that determine the inherent characteristics of the shoot apical meristem have been identified through genetic approaches. Recent advances in genome-wide studies generating extensive transcriptomic and DNA-binding datasets have increased our understanding of the interactions within the regulatory networks that control the activity of the meristem, identifying new regulators and uncovering connections between previously unlinked network components. In this review, we focus on recent studies that illustrate the contribution of whole genome analyses to understand meristem function. PMID:26956505

  4. Genome-wide identification and characterization of aquaporin gene family in moso bamboo (Phyllostachys edulis).

    PubMed

    Sun, Huayu; Li, Lichao; Lou, Yongfeng; Zhao, Hansheng; Gao, Zhimin

    2016-05-01

    Aquaporins (AQPs) are known to play a major role in maintaining water and hydraulic conductivity balance in the plant system. Numerous studies have showed AQPs execute multi-function throughout plant growth and development, including water transport, nitrogen, carbon, and micronutrient acquisition etc. However, little information on AQPs is known in bamboo. In this study, we present the first genome-wide identification and characterization of AQP genes in moso bamboo (Phyllostachys edulis) using bioinformatics. In total, 26 AQP genes were identified by homologous analysis, which were divided into four groups (PIPs, TIPs, NIPs, and SIPs) based on the phylogenetic analysis. All the genes were located on 26 different scaffolds respectively on basis of the gene mapped to bamboo genome. Evolutionary analysis indicated that Ph. edulis was more close to Oryza sativa than Zea mays in the genetic relationship. Besides, qRT-PCR was used to analyze gene expression profiles, which revealed that AQP genes were expressed constitutively in all the detected tissues, and were all responsive to the environmental cues such as drought, water, and NaCl stresses. This data suggested that AQPs may play fundamental roles in maintaining normal growth and development of bamboo, which would contribute to better understanding for the complex regulation mechanism involved in the fast-growing process of bamboo. Furthermore, the result could provide valuable information for further research on bamboo functional genomics. PMID:26993482

  5. Methods for Genome-Wide Analysis of Gene Expression Changes in Polyploids

    PubMed Central

    Wang, Jianlin; Lee, Jinsuk J.; Tian, Lu; Lee, Hyeon-Se; Chen, Meng; Rao, Sheetal; Wei, Edward N.; Doerge, R. W.; Comai, Luca; Jeffrey Chen, Z.

    2007-01-01

    Polyploidy is an evolutionary innovation, providing extra sets of genetic material for phenotypic variation and adaptation. It is predicted that changes of gene expression by genetic and epigenetic mechanisms are responsible for novel variation in nascent and established polyploids (Liu and Wendel, 2002; Osborn et al., 2003; Pikaard, 2001). Studying gene expression changes in allopolyploids is more complicated than in autopolyploids, because allopolyploids contain more than two sets of genomes originating from divergent, but related, species. Here we describe two methods that are applicable to the genome-wide analysis of gene expression differences resulting from genome duplication in autopolyploids or interactions between homoeologous genomes in allopolyploids. First, we describe an amplified fragment length polymorphism (AFLP)–complementary DNA (cDNA) display method that allows the discrimination of homoeologous loci based on restriction polymorphisms between the progenitors. Second, we describe microarray analyses that can be used to compare gene expression differences between the allopolyploids and respective progenitors using appropriate experimental design and statistical analysis. We demonstrate the utility of these two complementary methods and discuss the pros and cons of using the methods to analyze gene expression changes in autopolyploids and allopolyploids. Furthermore, we describe these methods in general terms to be of wider applicability for comparative gene expression in a variety of evolutionary, genetic, biological, and physiological contexts. PMID:15865985

  6. Genome-Wide Association Analyses Point to Candidate Genes for Electric Shock Avoidance in Drosophila melanogaster

    PubMed Central

    Appel, Mirjam; Scholz, Claus-Jürgen; Müller, Tobias; Dittrich, Marcus; König, Christian; Bockstaller, Marie; Oguz, Tuba; Khalili, Afshin; Antwi-Adjei, Emmanuel; Schauer, Tamas; Margulies, Carla; Tanimoto, Hiromu; Yarali, Ayse

    2015-01-01

    Electric shock is a common stimulus for nociception-research and the most widely used reinforcement in aversive associative learning experiments. Yet, nothing is known about the mechanisms it recruits at the periphery. To help fill this gap, we undertook a genome-wide association analysis using 38 inbred Drosophila melanogaster strains, which avoided shock to varying extents. We identified 514 genes whose expression levels and/ or sequences co-varied with shock avoidance scores. We independently scrutinized 14 of these genes using mutants, validating the effect of 7 of them on shock avoidance. This emphasizes the value of our candidate gene list as a guide for follow-up research. In addition, by integrating our association results with external protein-protein interaction data we obtained a shock avoidance-associated network of 38 genes. Both this network and the original candidate list contained a substantial number of genes that affect mechanosensory bristles, which are hair-like organs distributed across the fly’s body. These results may point to a potential role for mechanosensory bristles in shock sensation. Thus, we not only provide a first list of candidate genes for shock avoidance, but also point to an interesting new hypothesis on nociceptive mechanisms. PMID:25992709

  7. Genome-wide comparison of AP2/ERF superfamily genes between Gossypium arboreum and G. raimondii.

    PubMed

    Lei, Z P; He, D H; Xing, H Y; Tang, B S; Lu, B X

    2016-01-01

    The APETALA2/ethylene response factor (AP2/ERF) transcription factor superfamily is known to regulate diverse processes of plant development and stress responses. We conducted a genome-wide analysis of the AP2/ERF gene in Gossypium arboreum and G. raimondii. Using RPSBLAST and HMMsearch, a total of 271 and 269 AP2/ERF genes were identified in the G. arboreum and G. raimondii genomes, respectively. A phylogenetic analysis classified diploid Gossypium spp AP2/ERF genes into 4 families and 16 subfamilies. Orthologous genes predominated the terminal branch of the phylogenetic tree. Physical mapping showed at least 30% of AP2/ERF genes clustered together. A high level of intra- and inter-species collinearity involving AP2/ERF genes was observed, indicating common (before species divergence) or parallel (after species divergence) segmental duplications, along with tandem duplications, resulting in the species-specific expansion of AP2/ERF genes in diploid Gossypium species. Motif analyses of the AP2/ERF proteins revealed that motif arrangements were highly diverse among subfamilies, but shared by orthologous gene pairs. An examination of nucleotide divergence of AP2/ERF coding regions identified small and non-significant sequence differences among orthologs. Expression profiling of AP2/ERF orthologous gene pairs showed similar abundance levels of orthologous copies between G. arboreum and G. raimondii. Thus, cotton species possess abundant and diverse AP2/ERF genes, resulting from tandem and segmental duplications. Protein and nucleotide sequence and mRNA expression analyses revealed symmetrical evolution, indicating that most AP2/ ERF genes may not have undergone significant biochemical and morphological divergence between sister species. Our study provides detailed insights into the evolutionary characteristics and functional importance of AP2/ERF genes, and could aid in the genetic improvement of agriculturally significant crops in this genus. PMID:27525884

  8. Detecting Gene-Environment Interactions for a Quantitative Trait in a Genome-Wide Association Study.

    PubMed

    Zhang, Pingye; Lewinger, Juan Pablo; Conti, David; Morrison, John L; Gauderman, W James

    2016-07-01

    A genome-wide association study (GWAS) typically is focused on detecting marginal genetic effects. However, many complex traits are likely to be the result of the interplay of genes and environmental factors. These SNPs may have a weak marginal effect and thus unlikely to be detected from a scan of marginal effects, but may be detectable in a gene-environment (G × E) interaction analysis. However, a genome-wide interaction scan (GWIS) using a standard test of G × E interaction is known to have low power, particularly when one corrects for testing multiple SNPs. Two 2-step methods for GWIS have been previously proposed, aimed at improving efficiency by prioritizing SNPs most likely to be involved in a G × E interaction using a screening step. For a quantitative trait, these include a method that screens on marginal effects [Kooperberg and Leblanc, 2008] and a method that screens on variance heterogeneity by genotype [Paré et al., 2010] In this paper, we show that the Paré et al. approach has an inflated false-positive rate in the presence of an environmental marginal effect, and we propose an alternative that remains valid. We also propose a novel 2-step approach that combines the two screening approaches, and provide simulations demonstrating that the new method can outperform other GWIS approaches. Application of this method to a G × Hispanic-ethnicity scan for childhood lung function reveals a SNP near the MARCO locus that was not identified by previous marginal-effect scans. PMID:27230133

  9. Genome-Wide Screening for Genes Associated with FK506 Sensitivity in Fission Yeast

    PubMed Central

    Ma, Yan; Jiang, Weijuan; Liu, Qingbin; Ryuko, Sayomi; Kuno, Takayoshi

    2011-01-01

    We have been studying calcineurin signal transduction pathway in fission yeast Schizosaccharomyces pombe (S. pombe) by developing a genetic screen for mutants that show hypersensitivity to the immunosuppressive calcineurin inhibitor FK506 (tacrolimus). In the present study, to identify nonessential genes that are functionally related to the calcineurin signaling pathway, we performed a genome-wide screen of 3004 haploid deletion strains and confirmed 72 deletion strains to be FK506 sensitive. These 72 genes are classified into nine functional groups to include membrane trafficking (16 genes), signal transduction (10 genes), ubiquitination (8 genes), chromatin remodeling (6 genes), cytokinesis (4 genes), ribosomal protein (3 genes), RNA binding protein (3 genes), and a variety of other known functions (17 genes) or still unknown functions (5 genes) in the biological system. In our previous screening of FK506-sensitive mutants we isolated several membrane-trafficking mutants showing defective cell wall integrity. Here, we further examined the vacuolar fusion, the v-SNARE synaptobrevin Syb1 localization, and the sensitivity to the β-glucan synthase inhibitor micafungin in these 72 FK506-sensitive strains. Results showed that 25 deletion strains exhibited abnormal vacuole fusion, 19 deletion strains exhibited Syb1 mislocalization, and 14 deletion strains exhibited both abnormal vacuole fusion and Syb1 mislocalization, while 42 deletion strains showed both normal vacuole fusion and Syb1 localization. Likewise, 16 deletion strains showed sensitivity to micafungin. Altogether, our present study indicates that calcineurin mediates a plethora of physiological processes in fission yeast, and that calcineurin is extensively involved in cross-talk between signaling pathways. PMID:21850271

  10. Genome-Wide Identification and Expression Analysis of WRKY Gene Family in Capsicum annuum L.

    PubMed Central

    Diao, Wei-Ping; Snyder, John C.; Wang, Shu-Bin; Liu, Jin-Bing; Pan, Bao-Gui; Guo, Guang-Jun; Wei, Ge

    2016-01-01

    The WRKY family of transcription factors is one of the most important families of plant transcriptional regulators with members regulating multiple biological processes, especially in regulating defense against biotic and abiotic stresses. However, little information is available about WRKYs in pepper (Capsicum annuum L.). The recent release of completely assembled genome sequences of pepper allowed us to perform a genome-wide investigation for pepper WRKY proteins. In the present study, a total of 71 WRKY genes were identified in the pepper genome. According to structural features of their encoded proteins, the pepper WRKY genes (CaWRKY) were classified into three main groups, with the second group further divided into five subgroups. Genome mapping analysis revealed that CaWRKY were enriched on four chromosomes, especially on chromosome 1, and 15.5% of the family members were tandemly duplicated genes. A phylogenetic tree was constructed depending on WRKY domain' sequences derived from pepper and Arabidopsis. The expression of 21 selected CaWRKY genes in response to seven different biotic and abiotic stresses (salt, heat shock, drought, Phytophtora capsici, SA, MeJA, and ABA) was evaluated by quantitative RT-PCR; Some CaWRKYs were highly expressed and up-regulated by stress treatment. Our results will provide a platform for functional identification and molecular breeding studies of WRKY genes in pepper. PMID:26941768

  11. Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world.

    PubMed

    Vrieze, Scott I; Iacono, William G; McGue, Matt

    2012-11-01

    This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoffs. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention in the history of psychology and is informed by psychometrics, whereas the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene-environment correlation). Genetically informed designs, which are no longer limited to twin and adoption studies thanks to ever-cheaper genotyping, are required to understand environmental influences. Finally, we outline the vast amount of individual difference in structural genomic variation, most of which remains to be leveraged in genetic association tests. Although the genetic data can be massive and burdensome (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research but with less confusion and more payoff than candidate gene research has to date. PMID:23062291

  12. Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

    PubMed Central

    Mendes-Pereira, Ana M.; Sims, David; Dexter, Tim; Fenwick, Kerry; Assiotis, Ioannis; Kozarewa, Iwanka; Mitsopoulos, Costas; Hakas, Jarle; Zvelebil, Marketa; Lord, Christopher J.; Ashworth, Alan

    2012-01-01

    Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment. PMID:21482774

  13. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors

    PubMed Central

    Olsson, Maja; Beck, Stephan; Kogner, Per; Martinsson, Tommy; Carén, Helena

    2016-01-01

    ABSTRACT Neuroblastoma is a very heterogeneous tumor of childhood. The clinical spectra range from very aggressive metastatic disease to spontaneous regression, even without therapy. Aberrant DNA methylation pattern is a common feature of most cancers. For neuroblastoma, it has been demonstrated both for single genes as well as genome-wide, where a so-called methylator phenotype has been described. Here, we present a study using Illumina 450K methylation arrays on 60 neuroblastoma tumors. We show that aggressive tumors, characterized by International Neuroblastoma Risk Group (INRG) as stage M, are hypermethylated compared to low-grade tumors. On the contrary, INRG stage L tumors display more non-CpG methylation. The genes with the highest number of hypermethylated CpG sites in INRG M tumors are TERT, PCDHGA4, DLX5, and DLX6-AS1. Gene ontology analysis showed a representation of neuronal tumor relevant gene functions among the differentially methylated genes. For validation, we used a set of independent tumors previously analyzed with the Illumina 27K methylation arrays, which confirmed the differentially methylated sites. Top candidate genes with aberrant methylation were analyzed for altered gene expression through the R2 platform (http://r2.amc.nl), and for correlations between methylation and gene expression in a public dataset. Altered expression in nonsurvivors was found for the genes B3GALT4 and KIAA1949, CLIC5, DLX6-AS, TERT, and PIRT, and strongest correlations were found for TRIM36, KIAA0513, and PIRT. Our data indicate that methylation profiling can be used for patient stratification and informs on epigenetically deregulated genes with the potential of increasing our knowledge about the underlying mechanisms of tumor development. PMID:26786290

  14. Genome Wide Association Analysis Reveals New Production Trait Genes in a Male Duroc Population

    PubMed Central

    Wang, Kejun; Liu, Dewu; Hernandez-Sanchez, Jules; Chen, Jie; Liu, Chengkun; Wu, Zhenfang; Fang, Meiying; Li, Ning

    2015-01-01

    In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1), seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3), and one for average daily gain (COL27A1). Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection. PMID:26418247

  15. Genome-wide RNAi screening identifies genes inhibiting the migration of glioblastoma cells.

    PubMed

    Yang, Jian; Fan, Jing; Li, Ying; Li, Fuhai; Chen, Peikai; Fan, Yubo; Xia, Xiaofeng; Wong, Stephen T

    2013-01-01

    Glioblastoma Multiforme (GBM) cells are highly invasive, infiltrating into the surrounding normal brain tissue, making it impossible to completely eradicate GBM tumors by surgery or radiation. Increasing evidence also shows that these migratory cells are highly resistant to cytotoxic reagents, but decreasing their migratory capability can re-sensitize them to chemotherapy. These evidences suggest that the migratory cell population may serve as a better therapeutic target for more effective treatment of GBM. In order to understand the regulatory mechanism underlying the motile phenotype, we carried out a genome-wide RNAi screen for genes inhibiting the migration of GBM cells. The screening identified a total of twenty-five primary hits; seven of them were confirmed by secondary screening. Further study showed that three of the genes, FLNA, KHSRP and HCFC1, also functioned in vivo, and knocking them down caused multifocal tumor in a mouse model. Interestingly, two genes, KHSRP and HCFC1, were also found to be correlated with the clinical outcome of GBM patients. These two genes have not been previously associated with cell migration. PMID:23593504

  16. Genome-wide congealing and rapid transitions across the speciation continuum during speciation with gene flow.

    PubMed

    Feder, Jeffrey L; Nosil, Patrik; Wacholder, Aaron C; Egan, Scott P; Berlocher, Stewart H; Flaxman, Samuel M

    2014-01-01

    Our current understanding of speciation is often based on considering a relatively small number of genes, sometimes in isolation of one another. Here, we describe a possible emergent genome process involving the aggregate effect of many genes contributing to the evolution of reproductive isolation across the speciation continuum. When a threshold number of divergently selected mutations of modest to low fitness effects accumulate between populations diverging with gene flow, nonlinear transitions can occur in which levels of adaptive differentiation, linkage disequilibrium, and reproductive isolation dramatically increase. In effect, the genomes of the populations start to "congeal" into distinct entities representing different species. At this stage, reproductive isolation changes from being a characteristic of specific, divergently selected genes to a property of the genome. We examine conditions conducive to such genome-wide congealing (GWC), describe how to empirically test for GWC, and highlight a putative empirical example involving Rhagoletis fruit flies. We conclude with cautious optimism that the models and concepts discussed here, once extended to large numbers of neutral markers, may provide a framework for integrating information from genome scans, selection experiments, quantitative trait loci mapping, association studies, and natural history to develop a deeper understanding of the genomics of speciation. PMID:25149256

  17. A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes.

    PubMed

    Sidik, Saima M; Huet, Diego; Ganesan, Suresh M; Huynh, My-Hang; Wang, Tim; Nasamu, Armiyaw S; Thiru, Prathapan; Saeij, Jeroen P J; Carruthers, Vern B; Niles, Jacquin C; Lourido, Sebastian

    2016-09-01

    Apicomplexan parasites are leading causes of human and livestock diseases such as malaria and toxoplasmosis, yet most of their genes remain uncharacterized. Here, we present the first genome-wide genetic screen of an apicomplexan. We adapted CRISPR/Cas9 to assess the contribution of each gene from the parasite Toxoplasma gondii during infection of human fibroblasts. Our analysis defines ∼200 previously uncharacterized, fitness-conferring genes unique to the phylum, from which 16 were investigated, revealing essential functions during infection of human cells. Secondary screens identify as an invasion factor the claudin-like apicomplexan microneme protein (CLAMP), which resembles mammalian tight-junction proteins and localizes to secretory organelles, making it critical to the initiation of infection. CLAMP is present throughout sequenced apicomplexan genomes and is essential during the asexual stages of the malaria parasite Plasmodium falciparum. These results provide broad-based functional information on T. gondii genes and will facilitate future approaches to expand the horizon of antiparasitic interventions. PMID:27594426

  18. Genome-wide characterization of phenylalanine ammonia-lyase gene family in watermelon (Citrullus lanatus).

    PubMed

    Dong, Chun-Juan; Shang, Qing-Mao

    2013-07-01

    Phenylalanine ammonia-lyase (PAL), the first enzyme in the phenylpropanoid pathway, plays a critical role in plant growth, development, and adaptation. PAL enzymes are encoded by a gene family in plants. Here, we report a genome-wide search for PAL genes in watermelon. A total of 12 PAL genes, designated ClPAL1-12, are identified . Nine are arranged in tandem in two duplication blocks located on chromosomes 4 and 7, and the other three ClPAL genes are distributed as single copies on chromosomes 2, 3, and 8. Both the cDNA and protein sequences of ClPALs share an overall high identity with each other. A phylogenetic analysis places 11 of the ClPALs into a separate cucurbit subclade, whereas ClPAL2, which belongs to neither monocots nor dicots, may serve as an ancestral PAL in plants. In the cucurbit subclade, seven ClPALs form homologous pairs with their counterparts from cucumber. Expression profiling reveals that 11 of the ClPAL genes are expressed and show preferential expression in the stems and male and female flowers. Six of the 12 ClPALs are moderately or strongly expressed in the fruits, particularly in the pulp, suggesting the potential roles of PAL in the development of fruit color and flavor. A promoter motif analysis of the ClPAL genes implies redundant but distinctive cis-regulatory structures for stress responsiveness. Finally, duplication events during the evolution and expansion of the ClPAL gene family are discussed, and the relationships between the ClPAL genes and their cucumber orthologs are estimated. PMID:23546528

  19. Exploring systemic RNA interference in insects: a genome-wide survey for RNAi genes in Tribolium

    PubMed Central

    Tomoyasu, Yoshinori; Miller, Sherry C; Tomita, Shuichiro; Schoppmeier, Michael; Grossmann, Daniela; Bucher, Gregor

    2008-01-01

    Background RNA interference (RNAi) is a highly conserved cellular mechanism. In some organisms, such as Caenorhabditis elegans, the RNAi response can be transmitted systemically. Some insects also exhibit a systemic RNAi response. However, Drosophila, the leading insect model organism, does not show a robust systemic RNAi response, necessitating another model system to study the molecular mechanism of systemic RNAi in insects. Results We used Tribolium, which exhibits robust systemic RNAi, as an alternative model system. We have identified the core RNAi genes, as well as genes potentially involved in systemic RNAi, from the Tribolium genome. Both phylogenetic and functional analyses suggest that Tribolium has a somewhat larger inventory of core component genes than Drosophila, perhaps allowing a more sensitive response to double-stranded RNA (dsRNA). We also identified three Tribolium homologs of C. elegans sid-1, which encodes a possible dsRNA channel. However, detailed sequence analysis has revealed that these Tribolium homologs share more identity with another C. elegans gene, tag-130. We analyzed tag-130 mutants, and found that this gene does not have a function in systemic RNAi in C. elegans. Likewise, the Tribolium sid-like genes do not seem to be required for systemic RNAi. These results suggest that insect sid-1-like genes have a different function than dsRNA uptake. Moreover, Tribolium lacks homologs of several genes important for RNAi in C. elegans. Conclusion Although both Tribolium and C. elegans show a robust systemic RNAi response, our genome-wide survey reveals significant differences between the RNAi mechanisms of these organisms. Thus, insects may use an alternative mechanism for the systemic RNAi response. Understanding this process would assist with rendering other insects amenable to systemic RNAi, and may influence pest control approaches. PMID:18201385

  20. Genome-wide gene expression profiling reveals unsuspected molecular alterations in pemphigus foliaceus

    PubMed Central

    Malheiros, Danielle; Panepucci, Rodrigo A; Roselino, Ana M; Araújo, Amélia G; Zago, Marco A; Petzl-Erler, Maria Luiza

    2014-01-01

    Pemphigus foliaceus (PF) is a complex autoimmune disease characterized by bullous skin lesions and the presence of antibodies against desmoglein 1. In this study we sought to contribute to a better understanding of the molecular processes in endemic PF, as the identification of factors that participate in the pathogenesis is a prerequisite for understanding its biological basis and may lead to novel therapeutic interventions. CD4+ T lymphocytes are central to the development of the disease. Therefore, we compared genome-wide gene expression profiles of peripheral CD4+ T cells of various PF patient subgroups with each other and with that of healthy individuals. The patient sample was subdivided into three groups: untreated patients with the generalized form of the disease, patients submitted to immunosuppressive treatment, and patients with the localized form of the disease. Comparisons between different subgroups resulted in 135, 54 and 64 genes differentially expressed. These genes are mainly related to lymphocyte adhesion and migration, apoptosis, cellular proliferation, cytotoxicity and antigen presentation. Several of these genes were differentially expressed when comparing lesional and uninvolved skin from the same patient. The chromosomal regions 19q13 and 12p13 concentrate differentially expressed genes and are candidate regions for PF susceptibility genes and disease markers. Our results reveal genes involved in disease severity, potential therapeutic targets and previously unsuspected processes involved in the pathogenesis. Besides, this study adds original information that will contribute to the understanding of PF's pathogenesis and of the still poorly defined in vivo functions of most of these genes. PMID:24813052

  1. Genome-wide gene-environment interactions on quantitative traits using family data.

    PubMed

    Sitlani, Colleen M; Dupuis, Josée; Rice, Kenneth M; Sun, Fangui; Pitsillides, Achilleas N; Cupples, L Adrienne; Psaty, Bruce M

    2016-07-01

    Gene-environment interactions may provide a mechanism for targeting interventions to those individuals who would gain the most benefit from them. Searching for interactions agnostically on a genome-wide scale requires large sample sizes, often achieved through collaboration among multiple studies in a consortium. Family studies can contribute to consortia, but to do so they must account for correlation within families by using specialized analytic methods. In this paper, we investigate the performance of methods that account for within-family correlation, in the context of gene-environment interactions with binary exposures and quantitative outcomes. We simulate both cross-sectional and longitudinal measurements, and analyze the simulated data taking family structure into account, via generalized estimating equations (GEE) and linear mixed-effects models. With sufficient exposure prevalence and correct model specification, all methods perform well. However, when models are misspecified, mixed modeling approaches have seriously inflated type I error rates. GEE methods with robust variance estimates are less sensitive to model misspecification; however, when exposures are infrequent, GEE methods require modifications to preserve type I error rate. We illustrate the practical use of these methods by evaluating gene-drug interactions on fasting glucose levels in data from the Framingham Heart Study, a cohort that includes related individuals. PMID:26626313

  2. Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice.

    PubMed

    Parker, Clarissa C; Gopalakrishnan, Shyam; Carbonetto, Peter; Gonzales, Natalia M; Leung, Emily; Park, Yeonhee J; Aryee, Emmanuel; Davis, Joe; Blizard, David A; Ackert-Bicknell, Cheryl L; Lionikas, Arimantas; Pritchard, Jonathan K; Palmer, Abraham A

    2016-08-01

    Although mice are the most widely used mammalian model organism, genetic studies have suffered from limited mapping resolution due to extensive linkage disequilibrium (LD) that is characteristic of crosses among inbred strains. Carworth Farms White (CFW) mice are a commercially available outbred mouse population that exhibit rapid LD decay in comparison to other available mouse populations. We performed a genome-wide association study (GWAS) of behavioral, physiological and gene expression phenotypes using 1,200 male CFW mice. We used genotyping by sequencing (GBS) to obtain genotypes at 92,734 SNPs. We also measured gene expression using RNA sequencing in three brain regions. Our study identified numerous behavioral, physiological and expression quantitative trait loci (QTLs). We integrated the behavioral QTL and eQTL results to implicate specific genes, including Azi2 in sensitivity to methamphetamine and Zmynd11 in anxiety-like behavior. The combination of CFW mice, GBS and RNA sequencing constitutes a powerful approach to GWAS in mice. PMID:27376237

  3. Genome-wide identification and comparison of legume MLO gene family

    PubMed Central

    Rispail, Nicolas; Rubiales, Diego

    2016-01-01

    MLO proteins are highly conserved proteins with seven trans-membrane domains. Specific MLO genes have been linked to plant disease susceptibility. Others are involved in plant reproduction and in root thigmomorphogenesis. Functions of the remaining MLOs are still unknown. Here we performed a genome-wide survey of the MLO family in eight legume species from different clades of the Papillionoideae sub-family. A total of 118 MLO sequences were identified and characterized. Their deduced protein sequences shared the characteristics of MLO proteins. The total number of MLO genes per legume species varied from 13 to 20 depending on the species. Legume MLOs were evenly distributed over their genomes and tended to localize within syntenic blocks conserved across legume genomes. Phylogenetic analysis indicated that these sequences clustered in seven well-defined clades. Comparison of MLO protein sequences revealed 34 clade-specific motifs in the variable regions of the proteins. Comparative analyses of the MLO family between legume species also uncovered several evolutionary differences between the tropical legume species from the Phaseoloid clades and the other legume species. Altogether, this study provides interesting new features on the evolution of the MLO family. It also provides valuable clues to identify additional MLO genes from non-sequenced species. PMID:27596925

  4. Genome-wide identification and comparison of legume MLO gene family.

    PubMed

    Rispail, Nicolas; Rubiales, Diego

    2016-01-01

    MLO proteins are highly conserved proteins with seven trans-membrane domains. Specific MLO genes have been linked to plant disease susceptibility. Others are involved in plant reproduction and in root thigmomorphogenesis. Functions of the remaining MLOs are still unknown. Here we performed a genome-wide survey of the MLO family in eight legume species from different clades of the Papillionoideae sub-family. A total of 118 MLO sequences were identified and characterized. Their deduced protein sequences shared the characteristics of MLO proteins. The total number of MLO genes per legume species varied from 13 to 20 depending on the species. Legume MLOs were evenly distributed over their genomes and tended to localize within syntenic blocks conserved across legume genomes. Phylogenetic analysis indicated that these sequences clustered in seven well-defined clades. Comparison of MLO protein sequences revealed 34 clade-specific motifs in the variable regions of the proteins. Comparative analyses of the MLO family between legume species also uncovered several evolutionary differences between the tropical legume species from the Phaseoloid clades and the other legume species. Altogether, this study provides interesting new features on the evolution of the MLO family. It also provides valuable clues to identify additional MLO genes from non-sequenced species. PMID:27596925

  5. Genome-wide survey of the gene expression response to saprolegniasis in Atlantic salmon.

    PubMed

    Roberge, Christian; Páez, David J; Rossignol, Orlane; Guderley, Helga; Dodson, Julian; Bernatchez, Louis

    2007-02-01

    Pathogenic saprolegniaceae species are among the major disease-causing agents in farmed salmonids and in freshwater fish in general. Recent studies have used high-throughput cDNA-based methods to identify new potential actors of fish defence systems against various bacteria and viruses. However, the response of fish to fungal or fungus-like pathogens is still poorly documented. Here, we used a 16,006-gene salmonid cDNA microarray to identify genes which transcription levels are modified in juvenile Atlantic salmon (Salmo salar) affected with saprolegniasis compared to healthy fish from the same families. Our results confirmed the importance of non-specific immunity in the response of fish to saprolegniaceae infections and identified both similarities and differences in their genome-wide transcriptional response to oomycetes compared with their responses to bacterial or viral infections. Moreover, several clones with no known homologues were shown to be over-transcribed in infected fish. These may represent as yet unidentified immune-relevant genes in fish. PMID:16806477

  6. Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever

    PubMed Central

    Andersen, Kristian G.; Shylakhter, Ilya; Tabrizi, Shervin; Grossman, Sharon R.; Happi, Christian T.; Sabeti, Pardis C.

    2012-01-01

    Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit. PMID:22312054

  7. Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever.

    PubMed

    Andersen, Kristian G; Shylakhter, Ilya; Tabrizi, Shervin; Grossman, Sharon R; Happi, Christian T; Sabeti, Pardis C

    2012-03-19

    Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit. PMID:22312054

  8. Guilt by rewiring: gene prioritization through network rewiring in Genome Wide Association Studies

    PubMed Central

    Hou, Lin; Chen, Min; Zhang, Clarence K.; Cho, Judy; Zhao, Hongyu

    2014-01-01

    Although Genome Wide Association Studies (GWAS) have identified many susceptibility loci for common diseases, they only explain a small portion of heritability. It is challenging to identify the remaining disease loci because their association signals are likely weak and difficult to identify among millions of candidates. One potentially useful direction to increase statistical power is to incorporate functional genomics information, especially gene expression networks, to prioritize GWAS signals. Most current methods utilizing network information to prioritize disease genes are based on the ‘guilt by association’ principle, in which networks are treated as static, and disease-associated genes are assumed to locate closer with each other than random pairs in the network. In contrast, we propose a novel ‘guilt by rewiring’ principle. Studying the dynamics of gene networks between controls and patients, this principle assumes that disease genes more likely undergo rewiring in patients, whereas most of the network remains unaffected in disease condition. To demonstrate this principle, we consider the changes of co-expression networks in Crohn's disease patients and controls, and how network dynamics reveals information on disease associations. Our results demonstrate that network rewiring is abundant in the immune system, and disease-associated genes are more likely to be rewired in patients. To integrate this network rewiring feature and GWAS signals, we propose to use the Markov random field framework to integrate network information to prioritize genes. Applications in Crohn's disease and Parkinson's disease show that this framework leads to more replicable results, and implicates potentially disease-associated pathways. PMID:24381306

  9. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels.

    PubMed

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65-75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  10. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels

    PubMed Central

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65–75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  11. Genome-Wide Analysis and Characterization of Aux/IAA Family Genes in Brassica rapa

    PubMed Central

    Rameneni, Jana Jeevan; Li, Xiaonan; Sivanandhan, Ganesan; Choi, Su Ryun; Pang, Wenxing; Im, Subin; Lim, Yong Pyo

    2016-01-01

    Auxins are the key players in plant growth development involving leaf formation, phototropism, root, fruit and embryo development. Auxin/Indole-3-Acetic Acid (Aux/IAA) are early auxin response genes noted as transcriptional repressors in plant auxin signaling. However, many studies focus on Aux/ARF gene families and much less is known about the Aux/IAA gene family in Brassica rapa (B. rapa). Here we performed a comprehensive genome-wide analysis and identified 55 Aux/IAA genes in B. rapa using four conserved motifs of Aux/IAA family (PF02309). Chromosomal mapping of the B. rapa Aux/IAA (BrIAA) genes facilitated understanding cluster rearrangement of the crucifer building blocks in the genome. Phylogenetic analysis of BrIAA with Arabidopsis thaliana, Oryza sativa and Zea mays identified 51 sister pairs including 15 same species (BrIAA—BrIAA) and 36 cross species (BrIAA—AtIAA) IAA genes. Among the 55 BrIAA genes, expression of 43 and 45 genes were verified using Genebank B. rapa ESTs and in home developed microarray data from mature leaves of Chiifu and RcBr lines. Despite their huge morphological difference, tissue specific expression analysis of BrIAA genes between the parental lines Chiifu and RcBr showed that the genes followed a similar pattern of expression during leaf development and a different pattern during bud, flower and siliqua development stages. The response of the BrIAA genes to abiotic and auxin stress at different time intervals revealed their involvement in stress response. Single Nucleotide Polymorphisms between IAA genes of reference genome Chiifu and RcBr were focused and identified. Our study examines the scope of conservation and divergence of Aux/IAA genes and their structures in B. rapa. Analyzing the expression and structural variation between two parental lines will significantly contribute to functional genomics of Brassica crops and we belive our study would provide a foundation in understanding the Aux/IAA genes in B. rapa. PMID

  12. Genome-Wide Analysis and Characterization of Aux/IAA Family Genes in Brassica rapa.

    PubMed

    Paul, Parameswari; Dhandapani, Vignesh; Rameneni, Jana Jeevan; Li, Xiaonan; Sivanandhan, Ganesan; Choi, Su Ryun; Pang, Wenxing; Im, Subin; Lim, Yong Pyo

    2016-01-01

    Auxins are the key players in plant growth development involving leaf formation, phototropism, root, fruit and embryo development. Auxin/Indole-3-Acetic Acid (Aux/IAA) are early auxin response genes noted as transcriptional repressors in plant auxin signaling. However, many studies focus on Aux/ARF gene families and much less is known about the Aux/IAA gene family in Brassica rapa (B. rapa). Here we performed a comprehensive genome-wide analysis and identified 55 Aux/IAA genes in B. rapa using four conserved motifs of Aux/IAA family (PF02309). Chromosomal mapping of the B. rapa Aux/IAA (BrIAA) genes facilitated understanding cluster rearrangement of the crucifer building blocks in the genome. Phylogenetic analysis of BrIAA with Arabidopsis thaliana, Oryza sativa and Zea mays identified 51 sister pairs including 15 same species (BrIAA-BrIAA) and 36 cross species (BrIAA-AtIAA) IAA genes. Among the 55 BrIAA genes, expression of 43 and 45 genes were verified using Genebank B. rapa ESTs and in home developed microarray data from mature leaves of Chiifu and RcBr lines. Despite their huge morphological difference, tissue specific expression analysis of BrIAA genes between the parental lines Chiifu and RcBr showed that the genes followed a similar pattern of expression during leaf development and a different pattern during bud, flower and siliqua development stages. The response of the BrIAA genes to abiotic and auxin stress at different time intervals revealed their involvement in stress response. Single Nucleotide Polymorphisms between IAA genes of reference genome Chiifu and RcBr were focused and identified. Our study examines the scope of conservation and divergence of Aux/IAA genes and their structures in B. rapa. Analyzing the expression and structural variation between two parental lines will significantly contribute to functional genomics of Brassica crops and we belive our study would provide a foundation in understanding the Aux/IAA genes in B. rapa. PMID

  13. Genome-Wide Scans for Delineation of Candidate Genes Regulating Seed-Protein Content in Chickpea

    PubMed Central

    Upadhyaya, Hari D.; Bajaj, Deepak; Narnoliya, Laxmi; Das, Shouvik; Kumar, Vinod; Gowda, C. L. L.; Sharma, Shivali; Tyagi, Akhilesh K.; Parida, Swarup K.

    2016-01-01

    Identification of potential genes/alleles governing complex seed-protein content (SPC) is essential in marker-assisted breeding for quality trait improvement of chickpea. Henceforth, the present study utilized an integrated genomics-assisted breeding strategy encompassing trait association analysis, selective genotyping in traditional bi-parental mapping population and differential expression profiling for the first-time to understand the complex genetic architecture of quantitative SPC trait in chickpea. For GWAS (genome-wide association study), high-throughput genotyping information of 16376 genome-based SNPs (single nucleotide polymorphism) discovered from a structured population of 336 sequenced desi and kabuli accessions [with 150–200 kb LD (linkage disequilibrium) decay] was utilized. This led to identification of seven most effective genomic loci (genes) associated [10–20% with 41% combined PVE (phenotypic variation explained)] with SPC trait in chickpea. Regardless of the diverse desi and kabuli genetic backgrounds, a comparable level of association potential of the identified seven genomic loci with SPC trait was observed. Five SPC-associated genes were validated successfully in parental accessions and homozygous individuals of an intra-specific desi RIL (recombinant inbred line) mapping population (ICC 12299 × ICC 4958) by selective genotyping. The seed-specific expression, including differential up-regulation (>four fold) of six SPC-associated genes particularly in accessions, parents and homozygous individuals of the aforementioned mapping population with a high level of contrasting SPC (21–22%) was evident. Collectively, the integrated genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in six potential candidate genes regulating SPC trait in chickpea. Of these, a non-synonymous SNP allele-carrying zinc finger transcription factor gene exhibiting strong association with SPC trait was found to be the most

  14. Genome-Wide Scans for Delineation of Candidate Genes Regulating Seed-Protein Content in Chickpea.

    PubMed

    Upadhyaya, Hari D; Bajaj, Deepak; Narnoliya, Laxmi; Das, Shouvik; Kumar, Vinod; Gowda, C L L; Sharma, Shivali; Tyagi, Akhilesh K; Parida, Swarup K

    2016-01-01

    Identification of potential genes/alleles governing complex seed-protein content (SPC) is essential in marker-assisted breeding for quality trait improvement of chickpea. Henceforth, the present study utilized an integrated genomics-assisted breeding strategy encompassing trait association analysis, selective genotyping in traditional bi-parental mapping population and differential expression profiling for the first-time to understand the complex genetic architecture of quantitative SPC trait in chickpea. For GWAS (genome-wide association study), high-throughput genotyping information of 16376 genome-based SNPs (single nucleotide polymorphism) discovered from a structured population of 336 sequenced desi and kabuli accessions [with 150-200 kb LD (linkage disequilibrium) decay] was utilized. This led to identification of seven most effective genomic loci (genes) associated [10-20% with 41% combined PVE (phenotypic variation explained)] with SPC trait in chickpea. Regardless of the diverse desi and kabuli genetic backgrounds, a comparable level of association potential of the identified seven genomic loci with SPC trait was observed. Five SPC-associated genes were validated successfully in parental accessions and homozygous individuals of an intra-specific desi RIL (recombinant inbred line) mapping population (ICC 12299 × ICC 4958) by selective genotyping. The seed-specific expression, including differential up-regulation (>four fold) of six SPC-associated genes particularly in accessions, parents and homozygous individuals of the aforementioned mapping population with a high level of contrasting SPC (21-22%) was evident. Collectively, the integrated genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in six potential candidate genes regulating SPC trait in chickpea. Of these, a non-synonymous SNP allele-carrying zinc finger transcription factor gene exhibiting strong association with SPC trait was found to be the most

  15. Impact of high predation risk on genome-wide hippocampal gene expression in snowshoe hares.

    PubMed

    Lavergne, Sophia G; McGowan, Patrick O; Krebs, Charles J; Boonstra, Rudy

    2014-11-01

    The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada's boreal forest. During the 8- to 11-year population cycle, hare densities can fluctuate up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect population numbers not only through direct mortality but also through sublethal effects. The chronic stress hypothesis posits that high predation risk during the decline severely stresses hares, leading to greater stress responses, heightened ability to mobilize cortisol and energy, and a poorer body condition. These effects may result in, or be mediated by, differential gene expression. We used an oligonucleotide microarray designed for a closely-related species, the European rabbit (Oryctolagus cuniculus), to characterize differences in genome-wide hippocampal RNA transcript abundance in wild hares from the Yukon during peak and decline phases of a single cycle. A total of 106 genes were differentially regulated between phases. Array results were validated with quantitative real-time PCR, and mammalian protein sequence similarity was used to infer gene function. In comparison to hares from the peak, decline phase hares showed increased expression of genes involved in metabolic processes and hormone response, and decreased expression of immune response and blood cell formation genes. We found evidence for predation risk effects on the expression of genes whose putative functions correspond with physiological impacts known to be induced by predation risk in snowshoe hares. This study shows, for the first time, a link between changes in demography and alterations in neural RNA transcript abundance in a natural population. PMID:25234370

  16. GDSL esterase/lipase genes in Brassica rapa L.: genome-wide identification and expression analysis.

    PubMed

    Dong, Xiangshu; Yi, Hankuil; Han, Ching-Tack; Nou, Ill-Sup; Hur, Yoonkang

    2016-04-01

    GDSL esterase/lipase proteins (GELPs), a very large subfamily of lipolytic enzymes, have been identified in microbes and many plants, but only a few have been characterized with respect to their roles in growth, development, and stress responses. In Brassica crops, as in many other species, genome-wide systematic analysis and functional studies of these genes are still lacking. As a first step to study their function in B. rapa ssp. pekinensis (Chinese cabbage), we comprehensively identified all GELP genes in the genome. We found a total of 121 Brassica rapa GDSL esterase/lipase protein genes (BrGELPs), forming three clades in the phylogenetic analysis (two major and one minor), with an asymmetrical chromosomal distribution. Most BrGELPs possess four strictly conserved residues (Ser-Gly-Asn-His) in four separate conserved regions, along with short conserved and clade-specific blocks, suggesting functional diversification of these proteins. Detailed expression profiling revealed that BrGELPs were expressed in various tissues, including floral organs, implying that BrGELPs play diverse roles in various tissues and during development. Ten percent of BrGELPs were specifically expressed in fertile buds, rather than male-sterile buds, implying their involvement in pollen development. Analyses of EXL6 (extracellular lipase 6) expression and its co-expressed genes in both B. rapa and Arabidopsis, as well as knockdown of this gene in Arabidopsis, revealed that this gene plays an important role in pollen development in both species. The data described in this study will facilitate future investigations of other BrGELP functions. PMID:26423069

  17. Genome-wide analysis of antiviral signature genes in porcine macrophages at different activation statuses.

    PubMed

    Sang, Yongming; Brichalli, Wyatt; Rowland, Raymond R R; Blecha, Frank

    2014-01-01

    Macrophages (MФs) can be polarized to various activation statuses, including classical (M1), alternative (M2), and antiviral states. To study the antiviral activation status of porcine MФs during porcine reproductive and respiratory syndrome virus (PRRSV) infection, we used RNA Sequencing (RNA-Seq) for transcriptomic analysis of differentially expressed genes (DEGs). Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153-5,303 significant DEGs [false discovery rate (FDR) ≤0.001, fold change ≥2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS) and interferon (IFN)γ-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL)-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20-50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK) and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis. PMID:24505295

  18. Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses

    PubMed Central

    Sang, Yongming; Brichalli, Wyatt; Rowland, Raymond R. R.; Blecha, Frank

    2014-01-01

    Macrophages (MФs) can be polarized to various activation statuses, including classical (M1), alternative (M2), and antiviral states. To study the antiviral activation status of porcine MФs during porcine reproductive and respiratory syndrome virus (PRRSV) infection, we used RNA Sequencing (RNA-Seq) for transcriptomic analysis of differentially expressed genes (DEGs). Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153–5,303 significant DEGs [false discovery rate (FDR) ≤0.001, fold change ≥2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS) and interferon (IFN)γ-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL)-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20–50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK) and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis. PMID:24505295

  19. A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis

    PubMed Central

    Kang, Keunsoo; Bae, Jin-Han; Han, Kyudong; Kim, Eun Soo; Kim, Tae-Oh; Yi, Joo Mi

    2016-01-01

    The cause of inflammatory bowel disease (IBD) is still unknown, but there is growing evidence that environmental factors such as epigenetic changes can contribute to the disease etiology. The aim of this study was to identify newly hypermethylated genes in ulcerative colitis (UC) using a genome-wide DNA methylation approach. Using an Infinium HumanMethylation450 BeadChip array, we screened the DNA methylation changes in three normal colon controls and eight UC patients. Using these methylation profiles, 48 probes associated with CpG promoter methylation showed differential hypermethylation between UC patients and normal controls. Technical validations for methylation analyses in a larger series of UC patients (n = 79) were performed by methylation-specific PCR (MSP) and bisulfite sequencing analysis. We finally found that three genes (FAM217B, KIAA1614 and RIBC2) that were significantly elevating the promoter methylation levels in UC compared to normal controls. Interestingly, we confirmed that three genes were transcriptionally silenced in UC patient samples by qRT-PCR, suggesting that their silencing is correlated with the promoter hypermethylation. Pathway analyses were performed using GO and KEGG databases with differentially hypermethylated genes in UC. Our results highlight that aberrant hypermethylation was identified in UC patients which can be a potential biomarker for detecting UC. Moreover, pathway-enriched hypermethylated genes are possibly implicating important cellular function in the pathogenesis of UC. Overall, this study describes a newly hypermethylated gene panel in UC patients and provides new clinical information that can be used for the diagnosis and therapeutic treatment of IBD. PMID:27517910

  20. A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis.

    PubMed

    Kang, Keunsoo; Bae, Jin-Han; Han, Kyudong; Kim, Eun Soo; Kim, Tae-Oh; Yi, Joo Mi

    2016-01-01

    The cause of inflammatory bowel disease (IBD) is still unknown, but there is growing evidence that environmental factors such as epigenetic changes can contribute to the disease etiology. The aim of this study was to identify newly hypermethylated genes in ulcerative colitis (UC) using a genome-wide DNA methylation approach. Using an Infinium HumanMethylation450 BeadChip array, we screened the DNA methylation changes in three normal colon controls and eight UC patients. Using these methylation profiles, 48 probes associated with CpG promoter methylation showed differential hypermethylation between UC patients and normal controls. Technical validations for methylation analyses in a larger series of UC patients (n = 79) were performed by methylation-specific PCR (MSP) and bisulfite sequencing analysis. We finally found that three genes (FAM217B, KIAA1614 and RIBC2) that were significantly elevating the promoter methylation levels in UC compared to normal controls. Interestingly, we confirmed that three genes were transcriptionally silenced in UC patient samples by qRT-PCR, suggesting that their silencing is correlated with the promoter hypermethylation. Pathway analyses were performed using GO and KEGG databases with differentially hypermethylated genes in UC. Our results highlight that aberrant hypermethylation was identified in UC patients which can be a potential biomarker for detecting UC. Moreover, pathway-enriched hypermethylated genes are possibly implicating important cellular function in the pathogenesis of UC. Overall, this study describes a newly hypermethylated gene panel in UC patients and provides new clinical information that can be used for the diagnosis and therapeutic treatment of IBD. PMID:27517910

  1. Genome-wide gene expression profiles in response to plastid division perturbations.

    PubMed

    Maple, Jodi; Winge, Per; Tveitaskog, Astrid Elisabeth; Gargano, Daniela; Bones, Atle M; Møller, Simon Geir

    2011-11-01

    Plastids are vital organelles involved in important metabolic functions that directly affect plant growth and development. Plastids divide by binary fission involving the coordination of numerous protein components. A tight control of the plastid division process ensures that: there is a full plastid complement during and after cell division, specialized cell types have optimal plastid numbers; the division rate is modulated in response to stress, metabolic fluxes and developmental status. However, how this control is exerted by the host nucleus is unclear. Here, we report a genome-wide microarray analysis of three accumulation and replication of chloroplasts (arc) mutants that show a spectrum of altered plastid division characteristics. To ensure a comprehensive data set, we selected arc3, arc5 and arc11 because they harbour mutations in protein components of both the stromal and cytosolic division machinery, are of different evolutionary origin and display different phenotypic severities in terms of chloroplast number, size and volume. We show that a surprisingly low number of genes are affected by altered plastid division status, but that the affected genes encode proteins important for a variety of fundamental plant processes. PMID:21713643

  2. Analysis of gene-specific and genome-wide sperm DNA methylation.

    PubMed

    Hammoud, Saher Sue; Cairns, Bradley R; Carrell, Douglas T

    2013-01-01

    Epigenetic modifications on the DNA sequence (DNA methylation) or on chromatin-associated proteins (i.e., histones) comprise the "cellular epigenome"; together these modifications play an important role in the regulation of gene expression. Unlike the genome, the epigenome is highly variable between cells and is dynamic and plastic in response to cellular stress and environmental cues. The role of the epigenome, specifically, the methylome has been increasingly highlighted and has been implicated in many cellular and developmental processes such as embryonic reprogramming, cellular differentiation, imprinting, X chromosome inactivation, genomic stability, and complex diseases such as cancer. Over the past decade several methods have been developed and applied to characterize DNA methylation at gene-specific loci (using either traditional bisulfite sequencing or pyrosequencing) or its genome-wide distribution (microarray analysis following methylated DNA immunoprecipitation (MeDIP-chip), analysis by sequencing (MeDIP-seq), reduced representation bisulfite sequencing (RRBS), or shotgun bisulfite sequencing). This chapter reviews traditional bisulfite sequencing and shotgun bisulfite sequencing approaches, with a greater emphasis on shotgun bisulfite sequencing methods and data analysis. PMID:22992936

  3. Transport genes and chemotaxis in Laribacter hongkongensis: a genome-wide analysis

    PubMed Central

    2011-01-01

    Background Laribacter hongkongensis is a Gram-negative, sea gull-shaped rod associated with community-acquired gastroenteritis. The bacterium has been found in diverse freshwater environments including fish, frogs and drinking water reservoirs. Using the complete genome sequence data of L. hongkongensis, we performed a comprehensive analysis of putative transport-related genes and genes related to chemotaxis, motility and quorum sensing, which may help the bacterium adapt to the changing environments and combat harmful substances. Results A genome-wide analysis using Transport Classification Database TCDB, similarity and keyword searches revealed the presence of a large diversity of transporters (n = 457) and genes related to chemotaxis (n = 52) and flagellar biosynthesis (n = 40) in the L. hongkongensis genome. The transporters included those from all seven major transporter categories, which may allow the uptake of essential nutrients or ions, and extrusion of metabolic end products and hazardous substances. L. hongkongensis is unique among closely related members of Neisseriaceae family in possessing higher number of proteins related to transport of ammonium, urea and dicarboxylate, which may reflect the importance of nitrogen and dicarboxylate metabolism in this assacharolytic bacterium. Structural modeling of two C4-dicarboxylate transporters showed that they possessed similar structures to the determined structures of other DctP-TRAP transporters, with one having an unusual disulfide bond. Diverse mechanisms for iron transport, including hemin transporters for iron acquisition from host proteins, were also identified. In addition to the chemotaxis and flagella-related genes, the L. hongkongensis genome also contained two copies of qseB/qseC homologues of the AI-3 quorum sensing system. Conclusions The large number of diverse transporters and genes involved in chemotaxis, motility and quorum sensing suggested that the bacterium may utilize a complex system to

  4. Genome-Wide Profiling of PARP1 Reveals an Interplay with Gene Regulatory Regions and DNA Methylation

    PubMed Central

    Nalabothula, Narasimharao; Al-jumaily, Taha; Eteleeb, Abdallah M.; Flight, Robert M.; Xiaorong, Shao; Moseley, Hunter; Rouchka, Eric C.; Fondufe-Mittendorf, Yvonne N.

    2015-01-01

    Poly (ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme involved in DNA repair, chromatin remodeling and gene expression. PARP1 interactions with chromatin architectural multi-protein complexes (i.e. nucleosomes) alter chromatin structure resulting in changes in gene expression. Chromatin structure impacts gene regulatory processes including transcription, splicing, DNA repair, replication and recombination. It is important to delineate whether PARP1 randomly associates with nucleosomes or is present at specific nucleosome regions throughout the cell genome. We performed genome-wide association studies in breast cancer cell lines to address these questions. Our studies show that PARP1 associates with epigenetic regulatory elements genome-wide, such as active histone marks, CTCF and DNase hypersensitive sites. Additionally, the binding of PARP1 to chromatin genome-wide is mutually exclusive with DNA methylation pattern suggesting a functional interplay between PARP1 and DNA methylation. Indeed, inhibition of PARylation results in genome-wide changes in DNA methylation patterns. Our results suggest that PARP1 controls the fidelity of gene transcription and marks actively transcribed gene regions by selectively binding to transcriptionally active chromatin. These studies provide a platform for developing our understanding of PARP1’s role in gene regulation. PMID:26305327

  5. Genome-wide analysis of the omega-3 fatty acid desaturase gene family in Gossypium

    DOE PAGESBeta

    Yurchenko, Olga P.; Park, Sunjung; Ilut, Daniel C.; Inmon, Jay J.; Millhollon, Jon C.; Liechty, Zach; Page, Justin T.; Jenks, Matthew A.; Chapman, Kent D.; Udall, Joshua A.; et al

    2014-11-18

    The majority of commercial cotton varieties planted worldwide are derived from Gossypium hirsutum, which is a naturally occurring allotetraploid produced by interspecific hybridization of A- and D-genome diploid progenitor species. While most cotton species are adapted to warm, semi-arid tropical and subtropical regions, and thus perform well in these geographical areas, cotton seedlings are sensitive to cold temperature, which can significantly reduce crop yields. One of the common biochemical responses of plants to cold temperatures is an increase in omega-3 fatty acids, which protects cellular function by maintaining membrane integrity. The purpose of our study was to identify and characterizemore » the omega-3 fatty acid desaturase (FAD) gene family in G. hirsutum, with an emphasis on identifying omega-3 FADs involved in cold temperature adaptation. Results: Eleven omega-3 FAD genes were identified in G. hirsutum, and characterization of the gene family in extant A and D diploid species (G. herbaceum and G. raimondii, respectively) allowed for unambiguous genome assignment of all homoeologs in tetraploid G. hirsutum. The omega-3 FAD family of cotton includes five distinct genes, two of which encode endoplasmic reticulum-type enzymes (FAD3-1 and FAD3-2) and three that encode chloroplast-type enzymes (FAD7/8-1, FAD7/8-2, and FAD7/8-3). The FAD3-2 gene was duplicated in the A genome progenitor species after the evolutionary split from the D progenitor, but before the interspecific hybridization event that gave rise to modern tetraploid cotton. RNA-seq analysis revealed conserved, gene-specific expression patterns in various organs and cell types and semi-quantitative RT-PCR further revealed that FAD7/8-1 was specifically induced during cold temperature treatment of G. hirsutum seedlings. Conclusions: The omega-3 FAD gene family in cotton was characterized at the genome-wide level in three species, showing relatively ancient establishment of the gene family prior

  6. Integrative pathway analysis of genome-wide association studies and gene expression data in prostate cancer

    PubMed Central

    2012-01-01

    Background Pathway analysis of large-scale omics data assists us with the examination of the cumulative effects of multiple functionally related genes, which are difficult to detect using the traditional single gene/marker analysis. So far, most of the genomic studies have been conducted in a single domain, e.g., by genome-wide association studies (GWAS) or microarray gene expression investigation. A combined analysis of disease susceptibility genes across multiple platforms at the pathway level is an urgent need because it can reveal more reliable and more biologically important information. Results We performed an integrative pathway analysis of a GWAS dataset and a microarray gene expression dataset in prostate cancer. We obtained a comprehensive pathway annotation set from knowledge-based public resources, including KEGG pathways and the prostate cancer candidate gene set, and gene sets specifically defined based on cross-platform information. By leveraging on this pathway collection, we first searched for significant pathways in the GWAS dataset using four methods, which represent two broad groups of pathway analysis approaches. The significant pathways identified by each method varied greatly, but the results were more consistent within each method group than between groups. Next, we conducted a gene set enrichment analysis of the microarray gene expression data and found 13 pathways with cross-platform evidence, including "Fc gamma R-mediated phagocytosis" (PGWAS = 0.003, Pexpr < 0.001, and Pcombined = 6.18 × 10-8), "regulation of actin cytoskeleton" (PGWAS = 0.003, Pexpr = 0.009, and Pcombined = 3.34 × 10-4), and "Jak-STAT signaling pathway" (PGWAS = 0.001, Pexpr = 0.084, and Pcombined = 8.79 × 10-4). Conclusions Our results provide evidence at both the genetic variation and expression levels that several key pathways might have been involved in the pathological development of prostate cancer. Our framework that employs gene expression data to facilitate

  7. Genome-wide identification and expression analysis of the expansin gene family in tomato.

    PubMed

    Lu, Yongen; Liu, Lifeng; Wang, Xin; Han, Zhihui; Ouyang, Bo; Zhang, Junhong; Li, Hanxia

    2016-04-01

    Plant expansins are capable of inducing pH-dependent cell wall extension and stress relaxation. They may be useful as targets for crop improvement to enhance fruit development and stress resistance. Tomato is a major agricultural crop and a model plant for studying fruit development. Because only some tomato expansins have been studied, a genome-wide analysis of the tomato expansin family is necessary. In this study, we identified 25 SlEXPAs, eight SlEXPBs, one SlEXLA, four SlEXLBs, and five short homologs in the tomato genome. 25 of these genes were identified as being expressed. Bioinformatic analysis showed that although tomato expansins share similarities with those from other plants, they also exhibit specific features regarding genetic structure and amino acid sequences, which indicates a unique evolutionary process. Segmental and tandem duplication events have played important roles in expanding the tomato expansin family. Additionally, the 3-exon/2-intron structure may form the basic organization of expansin genes. We identified new expansin genes preferentially expressed in fruits (SlEXPA8, SlEXPB8, and SlEXLB1), roots (SlEXPA9, SlEXLB2, and SlEXLB4), and floral organs. Among the analyzed genes those that were inducible by hormone or stress treatments, including SlEXPA3, SlEXPA7, SlEXPB1-B2, SlEXPB8, SlEXLB1-LB2, and SlEXLB4. Our findings may further clarify the biological activities of tomato expansins, especially those related to fruit development and stress resistance, and contribute to the genetic modification of tomato plants to improve crop quality and yield. PMID:26499956

  8. Genome-wide gene expression analysis of mouse embryonic stem cells exposed to p-dichlorobenzene.

    PubMed

    Tani, Hidenori; Takeshita, Jun-Ichi; Aoki, Hiroshi; Abe, Ryosuke; Toyoda, Akinobu; Endo, Yasunori; Miyamoto, Sadaaki; Gamo, Masashi; Torimura, Masaki

    2016-09-01

    Because of the limitations of whole animal testing approaches for toxicological assessment, new cell-based assay systems have been widely studied. In this study, we focused on two biological products for toxicological assessment: mouse embryonic stem cells (mESCs) and long noncoding RNAs (lncRNAs). mESCs possess the abilities of self-renewal and differentiation into multiple cell types. LlncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to chemicals. We exposed mESCs to p-dichlorobenzene (p-DCB) for 1 or 28 days (daily dose), extracted total RNA, and performed deep sequencing analyses. The genome-wide gene expression analysis indicated that mechanisms modulating proteins occurred following acute and chronic exposures, and mechanisms modulating genomic DNA occurred following chronic exposure. Moreover, our results indicate that three novel lncRNAs (Snora41, Gm19947, and Scarna3a) in mESCs respond to p-DCB exposure. We propose that these lncRNAs have the potential to be surrogate indicators of p-DCB responses in mESCs. PMID:26975756

  9. Spotting and validation of a genome wide oligonucleotide chip with duplicate measurement of each gene

    SciTech Connect

    Thomassen, Mads . E-mail: mads.thomassen@ouh.fyns-amt.dk; Skov, Vibe; Eiriksdottir, Freyja; Tan, Qihua; Jochumsen, Kirsten; Fritzner, Niels; Brusgaard, Klaus; Dahlgaard, Jesper; Kruse, Torben A.

    2006-06-16

    The quality of DNA microarray based gene expression data relies on the reproducibility of several steps in a microarray experiment. We have developed a spotted genome wide microarray chip with oligonucleotides printed in duplicate in order to minimise undesirable biases, thereby optimising detection of true differential expression. The validation study design consisted of an assessment of the microarray chip performance using the MessageAmp and FairPlay labelling kits. Intraclass correlation coefficient (ICC) was used to demonstrate that MessageAmp was significantly more reproducible than FairPlay. Further examinations with MessageAmp revealed the applicability of the system. The linear range of the chips was three orders of magnitude, the precision was high, as 95% of measurements deviated less than 1.24-fold from the expected value, and the coefficient of variation for relative expression was 13.6%. Relative quantitation was more reproducible than absolute quantitation and substantial reduction of variance was attained with duplicate spotting. An analysis of variance (ANOVA) demonstrated no significant day-to-day variation.

  10. Recent advances in globin research using genome-wide association studies and gene editing.

    PubMed

    Orkin, Stuart H

    2016-03-01

    A long-sought goal in the hemoglobin field has been an improved understanding of the mechanisms that regulate the switch from fetal (HbF) to adult (HbA) hemoglobin during development. With such knowledge, the hope is that strategies for directed reactivation of HbF in adults could be devised as an approach to therapy for the β-hemoglobinopathies thalassemia and sickle cell disease. Recent genome-wide association studies (GWAS) led to identification of three loci (BCL11A, HBS1L-MYB, and the β-globin cluster itself) in which natural genetic variation is correlated with different HbF levels in populations. Here, the central role of BCL11A in control of HbF is reviewed from the perspective of how findings may be translated to gene therapy in the not-too-distant future. This summary traces the evolution of recent studies from the initial recognition of BCL11A through GWAS to identification of critical sequences in an enhancer required for its erythroid-specific expression, thereby highlighting an Achilles heel for genome editing. PMID:26866328

  11. A Refined Study of FCRL Genes from a Genome-Wide Association Study for Graves’ Disease

    PubMed Central

    Song, Zhi-Yi; Yang, Shao-Ying; Xue, Li-Qiong; Pan, Chun-Ming; Gu, Zhao-Hui; Liu, Bing-Li; Wang, Hai-Ning; Liang, Liming; Liang, Jun; Zhang, Xiao-Mei; Yuan, Guo-Yue; Li, Chang-Gui; Chen, Ming-Dao; Chen, Jia-Lun; Gao, Guan-Qi; Song, Huai-Dong

    2013-01-01

    To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves’ disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19+ B cells and CD8+ T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (Pcombined = 2.27×10−12 and 7.11×10−13, respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs. PMID:23505439

  12. Identification of genes promoting skin youthfulness by genome-wide association study.

    PubMed

    Chang, Anne L S; Atzmon, Gil; Bergman, Aviv; Brugmann, Samantha; Atwood, Scott X; Chang, Howard Y; Barzilai, Nir

    2014-03-01

    To identify genes that promote facial skin youthfulness (SY), a genome-wide association study on an Ashkenazi Jewish discovery group (n=428) was performed using Affymetrix 6.0 Single-Nucleotide Polymorphism (SNP) Array. After SNP quality controls, 901,470 SNPs remained for analysis. The eigenstrat method showed no stratification. Cases and controls were identified by global facial skin aging severity including intrinsic and extrinsic parameters. Linear regression adjusted for age and gender, with no significant differences in smoking history, body mass index, menopausal status, or personal or family history of centenarians. Six SNPs met the Bonferroni threshold with Pallele<10(-8); two of these six had Pgenotype<10(-8). Quantitative trait loci mapping confirmed linkage disequilibrium. The six SNPs were interrogated by MassARRAY in a replication group (n=436) with confirmation of rs6975107, an intronic region of KCND2 (potassium voltage-gated channel, Shal-related family member 2) (Pgenotype=0.023). A second replication group (n=371) confirmed rs318125, downstream of DIAPH2 (diaphanous homolog 2 (Drosophila)) (Pallele=0.010, Pgenotype=0.002) and rs7616661, downstream of EDEM1 (ER degradation enhancer, mannosidase α-like 1) (Pgenotype=0.042). DIAPH2 has been associated with premature ovarian insufficiency, an aging phenotype in humans. EDEM1 associates with lifespan in animal models, although not humans. KCND2 is expressed in human skin, but has not been associated with aging. These genes represent new candidate genes to study the molecular basis of healthy skin aging. PMID:24037343

  13. PICARA, an analytical pipeline providing probabilistic inference about a priori candidates genes underlying genome-wide association QTL in plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PICARA is an analytical pipeline designed to systematically summarize observed SNP/trait associations identified by genome wide association studies (GWAS) and to identify candidate genes involved in the regulation of complex trait variation. The pipeline provides probabilistic inference about a prio...

  14. Comprehensive Genome-wide Screen for Genes with Cis-acting Regulatory Elements That Respond to Marek's Disease Virus Infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The comprehensive identification of genes underlying phenotypic variation of complex traits such as disease resistance remains one of the greatest challenges in biology despite having genome sequences and more powerful tools. Most genome-wide screens lack sufficient resolving power as they typically...

  15. Alterations in hepatic gene expression and genome-wide DNA methylation in rat offspring exposed to maternal obesity in utero

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adult offspring from obese (OB) rat dams gain greater body weight and fat mass than controls when fed HFD. At PND21, we examined energy expenditure (EE) (indirect calorimetry), hepatic gene expression (microarrays), and changes in genome-wide and global DNA methylation (enrichment-coupled DNA seque...

  16. Maternal obesity influences hepatic gene expression and genome-wide DNA methylation in offspring liver at weaning

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Offspring from obese rat dams gain greater body weight and fat mass when fed HFD. Here we examine hepatic gene expression related to systemic energy expenditure and alterations in genome-wide DNA methylation. Maternal obesity was produced in rats prior to conception via overfeeding of diets. At PND2...

  17. Genome-wide profiling to analyze the effects of FXR activation on mouse renal proximal tubular cells.

    PubMed

    Gui, Ting; Gai, Zhibo

    2015-12-01

    To assess the effect of farnesoid X receptor (FXR), a bile acid nuclear receptor, on renal proximal tubular cells, primary cultured mouse kidney proximal tubular cells were treated with GW4064 (a FXR agonist) or DMSO (as controls) overnight. Analysis of gene expression in the proximal tubular cells by whole genome microarrays indicated that FXR activation induced genes involved in fatty acid degradation and oxidation reduction. Among them, genes involved in glutathione metabolism were mostly induced. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE70296). PMID:26697325

  18. Genome-wide profiling to analyze the effects of FXR activation on mouse renal proximal tubular cells

    PubMed Central

    Gui, Ting; Gai, Zhibo

    2015-01-01

    To assess the effect of farnesoid X receptor (FXR), a bile acid nuclear receptor, on renal proximal tubular cells, primary cultured mouse kidney proximal tubular cells were treated with GW4064 (a FXR agonist) or DMSO (as controls) overnight. Analysis of gene expression in the proximal tubular cells by whole genome microarrays indicated that FXR activation induced genes involved in fatty acid degradation and oxidation reduction. Among them, genes involved in glutathione metabolism were mostly induced. Here we describe in details the contents and quality controls for the gene expression and related results associated with the data uploaded to Gene Expression Omnibus (accession number GSE70296). PMID:26697325

  19. Genome-wide identification and characterization of aquaporin gene family in common bean (Phaseolus vulgaris L.).

    PubMed

    Ariani, Andrea; Gepts, Paul

    2015-10-01

    Plant aquaporins are a large and diverse family of water channel proteins that are essential for several physiological processes in living organisms. Numerous studies have linked plant aquaporins with a plethora of processes, such as nutrient acquisition, CO2 transport, plant growth and development, and response to abiotic stresses. However, little is known about this protein family in common bean. Here, we present a genome-wide identification of the aquaporin gene family in common bean (Phaseolus vulgaris L.), a legume crop essential for human nutrition. We identified 41 full-length coding aquaporin sequences in the common bean genome, divided by phylogenetic analysis into five sub-families (PIPs, TIPs, NIPs, SIPs and XIPs). Residues determining substrate specificity of aquaporins (i.e., NPA motifs and ar/R selectivity filter) seem conserved between common bean and other plant species, allowing inference of substrate specificity for these proteins. Thanks to the availability of RNA-sequencing datasets, expression levels in different organs and in leaves of wild and domesticated bean accessions were evaluated. Three aquaporins (PvTIP1;1, PvPIP2;4 and PvPIP1;2) have the overall highest mean expressions, with PvTIP1;1 having the highest expression among all aquaporins. We performed an EST database mining to identify drought-responsive aquaporins in common bean. This analysis showed a significant increase in expression for PvTIP1;1 in drought stress conditions compared to well-watered environments. The pivotal role suggested for PvTIP1;1 in regulating water homeostasis and drought stress response in the common bean should be verified by further field experimentation under drought stress. PMID:25846963

  20. Genome-Wide Association Study of Intelligence: Additive Effects of Novel Brain Expressed Genes

    ERIC Educational Resources Information Center

    Loo, Sandra K.; Shtir, Corina; Doyle, Alysa E.; Mick, Eric; McGough, James J.; McCracken, James; Biederman, Joseph; Smalley, Susan L.; Cantor, Rita M.; Faraone, Stephen V.; Nelson, Stanley F.

    2012-01-01

    Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally…

  1. A genome-wide regulatory framework identifies maize Pericarp Color1 (P1) controlled genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    P1 encodes an R2R3-MYB transcription factor responsible for the accumulation of insecticidal flavones in maize silks and red phlobaphene pigments in pericarps and other floral tissues. Using genome-wide expression analyses (RNA-Seq) in pericarps and silks of plants with contrasting P1 alleles combin...

  2. Genome-wide association study of maize identifies genes affecting leaf architecture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    U.S. maize yield has increased eightfold in the past 80 years with half of the improvement attributed to genetics. Changes in maize leaf angle and size provided a basis for more efficient light capture as plant densities increased. Through a genome wide association study (GWAS) of the maize nested a...

  3. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep

    PubMed Central

    Mousel, Michelle R.; Reynolds, James O.; White, Stephen N.

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10-5) were identified including markers in or near PIK3CB (P = 2.22x10-6; additive model), KCNB1 (P = 2.93x10-6; dominance model), ZC3H12C (P = 3.25x10-6; genotypic model), JPH1 (P = 4.68x20-6; genotypic model), and MYO3B (P = 5.74x10-6; recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID:26098909

  4. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.

    PubMed

    Mousel, Michelle R; Reynolds, James O; White, Stephen N

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID:26098909

  5. Genome-Wide Meta-Analyses of Plasma Renin Activity and Concentration Reveal Association with the Kininogen 1 and Prekallikrein Genes

    PubMed Central

    Lieb, Wolfgang; Chen, Ming-Huei; Teumer, Alexander; de Boer, Rudolf A.; Lin, Honghuang; Fox, Ervin R.; Musani, Solomon K.; Wilson, James G.; Wang, Thomas J.; Völzke, Henry; Petersen, Ann-Kristin; Meisinger, Christine; Nauck, Matthias; Schlesinger, Sabrina; Li, Yong; Menard, Jöel; Hercberg, Serge; Wichmann, H.-Erich; Völker, Uwe; Rawal, Rajesh; Bidlingmaier, Martin; Hannemann, Anke; Dörr, Marcus; Rettig, Rainer; van Gilst, Wiek H.; van Veldhuisen, Dirk J.; Bakker, Stephan J.L.; Navis, Gerjan; Wallaschofski, Henri; Meneton, Pierre; van der Harst, Pim; Reincke, Martin; Vasan, Ramachandran S.; Consortium, CKDGen

    2015-01-01

    Background The renin-angiotensin-aldosterone-system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood. Methods and Results We meta-analyzed genome-wide association data for plasma renin activity (n=5,275), plasma renin concentrations (n=8,014) and circulating aldosterone (n=13,289) from up to four population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6,487). Single nucleotide polymorphisms (SNPs) in two independent loci displayed associations with plasma renin activity atgenome-wide significance (p<5×10-8). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], p=5.5×10-8). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: p=0.001 for plasma renin, p=0.024 for plasma aldosterone concentration; rs4253311 with p<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911, p= 8.81×10-9), but did not replicate (p=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in African-Americans. Conclusions We identified two genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS. PMID:25477429

  6. Experimental evidence of genome-wide impact of ecological selection during early stages of speciation-with-gene-flow.

    PubMed

    Egan, Scott P; Ragland, Gregory J; Assour, Lauren; Powell, Thomas H Q; Hood, Glen R; Emrich, Scott; Nosil, Patrik; Feder, Jeffrey L

    2015-08-01

    Theory predicts that speciation-with-gene-flow is more likely when the consequences of selection for population divergence transitions from mainly direct effects of selection acting on individual genes to a collective property of all selected genes in the genome. Thus, understanding the direct impacts of ecologically based selection, as well as the indirect effects due to correlations among loci, is critical to understanding speciation. Here, we measure the genome-wide impacts of host-associated selection between hawthorn and apple host races of Rhagoletis pomonella (Diptera: Tephritidae), a model for contemporary speciation-with-gene-flow. Allele frequency shifts of 32 455 SNPs induced in a selection experiment based on host phenology were genome wide and highly concordant with genetic divergence between co-occurring apple and hawthorn flies in nature. This striking genome-wide similarity between experimental and natural populations of R. pomonella underscores the importance of ecological selection at early stages of divergence and calls for further integration of studies of eco-evolutionary dynamics and genome divergence. PMID:26077935

  7. Genome-wide gene expression and DNA methylation differences in abnormally cloned and normally natural mating piglets.

    PubMed

    Zou, C; Fu, Y; Li, C; Liu, H; Li, G; Li, J; Zhang, H; Wu, Y; Li, C

    2016-08-01

    Many studies have proved that DNA methylation can regulate gene expression and further affect skeletal muscle growth and development of pig, whereas the mechanisms of how DNA methylation or gene expression alteration ultimately lead to phenotypical differences between the cloned and natural mating pigs remain elusive. This study aimed to investigate genome-wide gene expression and DNA methylation differences between abnormally cloned and normally natural mating piglets and identify molecular markers related to skeletal muscle growth and development in pig. The DNA methylation and genome-wide gene expression in the two groups of piglets were analysed through methylated DNA immunoprecipitation binding high-throughput sequencing and RNA sequencing respectively. We detected 1493 differentially expressed genes between the two groups, of which 382 genes were also differentially methylated. The results of the integrative analysis between DNA methylation and gene expression revealed that the DNA methylation levels showed a significantly negative and monotonic correlation with gene expression levels around the transcription start site of genes. By contrast, no notable monotonic correlation was observed in other regions. Furthermore, we identified some interesting genes and signalling pathways (e.g. myosin, heavy chain 7 and mammalian target of rapamycin) which possibly play essential roles in skeletal muscle growth and development. The results of this study provide insights into the relationship of DNA methylation with gene expression in newborn piglets and into the mechanisms in abnormally cloned animals through somatic cell nuclear transfer. PMID:27028246

  8. The Phytocyanin Gene Family in Rice (Oryza sativa L.): Genome-Wide Identification, Classification and Transcriptional Analysis

    PubMed Central

    Ma, Haoli; Zhao, Heming; Liu, Zhi; Zhao, Jie

    2011-01-01

    Background Phytocyanins (PCs) are plant-specific blue copper proteins involved in electron transport, and a large number of known PCs are considered to be chimeric arabinogalactan proteins (AGPs). To date there has not been a genome-wide overview of the OsPC gene family. Therefore, as the first step and a useful strategy to elucidate the functions of OsPCs, there is an urgent need for a thorough genome-wide analysis of this gene family. Methodology/Principal Findings In this study, a total of 62 OsPC genes were identified through a comprehensive bioinformatics analysis of the rice (Oryza sativa L.) genome. Based on phylogeny and motif constitution, the family of OsPCs was classified into three subclasses: uclacyanin-like proteins (OsUCLs), stellacyanin-like proteins (OsSCLs) and early nodulin-like proteins (OsENODLs). Structure and glycosylation prediction indicated that 46 OsPCs were glycosylphosphatigylinositol-anchored proteins and 38 OsPCs were chimeric AGPs. Gene duplication analysis revealed that chromosomal segment and tandem duplications contributed almost equally to the expansion of this gene family, and duplication events were mostly happened in the OsUCL subfamily. The expression profiles of OsPC genes were analyzed at different stages of vegetative and reproductive development and under abiotic stresses. It revealed that a large number of OsPC genes were abundantly expressed in the various stages of development. Moreover, 17 genes were regulated under the treatments of abiotic stresses. Conclusions/Significance The genome-wide identification and expression analysis of OsPC genes should facilitate research in this gene family and give new insights toward elucidating their functions in higher plants. PMID:21984902

  9. Large-scale exploration of gene-gene interactions in prostate cancer using a multistage genome-wide association study.

    PubMed

    Ciampa, Julia; Yeager, Meredith; Amundadottir, Laufey; Jacobs, Kevin; Kraft, Peter; Chung, Charles; Wacholder, Sholom; Yu, Kai; Wheeler, William; Thun, Michael J; Divers, W Ryan; Gapstur, Susan; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Giovannucci, Edward; Willett, Walter C; Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine; Hunter, David; Hoover, Robert; Thomas, Gilles; Chanock, Stephen; Chatterjee, Nilanjan

    2011-05-01

    Recent genome-wide association studies have identified independent susceptibility loci for prostate cancer that could influence risk through interaction with other, possibly undetected, susceptibility loci. We explored evidence of interaction between pairs of 13 known susceptibility loci and single nucleotide polymorphisms (SNP) across the genome to generate hypotheses about the functionality of prostate cancer susceptibility regions. We used data from Cancer Genetic Markers of Susceptibility: Stage I included 523,841 SNPs in 1,175 cases and 1,100 controls; Stage II included 27,383 SNPs in an additional 3,941 cases and 3,964 controls. Power calculations assessed the magnitude of interactions our study is likely to detect. Logistic regression was used with alternative methods that exploit constraints of gene-gene independence between unlinked loci to increase power. Our empirical evaluation demonstrated that an empirical Bayes (EB) technique is powerful and robust to possible violation of the independence assumption. Our EB analysis identified several noteworthy interacting SNP pairs, although none reached genome-wide significance. We highlight a Stage II interaction between the major prostate cancer susceptibility locus in the subregion of 8q24 that contains POU5F1B and an intronic SNP in the transcription factor EPAS1, which has potentially important functional implications for 8q24. Another noteworthy result involves interaction of a known prostate cancer susceptibility marker near the prostate protease genes KLK2 and KLK3 with an intronic SNP in PRXX2. Overall, the interactions we have identified merit follow-up study, particularly the EPAS1 interaction, which has implications not only in prostate cancer but also in other epithelial cancers that are associated with the 8q24 locus. PMID:21372204

  10. Genome-wide gene-gene interaction analysis for next-generation sequencing.

    PubMed

    Zhao, Jinying; Zhu, Yun; Xiong, Momiao

    2016-03-01

    The critical barrier in interaction analysis for next-generation sequencing (NGS) data is that the traditional pairwise interaction analysis that is suitable for common variants is difficult to apply to rare variants because of their prohibitive computational time, large number of tests and low power. The great challenges for successful detection of interactions with NGS data are (1) the demands in the paradigm of changes in interaction analysis; (2) severe multiple testing; and (3) heavy computations. To meet these challenges, we shift the paradigm of interaction analysis between two SNPs to interaction analysis between two genomic regions. In other words, we take a gene as a unit of analysis and use functional data analysis techniques as dimensional reduction tools to develop a novel statistic to collectively test interaction between all possible pairs of SNPs within two genome regions. By intensive simulations, we demonstrate that the functional logistic regression for interaction analysis has the correct type 1 error rates and higher power to detect interaction than the currently used methods. The proposed method was applied to a coronary artery disease dataset from the Wellcome Trust Case Control Consortium (WTCCC) study and the Framingham Heart Study (FHS) dataset, and the early-onset myocardial infarction (EOMI) exome sequence datasets with European origin from the NHLBI's Exome Sequencing Project. We discovered that 6 of 27 pairs of significantly interacted genes in the FHS were replicated in the independent WTCCC study and 24 pairs of significantly interacted genes after applying Bonferroni correction in the EOMI study. PMID:26173972

  11. Genome-wide identification, isolation and expression analysis of auxin response factor (ARF) gene family in sweet orange (Citrus sinensis)

    PubMed Central

    Li, Si-Bei; OuYang, Wei-Zhi; Hou, Xiao-Jin; Xie, Liang-Liang; Hu, Chun-Gen; Zhang, Jin-Zhi

    2015-01-01

    Auxin response factors (ARFs) are an important family of proteins in auxin-mediated response, with key roles in various physiological and biochemical processes. To date, a genome-wide overview of the ARF gene family in citrus was not available. A systematic analysis of this gene family in citrus was begun by carrying out a genome-wide search for the homologs of ARFs. A total of 19 nonredundant ARF genes (CiARF) were found and validated from the sweet orange. A comprehensive overview of the CiARFs was undertaken, including the gene structures, phylogenetic analysis, chromosome locations, conserved motifs of proteins, and cis-elements in promoters of CiARF. Furthermore, expression profiling using real-time PCR revealed many CiARF genes, albeit with different patterns depending on types of tissues and/or developmental stages. Comprehensive expression analysis of these genes was also performed under two hormone treatments using real-time PCR. Indole-3-acetic acid (IAA) and N-1-napthylphthalamic acid (NPA) treatment experiments revealed differential up-regulation and down-regulation, respectively, of the 19 citrus ARF genes in the callus of sweet orange. Our comprehensive analysis of ARF genes further elucidates the roles of CiARF family members during citrus growth and development process. PMID:25870601

  12. PICARA, an Analytical Pipeline Providing Probabilistic Inference about A Priori Candidates Genes Underlying Genome-Wide Association QTL in Plants

    PubMed Central

    Chen, Charles; DeClerck, Genevieve; Tian, Feng; Spooner, William; McCouch, Susan; Buckler, Edward

    2012-01-01

    PICARA is an analytical pipeline designed to systematically summarize observed SNP/trait associations identified by genome wide association studies (GWAS) and to identify candidate genes involved in the regulation of complex trait variation. The pipeline provides probabilistic inference about a priori candidate genes using integrated information derived from genome-wide association signals, gene homology, and curated gene sets embedded in pathway descriptions. In this paper, we demonstrate the performance of PICARA using data for flowering time variation in maize – a key trait for geographical and seasonal adaption of plants. Among 406 curated flowering time-related genes from Arabidopsis, we identify 61 orthologs in maize that are significantly enriched for GWAS SNP signals, including key regulators such as FT (Flowering Locus T) and GI (GIGANTEA), and genes centered in the Arabidopsis circadian pathway, including TOC1 (Timing of CAB Expression 1) and LHY (Late Elongated Hypocotyl). In addition, we discover a regulatory feature that is characteristic of these a priori flowering time candidates in maize. This new probabilistic analytical pipeline helps researchers infer the functional significance of candidate genes associated with complex traits and helps guide future experiments by providing statistical support for gene candidates based on the integration of heterogeneous biological information. PMID:23144785

  13. Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

    PubMed Central

    Chasman, Daniel I.; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Böger, Carsten A.; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C.; O'Seaghdha, Conall M.; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V.; O'Connell, Jeffrey R.; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D.; Gierman, Hinco J.; Feitosa, Mary F.; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Lambert, Jean-Charles; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Coassin, Stefan; Pistis, Giorgio; Harris, Tamara B.; Launer, Lenore J.; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D.; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank; Demirkan, Ayse; Oostra, Ben A.; de Andrade, Mariza; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Giulianini, Franco; Koenig, Wolfgang; Illig, Thomas; Meisinger, Christa; Gieger, Christian; Zgaga, Lina; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E.; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H.; Wright, Alan F.; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K.; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Aulchenko, Yurii S.; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Stengel, Bénédicte; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K.; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J. Wouter; Probst-Hensch, Nicole M.; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R.; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S.; van Duijn, Cornelia M.; Borecki, Ingrid B.; Kardia, Sharon L.R.; Liu, Yongmei; Curhan, Gary C.; Rudan, Igor; Gyllensten, Ulf; Wilson, James F.; Franke, Andre; Pramstaller, Peter P.; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline; Hayward, Caroline; Ridker, Paul M; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Kao, W.H. Linda; Fox, Caroline S.; Köttgen, Anna

    2012-01-01

    In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general. PMID:22962313

  14. The missing story behind Genome Wide Association Studies: single nucleotide polymorphisms in gene deserts have a story to tell

    PubMed Central

    Schierding, William; Cutfield, Wayne S.; O'Sullivan, Justin M.

    2014-01-01

    Genome wide association studies are central to the evolution of personalized medicine. However, the propensity for single nucleotide polymorphisms (SNPs) to fall outside of genes means that understanding how these polymorphisms alter cellular function requires an expanded view of human genetics. Integrating the study of genome structure (chromosome conformation capture) into its function opens up new avenues of exploration. Changes in the epigenome associated with SNPs in gene deserts will allow us to define complex diseases in a much clearer manner, and usher in a new era of disease pathway exploration. PMID:24600475

  15. Genome-wide association study using whole-genome sequencing rapidly identifies new genes influencing agronomic traits in rice.

    PubMed

    Yano, Kenji; Yamamoto, Eiji; Aya, Koichiro; Takeuchi, Hideyuki; Lo, Pei-Ching; Hu, Li; Yamasaki, Masanori; Yoshida, Shinya; Kitano, Hidemi; Hirano, Ko; Matsuoka, Makoto

    2016-08-01

    A genome-wide association study (GWAS) can be a powerful tool for the identification of genes associated with agronomic traits in crop species, but it is often hindered by population structure and the large extent of linkage disequilibrium. In this study, we identified agronomically important genes in rice using GWAS based on whole-genome sequencing, followed by the screening of candidate genes based on the estimated effect of nucleotide polymorphisms. Using this approach, we identified four new genes associated with agronomic traits. Some genes were undetectable by standard SNP analysis, but we detected them using gene-based association analysis. This study provides fundamental insights relevant to the rapid identification of genes associated with agronomic traits using GWAS and will accelerate future efforts aimed at crop improvement. PMID:27322545

  16. A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke.

    PubMed

    Arning, Astrid; Hiersche, Milan; Witten, Anika; Kurlemann, Gerhard; Kurnik, Karin; Manner, Daniela; Stoll, Monika; Nowak-Göttl, Ulrike

    2012-12-20

    Pediatric stroke is a rare but highly penetrant disease with a strong genetic background. Although there are an increasing number of genome-wide association studies (GWASs) for stroke in adults, such studies for stroke of pediatric onset are lacking. Here we report the results of the first GWAS on pediatric stroke using a large cohort of 270 family-based trios. GWAS was performed using the Illumina 370 CNV single nucleotide polymorphisms array and analyzed using the transmission disequilibrium test as implemented in PLINK. An enrichment analysis was performed to identify additional true association signals among lower P value signals and searched for cumulatively associated genes within protein interaction data using dmGWAS. We observed clustering of association signals in 4 genes belonging to one family of metalloproteinases at high (ADAMTS12, P = 2.9 × 10(-6); ADAMTS2, P = 8.0 × 10(-6)) and moderate (ADAMTS13, P = 9.3 × 10(-4); ADAMTS17, P = 8.5 × 10(-4)) significance levels. Over-representation and gene-network analyses highlight the importance of the extracellular matrix in conjunction with members of the phosphoinositide and calcium signaling pathways in the susceptibility for pediatric stroke. Associated extracellular matrix components, such as ADAMTS proteins, in combination with misbalanced coagulation signals as unveiled by gene network analysis suggest a major role of postnatal vascular injury with subsequent thrombus formation as the leading cause of pediatric stroke. PMID:22990015

  17. Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

    PubMed Central

    Wheeler, Heather E.; Gorsic, Lidija K.; Welsh, Marleen; Stark, Amy L.; Gamazon, Eric R.; Cox, Nancy J.; Dolan, M. Eileen

    2011-01-01

    Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information. PMID:21755009

  18. Genome-wide identification, classification, and expression analysis of sHSP genes in Chinese cabbage (Brassica rapa ssp pekinensis).

    PubMed

    Tao, P; Guo, W L; Li, B Y; Wang, W H; Yue, Z C; Lei, J L; Zhong, X M

    2015-01-01

    Small heat shock proteins (sHSPs) are essential for the plant's normal development and stress responses, especially the heat stress response. The information regarding sHSP genes in Chinese cabbage (Brassica rapa ssp pekinensis) is sparse, hence we performed a genome-wide analysis to identify sHSP genes in this species. We identified 26 non-redundant sHSP genes distributed on all chromosomes, except chromosome A7, with one additional sHSP gene identified from an expressed sequence tag library. Chinese cabbage was found to contain more sHSP genes than Arabidopsis. The 27 sHSP genes were classified into 11 subfamilies. We identified 22 groups of sHSP syntenic orthologous genes between Chinese cabbage and Arabidopsis. In addition, eight groups of paralogous genes were uncovered in Chinese cabbage. Protein structures of the 27 Chinese cabbage sHSPs were modeled using Phyre2, which revealed that all of them contain several conserved β strands across different subfamilies. In general, gene structure was conserved within each subfamily between Chinese cabbage and Arabidopsis, except for peroxisome sHSP. Analysis of promoter motifs showed that most sHSP genes contain heat shock elements or variants. We also found that biased gene loss has occurred during the evolution of the sHSP subfamily in Chinese cabbage. Expression analysis indicated that the greatest transcript abundance of most Chinese cabbage sHSP genes was found in siliques and early cotyledon embryos. Thus, genome-wide identification and characterization of sHSP genes is a first and important step in the investigation of sHSPs in Chinese cabbage. PMID:26505345

  19. Towards understanding the breast cancer epigenome: a comparison of genome-wide DNA methylation and gene expression data

    PubMed Central

    Michiels, Stefan; Metzger-Filho, Otto; Saini, Kamal S.

    2016-01-01

    Until recently, an elevated disease risk has been ascribed to a genetic predisposition, however, exciting progress over the past years has discovered alternate elements of inheritance that involve epigenetic regulation. Epigenetic changes are heritably stable alterations that include DNA methylation, histone modifications and RNA-mediated silencing. Aberrant DNA methylation is a common molecular basis for a number of important human diseases, including breast cancer. Changes in DNA methylation profoundly affect global gene expression patterns. What is emerging is a more dynamic and complex association between DNA methylation and gene expression than previously believed. Although many tools have already been developed for analyzing genome-wide gene expression data, tools for analyzing genome-wide DNA methylation have not yet reached the same level of refinement. Here we provide an in-depth analysis of DNA methylation in parallel with gene expression data characteristics and describe the particularities of low-level and high-level analyses of DNA methylation data. Low-level analysis refers to pre-processing of methylation data (i.e. normalization, transformation and filtering), whereas high-level analysis is focused on illustrating the application of the widely used class comparison, class prediction and class discovery methods to DNA methylation data. Furthermore, we investigate the influence of DNA methylation on gene expression by measuring the correlation between the degree of CpG methylation and the level of expression and to explore the pattern of methylation as a function of the promoter region. PMID:26657508

  20. Genome-Wide Analysis of Wilms' Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms.

    PubMed

    Kann, Martin; Ettou, Sandrine; Jung, Youngsook L; Lenz, Maximilian O; Taglienti, Mary E; Park, Peter J; Schermer, Bernhard; Benzing, Thomas; Kreidberg, Jordan A

    2015-09-01

    The transcription factor Wilms' tumor suppressor 1 (WT1) is key to podocyte development and viability; however, WT1 transcriptional networks in podocytes remain elusive. We provide a comprehensive analysis of the genome-wide WT1 transcriptional network in podocytes in vivo using chromatin immunoprecipitation followed by sequencing (ChIPseq) and RNA sequencing techniques. Our data show a specific role for WT1 in regulating the podocyte-specific transcriptome through binding to both promoters and enhancers of target genes. Furthermore, we inferred a podocyte transcription factor network consisting of WT1, LMX1B, TCF21, Fox-class and TEAD family transcription factors, and MAFB that uses tissue-specific enhancers to control podocyte gene expression. In addition to previously described WT1-dependent target genes, ChIPseq identified novel WT1-dependent signaling systems. These targets included components of the Hippo signaling system, underscoring the power of genome-wide transcriptional-network analyses. Together, our data elucidate a comprehensive gene regulatory network in podocytes suggesting that WT1 gene regulatory function and podocyte cell-type specification can best be understood in the context of transcription factor-regulatory element network interplay. PMID:25636411

  1. A genome-wide RNAi screening method to discover novel genes involved in virus infection.

    PubMed

    Panda, Debasis; Cherry, Sara

    2015-12-01

    Systematic and comprehensive analysis of host cell proteins involved in virus infection has been difficult in large part due to the lack of robust unbiased methods for their identification. Recent technological breakthroughs allowing development of cell-based genetic screens have greatly facilitated our understanding of virus-host interactions. These include instrumentation for processing in microtiter plates (e.g., 384 well), coupled with sensitive readers and off-the-shelf analysis and informatics pipelines. Because viruses are a significant threat to human health, a better understanding of the cellular factors that impact infection would pave the way for the development of new therapeutics. Here we describe the development and implementation of a genome-wide siRNA screen against a virus using human cells. PMID:26164699

  2. Promising Loci and Genes for Yolk and Ovary Weight in Chickens Revealed by a Genome-Wide Association Study

    PubMed Central

    Yi, Guoqiang; Yuan, Jingwei; Duan, Zhongyi; Qu, Lujiang; Xu, Guiyun; Wang, Kehua; Yang, Ning

    2015-01-01

    Because it serves as the cytoplasm of the oocyte and provides a large amount of reserves, the egg yolk has biological significance for developing embryos. The ovary and its hierarchy of follicles are the main reproductive organs responsible for yolk deposition in chickens. However, the genetic architecture underlying the yolk and ovarian follicle weights remains elusive. Here, we measured the yolk weight (YW) at 11 age points from onset of egg laying to 72 weeks of age and measured the follicle weight (FW) and ovary weight (OW) at 73 weeks as part of a comprehensive genome-wide association study (GWAS) in 1,534 F2 hens derived from reciprocal crosses between White Leghorn (WL) and Dongxiang chickens (DX). For all ages, YWs exhibited moderate single nucleotide polymorphism (SNP)-based heritability estimates (0.25–0.38), while the estimates for FW (0.16) and OW (0.20) were relatively low. Independent univariate genome-wide screens for each trait identified 12, 3, and 31 novel significant associations with YW, FW, and OW, respectively. A list of candidate genes such as ZAR1, STARD13, ACER1b, ACSBG2, and DHRS12 were identified for having a plausible function in yolk and follicle development. These genes are important to the initiation of embryogenesis, lipid transport, lipoprotein synthesis, lipid droplet promotion, and steroid hormone metabolism, respectively. Our study provides for the first time a genome-wide association (GWA) analysis for follicle and ovary weight. Identification of the promising loci as well as potential candidate genes will greatly advance our understanding of the genetic basis underlying dynamic yolk weight and ovarian follicle development and has practical significance in breeding programs for the alteration of yolk weight at different age points. PMID:26332579

  3. GENOME WIDE IDENTIFICATION OF NEW GENES AND PATHWAYS IN PATIENTS WITH BOTH AUTOIMMUNE THYROIDITIS AND TYPE 1 DIABETES

    PubMed Central

    Tomer, Yaron; Dolan, Lawrence M.; Kahaly, George; Divers, Jasmin; D’Agostino, Ralph B.; Imperatore, Giuseppina; Dabelea, Dana; Marcovina, Santica; Black, Mary Helen; Pihoker, Catherine; Hasham, Alia; Salehi Hammerstad, Sara; Greenberg, David A.; Lotay, Vaneet; Zhang, Weijia; Monti, Maria Cristina; Matheis, Nina

    2015-01-01

    Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the cooccurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D+AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p<5×10−8). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D. PMID:25936594

  4. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.

    PubMed

    Tomer, Yaron; Dolan, Lawrence M; Kahaly, George; Divers, Jasmin; D'Agostino, Ralph B; Imperatore, Giuseppina; Dabelea, Dana; Marcovina, Santica; Black, Mary Helen; Pihoker, Catherine; Hasham, Alia; Hammerstad, Sara Salehi; Greenberg, David A; Lotay, Vaneet; Zhang, Weijia; Monti, Maria Cristina; Matheis, Nina

    2015-06-01

    Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10(-8)). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D. PMID:25936594

  5. Genome-Wide Analysis of the Musa WRKY Gene Family: Evolution and Differential Expression during Development and Stress.

    PubMed

    Goel, Ridhi; Pandey, Ashutosh; Trivedi, Prabodh K; Asif, Mehar H

    2016-01-01

    The WRKY gene family plays an important role in the development and stress responses in plants. As information is not available on the WRKY gene family in Musa species, genome-wide analysis has been carried out in this study using available genomic information from two species, Musa acuminata and Musa balbisiana. Analysis identified 147 and 132 members of the WRKY gene family in M. acuminata and M. balbisiana, respectively. Evolutionary analysis suggests that the WRKY gene family expanded much before the speciation in both the species. Most of the orthologs retained in two species were from the γ duplication event which occurred prior to α and β genome-wide duplication (GWD) events. Analysis also suggests that subtle changes in nucleotide sequences during the course of evolution have led to the development of new motifs which might be involved in neo-functionalization of different WRKY members in two species. Expression and cis-regulatory motif analysis suggest possible involvement of Group II and Group III WRKY members during various stresses and growth/development including fruit ripening process respectively. PMID:27014321

  6. The Csr system regulates genome-wide mRNA stability and transcription and thus gene expression in Escherichia coli.

    PubMed

    Esquerré, Thomas; Bouvier, Marie; Turlan, Catherine; Carpousis, Agamemnon J; Girbal, Laurence; Cocaign-Bousquet, Muriel

    2016-01-01

    Bacterial adaptation requires large-scale regulation of gene expression. We have performed a genome-wide analysis of the Csr system, which regulates many important cellular functions. The Csr system is involved in post-transcriptional regulation, but a role in transcriptional regulation has also been suggested. Two proteins, an RNA-binding protein CsrA and an atypical signaling protein CsrD, participate in the Csr system. Genome-wide transcript stabilities and levels were compared in wildtype E. coli (MG1655) and isogenic mutant strains deficient in CsrA or CsrD activity demonstrating for the first time that CsrA and CsrD are global negative and positive regulators of transcription, respectively. The role of CsrA in transcription regulation may be indirect due to the 4.6-fold increase in csrD mRNA concentration in the CsrA deficient strain. Transcriptional action of CsrA and CsrD on a few genes was validated by transcriptional fusions. In addition to an effect on transcription, CsrA stabilizes thousands of mRNAs. This is the first demonstration that CsrA is a global positive regulator of mRNA stability. For one hundred genes, we predict that direct control of mRNA stability by CsrA might contribute to metabolic adaptation by regulating expression of genes involved in carbon metabolism and transport independently of transcriptional regulation. PMID:27112822

  7. The Csr system regulates genome-wide mRNA stability and transcription and thus gene expression in Escherichia coli

    PubMed Central

    Esquerré, Thomas; Bouvier, Marie; Turlan, Catherine; Carpousis, Agamemnon J.; Girbal, Laurence; Cocaign-Bousquet, Muriel

    2016-01-01

    Bacterial adaptation requires large-scale regulation of gene expression. We have performed a genome-wide analysis of the Csr system, which regulates many important cellular functions. The Csr system is involved in post-transcriptional regulation, but a role in transcriptional regulation has also been suggested. Two proteins, an RNA-binding protein CsrA and an atypical signaling protein CsrD, participate in the Csr system. Genome-wide transcript stabilities and levels were compared in wildtype E. coli (MG1655) and isogenic mutant strains deficient in CsrA or CsrD activity demonstrating for the first time that CsrA and CsrD are global negative and positive regulators of transcription, respectively. The role of CsrA in transcription regulation may be indirect due to the 4.6-fold increase in csrD mRNA concentration in the CsrA deficient strain. Transcriptional action of CsrA and CsrD on a few genes was validated by transcriptional fusions. In addition to an effect on transcription, CsrA stabilizes thousands of mRNAs. This is the first demonstration that CsrA is a global positive regulator of mRNA stability. For one hundred genes, we predict that direct control of mRNA stability by CsrA might contribute to metabolic adaptation by regulating expression of genes involved in carbon metabolism and transport independently of transcriptional regulation. PMID:27112822

  8. Genome-Wide Analysis of the Musa WRKY Gene Family: Evolution and Differential Expression during Development and Stress

    PubMed Central

    Goel, Ridhi; Pandey, Ashutosh; Trivedi, Prabodh K.; Asif, Mehar H.

    2016-01-01

    The WRKY gene family plays an important role in the development and stress responses in plants. As information is not available on the WRKY gene family in Musa species, genome-wide analysis has been carried out in this study using available genomic information from two species, Musa acuminata and Musa balbisiana. Analysis identified 147 and 132 members of the WRKY gene family in M. acuminata and M. balbisiana, respectively. Evolutionary analysis suggests that the WRKY gene family expanded much before the speciation in both the species. Most of the orthologs retained in two species were from the γ duplication event which occurred prior to α and β genome-wide duplication (GWD) events. Analysis also suggests that subtle changes in nucleotide sequences during the course of evolution have led to the development of new motifs which might be involved in neo-functionalization of different WRKY members in two species. Expression and cis-regulatory motif analysis suggest possible involvement of Group II and Group III WRKY members during various stresses and growth/development including fruit ripening process respectively. PMID:27014321

  9. Rapid genome-wide evolution in Brassica rapa populations following drought revealed by sequencing of ancestral and descendant gene pools.

    PubMed

    Franks, Steven J; Kane, Nolan C; O'Hara, Niamh B; Tittes, Silas; Rest, Joshua S

    2016-08-01

    There is increasing evidence that evolution can occur rapidly in response to selection. Recent advances in sequencing suggest the possibility of documenting genetic changes as they occur in populations, thus uncovering the genetic basis of evolution, particularly if samples are available from both before and after selection. Here, we had a unique opportunity to directly assess genetic changes in natural populations following an evolutionary response to a fluctuation in climate. We analysed genome-wide differences between ancestors and descendants of natural populations of Brassica rapa plants from two locations that rapidly evolved changes in multiple phenotypic traits, including flowering time, following a multiyear late-season drought in California. These ancestor-descendant comparisons revealed evolutionary shifts in allele frequencies in many genes. Some genes showing evolutionary shifts have functions related to drought stress and flowering time, consistent with an adaptive response to selection. Loci differentiated between ancestors and descendants (FST outliers) were generally different from those showing signatures of selection based on site frequency spectrum analysis (Tajima's D), indicating that the loci that evolved in response to the recent drought and those under historical selection were generally distinct. Very few genes showed similar evolutionary responses between two geographically distinct populations, suggesting independent genetic trajectories of evolution yielding parallel phenotypic changes. The results show that selection can result in rapid genome-wide evolutionary shifts in allele frequencies in natural populations, and highlight the usefulness of combining resurrection experiments in natural populations with genomics for studying the genetic basis of adaptive evolution. PMID:27072809

  10. Genome Wide Association Mapping in Arabidopsis thaliana Identifies Novel Genes Involved in Linking Allyl Glucosinolate to Altered Biomass and Defense

    PubMed Central

    Francisco, Marta; Joseph, Bindu; Caligagan, Hart; Li, Baohua; Corwin, Jason A.; Lin, Catherine; Kerwin, Rachel E.; Burow, Meike; Kliebenstein, Daniel J.

    2016-01-01

    A key limitation in modern biology is the ability to rapidly identify genes underlying newly identified complex phenotypes. Genome wide association studies (GWAS) have become an increasingly important approach for dissecting natural variation by associating phenotypes with genotypes at a genome wide level. Recent work is showing that the Arabidopsis thaliana defense metabolite, allyl glucosinolate (GSL), may provide direct feedback regulation, linking defense metabolism outputs to the growth, and defense responses of the plant. However, there is still a need to identify genes that underlie this process. To start developing a deeper understanding of the mechanism(s) that modulate the ability of exogenous allyl GSL to alter growth and defense, we measured changes in plant biomass and defense metabolites in a collection of natural 96 A. thaliana accessions fed with 50 μM of allyl GSL. Exogenous allyl GSL was introduced exclusively to the roots and the compound transported to the leaf leading to a wide range of heritable effects upon plant biomass and endogenous GSL accumulation. Using natural variation we conducted GWAS to identify a number of new genes which potentially control allyl responses in various plant processes. This is one of the first instances in which this approach has been successfully utilized to begin dissecting a novel phenotype to the underlying molecular/polygenic basis. PMID:27462337

  11. Genome-wide digital transcript analysis of putative fruitlet abscission related genes regulated by ethephon in litchi

    PubMed Central

    Li, Caiqin; Wang, Yan; Ying, Peiyuan; Ma, Wuqiang; Li, Jianguo

    2015-01-01

    The high level of physiological fruitlet abscission in litchi (Litchi chinensis Sonn.) causes severe yield loss. Cell separation occurs at the fruit abscission zone (FAZ) and can be triggered by ethylene. However, a deep knowledge of the molecular events occurring in the FAZ is still unknown. Here, genome-wide digital transcript abundance (DTA) analysis of putative fruit abscission related genes regulated by ethephon in litchi were studied. More than 81 million high quality reads from seven ethephon treated and untreated control libraries were obtained by high-throughput sequencing. Through DTA profile analysis in combination with Gene Ontology and KEGG pathway enrichment analyses, a total of 2730 statistically significant candidate genes were involved in the ethephon-promoted litchi fruitlet abscission. Of these, there were 1867 early-responsive genes whose expressions were up- or down-regulated from 0 to 1 d after treatment. The most affected genes included those related to ethylene biosynthesis and signaling, auxin transport and signaling, transcription factors (TFs), protein ubiquitination, ROS response, calcium signal transduction, and cell wall modification. These genes could be clustered into four groups and 13 subgroups according to their similar expression patterns. qRT-PCR displayed the expression pattern of 41 selected candidate genes, which proved the accuracy of our DTA data. Ethephon treatment significantly increased fruit abscission and ethylene production of fruitlet. The possible molecular events to control the ethephon-promoted litchi fruitlet abscission were prompted out. The increased ethylene evolution in fruitlet would suppress the synthesis and polar transport of auxin and trigger abscission signaling. To the best of our knowledge, it is the first time to monitor the gene expression profile occurring in the FAZ-enriched pedicel during litchi fruit abscission induced by ethephon on the genome-wide level. This study will contribute to a better

  12. Genome-Wide Identification and Expression Profile of Dof Transcription Factor Gene Family in Pepper (Capsicum annuum L.).

    PubMed

    Wu, Zhiming; Cheng, Jiaowen; Cui, Junjie; Xu, Xiaowan; Liang, Guansheng; Luo, Xirong; Chen, Xiaocui; Tang, Xiangqun; Hu, Kailin; Qin, Cheng

    2016-01-01

    Dof (DNA-binding One Zinc Finger) transcription factor family is unique to plants and has diverse roles associated with plant-specific phenomena, such as light, phytohormone and defense responses as well as seed development and germination. Although, genome-wide analysis of this family has been performed in many species, information regarding Dof genes in the pepper, Capsicum annuum L., is extremely limited. In this study, exhaustive searches of pepper genome revealed 33 potential CaDofs that were phylogenetically clustered into four subgroups. Twenty-nine of the 33 Dof genes could be mapped on 11 chromosomes, except for chromosome 7. The intron/exon organizations and conserved motif compositions of these genes were also analyzed. Additionally, phylogenetic analysis and classification of the Dof transcription factor family in eight plant species revealed that S. lycopersicum and C. annuum as well as O. sativa and S. bicolor Dof proteins may have evolved conservatively. Moreover, comprehensive expression analysis of CaDofs using a RNA-seq atlas and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that these genes exhibit a variety of expression patterns. Most of the CaDofs were expressed in at least one of the tissues tested, whereas several genes were identified as being highly responsive to heat and salt stresses. Overall, this study describes the first genome-wide analysis of the pepper Dof family, whose genes exhibited different expression patterns in all primary fruit developmental stages and tissue types, as in response to abiotic stress. In particular, some Dof genes might be used as biomarkers for heat and salt stress. The results could expand our understanding of the roles of Dof genes in pepper. PMID:27200047

  13. Genome-Wide Identification and Expression Profile of Dof Transcription Factor Gene Family in Pepper (Capsicum annuum L.)

    PubMed Central

    Wu, Zhiming; Cheng, Jiaowen; Cui, Junjie; Xu, Xiaowan; Liang, Guansheng; Luo, Xirong; Chen, Xiaocui; Tang, Xiangqun; Hu, Kailin; Qin, Cheng

    2016-01-01

    Dof (DNA-binding One Zinc Finger) transcription factor family is unique to plants and has diverse roles associated with plant-specific phenomena, such as light, phytohormone and defense responses as well as seed development and germination. Although, genome-wide analysis of this family has been performed in many species, information regarding Dof genes in the pepper, Capsicum annuum L., is extremely limited. In this study, exhaustive searches of pepper genome revealed 33 potential CaDofs that were phylogenetically clustered into four subgroups. Twenty-nine of the 33 Dof genes could be mapped on 11 chromosomes, except for chromosome 7. The intron/exon organizations and conserved motif compositions of these genes were also analyzed. Additionally, phylogenetic analysis and classification of the Dof transcription factor family in eight plant species revealed that S. lycopersicum and C. annuum as well as O. sativa and S. bicolor Dof proteins may have evolved conservatively. Moreover, comprehensive expression analysis of CaDofs using a RNA-seq atlas and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that these genes exhibit a variety of expression patterns. Most of the CaDofs were expressed in at least one of the tissues tested, whereas several genes were identified as being highly responsive to heat and salt stresses. Overall, this study describes the first genome-wide analysis of the pepper Dof family, whose genes exhibited different expression patterns in all primary fruit developmental stages and tissue types, as in response to abiotic stress. In particular, some Dof genes might be used as biomarkers for heat and salt stress. The results could expand our understanding of the roles of Dof genes in pepper. PMID:27200047

  14. Genome-wide digital transcript analysis of putative fruitlet abscission related genes regulated by ethephon in litchi.

    PubMed

    Li, Caiqin; Wang, Yan; Ying, Peiyuan; Ma, Wuqiang; Li, Jianguo

    2015-01-01

    The high level of physiological fruitlet abscission in litchi (Litchi chinensis Sonn.) causes severe yield loss. Cell separation occurs at the fruit abscission zone (FAZ) and can be triggered by ethylene. However, a deep knowledge of the molecular events occurring in the FAZ is still unknown. Here, genome-wide digital transcript abundance (DTA) analysis of putative fruit abscission related genes regulated by ethephon in litchi were studied. More than 81 million high quality reads from seven ethephon treated and untreated control libraries were obtained by high-throughput sequencing. Through DTA profile analysis in combination with Gene Ontology and KEGG pathway enrichment analyses, a total of 2730 statistically significant candidate genes were involved in the ethephon-promoted litchi fruitlet abscission. Of these, there were 1867 early-responsive genes whose expressions were up- or down-regulated from 0 to 1 d after treatment. The most affected genes included those related to ethylene biosynthesis and signaling, auxin transport and signaling, transcription factors (TFs), protein ubiquitination, ROS response, calcium signal transduction, and cell wall modification. These genes could be clustered into four groups and 13 subgroups according to their similar expression patterns. qRT-PCR displayed the expression pattern of 41 selected candidate genes, which proved the accuracy of our DTA data. Ethephon treatment significantly increased fruit abscission and ethylene production of fruitlet. The possible molecular events to control the ethephon-promoted litchi fruitlet abscission were prompted out. The increased ethylene evolution in fruitlet would suppress the synthesis and polar transport of auxin and trigger abscission signaling. To the best of our knowledge, it is the first time to monitor the gene expression profile occurring in the FAZ-enriched pedicel during litchi fruit abscission induced by ethephon on the genome-wide level. This study will contribute to a better

  15. Joint Association of Genome-Wide Association Study–Identified Susceptibility Loci and Dietary Patterns in Risk of Renal Cell Carcinoma Among Non-Hispanic Whites

    PubMed Central

    Melkonian, Stephanie C.; Daniel, Carrie R.; Hildebrandt, Michelle A. T.; Tannir, Nizar M.; Ye, Yuanqing; Chow, Wong-Ho; Wood, Christopher G.; Wu, Xifeng

    2014-01-01

    Dietary factors may affect risk of renal cell carcinoma (RCC). In an ongoing case-control study of RCC initiated in Houston, Texas, in 2002, we identified 3 empirically derived dietary patterns: “fruits and vegetables,” “American/Western,” and “Tex-Mex.” Among 659 RCC cases and 699 controls, we evaluated associations of these dietary patterns with RCC risk and whether the associations varied by obesity status, smoking status, physical activity level, history of hypertension, and genetic variants previously identified via genome-wide association studies. Among persons in the highest categories of adherence versus the lowest, the “fruits and vegetables” dietary pattern was associated with an approximately 50% lower RCC risk (Ptrend < 0.001), while “American/Western” dietary pattern scores were positively associated with a 2-fold higher risk (Ptrend < 0.001). We observed synergistic interaction between the American/Western pattern and hypertension status: The odds ratio (highest tertile vs. lowest) among persons with hypertension was 2.23 (95% confidence interval: 1.43, 3.45), as compared with 1.76 (95% confidence interval: 1.16, 2.70) among persons without hypertension (additive Pinteraction = 0.01). A variant (rs718314) in the inositol 1,4,5-trisphosphate receptor, type 2 gene (ITPR2) was found to interact with the American/Western dietary pattern in relation to RCC risk (additive Pinteraction = 0.03). ITPR2 has been shown to affect nutrient metabolism and central obesity. Dietary patterns, genetic variants, and host characteristics may individually and jointly influence susceptibility to RCC. PMID:25053674

  16. Effect of MTHFR Gene Polymorphism Impact on Atherosclerosis via Genome-Wide Methylation

    PubMed Central

    Lin, Xuefeng; Zhang, Wei; Lu, Qun; Lei, Xinjun; Wang, Tingzhong; Han, Xuanmao; Ma, Aiqun

    2016-01-01

    Background Atherosclerosis seriously threats human health. Homocysteine is an independent risk factor closely related to DNA methylation. MTHFR C667T loci polymorphism is closely associated with homocysteine level. This study aimed to investigate the relationship among MTHFR C667T loci polymorphism, genome-wide methylation, and atherosclerosis. Material/Methods Blood sample was collected from 105 patients with coronary atherosclerosis and 105 healthy controls. Pyrosequencing methylation was used to detect LINE-1 methylation level. Polymerase chain reaction-restriction enzyme fragment length polymorphism (PCR-RFLP) was used to test MTHFR. Results LINE-1 methylation level in the patient group was significantly lower than in the controls (t=5.007, P<0.001). MTHFR C667T genotype distribution presented marked differences in the 2 groups. TT genotype carriers had significantly increased risk of atherosclerosis (OR=3.56, P=0.009). Three different genotypes of MTHFR C667T loci showed different LINE-1 methylation level between the 2 groups (P<0.01). LINE-1 methylation level in TT and CT genotype carriers was obviously lower than in CC genotype carriers (P<0.05). Conclusions MTHFR C667T loci polymorphism may affect atherosclerosis by regulating genome methylation level. PMID:26828698

  17. Functional Annotation of Rheumatoid Arthritis and Osteoarthritis Associated Genes by Integrative Genome-Wide Gene Expression Profiling Analysis

    PubMed Central

    Li, Zhan-Chun; Xiao, Jie; Peng, Jin-Liang; Chen, Jian-Wei; Ma, Tao; Cheng, Guang-Qi; Dong, Yu-Qi; Wang, Wei-li; Liu, Zu-De

    2014-01-01

    Background Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major types of joint diseases that share multiple common symptoms. However, their pathological mechanism remains largely unknown. The aim of our study is to identify RA and OA related-genes and gain an insight into the underlying genetic basis of these diseases. Methods We collected 11 whole genome-wide expression profiling datasets from RA and OA cohorts and performed a meta-analysis to comprehensively investigate their expression signatures. This method can avoid some pitfalls of single dataset analyses. Results and Conclusion We found that several biological pathways (i.e., the immunity, inflammation and apoptosis related pathways) are commonly involved in the development of both RA and OA. Whereas several other pathways (i.e., vasopressin-related pathway, regulation of autophagy, endocytosis, calcium transport and endoplasmic reticulum stress related pathways) present significant difference between RA and OA. This study provides novel insights into the molecular mechanisms underlying this disease, thereby aiding the diagnosis and treatment of the disease. PMID:24551036

  18. Racial differences in genome-wide methylation profiling and gene expression in breast tissues from healthy women.

    PubMed

    Song, Min-Ae; Brasky, Theodore M; Marian, Catalin; Weng, Daniel Y; Taslim, Cenny; Dumitrescu, Ramona G; Llanos, Adana A; Freudenheim, Jo L; Shields, Peter G

    2015-12-01

    Breast cancer is more common in European Americans (EAs) than in African Americans (AAs) but mortality from breast cancer is higher among AAs. While there are racial differences in DNA methylation and gene expression in breast tumors, little is known whether such racial differences exist in breast tissues of healthy women. Genome-wide DNA methylation and gene expression profiling was performed in histologically normal breast tissues of healthy women. Linear regression models were used to identify differentially-methylated CpG sites (CpGs) between EAs (n = 61) and AAs (n = 22). Correlations for methylation and expression were assessed. Biological functions of the differentially-methylated genes were assigned using the Ingenuity Pathway Analysis. Among 485 differentially-methylated CpGs by race, 203 were hypermethylated in EAs, and 282 were hypermethylated in AAs. Promoter-related differentially-methylated CpGs were more frequently hypermethylated in EAs (52%) than AAs (27%) while gene body and intergenic CpGs were more frequently hypermethylated in AAs. The differentially-methylated CpGs were enriched for cancer-associated genes with roles in cell death and survival, cellular development, and cell-to-cell signaling. In a separate analysis for correlation in EAs and AAs, different patterns of correlation were found between EAs and AAs. The correlated genes showed different biological networks between EAs and AAs; networks were connected by Ubiquitin C. To our knowledge, this is the first comprehensive genome-wide study to identify differences in methylation and gene expression between EAs and AAs in breast tissues from healthy women. These findings may provide further insights regarding the contribution of epigenetic differences to racial disparities in breast cancer. PMID:26680018

  19. Genome-wide analysis of the SBP-box gene family in Chinese cabbage (Brassica rapa subsp. pekinensis).

    PubMed

    Tan, Hua-Wei; Song, Xiao-Ming; Duan, Wei-Ke; Wang, Yan; Hou, Xi-Lin

    2015-11-01

    The SQUAMOSA PROMOTER BINDING PROTEIN (SBP)-box gene family contains highly conserved plant-specific transcription factors that play an important role in plant development, especially in flowering. Chinese cabbage (Brassica rapa subsp. pekinensis) is a leafy vegetable grown worldwide and is used as a model crop for research in genome duplication. The present study aimed to characterize the SBP-box transcription factor genes in Chinese cabbage. Twenty-nine SBP-box genes were identified in the Chinese cabbage genome and classified into six groups. We identified 23 orthologous and 5 co-orthologous SBP-box gene pairs between Chinese cabbage and Arabidopsis. An interaction network among these genes was constructed. Sixteen SBP-box genes were expressed more abundantly in flowers than in other tissues, suggesting their involvement in flowering. We show that the MiR156/157 family members may regulate the coding regions or 3'-UTR regions of Chinese cabbage SBP-box genes. As SBP-box genes were found to potentially participate in some plant development pathways, quantitative real-time PCR analysis was performed and showed that Chinese cabbage SBP-box genes were also sensitive to the exogenous hormones methyl jasmonic acid and salicylic acid. The SBP-box genes have undergone gene duplication and loss, evolving a more refined regulation for diverse stimulation in plant tissues. Our comprehensive genome-wide analysis provides insights into the SBP-box gene family of Chinese cabbage. PMID:26599708

  20. The Effects of Sequence Variation on Genome-wide NRF2 Binding—New Target Genes and Regulatory SNPs

    PubMed Central

    Kuosmanen, Suvi M.; Viitala, Sari; Laitinen, Tuomo; Peräkylä, Mikael; Pölönen, Petri; Kansanen, Emilia; Leinonen, Hanna; Raju, Suresh; Wienecke-Baldacchino, Anke; Närvänen, Ale; Poso, Antti; Heinäniemi, Merja; Heikkinen, Sami; Levonen, Anna-Liisa

    2016-01-01

    Transcription factor binding specificity is crucial for proper target gene regulation. Motif discovery algorithms identify the main features of the binding patterns, but the accuracy on the lower affinity sites is often poor. Nuclear factor E2-related factor 2 (NRF2) is a ubiquitous redox-activated transcription factor having a key protective role against endogenous and exogenous oxidant and electrophile stress. Herein, we decipher the effects of sequence variation on the DNA binding sequence of NRF2, in order to identify both genome-wide binding sites for NRF2 and disease-associated regulatory SNPs (rSNPs) with drastic effects on NRF2 binding. Interactions between NRF2 and DNA were studied using molecular modelling, and NRF2 chromatin immunoprecipitation-sequence datasets together with protein binding microarray measurements were utilized to study binding sequence variation in detail. The binding model thus generated was used to identify genome-wide binding sites for NRF2, and genomic binding sites with rSNPs that have strong effects on NRF2 binding and reside on active regulatory elements in human cells. As a proof of concept, miR-126–3p and -5p were identified as NRF2 target microRNAs, and a rSNP (rs113067944) residing on NRF2 target gene (Ferritin, light polypeptide, FTL) promoter was experimentally verified to decrease NRF2 binding and result in decreased transcriptional activity. PMID:26826707

  1. A genome-wide survey of the secondary metabolite biosynthesis genes in the wheat pathogen Parastagonospora nodorum

    PubMed Central

    Chooi, Yit-Heng; Muria-Gonzalez, Mariano Jordi; Solomon, Peter S.

    2014-01-01

    The model pathogen Parastagonospora nodorum is a necrotroph and the causal agent of the wheat disease Septoria nodorum blotch (SNB). The sequenced P. nodorum genome has revealed that the fungus harbours a large number of secondary metabolite genes. Secondary metabolites are known to play important roles in the virulence of plant pathogens, but limited knowledge is available about the SM repertoire of this wheat pathogen. Here, we review the secondary metabolites that have been isolated from P. nodorum and related species of the same genus and provide an in-depth genome-wide overview of the secondary metabolite gene clusters encoded in the P. nodorum genome. The secondary metabolite gene survey reveals that P. nodorum is capable of producing a diverse range of small molecules and exciting prospects exist for discovery of novel virulence factors and bioactive molecules. PMID:25379341

  2. Genome-wide identification of WRKY family genes in peach and analysis of WRKY expression during bud dormancy.

    PubMed

    Chen, Min; Tan, Qiuping; Sun, Mingyue; Li, Dongmei; Fu, Xiling; Chen, Xiude; Xiao, Wei; Li, Ling; Gao, Dongsheng

    2016-06-01

    Bud dormancy in deciduous fruit trees is an important adaptive mechanism for their survival in cold climates. The WRKY genes participate in several developmental and physiological processes, including dormancy. However, the dormancy mechanisms of WRKY genes have not been studied in detail. We conducted a genome-wide analysis and identified 58 WRKY genes in peach. These putative genes were located on all eight chromosomes. In bioinformatics analyses, we compared the sequences of WRKY genes from peach, rice, and Arabidopsis. In a cluster analysis, the gene sequences formed three groups, of which group II was further divided into five subgroups. Gene structure was highly conserved within each group, especially in groups IId and III. Gene expression analyses by qRT-PCR showed that WRKY genes showed different expression patterns in peach buds during dormancy. The mean expression levels of six WRKY genes (Prupe.6G286000, Prupe.1G393000, Prupe.1G114800, Prupe.1G071400, Prupe.2G185100, and Prupe.2G307400) increased during endodormancy and decreased during ecodormancy, indicating that these six WRKY genes may play a role in dormancy in a perennial fruit tree. This information will be useful for selecting fruit trees with desirable dormancy characteristics or for manipulating dormancy in genetic engineering programs. PMID:26951048

  3. Dorothy Hodgkin Lecture 2014. Understanding genes identified by genome-wide association studies for type 2 diabetes.

    PubMed

    Rutter, G A

    2014-12-01

    Whilst the heritable nature of Type 2 diabetes has been recognized for many years, only in the past two decades have linkage analyses in families and genome-wide association studies in large populations begun to reveal the genetic landscape of the disease in detail. Whilst the former have provided a powerful means of identifying the genes responsible for monogenic forms of the disease, the latter highlight relatively large genomic regions. These often harbour multiple genes, whose relative contribution to exaggerated disease risk is uncertain. In the present study, the approaches that have been used to dissect the role of just a few (TCF7L2, SLC30A8, ADCY5, MTNR1B and CDKAL1) of the ~ 500 genes identified at dozens of implicated loci are described. These are usually selected based on the strength of their effect on disease risk, and predictions as to their likely biological role. Direct determination of the effects of identified polymorphisms on gene expression in disease-relevant tissues, notably the pancreatic islet, are then performed to identify genes whose expression is affected by a particular polymorphism. Subsequent functional analyses then involve perturbing gene expression in vitro in β-cell lines or isolated islets and in vivo in animal models. Although the majority of polymorphisms affect insulin production rather than action, and mainly affect the β cell, effects via other tissues may also contribute, requiring careful consideration in the design and interpretation of experiments in model systems. These considerations illustrate the scale of the task needed to exploit genome-wide association study data for the development of new therapeutic strategies. PMID:25186316

  4. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

    PubMed

    Forstner, A J; Hofmann, A; Maaser, A; Sumer, S; Khudayberdiev, S; Mühleisen, T W; Leber, M; Schulze, T G; Strohmaier, J; Degenhardt, F; Treutlein, J; Mattheisen, M; Schumacher, J; Breuer, R; Meier, S; Herms, S; Hoffmann, P; Lacour, A; Witt, S H; Reif, A; Müller-Myhsok, B; Lucae, S; Maier, W; Schwarz, M; Vedder, H; Kammerer-Ciernioch, J; Pfennig, A; Bauer, M; Hautzinger, M; Moebus, S; Priebe, L; Sivalingam, S; Verhaert, A; Schulz, H; Czerski, P M; Hauser, J; Lissowska, J; Szeszenia-Dabrowska, N; Brennan, P; McKay, J D; Wright, A; Mitchell, P B; Fullerton, J M; Schofield, P R; Montgomery, G W; Medland, S E; Gordon, S D; Martin, N G; Krasnov, V; Chuchalin, A; Babadjanova, G; Pantelejeva, G; Abramova, L I; Tiganov, A S; Polonikov, A; Khusnutdinova, E; Alda, M; Cruceanu, C; Rouleau, G A; Turecki, G; Laprise, C; Rivas, F; Mayoral, F; Kogevinas, M; Grigoroiu-Serbanescu, M; Propping, P; Becker, T; Rietschel, M; Cichon, S; Schratt, G; Nöthen, M M

    2015-01-01

    Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD. PMID:26556287

  5. Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression.

    PubMed

    Müller-Calleja, Nadine; Rossmann, Heidi; Müller, Christian; Wild, Philipp; Blankenberg, Stefan; Pfeiffer, Norbert; Binder, Harald; Beutel, Manfred E; Manukyan, Davit; Zeller, Tanja; Lackner, Karl J

    2016-07-01

    The antiphospholipid syndrome (APS) is characterised by venous and/or arterial thrombosis and pregnancy morbidity in women combined with the persistent presence of antiphospholipid antibodies (aPL). We aimed to identify genetic factors associated with the presence of aPL in a population based cohort. Furthermore, we wanted to clarify if the presence of aPL affects gene expression in circulating monocytes. Titres of IgG and IgM against cardiolipin, β2glycoprotein 1 (anti-β2GPI), and IgG against domain 1 of β2GPI (anti-domain 1) were determined in approx. 5,000 individuals from the Gutenberg Health Study (GHS) a population based cohort of German descent. Genotyping was conducted on Affymetrix Genome-Wide Human SNP 6.0 arrays. Monocyte gene expression was determined in a subgroup of 1,279 individuals by using the Illumina HT-12 v3 BeadChip. Gene expression data were confirmed in vitro and ex vivo by qRT-PCR. Genome wide analysis revealed significant associations of anti-β2GPI IgG and APOH on chromosome 17, which had been previously identified by candidate gene approaches, and of anti-domain1 and MACROD2 on chromosome 20 which has been listed in a previous GWAS as a suggestive locus associated with the occurrence of anti-β2GPI antibodies. Expression analysis confirmed increased expression of TNFα in monocytes and identified and confirmed neuron navigator 3 (NAV3) as a novel gene induced by aPL. In conclusion, MACROD2 represents a novel genetic locus associated with aPL. Furthermore, we show that aPL induce the expression of NAV3 in monocytes and endothelial cells. This will stimulate further research into the role of these genes in the APS. PMID:27098658

  6. Placental Genome and Maternal-Placental Genetic Interactions: A Genome-Wide and Candidate Gene Association Study of Placental Abruption

    PubMed Central

    Denis, Marie; Enquobahrie, Daniel A.; Tadesse, Mahlet G.; Gelaye, Bizu; Sanchez, Sixto E.; Salazar, Manuel; Ananth, Cande V.; Williams, Michelle A.

    2014-01-01

    While available evidence supports the role of genetics in the pathogenesis of placental abruption (PA), PA-related placental genome variations and maternal-placental genetic interactions have not been investigated. Maternal blood and placental samples collected from participants in the Peruvian Abruptio Placentae Epidemiology study were genotyped using Illumina’s Cardio-Metabochip platform. We examined 118,782 genome-wide SNPs and 333 SNPs in 32 candidate genes from mitochondrial biogenesis and oxidative phosphorylation pathways in placental DNA from 280 PA cases and 244 controls. We assessed maternal-placental interactions in the candidate gene SNPS and two imprinted regions (IGF2/H19 and C19MC). Univariate and penalized logistic regression models were fit to estimate odds ratios. We examined the combined effect of multiple SNPs on PA risk using weighted genetic risk scores (WGRS) with repeated ten-fold cross-validations. A multinomial model was used to investigate maternal-placental genetic interactions. In placental genome-wide and candidate gene analyses, no SNP was significant after false discovery rate correction. The top genome-wide association study (GWAS) hits were rs544201, rs1484464 (CTNNA2), rs4149570 (TNFRSF1A) and rs13055470 (ZNRF3) (p-values: 1.11e-05 to 3.54e-05). The top 200 SNPs of the GWAS overrepresented genes involved in cell cycle, growth and proliferation. The top candidate gene hits were rs16949118 (COX10) and rs7609948 (THRB) (p-values: 6.00e-03 and 8.19e-03). Participants in the highest quartile of WGRS based on cross-validations using SNPs selected from the GWAS and candidate gene analyses had a 8.40-fold (95% CI: 5.8–12.56) and a 4.46-fold (95% CI: 2.94–6.72) higher odds of PA compared to participants in the lowest quartile. We found maternal-placental genetic interactions on PA risk for two SNPs in PPARG (chr3∶12313450 and chr3∶12412978) and maternal imprinting effects for multiple SNPs in the C19MC and IGF2/H19 regions

  7. Biological interpretation of genome-wide association studies using predicted gene functions.

    PubMed

    Pers, Tune H; Karjalainen, Juha M; Chan, Yingleong; Westra, Harm-Jan; Wood, Andrew R; Yang, Jian; Lui, Julian C; Vedantam, Sailaja; Gustafsson, Stefan; Esko, Tonu; Frayling, Tim; Speliotes, Elizabeth K; Boehnke, Michael; Raychaudhuri, Soumya; Fehrmann, Rudolf S N; Hirschhorn, Joel N; Franke, Lude

    2015-01-01

    The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes. PMID:25597830

  8. A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila.

    PubMed

    Allebrandt, K V; Amin, N; Müller-Myhsok, B; Esko, T; Teder-Laving, M; Azevedo, R V D M; Hayward, C; van Mill, J; Vogelzangs, N; Green, E W; Melville, S A; Lichtner, P; Wichmann, H-E; Oostra, B A; Janssens, A C J W; Campbell, H; Wilson, J F; Hicks, A A; Pramstaller, P P; Dogas, Z; Rudan, I; Merrow, M; Penninx, B; Kyriacou, C P; Metspalu, A; van Duijn, C M; Meitinger, T; Roenneberg, T

    2013-01-01

    Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains ≈5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism. PMID:22105623

  9. Genome-wide gene expression perturbation induced by loss of C2 chromosome in allotetraploid Brassica napus L.

    PubMed Central

    Zhu, Bin; Shao, Yujiao; Pan, Qi; Ge, Xianhong; Li, Zaiyun

    2015-01-01

    Aneuploidy with loss of entire chromosomes from normal complement disrupts the balanced genome and is tolerable only by polyploidy plants. In this study, the monosomic and nullisomic plants losing one or two copies of C2 chromosome from allotetraploid Brassica napus L. (2n = 38, AACC) were produced and compared for their phenotype and transcriptome. The monosomics gave a plant phenotype very similar to the original donor, but the nullisomics had much smaller stature and also shorter growth period. By the comparative analyses on the global transcript profiles with the euploid donor, genome-wide alterations in gene expression were revealed in two aneuploids, and their majority of differentially expressed genes (DEGs) resulted from the trans-acting effects of the zero and one copy of C2 chromosome. The higher number of up-regulated genes than down-regulated genes on other chromosomes suggested that the genome responded to the C2 loss via enhancing the expression of certain genes. Particularly, more DEGs were detected in the monosomics than nullisomics, contrasting with their phenotypes. The gene expression of the other chromosomes was differently affected, and several dysregulated domains in which up- or downregulated genes obviously clustered were identifiable. But the mean gene expression (MGE) for homoeologous chromosome A2 reduced with the C2 loss. Some genes and their expressions on C2 were correlated with the phenotype deviations in the aneuploids. These results provided new insights into the transcriptomic perturbation of the allopolyploid genome elicited by the loss of individual chromosome. PMID:26442076

  10. Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Network of Salt-Sensitivity Study.

    PubMed

    Li, Changwei; He, Jiang; Chen, Jing; Zhao, Jinying; Gu, Dongfeng; Hixson, James E; Rao, Dabeeru C; Jaquish, Cashell E; Gu, Charles C; Chen, Jichun; Huang, Jianfeng; Chen, Shufeng; Kelly, Tanika N

    2016-08-01

    We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10(-9)). The 2 df tests additionally identified associations for CLGN rs2567241 (P=3.90×10(-12)) and LOC105369882 rs11104632 (P=4.51×10(-8)) with systolic BP. The CLGN variant rs2567241 was also associated with diastolic BP (P=3.11×10(-22)) and mean arterial pressure (P=2.86×10(-15)). Genome-wide gene-based analysis identified MKNK1 (P=6.70×10(-7)), C2orf80 (P<1.00×10(-12)), EPHA6 (P=2.88×10(-7)), SCOC-AS1 (P=4.35×10(-14)), SCOC (P=6.46×10(-11)), CLGN (P=3.68×10(-13)), MGAT4D (P=4.73×10(-11)), ARHGAP42 (P≤1.00×10(-12)), CASP4 (P=1.31×10(-8)), and LINC01478 (P=6.75×10(-10)) that were associated with at least 1 BP phenotype. In summary, we identified 8 novel and 1 previously reported BP loci through the examination of single-nucleotide polymorphism and gene-based interactions with sodium. PMID:27271309

  11. Genome-wide selection of superior reference genes for expression studies in Ganoderma lucidum.

    PubMed

    Xu, Zhichao; Xu, Jiang; Ji, Aijia; Zhu, Yingjie; Zhang, Xin; Hu, Yuanlei; Song, Jingyuan; Chen, Shilin

    2015-12-15

    Quantitative real-time polymerase chain reaction (qRT-PCR) is widely used for the accurate analysis of gene expression. However, high homology among gene families might result in unsuitability of reference genes, which leads to the inaccuracy of qRT-PCR analysis. The release of the Ganoderma lucidum genome has triggered numerous studies to be done on the homology among gene families with the purpose of selecting reliable reference genes. Based on the G. lucdum genome and transcriptome database, 38 candidate reference genes including 28 novel genes were systematically selected and evaluated for qRT-PCR normalization. The result indicated that commonly used polyubiquitin (PUB), beta-actin (BAT), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were unsuitable reference genes because of the high sequence similarity and low primer specificity. According to the evaluation of RefFinder, cyclophilin 5 (CYP5) was ranked as the most stable reference gene for 27 tested samples under all experimental conditions and eighteen mycelial samples. Based on sequence analysis and expression analysis, our study suggested that gene characteristic, primer specificity of high homologous genes, allele-specificity expression of candidate genes and under-evaluation of reference genes influenced the accuracy and sensitivity of qRT-PCR analysis. This investigation not only revealed potential factors influencing the unsuitability of reference genes but also selected the superior reference genes from more candidate genes and testing samples than those used in the previous study. Furthermore, our study established a model for reference gene analysis by using the genomic sequence. PMID:26277249

  12. Genome-wide identification of lineage-specific genes in Arabidopsis, Oryza and Populus

    SciTech Connect

    Yang, Xiaohan; Jawdy, Sara; Tschaplinski, Timothy J; Tuskan, Gerald A

    2009-01-01

    Protein sequences were compared among Arabidopsis, Oryza and Populus to identify differential gene (DG) sets that are in one but not the other two genomes. The DG sets were screened against a plant transcript database, the NR protein database and six newly-sequenced genomes (Carica, Glycine, Medicago, Sorghum, Vitis and Zea) to identify a set of species-specific genes (SS). Gene expression, protein motif and intron number were examined. 192, 641 and 109 SS genes were identified in Arabidopsis, Oryza and Populus, respectively. Some SS genes were preferentially expressed in flowers, roots, xylem and cambium or up-regulated by stress. Six conserved motifs in Arabidopsis and Oryza SS proteins were found in other distant lineages. The SS gene sets were enriched with intronless genes. The results reflect functional and/or anatomical differences between monocots and eudicots or between herbaceous and woody plants. The Populus-specific genes are candidates for carbon sequestration and biofuel research.

  13. A genome-wide survey reveals abundant rice blast R genes in resistant cultivars.

    PubMed

    Zhang, Xiaohui; Yang, Sihai; Wang, Jiao; Jia, Yanxiao; Huang, Ju; Tan, Shengjun; Zhong, Yan; Wang, Ling; Gu, Longjiang; Chen, Jian-Qun; Pan, Qinghua; Bergelson, Joy; Tian, Dacheng

    2015-10-01

    Plant resistance genes (R genes) harbor tremendous allelic diversity, constituting a robust immune system effective against microbial pathogens. Nevertheless, few functional R genes have been identified for even the best-studied pathosystems. Does this limited repertoire reflect specificity, with most R genes having been defeated by former pests, or do plants harbor a rich diversity of functional R genes, the composite behavior of which is yet to be characterized? Here, we survey 332 NBS-LRR genes cloned from five resistant Oryza sativa (rice) cultivars for their ability to confer recognition of 12 rice blast isolates when transformed into susceptible cultivars. Our survey reveals that 48.5% of the 132 NBS-LRR loci tested contain functional rice blast R genes, with most R genes deriving from multi-copy clades containing especially diversified loci. Each R gene recognized, on average, 2.42 of the 12 isolates screened. The abundant R genes identified in resistant genomes provide extraordinary redundancy in the ability of host genotypes to recognize particular isolates. If the same is true for other pathogens, many extant NBS-LRR genes retain functionality. Our success at identifying rice blast R genes also validates a highly efficient cloning and screening strategy. PMID:26248689

  14. Genome-Wide Gene Expression in relation to Age in Large Laboratory Cohorts of Drosophila melanogaster

    PubMed Central

    Carlson, Kimberly A.; Gardner, Kylee; Pashaj, Anjeza; Carlson, Darby J.; Yu, Fang; Eudy, James D.; Zhang, Chi; Harshman, Lawrence G.

    2015-01-01

    Aging is a complex process characterized by a steady decline in an organism's ability to perform life-sustaining tasks. In the present study, two cages of approximately 12,000 mated Drosophila melanogaster females were used as a source of RNA from individuals sampled frequently as a function of age. A linear model for microarray data method was used for the microarray analysis to adjust for the box effect; it identified 1,581 candidate aging genes. Cluster analyses using a self-organizing map algorithm on the 1,581 significant genes identified gene expression patterns across different ages. Genes involved in immune system function and regulation, chorion assembly and function, and metabolism were all significantly differentially expressed as a function of age. The temporal pattern of data indicated that gene expression related to aging is affected relatively early in life span. In addition, the temporal variance in gene expression in immune function genes was compared to a random set of genes. There was an increase in the variance of gene expression within each cohort, which was not observed in the set of random genes. This observation is compatible with the hypothesis that D. melanogaster immune function genes lose control of gene expression as flies age. PMID:26090231

  15. Identification of potential driver genes in human liver carcinoma by genome-wide screening

    PubMed Central

    Woo, Hyun Goo; Park, Eun Sung; Lee, Ju-Seog; Lee, Yun-Han; Ishikawa, Tsuyoshi; Kim, Yoon Jun; Thorgeirsson, Snorri S.

    2009-01-01

    Genomic copy number aberrations and corresponding transcriptional deregulation in the cancer genome have been suggested to have regulatory roles in cancer development and progression. However, functional evaluation of individual genes from lengthy lists of candidate genes from genomic datasets presents a significant challenge. Here we report effective gene selection strategies to identify potential driver genes based on systematic integration of genome scale data of DNA copy numbers and gene expression profiles. Using regional pattern recognition approaches, we discovered the most probable copy number-dependent regions and 50 potential driver genes. At each step of gene selection process, functional relevance of the selected genes was evaluated by estimating the prognostic significance of the selected genes. Further validation using small interference RNA (siRNA)-mediated knockdown experiments demonstrated proof-of-principle evidence for the potential driver roles of the genes in HCC progression (i.e., NCSTN and SCRIB). In addition, systemic prediction of drug responses implicated the association of the 50 genes with specific signaling molecules (mTOR, AMPK, and EGFR). In conclusion, the application of an unbiased and integrative analysis of multidimensional genomic datasets can effectively screen for potential driver genes and provides novel mechanistic and clinical insights into pathobiology of HCC. PMID:19366792

  16. Genome-wide analysis of BURP domain-containing genes in maize and sorghum.

    PubMed

    Gan, Defang; Jiang, Haiyang; Zhang, Jiao; Zhao, Yang; Zhu, Suwen; Cheng, Beijiu

    2011-10-01

    BURP domain-containing genes comprise a large plant-specific family, yet the functions are very poorly understood, especially in maize (Zea mays) and sorghum (Sorghum vulgare). In this study, 26 BURP family genes in maize (ZmBURP01-15) and sorghum (SbBURP01-11) were identified including the gene structure, phylogenetic relationship, conserved protein motifs and chromosome locations. These genes have diverse exon-intron structures and distinct organization of putative motifs. The distributions of the genes vary: 15 ZmBURP genes are located in maize on five chromosomes, and 11 SbBURP genes in sorghum are on six chromosomes. Based on the phylogenetic analysis of BURP protein sequences from maize, sorghum and other plants, the BURP genes in maize and sorghum were categorized into five subfamilies (RD22-like, PG1β-like, BURP VI, BURP VII and BURP VIII). Transcript level analysis of ZmBURP genes revealed the expression patterns of BURP genes in maize under diffferent stress conditions. The results suggested that only eight ZmBURP genes were responsive to at least one of the stress treatments applied. Among these genes, seven genes (ZmBURP04, ZmBURP05, ZmBURP08, ZmBURP09, ZmBURP12, ZmBURP14, ZmBURP15) were responsive to ABA and cold respectively, two genes (ZmBURP06 and ZmBURP14) were responsive to NaCl. The results presented here provide useful information for further functional analysis of the BURP gene family in maize and sorghum. PMID:21127990

  17. Genome-wide analyses of proliferation-important genes of Iridovirus-tiger frog virus by RNAi.

    PubMed

    Xie, Jun-Feng; Lai, Yu-Xiong; Huang, Li-Jie; Huang, Run-Qing; Yang, Shao-Wei; Shi, Yan; Weng, Shao-Ping; Zhang, Yong; He, Jian-Guo

    2014-08-30

    Tiger frog virus (TFV), a species of genus Ranavirus in the family Iridoviridae, is a nuclear cytoplasmic large DNA virus that infects aquatic vertebrates such as tiger frog (Rana tigrina rugulosa) and Chinese soft-shelled turtle (Trionyx sinensis). Based on the available genome sequences of TFV, the well-developed RNA interference (RNAi) technique, and the reliable cell line for infection model, we decided to analyze the functional importance of all predicted genes. Firstly, a relative quantitative cytopathogenic effect (Q-CPE) assay was established to monitor the viral proliferation in fish cells. Then, genome-wide RNAi screens of 95 small interference (si) RNAs against TFV were performed to characterize the functional importance of nearly all (95%) predicted TFV genes by Q-CPE scaling system. We identified 32 (33.7%) genes as essential, 50 (52.6%) genes as semi-essential and 13 (13.7%) genes as nonessential for TFV proliferation. Quantitative RT-PCR and titer assays of selected genes were performed to verify the screen results. Furthermore, the screened essential genes were analyzed for their genome distribution and conservative comparison within Ranavirus. Such a systematic screen for viral functional genes by cell phenotypes should provide further insights into understanding of the information in antiviral targets, and in viral replication and pathogenesis of iridovirus. PMID:24886972

  18. Genome-wide prediction and analysis of human tissue-selective genes using microarray expression data

    PubMed Central

    2013-01-01

    Background Understanding how genes are expressed specifically in particular tissues is a fundamental question in developmental biology. Many tissue-specific genes are involved in the pathogenesis of complex human diseases. However, experimental identification of tissue-specific genes is time consuming and difficult. The accurate predictions of tissue-specific gene targets could provide useful information for biomarker development and drug target identification. Results In this study, we have developed a machine learning approach for predicting the human tissue-specific genes using microarray expression data. The lists of known tissue-specific genes for different tissues were collected from UniProt database, and the expression data retrieved from the previously compiled dataset according to the lists were used for input vector encoding. Random Forests (RFs) and Support Vector Machines (SVMs) were used to construct accurate classifiers. The RF classifiers were found to outperform SVM models for tissue-specific gene prediction. The results suggest that the candidate genes for brain or liver specific expression can provide valuable information for further experimental studies. Our approach was also applied for identifying tissue-selective gene targets for different types of tissues. Conclusions A machine learning approach has been developed for accurately identifying the candidate genes for tissue specific/selective expression. The approach provides an efficient way to select some interesting genes for developing new biomedical markers and improve our knowledge of tissue-specific expression. PMID:23369200

  19. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

    PubMed Central

    White, Jacqueline K.; Gerdin, Anna-Karin; Karp, Natasha A.; Ryder, Ed; Buljan, Marija; Bussell, James N.; Salisbury, Jennifer; Clare, Simon; Ingham, Neil J.; Podrini, Christine; Houghton, Richard; Estabel, Jeanne; Bottomley, Joanna R.; Melvin, David G.; Sunter, David; Adams, Niels C.; Baker, Lauren; Barnes, Caroline; Beveridge, Ryan; Cambridge, Emma; Carragher, Damian; Chana, Prabhjoat; Clarke, Kay; Hooks, Yvette; Igosheva, Natalia; Ismail, Ozama; Jackson, Hannah; Kane, Leanne; Lacey, Rosalind; Lafont, David Tino; Lucas, Mark; Maguire, Simon; McGill, Katherine; McIntyre, Rebecca E.; Messager, Sophie; Mottram, Lynda; Mulderrig, Lee; Pearson, Selina; Protheroe, Hayley J.; Roberson, Laura-Anne; Salsbury, Grace; Sanderson, Mark; Sanger, Daniel; Shannon, Carl; Thompson, Paul C.; Tuck, Elizabeth; Vancollie, Valerie E.; Brackenbury, Lisa; Bushell, Wendy; Cook, Ross; Dalvi, Priya; Gleeson, Diane; Habib, Bishoy; Hardy, Matt; Liakath-Ali, Kifayathullah; Miklejewska, Evelina; Price, Stacey; Sethi, Debarati; Trenchard, Elizabeth; von Schiller, Dominique; Vyas, Sapna; West, Anthony P.; Woodward, John; Wynn, Elizabeth; Evans, Arthur; Gannon, David; Griffiths, Mark; Holroyd, Simon; Iyer, Vivek; Kipp, Christian; Lewis, Morag; Li, Wei; Oakley, Darren; Richardson, David; Smedley, Damian; Agu, Chukwuma; Bryant, Jackie; Delaney, Liz; Gueorguieva, Nadia I.; Tharagonnet, Helen; Townsend, Anne J.; Biggs, Daniel; Brown, Ellen; Collinson, Adam; Dumeau, Charles-Etienne; Grau, Evelyn; Harrison, Sarah; Harrison, James; Ingle, Catherine E.; Kundi, Helen; Madich, Alla; Mayhew, Danielle; Metcalf, Tom; Newman, Stuart; Pass, Johanna; Pearson, Laila; Reynolds, Helen; Sinclair, Caroline; Wardle-Jones, Hannah; Woods, Michael; Alexander, Liam; Brown, Terry; Flack, Francesca; Frost, Carole; Griggs, Nicola; Hrnciarova, Silvia; Kirton, Andrea; McDermott, Jordan; Rogerson, Claire; White, Gemma; Zielezinski, Pawel; DiTommaso, Tia; Edwards, Andrew; Heath, Emma; Mahajan, Mary Ann; Yalcin, Binnaz; Tannahill, David; Logan, Darren W.; MacArthur, Daniel G.; Flint, Jonathan; Mahajan, Vinit B.; Tsang, Stephen H.; Smyth, Ian; Watt, Fiona M.; Skarnes, William C.; Dougan, Gordon; Adams, David J.; Ramirez-Solis, Ramiro; Bradley, Allan; Steel, Karen P.

    2013-01-01

    Summary Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PaperClip PMID:23870131

  20. Genome-wide characterization of the CBF/DREB1 gene family in Brassica rapa.

    PubMed

    Lee, Sang-Choon; Lim, Myung-Ho; Yu, Jae-Gyeong; Park, Beom-Seok; Yang, Tae-Jin

    2012-12-01

    The C-repeat/dehydration-responsive element binding transcription factors (CBF/DREBs) are important proteins in involved in responses to abiotic stress in plants. We identified ten BrDREB1 genes belonging to the CBF/DREB1 gene family in the Brassica rapa whole genome sequence, whereas six genes are found in the Arabidopsis thaliana genome. The deduced amino acid sequences of the B. rapa genes showed conserved motifs shared with other known plant CBF/DREB1s. Comparative analysis revealed that nine of the BrDREB1 genes were derived from the recent genome triplication in the tribe Brassiceae and the other one was translocated. The nine genes were located in seven of the 12 macrosyntenic blocks that are triplicated counterparts of four Arabidopsis macrosyntenic blocks harboring six CBF/DREB1 genes: one gene on each of three blocks and three tandemly arrayed genes on another block. We inspected the expression patterns of eight BrDREB1 genes by RT-PCR and microarray database searches. All eight genes were highly up-regulated during cold (4 °C) treatment, and some of them were also responsive to salt (250 mM NaCl), drought (air drying), and ABA (100 μM) treatment. Microarray data for plant developmental stages revealed that BrDREB1C2 was highly expressed during a period of cold treatment for vernalization, similar to abiotic stress-inducible genes homologous to Bn28a, Bn47, Bn115, and BoRS1, but almost opposite of BrFLC genes. Taken together, the number of BrDREB1 genes increased to 10 by genome triplication and reorganization, providing additional functions in B. rapa abiotic stress responses and development, as distinct from their Arabidopsis homologs. PMID:23148914

  1. Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor coregulators.

    PubMed

    Wu, Dai-Ying; Ou, Chen-Yin; Chodankar, Rajas; Siegmund, Kimberly D; Stallcup, Michael R

    2014-01-01

    Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated gene expression after siRNA mediated depletion of coregulators confirmed that each coregulator acted in a selective and gene-specific manner and demonstrated both positive and negative effects on glucocorticoid-regulated expression of different genes. We identified several classes of hormone-regulated genes based on the effects of coregulator depletion. Each coregulator supported hormonal regulation of some genes and opposed hormonal regulation of other genes (coregulator-modulated genes), blocked hormonal regulation of a second class of genes (coregulator-blocked genes), and had no effect on hormonal regulation of a third gene class (coregulator-independent genes). In spite of previously demonstrated physical and functional interactions among these four coregulators, the majority

  2. Genome-Wide Linkage, Exome Sequencing and Functional Analyses Identify ABCB6 as the Pathogenic Gene of Dyschromatosis Universalis Hereditaria

    PubMed Central

    Wang, Na; Wang, Chuan; Chen, Xuechao; Sheng, Donglai; Fu, Xi’an; See, Kelvin; Foo, Jia Nee; Low, Huiqi; Liany, Herty; Irwan, Ishak Darryl; Liu, Jian; Yang, Baoqi; Chen, Mingfei; Yu, Yongxiang; Yu, Gongqi; Niu, Guiye; You, Jiabao; Zhou, Yan; Ma, Shanshan; Wang, Ting; Yan, Xiaoxiao; Goh, Boon Kee; Common, John E. A.; Lane, Birgitte E.; Sun, Yonghu; Zhou, Guizhi; Lu, Xianmei; Wang, Zhenhua; Tian, Hongqing; Cao, Yuanhua; Chen, Shumin; Liu, Qiji; Liu, Jianjun; Zhang, Furen

    2014-01-01

    Background As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH) had remained unclear until recently when ABCB6 was reported as a causative gene of DUH. Methodology We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation. Results Genome-wide linkage (assuming autosomal dominant inheritance mode) and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val) that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val) and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys) in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them. Conclusion Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma. PMID:24498303

  3. Identification of disease-associated pathways in pancreatic cancer by integrating genome-wide association study and gene expression data

    PubMed Central

    LONG, JIN; LIU, ZHE; WU, XINGDA; XU, YUANHONG; GE, CHUNLIN

    2016-01-01

    In order to additionally understand the pathogenesis of pancreatic cancer (PC), the present study conducted pathway analysis based on genome-wide association study (GWAS) and gene expression data to predict genes that are associated with PC. GWAS data (accession no., pha002874.1) were downloaded from National Center for Biotechnology Information (NCBI) database of Genotypes and Phenotypes, which included data concerning 1,896 patients with PC and 1,939 control individuals. Gene expression data [accession no., GSE23952; human pancreatic carcinoma Panc-1 transforming growth factor-β (TGF-β) treatment assay] were downloaded from NCBI Gene Expression Omnibus. Gene set enrichment analysis was used to identify significant pathways in the GWAS or gene expression profiles. Meta-analysis was performed based on pathway analysis of the two data sources. In total, 58 and 280 pathways were identified to be significant in the GWAS and gene expression data, respectively, with 7 pathways significant in both the data profiles. Hsa 04350 TGF-β signaling pathway had the smallest meta P-value. Other significant pathways in the two data sources were negative regulation of DNA-dependent transcription, the nucleolus, negative regulation of RNA metabolic process, the cellular defense response, exocytosis and galactosyltransferase activity. By constructing the gene-pathway network, 5 pathways were closely associated, apart from exocytosis and galactosyltransferase activity pathways. Among the 7 pathways, 11 key genes (2.9% out of a total of 380 genes) from the GWAS data and 43 genes (10.5% out of a total of 409 genes) from the gene expression data were differentially expressed. Only Abelson murine leukemia viral oncogene homolog 1 from the nucleolus pathway was significantly expressed in by both data sources. Overall, the results of the present analysis provide possible factors for the occurrence of PC, and the identification of the pathways and genes associated with PC provides

  4. Comparative analysis of genome-wide Mlo gene family in Cajanus cajan and Phaseolus vulgaris.

    PubMed

    Deshmukh, Reena; Singh, V K; Singh, B D

    2016-04-01

    The Mlo gene was discovered in barley because the mutant 'mlo' allele conferred broad-spectrum, non-race-specific resistance to powdery mildew caused by Blumeria graminis f. sp. hordei. The Mlo genes also play important roles in growth and development of plants, and in responses to biotic and abiotic stresses. The Mlo gene family has been characterized in several crop species, but only a single legume species, soybean (Glycine max L.), has been investigated so far. The present report describes in silico identification of 18 CcMlo and 20 PvMlo genes in the important legume crops Cajanus cajan (L.) Millsp. and Phaseolus vulgaris L., respectively. In silico analysis of gene organization, protein properties and conserved domains revealed that the C. cajan and P. vulgaris Mlo gene paralogs are more divergent from each other than from their orthologous pairs. The comparative phylogenetic analysis classified CcMlo and PvMlo genes into three major clades. A comparative analysis of CcMlo and PvMlo proteins with the G. max Mlo proteins indicated close association of one CcMlo, one PvMlo with two GmMlo genes, indicating that there was no further expansion of the Mlo gene family after the separation of these species. Thus, most of the diploid species of eudicots might be expected to contain 15-20 Mlo genes. The genes CcMlo12 and 14, and PvMlo11 and 12 are predicted to participate in powdery mildew resistance. If this prediction were verified, these genes could be targeted by TILLING or CRISPR to isolate powdery mildew resistant mutants. PMID:26961357

  5. Genome-wide analysis of the MYB gene family in physic nut (Jatropha curcas L.).

    PubMed

    Zhou, Changpin; Chen, Yanbo; Wu, Zhenying; Lu, Wenjia; Han, Jinli; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Jiang, Huawu; Wu, Guojiang

    2015-11-01

    The MYB proteins comprise one of the largest transcription factor families in plants, and play key roles in regulatory networks controlling development, metabolism, and stress responses. A total of 125 MYB genes (JcMYB) have been identified in the physic nut (Jatropha curcas L.) genome, including 120 2R-type MYB, 4 3R-MYB, and 1 4R-MYB genes. Based on exon-intron arrangement of MYBs from both lower (Physcomitrella patens) and higher (physic nut, Arabidopsis, and rice) plants, we can classify plant MYB genes into ten groups (MI-X), except for MIX genes which are nonexistent in higher plants. We also observed that MVIII genes may be one of the most ancient MYB types which consist of both R2R3- and 3R-MYB genes. Most MYB genes (76.8% in physic nut) belong to the MI group which can be divided into 34 subgroups. The JcMYB genes were nonrandomly distributed on its 11 linkage groups (LGs). The expansion of MYB genes across several subgroups was observed and resulted from genome triplication of ancient dicotyledons and from both ancient and recent tandem duplication events in the physic nut genome. The expression patterns of several MYB duplicates in the physic nut showed differences in four tissues (root, stem, leaf, and seed), and 34 MYB genes responded to at least one abiotic stressor (drought, salinity, phosphate starvation, and nitrogen starvation) in leaves and/or roots based on the data analysis of digital gene expression tags. Overexpression of the JcMYB001 gene in Arabidopsis increased its sensitivity to drought and salinity stresses. PMID:26142104

  6. Genome-Wide RNAi Screens in C. elegans to Identify Genes Influencing Lifespan and Innate Immunity.

    PubMed

    Sinha, Amit; Rae, Robbie

    2016-01-01

    RNA interference is a rapid, inexpensive, and highly effective tool used to inhibit gene function. In C. elegans, whole genome screens have been used to identify genes involved with numerous traits including aging and innate immunity. RNAi in C. elegans can be carried out via feeding, soaking, or injection. Here we outline protocols used to maintain, grow, and carry out RNAi via feeding in C. elegans and determine whether the inhibited genes are essential for lifespan or innate immunity. PMID:27581293

  7. Genome-wide identification and expression analysis of the IQD gene family in moso bamboo (Phyllostachys edulis)

    PubMed Central

    Wu, Min; Li, Yuan; Chen, Danmei; Liu, Huanlong; Zhu, Dongyue; Xiang, Yan

    2016-01-01

    Members of the plant-specific IQ67-domain (IQD) protein family are involved in various aspects of normal plant growth and developmental processes as well as basal defence response. Although hundreds of IQD proteins have been identified, only a small number of IQDs have been functionally characterized. Moreover, no systematic study has been performed on moso bamboo. In this study, we performed for the first time a genome-wide identification and expression analysis of the IQD gene family in moso bamboo. We identified 29 non-redundant PeIQD encoding genes. Analysis of the evolutionary patterns and divergence revealed that the IQD genes underwent a large-scale event around 12 million years ago and the division times of IQD family genes between moso bamboo and rice, and, between moso bamboo and Brachypodium, were found to be 20–35 MYA and 25–40 MYA, respectively. We surveyed the putative promoter regions of the PeIQD genes, which showed that largely stress-related cis-elements existed in these genes. The expression profiles of the IQD genes shed light on their functional divergence. Additionally, a yeast two-hybrid assay proved that PeIQD8 can interact with PeCaM2 and that IQ or I in the IQ motif is required for PeIQD8 to combine with CaM2. PMID:27094318

  8. Genome-Wide Methylation and Gene Expression Changes in Newborn Rats following Maternal Protein Restriction and Reversal by Folic Acid

    PubMed Central

    Stupka, Elia; Clark, Adrian J. L.; Langley-Evans, Simon

    2013-01-01

    A large body of evidence from human and animal studies demonstrates that the maternal diet during pregnancy can programme physiological and metabolic functions in the developing fetus, effectively determining susceptibility to later disease. The mechanistic basis of such programming is unclear but may involve resetting of epigenetic marks and fetal gene expression. The aim of this study was to evaluate genome-wide DNA methylation and gene expression in the livers of newborn rats exposed to maternal protein restriction. On day one postnatally, there were 618 differentially expressed genes and 1183 differentially methylated regions (FDR 5%). The functional analysis of differentially expressed genes indicated a significant effect on DNA repair/cycle/maintenance functions and of lipid, amino acid metabolism and circadian functions. Enrichment for known biological functions was found to be associated with differentially methylated regions. Moreover, these epigenetically altered regions overlapped genetic loci associated with metabolic and cardiovascular diseases. Both expression changes and DNA methylation changes were largely reversed by supplementing the protein restricted diet with folic acid. Although the epigenetic and gene expression signatures appeared to underpin largely different biological processes, the gene expression profile of DNA methyl transferases was altered, providing a potential link between the two molecular signatures. The data showed that maternal protein restriction is associated with widespread differential gene expression and DNA methylation across the genome, and that folic acid is able to reset both molecular signatures. PMID:24391732

  9. Genome-wide identification and expression analysis of the IQD gene family in moso bamboo (Phyllostachys edulis).

    PubMed

    Wu, Min; Li, Yuan; Chen, Danmei; Liu, Huanlong; Zhu, Dongyue; Xiang, Yan

    2016-01-01

    Members of the plant-specific IQ67-domain (IQD) protein family are involved in various aspects of normal plant growth and developmental processes as well as basal defence response. Although hundreds of IQD proteins have been identified, only a small number of IQDs have been functionally characterized. Moreover, no systematic study has been performed on moso bamboo. In this study, we performed for the first time a genome-wide identification and expression analysis of the IQD gene family in moso bamboo. We identified 29 non-redundant PeIQD encoding genes. Analysis of the evolutionary patterns and divergence revealed that the IQD genes underwent a large-scale event around 12 million years ago and the division times of IQD family genes between moso bamboo and rice, and, between moso bamboo and Brachypodium, were found to be 20-35 MYA and 25-40 MYA, respectively. We surveyed the putative promoter regions of the PeIQD genes, which showed that largely stress-related cis-elements existed in these genes. The expression profiles of the IQD genes shed light on their functional divergence. Additionally, a yeast two-hybrid assay proved that PeIQD8 can interact with PeCaM2 and that IQ or I in the IQ motif is required for PeIQD8 to combine with CaM2. PMID:27094318

  10. Genome-Wide Identification, Evolution and Expression Analysis of mTERF Gene Family in Maize

    PubMed Central

    Zhao, Yanxin; Cai, Manjun; Zhang, Xiaobo; Li, Yurong; Zhang, Jianhua; Zhao, Hailiang; Kong, Fei; Zheng, Yonglian; Qiu, Fazhan

    2014-01-01

    Plant mitochondrial transcription termination factor (mTERF) genes comprise a large family with important roles in regulating organelle gene expression. In this study, a comprehensive database search yielded 31 potential mTERF genes in maize (Zea mays L.) and most of them were targeted to mitochondria or chloroplasts. Maize mTERF were divided into nine main groups based on phylogenetic analysis, and group IX represented the mitochondria and species-specific clade that diverged from other groups. Tandem and segmental duplication both contributed to the expansion of the mTERF gene family in the maize genome. Comprehensive expression analysis of these genes, using microarray data and RNA-seq data, revealed that these genes exhibit a variety of expression patterns. Environmental stimulus experiments revealed differential up or down-regulation expression of maize mTERF genes in seedlings exposed to light/dark, salts and plant hormones, respectively, suggesting various important roles of maize mTERF genes in light acclimation and stress-related responses. These results will be useful for elucidating the roles of mTERF genes in the growth, development and stress response of maize. PMID:24718683

  11. Genome-Wide Comparative Analysis of Flowering-Related Genes in Arabidopsis, Wheat, and Barley

    PubMed Central

    Peng, Fred Y.; Hu, Zhiqiu; Yang, Rong-Cai

    2015-01-01

    Early flowering is an important trait influencing grain yield and quality in wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) in short-season cropping regions. However, due to large and complex genomes of these species, direct identification of flowering genes and their molecular characterization remain challenging. Here, we used a bioinformatic approach to predict flowering-related genes in wheat and barley from 190 known Arabidopsis (Arabidopsis thaliana (L.) Heynh.) flowering genes. We identified 900 and 275 putative orthologs in wheat and barley, respectively. The annotated flowering-related genes were clustered into 144 orthologous groups with one-to-one, one-to-many, many-to-one, and many-to-many orthology relationships. Our approach was further validated by domain and phylogenetic analyses of flowering-related proteins and comparative analysis of publicly available microarray data sets for in silico expression profiling of flowering-related genes in 13 different developmental stages of wheat and barley. These further analyses showed that orthologous gene pairs in three critical flowering gene families (PEBP, MADS, and BBX) exhibited similar expression patterns among 13 developmental stages in wheat and barley, suggesting similar functions among the orthologous genes with sequence and expression similarities. The predicted candidate flowering genes can be confirmed and incorporated into molecular breeding for early flowering wheat and barley in short-season cropping regions. PMID:26435710

  12. Genome-Wide Comparative Analysis of Flowering-Related Genes in Arabidopsis, Wheat, and Barley.

    PubMed

    Peng, Fred Y; Hu, Zhiqiu; Yang, Rong-Cai

    2015-01-01

    Early flowering is an important trait influencing grain yield and quality in wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) in short-season cropping regions. However, due to large and complex genomes of these species, direct identification of flowering genes and their molecular characterization remain challenging. Here, we used a bioinformatic approach to predict flowering-related genes in wheat and barley from 190 known Arabidopsis (Arabidopsis thaliana (L.) Heynh.) flowering genes. We identified 900 and 275 putative orthologs in wheat and barley, respectively. The annotated flowering-related genes were clustered into 144 orthologous groups with one-to-one, one-to-many, many-to-one, and many-to-many orthology relationships. Our approach was further validated by domain and phylogenetic analyses of flowering-related proteins and comparative analysis of publicly available microarray data sets for in silico expression profiling of flowering-related genes in 13 different developmental stages of wheat and barley. These further analyses showed that orthologous gene pairs in three critical flowering gene families (PEBP, MADS, and BBX) exhibited similar expression patterns among 13 developmental stages in wheat and barley, suggesting similar functions among the orthologous genes with sequence and expression similarities. The predicted candidate flowering genes can be confirmed and incorporated into molecular breeding for early flowering wheat and barley in short-season cropping regions. PMID:26435710

  13. Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.).

    PubMed

    Wu, Zhenying; Xu, Xueqin; Xiong, Wangdan; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Wu, Guojiang; Jiang, Huawu

    2015-01-01

    The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue-specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut. PMID:26125188

  14. Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.)

    PubMed Central

    Wu, Zhenying; Xu, Xueqin; Xiong, Wangdan; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Wu, Guojiang; Jiang, Huawu

    2015-01-01

    The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue-specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut. PMID:26125188

  15. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays.

    PubMed

    Chen, Meng; Ye, Yuanqing; Yang, Hushan; Tamboli, Pheroze; Matin, Surena; Tannir, Nizar M; Wood, Christopher G; Gu, Jian; Wu, Xifeng

    2009-11-15

    The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis and treatment. We applied Illumina's 317K high-density single nucleotide polymorphism (SNP) arrays to profile chromosomal aberrations in clear cell renal cell carcinoma (ccRCC) from 80 patients and analyzed the association of LOH/amplification events with clinicopathological characteristics and telomere length. The most common loss of heterozygosity (LOH) were 3p (69 cases) including 38 whole 3p arm losses, 30 large fragment LOH (spanning 3p21-36), and 1 interstitial LOH (spanning 3p12-14, 3p21-22, 3p24.1-24.2 and 3p24.3), followed by chromosome losses at 8p12-pter, 6q23.3-27, 14q24.1-qter, 9q32-qter, 10q22.3-qter, 9p13.3-pter, 4q28.3-qter and 13q12.1-21.1. We also found several smallest overlapping regions of LOH that contained tumor suppressor genes. One smallest LOH in 8p12 had a size of 0.29 Mb and only contained one gene (NRG1). The most frequent chromosome gains were at 5q (32 cases), including 10 whole 5q amplification, 21 large amplifications encompassing 5q32-ter and 1 focal amplification in 5q35.3 (0.42 Mb). The other common chromosome gains were 1q25.1-qter, 7q21.13-qter, 8q24.12-qter and whole 7p arm. Significant associations of LOH at 9p, 9q, 14q and 18q were observed with higher nuclear grade. Significant associations with tumor stage were observed for LOH at 14q, 18p and 21q. Finally, we found that tumors with LOH at 2q, 6p, 6q, 9p, 9q and 17p had significantly shorter telomere length than those without LOH. This is the first study to use Illumina's SNP-CGH array that provides a close estimate of the size and frequency of chromosome LOH and amplifications of ccRCC. The identified regions and genes may become diagnostic and prognostic biomarkers as well as potential targets of therapy. PMID:19521957

  16. Genome-Wide Evolutionary Characterization and Expression Analyses of WRKY Family Genes in Brachypodium distachyon

    PubMed Central

    Wen, Feng; Zhu, Hong; Li, Peng; Jiang, Min; Mao, Wenqing; Ong, Chermaine; Chu, Zhaoqing

    2014-01-01

    Members of plant WRKY gene family are ancient transcription factors that function in plant growth and development and respond to biotic and abiotic stresses. In our present study, we have investigated WRKY family genes in Brachypodium distachyon, a new model plant of family Poaceae. We identified a total of 86 WRKY genes from B. distachyon and explored their chromosomal distribution and evolution, domain alignment, promoter cis-elements, and expression profiles. Combining the analysis of phylogenetic tree of BdWRKY genes and the result of expression profiling, results showed that most of clustered gene pairs had higher similarities in the WRKY domain, suggesting that they might be functionally redundant. Neighbour-joining analysis of 301 WRKY domains from Oryza sativa, Arabidopsis thaliana, and B. distachyon suggested that BdWRKY domains are evolutionarily more closely related to O. sativa WRKY domains than those of A. thaliana. Moreover, tissue-specific expression profile of BdWRKY genes and their responses to phytohormones and several biotic or abiotic stresses were analysed by quantitative real-time PCR. The results showed that the expression of BdWRKY genes was rapidly regulated by stresses and phytohormones, and there was a strong correlation between promoter cis-elements and the phytohormones-induced BdWRKY gene expression. PMID:24453041

  17. Gene-Environment Interactions in Genome-Wide Association Studies: Current Approaches and New Directions

    ERIC Educational Resources Information Center

    Winham, Stacey J.; Biernacka, Joanna M.

    2013-01-01

    Background: Complex psychiatric traits have long been thought to be the result of a combination of genetic and environmental factors, and gene-environment interactions are thought to play a crucial role in behavioral phenotypes and the susceptibility and progression of psychiatric disorders. Candidate gene studies to investigate hypothesized…

  18. Insights into GATA-1 Mediated Gene Activation versus Repression via Genome-wide Chromatin Occupancy Analysis

    PubMed Central

    Yu, Ming; Riva, Laura; Xie, Huafeng; Schindler, Yocheved; Moran, Tyler B.; Cheng, Yong; Yu, Duonan; Hardison, Ross; Weiss, Mitchell J; Orkin, Stuart H.; Bernstein, Bradley E.; Fraenkel, Ernest; Cantor, Alan B.

    2009-01-01

    Summary The transcription factor GATA-1 is required for terminal erythroid maturation and functions as an activator or repressor depending on gene context. Yet its in vivo site selectivity and ability to distinguish between activated versus repressed genes remain incompletely understood. In this study, we performed GATA-1 ChIP-seq in erythroid cells and compared it to GATA-1 induced gene expression changes. Bound and differentially expressed genes contain a greater number of GATA binding motifs, a higher frequency of palindromic GATA sites, and closer occupancy to the transcriptional start site versus non-differentially expressed genes. Moreover, we show that the transcription factor Zbtb7a occupies GATA-1 bound regions of some direct GATA-1 target genes, that the presence of SCL/TAL1 helps distinguish transcriptional activation versus repression, and that Polycomb Repressive Complex 2 (PRC2) is involved in epigenetic silencing of a subset of GATA-1 repressed genes. These data provide insights into GATA-1 mediated gene regulation in vivo. PMID:19941827

  19. Genome-wide analysis of spatiotemporal gene expression patterns during early embryogenesis in rice.

    PubMed

    Itoh, Jun-Ichi; Sato, Yutaka; Sato, Yutaka; Hibara, Ken-Ichiro; Shimizu-Sato, Sae; Kobayashi, Hiromi; Takehisa, Hinako; Sanguinet, Karen A; Namiki, Nobukazu; Nagamura, Yoshiaki

    2016-04-01

    Embryogenesis in rice is different from that of most dicotolydonous plants in that it shows a non-stereotypic cell division pattern, formation of dorsal-ventral polarity, and endogenous initiation of the radicle. To reveal the transcriptional features associated with developmental events during rice early embryogenesis, we used microarray analysis coupled with laser microdissection to obtain both spatial and temporal transcription profiles. Our results allowed us to determine spatial expression foci for each expressed gene in the globular embryo, which revealed the importance of phytohormone-related genes and a suite of transcription factors to early embryogenesis. Our analysis showed the polarized expression of a small number of genes along the apical-basal and dorsal-ventral axes in the globular embryo, which tended to fluctuate in later developmental stages. We also analyzed gene expression patterns in the early globular embryo and how this relates to expression in embryonic organs at later stages. We confirmed the accuracy of the expression patterns found by microarray analysis of embryo subdomains usingin situhybridization. Our study identified homologous genes fromArabidopsis thalianawith known functions in embryogenesis in addition to unique and uncharacterized genes that show polarized expression patterns during embryogenesis. The results of this study are presented in a database to provide a framework for spatiotemporal gene expression during rice embryogenesis, to serve as a resource for future functional analysis of genes, and as a basis for comparative studies of plant embryogenesis. PMID:26903508

  20. Genome-wide prediction of cancer driver genes based on SNP and cancer SNV data.

    PubMed

    He, Quanze; He, Quanyuan; Liu, Xiaohui; Wei, Youheng; Shen, Suqin; Hu, Xiaohui; Li, Qiao; Peng, Xiangwen; Wang, Lin; Yu, Long

    2014-01-01

    Identifying cancer driver genes and exploring their functions are essential and the most urgent need in basic cancer research. Developing efficient methods to differentiate between driver and passenger somatic mutations revealed from large-scale cancer genome sequencing data is critical to cancer driver gene discovery. Here, we compared distinct features of SNP with SNV data in detail and found that the weighted ratio of SNV to SNP (termed as WVPR) is an excellent indicator for cancer driver genes. The power of WVPR was validated by accurate predictions of known drivers. We ranked most of human genes by WVPR and did functional analyses on the list. The results demonstrate that driver genes are usually highly enriched in chromatin organization related genes/pathways. And some protein complexes, such as histone acetyltransferase, histone methyltransferase, telomerase, centrosome, sin3 and U12-type spliceosomal complexes, are hot spots of driver mutations. Furthermore, this study identified many new potential driver genes (e.g. NTRK3 and ZIC4) and pathways including oxidative phosphorylation pathway, which were not deemed by previous methods. Taken together, our study not only developed a method to identify cancer driver genes/pathways but also provided new insights into molecular mechanisms of cancer development. PMID:25057442

  1. Genome-Wide Analysis of Syntenic Gene Deletion in the Grasses

    PubMed Central

    Schnable, James C.; Freeling, Michael; Lyons, Eric

    2012-01-01

    The grasses, Poaceae, are one of the largest and most successful angiosperm families. Like many radiations of flowering plants, the divergence of the major grass lineages was preceded by a whole-genome duplication (WGD), although these events are not rare for flowering plants. By combining identification of syntenic gene blocks with measures of gene pair divergence and different frequencies of ancient gene loss, we have separated the two subgenomes present in modern grasses. Reciprocal loss of duplicated genes or genomic regions has been hypothesized to reproductively isolate populations and, thus, speciation. However, in contrast to previous studies in yeast and teleost fishes, we found very little evidence of reciprocal loss of homeologous genes between the grasses, suggesting that post-WGD gene loss may not be the cause of the grass radiation. The sets of homeologous and orthologous genes and predicted locations of deleted genes identified in this study, as well as links to the CoGe comparative genomics web platform for analyzing pan-grass syntenic regions, are provided along with this paper as a resource for the grass genetics community. PMID:22275519

  2. Genome-Wide Expression Analysis of Soybean MADS Genes Showing Potential Function in the Seed Development

    PubMed Central

    Hu, Rui-Bo; Zhang, Xiao-Mei; Chen, Jian-Xin; Fu, Yong-Fu

    2013-01-01

    The MADS family is an ancient and best-studied transcription factor and plays fundamental roles in almost every developmental process in plants. In the plant evolutionary history, the whole genome duplication (WGD) events are important not only to the plant species evolution, but to expansion of members of the gene families. Soybean as a model legume crop has experience three rounds of WGD events. Members of some MIKCC subfamilies, such as SOC, AGL6, SQUA, SVP, AGL17 and DEF/GLO, were expanded after soybean three rounds of WGD events. And some MIKCC subfamilies, MIKC* and type I MADS families had experienced faster birth-and-death evolution and their traces before the Glycine WGD event were not found. Transposed duplication played important roles in tandem arrangements among the members of different subfamilies. According to the expression profiles of type I and MIKC paralog pair genes, the fates of MIKC paralog gene pairs were subfunctionalization, and the fates of type I MADS paralog gene pairs were nonfunctionalization. 137 out of 163 MADS genes were close to 186 loci within 2 Mb genomic regions associated with seed-relative QTLs, among which 115 genes expressed during the seed development. Although MIKCC genes kept the important and conserved functions of the flower development, most MIKCC genes showed potentially essential roles in the seed development as well as the type I MADS. PMID:23638026

  3. Genome-wide experimental determination of barriers to horizontal gene transfer.

    PubMed

    Sorek, Rotem; Zhu, Yiwen; Creevey, Christopher J; Francino, M Pilar; Bork, Peer; Rubin, Edward M

    2007-11-30

    Horizontal gene transfer, in which genetic material is transferred from the genome of one organism to that of another, has been investigated in microbial species mainly through computational sequence analyses. To address the lack of experimental data, we studied the attempted movement of 246,045 genes from 79 prokaryotic genomes into Escherichia coli and identified genes that consistently fail to transfer. We studied the mechanisms underlying transfer inhibition by placing coding regions from different species under the control of inducible promoters. Our data suggest that toxicity to the host inhibited transfer regardless of the species of origin and that increased gene dosage and associated increased expression may be a predominant cause for transfer failure. Although these experimental studies examined transfer solely into E. coli, a computational analysis of gene-transfer rates across available bacterial and archaeal genomes supports that the barriers observed in our study are general across the tree of life. PMID:17947550

  4. The catalase gene family in cucumber: genome-wide identification and organization.

    PubMed

    Hu, Lifang; Yang, Yingui; Jiang, Lunwei; Liu, Shiqiang

    2016-01-01

    Catalase (CAT) is a common antioxidant enzyme in almost all living organisms. Currently, detailed reports on cucumber (Cucumis sativus L.) CAT (CsCAT) genes and tissue expression profiling are limited. In the present study, four candidate CsCAT genes were identified in cucumber. Phylogenetic analysis indicated that CsCAT1-CsCAT3 are closely related to Arabidopsis AtCAT1-AtCAT3, but no obvious counterpart was observed for CsCAT4. Intron/exon structure analysis revealed that only one of the 15 positions was completely conserved. Motif analysis showed that, unlike the CAT genes of other species, none of CsCAT genes contained all 10 motifs. Expression data showed that transcripts of all of the CsCAT genes, except CsCAT4, were detected in five tissues. Moreover, their transcription levels displayed differences under different stress treatments. PMID:27560990

  5. Genome-wide experimental determination of barriers to horizontal gene transfer

    SciTech Connect

    Rubin, Edward; Sorek, Rotem; Zhu, Yiwen; Creevey, Christopher J.; Francino, M. Pilar; Bork, Peer; Rubin, Edward M.

    2007-09-24

    Horizontal gene transfer, in which genetic material is transferred from the genome of one organism to another, has been investigated in microbial species mainly through computational sequence analyses. To address the lack of experimental data, we studied the attempted movement of 246,045 genes from 79 prokaryotic genomes into E. coli and identified genes that consistently fail to transfer. We studied the mechanisms underlying transfer inhibition by placing coding regions from different species under the control of inducible promoters. Their toxicity to the host inhibited transfer regardless of the species of origin and our data suggest that increased gene dosage and associated increased expression is a predominant cause for transfer failure. While these experimental studies examined transfer solely into E. coli, a computational analysis of gene transfer rates across available bacterial and archaeal genomes indicates that the barriers observed in our study are general across the tree of life.

  6. The catalase gene family in cucumber: genome-wide identification and organization

    PubMed Central

    Hu, Lifang; Yang, Yingui; Jiang, Lunwei; Liu, Shiqiang

    2016-01-01

    Abstract Catalase (CAT) is a common antioxidant enzyme in almost all living organisms. Currently, detailed reports on cucumber (Cucumis sativus L.) CAT (CsCAT) genes and tissue expression profiling are limited. In the present study, four candidate CsCAT genes were identified in cucumber. Phylogenetic analysis indicated that CsCAT1-CsCAT3 are closely related to Arabidopsis AtCAT1-AtCAT3, but no obvious counterpart was observed for CsCAT4. Intron/exon structure analysis revealed that only one of the 15 positions was completely conserved. Motif analysis showed that, unlike the CAT genes of other species, none of CsCAT genes contained all 10 motifs. Expression data showed that transcripts of all of the CsCAT genes, except CsCAT4, were detected in five tissues. Moreover, their transcription levels displayed differences under different stress treatments. PMID:27560990

  7. Genome-wide analysis of Aux/IAA and ARF gene families in Populus trichocarpa

    SciTech Connect

    Kalluri, Udaya C; DiFazio, Stephen P; Brunner, A.; Tuskan, Gerald A

    2007-01-01

    Auxin/Indole-3-Acetic Acid (Aux/IAA) and Auxin Response Factor (ARF) transcription factors are key regulators of auxin responses in plants. A total of 35 Aux/IAA and 39 ARF genes were identified in the Populus genome. Comparative phylogenetic analysis revealed that the subgroups PoptrARF2, 6, 9 and 16 and PoptrIAA3, 16, 27 and 29 have differentially expanded in Populus relative to Arabidopsis. Activator ARFs were found to be two fold-overrepresented in the Populus genome. PoptrIAA and PoptrARF gene families appear to have expanded due to high segmental and low tandem duplication events. Furthermore, expression studies showed that genes in the expanded PoptrIAA3 subgroup display differential expression. The gene-family analysis reported here will be useful in conducting future functional genomics studies to understand how the molecular roles of these large gene families translate into a diversity of biologically meaningful auxin effects.

  8. The catalase gene family in cucumber: genome-wide identification and organization.

    PubMed

    Hu, Lifang; Yang, Yingui; Jiang, Lunwei; Liu, Shiqiang

    2016-07-25

    Catalase (CAT) is a common antioxidant enzyme in almost all living organisms. Currently, detailed reports on cucumber (Cucumis sativus L.) CAT (CsCAT) genes and tissue expression profiling are limited. In the present study, four candidate CsCAT genes were identified in cucumber. Phylogenetic analysis indicated that CsCAT1-CsCAT3 are closely related to Arabidopsis AtCAT1-AtCAT3, but no obvious counterpart was observed for CsCAT4. Intron/exon structure analysis revealed that only one of the 15 positions was completely conserved. Motif analysis showed that, unlike the CAT genes of other species, none of CsCAT genes contained all 10 motifs. Expression data showed that transcripts of all of the CsCAT genes, except CsCAT4, were detected in five tissues. Moreover, their transcription levels displayed differences under different stress treatments. PMID:27459261

  9. Genome-Wide Transcriptome Directed Pathway Analysis of Maternal Pre-Eclampsia Susceptibility Genes

    PubMed Central

    Yong, Hannah E. J.; Melton, Phillip E.; Johnson, Matthew P.; Freed, Katy A.; Kalionis, Bill; Murthi, Padma; Brennecke, Shaun P.; Keogh, Rosemary J.; Moses, Eric K.

    2015-01-01

    Background Preeclampsia (PE) is a serious hypertensive pregnancy disorder with a significant genetic component. Numerous genetic studies, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling of tissues at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between these two approaches, although genes identified in both approaches are significantly associated with PE. We have thus taken a novel integrative bioinformatics approach of analysing pathways common to the susceptibility genes and the PE transcriptome. Methods Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n = 65 normotensive and n = 60 PE decidua basalis tissues collected at delivery. The R software package libraries lumi and limma were used to preprocess transcript data for pathway analysis. Pathways were analysed and constructed using Pathway Studio. We examined ten candidate genes, which are from these functional groups: activin/inhibin signalling—ACVR1, ACVR1C, ACVR2A, INHA, INHBB; structural components—COL4A1, COL4A2 and M1 family aminopeptidases—ERAP1, ERAP2 and LNPEP. Results/Conclusion Major common regulators/targets of these susceptibility genes identified were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA. The top two categories of pathways associated with the susceptibility genes, which were significantly altered in the PE decidual transcriptome, were apoptosis and cell signaling (p < 0.001). Thus, susceptibility genes from distinct functional groups share similar downstream pathways through common regulators/targets, some of which are altered in PE. This study contributes to a better understanding of how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their

  10. Genome wide transcriptome profiling reveals differential gene expression in secondary metabolite pathway of Cymbopogon winterianus.

    PubMed

    Devi, Kamalakshi; Mishra, Surajit K; Sahu, Jagajjit; Panda, Debashis; Modi, Mahendra K; Sen, Priyabrata

    2016-01-01

    Advances in transcriptome sequencing provide fast, cost-effective and reliable approach to generate large expression datasets especially suitable for non-model species to identify putative genes, key pathway and regulatory mechanism. Citronella (Cymbopogon winterianus) is an aromatic medicinal grass used for anti-tumoral, antibacterial, anti-fungal, antiviral, detoxifying and natural insect repellent properties. Despite of having number of utilities, the genes involved in terpenes biosynthetic pathway is not yet clearly elucidated. The present study is a pioneering attempt to generate an exhaustive molecular information of secondary metabolite pathway and to increase genomic resources in Citronella. Using high-throughput RNA-Seq technology, root and leaf transcriptome was analysed at an unprecedented depth (11.7 Gb). Targeted searches identified majority of the genes associated with metabolic pathway and other natural product pathway viz. antibiotics synthesis along with many novel genes. Terpenoid biosynthesis genes comparative expression results were validated for 15 unigenes by RT-PCR and qRT-PCR. Thus the coverage of these transcriptome is comprehensive enough to discover all known genes of major metabolic pathways. This transcriptome dataset can serve as important public information for gene expression, genomics and function genomics studies in Citronella and shall act as a benchmark for future improvement of the crop. PMID:26877149

  11. Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer

    PubMed Central

    He, Dong-Xu; Gu, Feng; Gao, Fei; Hao, Jun-jun; Gong, Desheng; Gu, Xiao-Ting; Mao, Ai-Qin; Jin, Jian; Fu, Li; Ma, Xin

    2016-01-01

    Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance. PMID:27094684

  12. Genome-Wide Identification of the Invertase Gene Family in Populus

    PubMed Central

    Su, Xiaoxing; Rao, Pian; An, Xinmin

    2015-01-01

    Invertase plays a crucial role in carbohydrate partitioning and plant development as it catalyses the irreversible hydrolysis of sucrose into glucose and fructose. The invertase family in plants is composed of two sub-families: acid invertases, which are targeted to the cell wall and vacuole; and neutral/alkaline invertases, which function in the cytosol. In this study, 5 cell wall invertase genes (PtCWINV1-5), 3 vacuolar invertase genes (PtVINV1-3) and 16 neutral/alkaline invertase genes (PtNINV1-16) were identified in the Populus genome and found to be distributed on 14 chromosomes. A comprehensive analysis of poplar invertase genes was performed, including structures, chromosome location, phylogeny, evolutionary pattern and expression profiles. Phylogenetic analysis indicated that the two sub-families were both divided into two clades. Segmental duplication is contributed to neutral/alkaline sub-family expansion. Furthermore, the Populus invertase genes displayed differential expression in roots, stems, leaves, leaf buds and in response to salt/cold stress and pathogen infection. In addition, the analysis of enzyme activity and sugar content revealed that invertase genes play key roles in the sucrose metabolism of various tissues and organs in poplar. This work lays the foundation for future functional analysis of the invertase genes in Populus and other woody perennials. PMID:26393355

  13. Genome-wide analysis of the GRAS gene family in physic nut (Jatropha curcas L.).

    PubMed

    Wu, Z Y; Wu, P Z; Chen, Y P; Li, M R; Wu, G J; Jiang, H W

    2015-01-01

    GRAS proteins play vital roles in plant growth and development. Physic nut (Jatropha curcas L.) was found to have a total of 48 GRAS family members (JcGRAS), 15 more than those found in Arabidopsis. The JcGRAS genes were divided into 12 subfamilies or 15 ancient monophyletic lineages based on the phylogenetic analysis of GRAS proteins from both flowering and lower plants. The functions of GRAS genes in 9 subfamilies have been reported previously for several plants, while the genes in the remaining 3 subfamilies were of unknown function; we named the latter families U1 to U3. No member of U3 subfamily is present in Arabidopsis and Poaceae species according to public genome sequence data. In comparison with the number of GRAS genes in Arabidopsis, more were detected in physic nut, resulting from the retention of many ancient GRAS subfamilies and the formation of tandem repeats during evolution. No evidence of recent duplication among JcGRAS genes was observed in physic nut. Based on digital gene expression data, 21 of the 48 genes exhibited differential expression in four tissues analyzed. Two members of subfamily U3 were expressed only in buds and flowers, implying that they may play specific roles. Our results provide valuable resources for future studies on the functions of GRAS proteins in physic nut. PMID:26782574

  14. Genome-wide distribution of Auts2 binding localizes with active neurodevelopmental genes

    PubMed Central

    Oksenberg, N; Haliburton, G D E; Eckalbar, W L; Oren, I; Nishizaki, S; Murphy, K; Pollard, K S; Birnbaum, R Y; Ahituv, N

    2014-01-01

    The autism susceptibility candidate 2 gene (AUTS2) has been associated with multiple neurological diseases including autism spectrum disorders (ASDs). Previous studies showed that AUTS2 has an important neurodevelopmental function and is a suspected master regulator of genes implicated in ASD-related pathways. However, the regulatory role and targets of Auts2 are not well known. Here, by using ChIP-seq (chromatin immunoprecipitation followed by deep sequencing) and RNA-seq on mouse embryonic day 16.5 forebrains, we elucidated the gene regulatory networks of Auts2. We find that the majority of promoters bound by Auts2 belong to genes highly expressed in the developing forebrain, suggesting that Auts2 is involved in transcriptional activation. Auts2 non-promoter-bound regions significantly overlap developing brain-associated enhancer marks and are located near genes involved in neurodevelopment. Auts2-marked sequences are enriched for binding site motifs of neurodevelopmental transcription factors, including Pitx3 and TCF3. In addition, we characterized two functional brain enhancers marked by Auts2 near NRXN1 and ATP2B2, both ASD-implicated genes. Our results implicate Auts2 as an active regulator of important neurodevelopmental genes and pathways and identify novel genomic regions that could be associated with ASD and other neurodevelopmental diseases. PMID:25180570

  15. Genome-Wide Analysis of Positively Selected Genes in Seasonal and Non-Seasonal Breeding Species

    PubMed Central

    Liu, Mingyu; Chen, Junhui; Tian, Shuai; Zhuo, Min; Zhang, Yu; Zhong, Yang; Du, Hongli; Wang, Xiaoning

    2015-01-01

    Some mammals breed throughout the year, while others breed only at certain times of year. These differences in reproductive behavior can be explained by evolution. We identified positively-selected genes in two sets of species with different degrees of relatedness including seasonal and non-seasonal breeding species, using branch-site models. After stringent filtering by sum of pairs scoring, we revealed that more genes underwent positive selection in seasonal compared with non-seasonal breeding species. Positively-selected genes were verified by cDNA mapping of the positive sites with the corresponding cDNA sequences. The design of the evolutionary analysis can effectively lower the false-positive rate and thus identify valid positive genes. Validated, positively-selected genes, including CGA, DNAH1, INVS, and CD151, were related to reproductive behaviors such as spermatogenesis and cell proliferation in non-seasonal breeding species. Genes in seasonal breeding species, including THRAP3, TH1L, and CMTM6, may be related to the evolution of sperm and the circadian rhythm system. Identification of these positively-selected genes might help to identify the molecular mechanisms underlying seasonal and non-seasonal reproductive behaviors. PMID:26000771

  16. Genome-Wide Identification and Expression Analysis of Two-Component System Genes in Tomato

    PubMed Central

    He, Yanjun; Liu, Xue; Ye, Lei; Pan, Changtian; Chen, Lifei; Zou, Tao; Lu, Gang

    2016-01-01

    The two-component system (TCS), which comprises histidine kinases (HKs), phosphotransfers (HPs), and response regulator proteins (RRs), plays pivotal roles in regulating plant growth, development, and responses to biotic and abiotic stresses. TCS genes have been comprehensively identified and investigated in various crops but poorly characterized in tomato. In this work, a total of 65 TCS genes consisting of 20 HK(L)s, six HPs, and 39 RRs were identified from tomato genome. The classification, gene structures, conserved domains, chromosome distribution, phylogenetic relationship, gene duplication events, and subcellular localization of the TCS gene family were predicted and analyzed in detail. The amino acid sequences of tomato TCS family members, except those of type-B RRs, are highly conserved. The gene duplication events of the TCS family mainly occurred in the RR family. Furthermore, the expansion of RRs was attributed to both segment and tandem duplication. The subcellular localizations of the selected green fluorescent protein (GFP) fusion proteins exhibited a diverse subcellular targeting, thereby confirming their predicted divergent functionality. The majority of TCS family members showed distinct organ- or development-specific expression patterns. In addition, most of TCS genes were induced by abiotic stresses and exogenous phytohormones. The full elucidation of TCS elements will be helpful for comprehensive analysis of the molecular biology and physiological role of the TCS superfamily. PMID:27472316

  17. Genome-wide analysis of immune system genes by expressed sequence Tag profiling.

    PubMed

    Giallourakis, Cosmas C; Benita, Yair; Molinie, Benoit; Cao, Zhifang; Despo, Orion; Pratt, Henry E; Zukerberg, Lawrence R; Daly, Mark J; Rioux, John D; Xavier, Ramnik J

    2013-06-01

    Profiling studies of mRNA and microRNA, particularly microarray-based studies, have been extensively used to create compendia of genes that are preferentially expressed in the immune system. In some instances, functional studies have been subsequently pursued. Recent efforts such as the Encyclopedia of DNA Elements have demonstrated the benefit of coupling RNA sequencing analysis with information from expressed sequence tags (ESTs) for transcriptomic analysis. However, the full characterization and identification of transcripts that function as modulators of human immune responses remains incomplete. In this study, we demonstrate that an integrated analysis of human ESTs provides a robust platform to identify the immune transcriptome. Beyond recovering a reference set of immune-enriched genes and providing large-scale cross-validation of previous microarray studies, we discovered hundreds of novel genes preferentially expressed in the immune system, including noncoding RNAs. As a result, we have established the Immunogene database, representing an integrated EST road map of gene expression in human immune cells, which can be used to further investigate the function of coding and noncoding genes in the immune system. Using this approach, we have uncovered a unique metabolic gene signature of human macrophages and identified PRDM15 as a novel overexpressed gene in human lymphomas. Thus, we demonstrate the utility of EST profiling as a basis for further deconstruction of physiologic and pathologic immune processes. PMID:23616578

  18. Genome-Wide Identification and Expression Analysis of Two-Component System Genes in Tomato.

    PubMed

    He, Yanjun; Liu, Xue; Ye, Lei; Pan, Changtian; Chen, Lifei; Zou, Tao; Lu, Gang

    2016-01-01

    The two-component system (TCS), which comprises histidine kinases (HKs), phosphotransfers (HPs), and response regulator proteins (RRs), plays pivotal roles in regulating plant growth, development, and responses to biotic and abiotic stresses. TCS genes have been comprehensively identified and investigated in various crops but poorly characterized in tomato. In this work, a total of 65 TCS genes consisting of 20 HK(L)s, six HPs, and 39 RRs were identified from tomato genome. The classification, gene structures, conserved domains, chromosome distribution, phylogenetic relationship, gene duplication events, and subcellular localization of the TCS gene family were predicted and analyzed in detail. The amino acid sequences of tomato TCS family members, except those of type-B RRs, are highly conserved. The gene duplication events of the TCS family mainly occurred in the RR family. Furthermore, the expansion of RRs was attributed to both segment and tandem duplication. The subcellular localizations of the selected green fluorescent protein (GFP) fusion proteins exhibited a diverse subcellular targeting, thereby confirming their predicted divergent functionality. The majority of TCS family members showed distinct organ- or development-specific expression patterns. In addition, most of TCS genes were induced by abiotic stresses and exogenous phytohormones. The full elucidation of TCS elements will be helpful for comprehensive analysis of the molecular biology and physiological role of the TCS superfamily. PMID:27472316

  19. Genome-Wide Identification of the Invertase Gene Family in Populus.

    PubMed

    Chen, Zhong; Gao, Kai; Su, Xiaoxing; Rao, Pian; An, Xinmin

    2015-01-01

    Invertase plays a crucial role in carbohydrate partitioning and plant development as it catalyses the irreversible hydrolysis of sucrose into glucose and fructose. The invertase family in plants is composed of two sub-families: acid invertases, which are targeted to the cell wall and vacuole; and neutral/alkaline invertases, which function in the cytosol. In this study, 5 cell wall invertase genes (PtCWINV1-5), 3 vacuolar invertase genes (PtVINV1-3) and 16 neutral/alkaline invertase genes (PtNINV1-16) were identified in the Populus genome and found to be distributed on 14 chromosomes. A comprehensive analysis of poplar invertase genes was performed, including structures, chromosome location, phylogeny, evolutionary pattern and expression profiles. Phylogenetic analysis indicated that the two sub-families were both divided into two clades. Segmental duplication is contributed to neutral/alkaline sub-family expansion. Furthermore, the Populus invertase genes displayed differential expression in roots, stems, leaves, leaf buds and in response to salt/cold stress and pathogen infection. In addition, the analysis of enzyme activity and sugar content revealed that invertase genes play key roles in the sucrose metabolism of various tissues and organs in poplar. This work lays the foundation for future functional analysis of the invertase genes in Populus and other woody perennials. PMID:26393355

  20. Genome wide transcriptome profiling reveals differential gene expression in secondary metabolite pathway of Cymbopogon winterianus

    PubMed Central

    Devi, Kamalakshi; Mishra, Surajit K.; Sahu, Jagajjit; Panda, Debashis; Modi, Mahendra K.; Sen, Priyabrata

    2016-01-01

    Advances in transcriptome sequencing provide fast, cost-effective and reliable approach to generate large expression datasets especially suitable for non-model species to identify putative genes, key pathway and regulatory mechanism. Citronella (Cymbopogon winterianus) is an aromatic medicinal grass used for anti-tumoral, antibacterial, anti-fungal, antiviral, detoxifying and natural insect repellent properties. Despite of having number of utilities, the genes involved in terpenes biosynthetic pathway is not yet clearly elucidated. The present study is a pioneering attempt to generate an exhaustive molecular information of secondary metabolite pathway and to increase genomic resources in Citronella. Using high-throughput RNA-Seq technology, root and leaf transcriptome was analysed at an unprecedented depth (11.7 Gb). Targeted searches identified majority of the genes associated with metabolic pathway and other natural product pathway viz. antibiotics synthesis along with many novel genes. Terpenoid biosynthesis genes comparative expression results were validated for 15 unigenes by RT-PCR and qRT-PCR. Thus the coverage of these transcriptome is comprehensive enough to discover all known genes of major metabolic pathways. This transcriptome dataset can serve as important public information for gene expression, genomics and function genomics studies in Citronella and shall act as a benchmark for future improvement of the crop. PMID:26877149

  1. Genome-wide profiles of methylation, microRNAs, and gene expression in chemoresistant breast cancer.

    PubMed

    He, Dong-Xu; Gu, Feng; Gao, Fei; Hao, Jun-Jun; Gong, Desheng; Gu, Xiao-Ting; Mao, Ai-Qin; Jin, Jian; Fu, Li; Ma, Xin

    2016-01-01

    Cancer chemoresistance is regulated by complex genetic and epigenetic networks. In this study, the features of gene expression, methylation, and microRNA (miRNA) expression were investigated with high-throughput sequencing in human breast cancer MCF-7 cells resistant to adriamycin (MCF-7/ADM) and paclitaxel (MCF-7/PTX). We found that: ① both of the chemoresistant cell lines had similar, massive changes in gene expression, methylation, and miRNA expression versus chemosensitive controls. ② Pairwise integration of the data highlighted sets of genes that were regulated by either methylation or miRNAs, and sets of miRNAs whose expression was controlled by DNA methylation in chemoresistant cells. ③ By combining the three sets of high-throughput data, we obtained a list of genes whose expression was regulated by both methylation and miRNAs in chemoresistant cells; ④ Expression of these genes was then validated in clinical breast cancer samples to generate a 17-gene signature that showed good predictive and prognostic power in triple-negative breast cancer patients receiving anthracycline-taxane-based neoadjuvant chemotherapy. In conclusion, our results have generated a new workflow for the integrated analysis of the effects of miRNAs and methylation on gene expression during the development of chemoresistance. PMID:27094684

  2. Genome-Wide Analysis Indicates Lineage-Specific Gene Loss during Papilionoideae Evolution

    PubMed Central

    Gu, Yongzhe; Xing, Shilai; He, Chaoying

    2016-01-01

    Gene loss is the driving force for changes in genome and morphology; however, this particular evolutionary event has been poorly investigated in leguminous plants. Legumes (Fabaceae) have some lineage-specific and diagnostic characteristics that are distinct from other angiosperms. To understand the potential role of gene loss in the evolution of legumes, we compared six genome-sequenced legume species of Papilionoideae, the largest representative clade of Fabaceae, such as Glycine max, with 34 nonlegume plant species, such as Arabidopsis thaliana. The results showed that the putative orthologs of the 34 Arabidopsis genes belonging to 29 gene families were absent in these legume species but these were conserved in the sequenced nonlegume angiosperm lineages. Further evolutionary analyses indicated that the orthologs of these genes were almost completely lost in the Papillionoideae ancestors, thus designated as the legume lost genes (LLGs), and these underwent purifying selection in nonlegume plants. Most LLGs were functionally unknown. In Arabidopsis, two LLGs were well-known genes that played a role in plant immunity such as HARMLESS TO OZONE LAYER 1 and HOPZ-ACTIVATED RESISTANCE 1, and 16 additional LLGs were predicted to participate in plant–pathogen interactions in in silico expression and protein–protein interaction network analyses. Most of these LLGs’ orthologs in various plants were also found to be associated with biotic stress response, indicating the conserved role of these genes in plant defense. The evolutionary implication of LLGs during the development of the ability of symbiotic nitrogen fixation involving plant and bacterial interactions, which is a well-known characteristic of most legumes, is also discussed. Our work sheds light on the evolutionary implication of gene loss events in Papilionoideae evolution, as well as provides new insights into crop design to improve nitrogen fixation capacity. PMID:26868598

  3. Genome-Wide Identification and Expression Analysis of the WRKY Gene Family in Cassava.

    PubMed

    Wei, Yunxie; Shi, Haitao; Xia, Zhiqiang; Tie, Weiwei; Ding, Zehong; Yan, Yan; Wang, Wenquan; Hu, Wei; Li, Kaimian

    2016-01-01

    The WRKY family, a large family of transcription factors (TFs) found in higher plants, plays central roles in many aspects of physiological processes and adaption to environment. However, little information is available regarding the WRKY family in cassava (Manihot esculenta). In the present study, 85 WRKY genes were identified from the cassava genome and classified into three groups according to conserved WRKY domains and zinc-finger structure. Conserved motif analysis showed that all of the identified MeWRKYs had the conserved WRKY domain. Gene structure analysis suggested that the number of introns in MeWRKY genes varied from 1 to 5, with the majority of MeWRKY genes containing three exons. Expression profiles of MeWRKY genes in different tissues and in response to drought stress were analyzed using the RNA-seq technique. The results showed that 72 MeWRKY genes had differential expression in their transcript abundance and 78 MeWRKY genes were differentially expressed in response to drought stresses in different accessions, indicating their contribution to plant developmental processes and drought stress resistance in cassava. Finally, the expression of 9 WRKY genes was analyzed by qRT-PCR under osmotic, salt, ABA, H2O2, and cold treatments, indicating that MeWRKYs may be involved in different signaling pathways. Taken together, this systematic analysis identifies some tissue-specific and abiotic stress-responsive candidate MeWRKY genes for further functional assays in planta, and provides a solid foundation for understanding of abiotic stress responses and signal transduction mediated by WRKYs in cassava. PMID:26904033

  4. Genome-Wide Analysis Indicates Lineage-Specific Gene Loss during Papilionoideae Evolution.

    PubMed

    Gu, Yongzhe; Xing, Shilai; He, Chaoying

    2016-03-01

    Gene loss is the driving force for changes in genome and morphology; however, this particular evolutionary event has been poorly investigated in leguminous plants. Legumes (Fabaceae) have some lineage-specific and diagnostic characteristics that are distinct from other angiosperms. To understand the potential role of gene loss in the evolution of legumes, we compared six genome-sequenced legume species of Papilionoideae, the largest representative clade of Fabaceae, such as Glycine max, with 34 nonlegume plant species, such as Arabidopsis thaliana. The results showed that the putative orthologs of the 34 Arabidopsis genes belonging to 29 gene families were absent in these legume species but these were conserved in the sequenced nonlegume angiosperm lineages. Further evolutionary analyses indicated that the orthologs of these genes were almost completely lost in the Papillionoideae ancestors, thus designated as the legume lost genes (LLGs), and these underwent purifying selection in nonlegume plants. Most LLGs were functionally unknown. In Arabidopsis, two LLGs were well-known genes that played a role in plant immunity such as HARMLESS TO OZONE LAYER 1 and HOPZ-ACTIVATED RESISTANCE 1, and 16 additional LLGs were predicted to participate in plant-pathogen interactions in in silico expression and protein-protein interaction network analyses. Most of these LLGs' orthologs in various plants were also found to be associated with biotic stress response, indicating the conserved role of these genes in plant defense. The evolutionary implication of LLGs during the development of the ability of symbiotic nitrogen fixation involving plant and bacterial interactions, which is a well-known characteristic of most legumes, is also discussed. Our work sheds light on the evolutionary implication of gene loss events in Papilionoideae evolution, as well as provides new insights into crop design to improve nitrogen fixation capacity. PMID:26868598

  5. Genome-wide analysis of the MADS-box gene family in Brassica rapa (Chinese cabbage).

    PubMed

    Duan, Weike; Song, Xiaoming; Liu, Tongkun; Huang, Zhinan; Ren, Jun; Hou, Xilin; Li, Ying

    2015-02-01

    The MADS-box gene family is an ancient and well-studied transcription factor family that functions in almost every developmental process in plants. There are a number of reports about the MADS-box family in different plant species, but systematic analysis of the MADS-box transcription factor family in Brassica rapa (Chinese cabbage) is still lacking. In this study, 160 MADS-box transcription factors were identified from the entire Chinese cabbage genome and compared with the MADS-box factors from 21 other representative plant species. A detailed list of MADS proteins from these 22 species was sorted. Phylogenetic analysis of the BrMADS genes, together with their Arabidopsis and rice counterparts, showed that the BrMADS genes were categorised into type I (Mα, Mβ, Mγ) and type II (MIKC(C), MIKC*) groups, and the MIKC(C) proteins were further divided into 13 subfamilies. The Chinese cabbage type II group has 95 members, which is twice as much as the Arabidopsis type II group, indicating that the Chinese cabbage type II genes have been retained more frequently than the type I genes. Finally, RNA-seq transcriptome data and quantitative real-time PCR analysis revealed that BrMADS genes are expressed in a tissue-specific manner similar to Arabidopsis. Interestingly, a number of BrMIKC genes showed responses to different abiotic stress treatments, suggesting a function for some of the genes in these processes as well. Taken together, the characterization of the B. rapa MADS-box family presented here, will certainly help in the selection of appropriate candidate genes and further facilitate functional studies in Chinese cabbage. PMID:25216934

  6. Genome-Wide Identification and Expression Analysis of the WRKY Gene Family in Cassava

    PubMed Central

    Wei, Yunxie; Shi, Haitao; Xia, Zhiqiang; Tie, Weiwei; Ding, Zehong; Yan, Yan; Wang, Wenquan; Hu, Wei; Li, Kaimian

    2016-01-01

    The WRKY family, a large family of transcription factors (TFs) found in higher plants, plays central roles in many aspects of physiological processes and adaption to environment. However, little information is available regarding the WRKY family in cassava (Manihot esculenta). In the present study, 85 WRKY genes were identified from the cassava genome and classified into three groups according to conserved WRKY domains and zinc-finger structure. Conserved motif analysis showed that all of the identified MeWRKYs had the conserved WRKY domain. Gene structure analysis suggested that the number of introns in MeWRKY genes varied from 1 to 5, with the majority of MeWRKY genes containing three exons. Expression profiles of MeWRKY genes in different tissues and in response to drought stress were analyzed using the RNA-seq technique. The results showed that 72 MeWRKY genes had differential expression in their transcript abundance and 78 MeWRKY genes were differentially expressed in response to drought stresses in different accessions, indicating their contribution to plant developmental processes and drought stress resistance in cassava. Finally, the expression of 9 WRKY genes was analyzed by qRT-PCR under osmotic, salt, ABA, H2O2, and cold treatments, indicating that MeWRKYs may be involved in different signaling pathways. Taken together, this systematic analysis identifies some tissue-specific and abiotic stress-responsive candidate MeWRKY genes for further functional assays in planta, and provides a solid foundation for understanding of abiotic stress responses and signal transduction mediated by WRKYs in cassava. PMID:26904033

  7. Genome-wide linkage and association analysis identifies major gene loci for guttural pouch tympany in Arabian and German warmblood horses.

    PubMed

    Metzger, Julia; Ohnesorge, Bernhard; Distl, Ottmar

    2012-01-01

    Equine guttural pouch tympany (GPT) is a hereditary condition affecting foals in their first months of life. Complex segregation analyses in Arabian and German warmblood horses showed the involvement of a major gene as very likely. Genome-wide linkage and association analyses including a high density marker set of single nucleotide polymorphisms (SNPs) were performed to map the genomic region harbouring the potential major gene for GPT. A total of 85 Arabian and 373 German warmblood horses were genotyped on the Illumina equine SNP50 beadchip. Non-parametric multipoint linkage analyses showed genome-wide significance on horse chromosomes (ECA) 3 for German warmblood at 16-26 Mb and 34-55 Mb and for Arabian on ECA15 at 64-65 Mb. Genome-wide association analyses confirmed the linked regions for both breeds. In Arabian, genome-wide association was detected at 64 Mb within the region with the highest linkage peak on ECA15. For German warmblood, signals for genome-wide association were close to the peak region of linkage at 52 Mb on ECA3. The odds ratio for the SNP with the highest genome-wide association was 0.12 for the Arabian. In conclusion, the refinement of the regions with the Illumina equine SNP50 beadchip is an important step to unravel the responsible mutations for GPT. PMID:22848553

  8. Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption.

    PubMed

    Pirastu, Nicola; Kooyman, Maarten; Robino, Antonietta; van der Spek, Ashley; Navarini, Luciano; Amin, Najaf; Karssen, Lennart C; Van Duijn, Cornelia M; Gasparini, Paolo

    2016-01-01

    Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption. PMID:27561104

  9. Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption

    PubMed Central

    Pirastu, Nicola; Kooyman, Maarten; Robino, Antonietta; van der Spek, Ashley; Navarini, Luciano; Amin, Najaf; Karssen, Lennart C.; Van Duijn, Cornelia M; Gasparini, Paolo

    2016-01-01

    Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption. PMID:27561104

  10. Genome-wide transcriptional analysis of flagellar regeneration in Chlamydomonas reinhardtii identifies orthologs of ciliary disease genes

    NASA Technical Reports Server (NTRS)

    Stolc, Viktor; Samanta, Manoj Pratim; Tongprasit, Waraporn; Marshall, Wallace F.

    2005-01-01

    The important role that cilia and flagella play in human disease creates an urgent need to identify genes involved in ciliary assembly and function. The strong and specific induction of flagellar-coding genes during flagellar regeneration in Chlamydomonas reinhardtii suggests that transcriptional profiling of such cells would reveal new flagella-related genes. We have conducted a genome-wide analysis of RNA transcript levels during flagellar regeneration in Chlamydomonas by using maskless photolithography method-produced DNA oligonucleotide microarrays with unique probe sequences for all exons of the 19,803 predicted genes. This analysis represents previously uncharacterized whole-genome transcriptional activity profiling study in this important model organism. Analysis of strongly induced genes reveals a large set of known flagellar components and also identifies a number of important disease-related proteins as being involved with cilia and flagella, including the zebrafish polycystic kidney genes Qilin, Reptin, and Pontin, as well as the testis-expressed tubby-like protein TULP2.