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Sample records for genome-wide analysis reveals

  1. Genome Wide Analysis of Chromatin Regulation by Cocaine Reveals a Novel Role for Sirtuins

    PubMed Central

    Renthal, William; Kumar, Arvind; Xiao, Guanghua; Wilkinson, Matthew; Covington, Herbert E.; Maze, Ian; Sikder, Devanjan; Robison, Alfred J.; LaPlant, Quincey; Dietz, David M.; Russo, Scott J.; Vialou, Vincent; Chakravarty, Sumana; Kodadek, Thomas J.; Stack, Ashley; Kabbaj, Mohammed; Nestler, Eric J.

    2009-01-01

    Summary Changes in gene expression contribute to the long-lasting regulation of the brain’s reward circuitry seen in drug addiction, however, the specific genes regulated and the transcriptional mechanisms underlying such regulation remain poorly understood. Here, we used chromatin immunoprecipitation coupled with promoter microarray analysis to characterize genome-wide chromatin changes in the mouse nucleus accumbens, a crucial brain reward region, after repeated cocaine administration. Our findings reveal several interesting principles of gene regulation by cocaine and of the role of ΔFosB and CREB, two prominent cocaine-induced transcription factors, in this brain region. The findings also provide novel and comprehensive insight into the molecular pathways regulated by cocaine – including a new role for sirtuins (Sirt1 and Sirt2) –which are induced in the nucleus accumbens by cocaine and, in turn, dramatically enhance the behavioral effects of the drug. PMID:19447090

  2. Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep

    PubMed Central

    Wei, Caihong; Wang, Huihua; Liu, Gang; Zhao, Fuping; Kijas, James W.; Ma, Youji; Lu, Jian; Zhang, Li; Cao, Jiaxue; Wu, Mingming; Wang, Guangkai; Liu, Ruizao; Liu, Zhen; Zhang, Shuzhen; Liu, Chousheng; Du, Lixin

    2016-01-01

    Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3′ untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation. PMID:27230812

  3. Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions.

    PubMed

    Di, Zhiyong; Yu, Yao; Wu, Yingliang; Hao, Pei; He, Yawen; Zhao, Huabin; Li, Yixue; Zhao, Guoping; Li, Xuan; Li, Wenxin; Cao, Zhijian

    2015-06-01

    Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 × coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes.

  4. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster

    PubMed Central

    Vonesch, Sibylle Chantal; Lamparter, David; Mackay, Trudy F. C.; Bergmann, Sven; Hafen, Ernst

    2016-01-01

    Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA) analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity. PMID:26751788

  5. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci

    PubMed Central

    Rahmioglu, Nilufer; Macgregor, Stuart; Drong, Alexander W.; Hedman, Åsa K.; Harris, Holly R.; Randall, Joshua C.; Prokopenko, Inga; Nyholt, Dale R.; Morris, Andrew P.; Montgomery, Grant W.; Missmer, Stacey A.; Lindgren, Cecilia M.; Zondervan, Krina T.

    2015-01-01

    Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10−3), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10−4). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10−4) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other. PMID:25296917

  6. Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.

    PubMed

    Feldmann, Radmila; Fischer, Cornelius; Kodelja, Vitam; Behrens, Sarah; Haas, Stefan; Vingron, Martin; Timmermann, Bernd; Geikowski, Anne; Sauer, Sascha

    2013-04-01

    Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

  7. Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1

    PubMed Central

    Ye, Zhenqing; Chen, Zhong; Sunkel, Benjamin; Frietze, Seth; Huang, Tim H.-M.; Wang, Qianben; Jin, Victor X.

    2016-01-01

    The compaction of nucleosomal structures creates a barrier for DNA-binding transcription factors (TFs) to access their cognate cis-regulatory elements. Pioneer factors (PFs) such as FOXA1 are able to directly access these cis-targets within compact chromatin. However, how these PFs interplay with nucleosomes remains to be elucidated, and is critical for us to understand the underlying mechanism of gene regulation. Here, we have conducted a computational analysis on a strand-specific paired-end ChIP-exo (termed as ChIP-ePENS) data of FOXA1 in LNCaP cells by our novel algorithm ePEST. We find that FOXA1 chromatin binding occurs via four distinct border modes (or footprint boundary patterns), with a preferential footprint boundary patterns relative to FOXA1 motif orientation. In addition, from this analysis three fundamental nucleotide positions (oG, oS and oH) emerged as major determinants for blocking exo-digestion and forming these four distinct border modes. By integrating histone MNase-seq data, we found an astonishingly consistent, ‘well-positioned’ configuration occurs between FOXA1 motifs and dyads of nucleosomes genome-wide. We further performed ChIP-seq of eight chromatin remodelers and found an increased occupancy of these remodelers on FOXA1 motifs for all four border modes (or footprint boundary patterns), indicating the full occupancy of FOXA1 complex on the three blocking sites (oG, oS and oH) likely produces an active regulatory status with well-positioned phasing for protein binding events. Together, our results suggest a positional-nucleosome-oriented accessing model for PFs seeking target motifs, in which FOXA1 can examine each underlying DNA nucleotide and is able to sense all potential motifs regardless of whether they face inward or outward from histone octamers along the DNA helix axis. PMID:27458208

  8. Genome-wide CNV analysis reveals variants associated with growth traits in Bos indicus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Apart from single nucleotide polymorphism (SNP), copy number variation (CNV) is another important type of genetic variation, which may affect growth traits and play key roles for the production of beef cattle. To date, no genome-wide association study (GWAS) for CNV and body traits in be...

  9. Genome-Wide Analysis in Brazilians Reveals Highly Differentiated Native American Genome Regions.

    PubMed

    Mychaleckyj, Josyf C; Havt, Alexandre; Nayak, Uma; Pinkerton, Relana; Farber, Emily; Concannon, Patrick; Lima, Aldo A; Guerrant, Richard L

    2017-03-01

    Despite its population, geographic size, and emerging economic importance, disproportionately little genome-scale research exists into genetic factors that predispose Brazilians to disease, or the population genetics of risk. After identification of suitable proxy populations and careful analysis of tri-continental admixture in 1,538 North-Eastern Brazilians to estimate individual ancestry and ancestral allele frequencies, we computed 400,000 genome-wide locus-specific branch length (LSBL) Fst statistics of Brazilian Amerindian ancestry compared to European and African; and a similar set of differentiation statistics for their Amerindian component compared with the closest Asian 1000 Genomes population (surprisingly, Bengalis in Bangladesh). After ranking SNPs by these statistics, we identified the top 10 highly differentiated SNPs in five genome regions in the LSBL tests of Brazilian Amerindian ancestry compared to European and African; and the top 10 SNPs in eight regions comparing their Amerindian component to the closest Asian 1000 Genomes population. We found SNPs within or proximal to the genes CIITA (rs6498115), SMC6 (rs1834619), and KLHL29 (rs2288697) were most differentiated in the Amerindian-specific branch, while SNPs in the genes ADAMTS9 (rs7631391), DOCK2 (rs77594147), SLC28A1 (rs28649017), ARHGAP5 (rs7151991), and CIITA (rs45601437) were most highly differentiated in the Asian comparison. These genes are known to influence immune function, metabolic and anthropometry traits, and embryonic development. These analyses have identified candidate genes for selection within Amerindian ancestry, and by comparison of the two analyses, those for which the differentiation may have arisen during the migration from Asia to the Americas.

  10. Genome wide analysis of Silurana (Xenopus) tropicalis development reveals dynamic expression using network enrichment analysis.

    PubMed

    Langlois, Valérie S; Martyniuk, Christopher J

    2013-01-01

    Development involves precise timing of gene expression and coordinated pathways for organogenesis and morphogenesis. Functional and sub-network enrichment analysis provides an integrated approach for identifying networks underlying development. The objectives of this study were to characterize early gene regulatory networks over Silurana tropicalis development from NF stage 2 to 46 using a custom Agilent 4×44K microarray. There were >8000 unique gene probes that were differentially expressed between Nieuwkoop-Faber (NF) stage 2 and stage 16, and >2000 gene probes differentially expressed between NF 34 and 46. Gene ontology revealed that genes involved in nucleosome assembly, cell division, pattern specification, neurotransmission, and general metabolism were increasingly regulated throughout development, consistent with active development. Sub-network enrichment analysis revealed that processes such as membrane hyperpolarisation, retinoic acid, cholesterol, and dopamine metabolic gene networks were activated/inhibited over time. This study identifies RNA transcripts that are potentially maternally inherited in an anuran species, provides evidence that the expression of genes involved in retinoic acid receptor signaling may increase prior to those involved in thyroid receptor signaling, and characterizes novel gene expression networks preceding organogenesis which increases understanding of the spatiotemporal embryonic development in frogs.

  11. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

    PubMed Central

    Lipinski, Marta M.; Zheng, Bin; Lu, Tao; Yan, Zhenyu; Py, Bénédicte F.; Ng, Aylwin; Xavier, Ramnik J.; Li, Cheng; Yankner, Bruce A.; Scherzer, Clemens R.; Yuan, Junying

    2010-01-01

    Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid β peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by Aβ is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death. PMID:20660724

  12. Genome-wide analysis of transcriptional regulators in human HSPCs reveals a densely interconnected network of coding and noncoding genes.

    PubMed

    Beck, Dominik; Thoms, Julie A I; Perera, Dilmi; Schütte, Judith; Unnikrishnan, Ashwin; Knezevic, Kathy; Kinston, Sarah J; Wilson, Nicola K; O'Brien, Tracey A; Göttgens, Berthold; Wong, Jason W H; Pimanda, John E

    2013-10-03

    Genome-wide combinatorial binding patterns for key transcription factors (TFs) have not been reported for primary human hematopoietic stem and progenitor cells (HSPCs), and have constrained analysis of the global architecture of molecular circuits controlling these cells. Here we provide high-resolution genome-wide binding maps for a heptad of key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1, and LMO2) in human CD34(+) HSPCs, together with quantitative RNA and microRNA expression profiles. We catalog binding of TFs at coding genes and microRNA promoters, and report that combinatorial binding of all 7 TFs is favored and associated with differential expression of genes and microRNA in HSPCs. We also uncover a previously unrecognized association between FLI1 and RUNX1 pairing in HSPCs, we establish a correlation between the density of histone modifications that mark active enhancers and the number of overlapping TFs at a peak, we demonstrate bivalent histone marks at promoters of heptad target genes in CD34(+) cells that are poised for later expression, and we identify complex relationships between specific microRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor sequencing of chromatin immunoprecipitates with coding and noncoding gene expression to identify regulatory circuits controlling cell identity.

  13. Genome-wide analysis reveals the ancient and recent admixture history of East African Shorthorn Zebu (EASZ)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Indigenous zebu cattle are widespread across East Africa owing to their tropically-adapted physiology. Previous studies using microsatellite loci revealed the complex history of these populations with the presence of taurine and zebu genetic backgrounds. Here, we estimate at the genome-wide level th...

  14. Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

    PubMed Central

    Akagi, Keiko; Li, Jingfeng; Broutian, Tatevik R.; Padilla-Nash, Hesed; Xiao, Weihong; Jiang, Bo; Rocco, James W.; Teknos, Theodoros N.; Kumar, Bhavna; Wangsa, Danny; He, Dandan; Ried, Thomas; Symer, David E.; Gillison, Maura L.

    2014-01-01

    Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of “looping” by which HPV integrant-mediated DNA replication and recombination may result in viral–host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability. PMID:24201445

  15. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins.

    PubMed

    Huelga, Stephanie C; Vu, Anthony Q; Arnold, Justin D; Liang, Tiffany Y; Liu, Patrick P; Yan, Bernice Y; Donohue, John Paul; Shiue, Lily; Hoon, Shawn; Brenner, Sydney; Ares, Manuel; Yeo, Gene W

    2012-02-23

    Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here, we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq), and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and autoregulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.

  16. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins

    PubMed Central

    Huelga, Stephanie C.; Vu, Anthony Q.; Arnold, Justin D.; Liang, Tiffany Y.; Liu, Patrick P.; Yan, Bernice Y.; Donohue, John Paul; Shiue, Lily; Hoon, Shawn; Brenner, Sydney; Ares, Manuel; Yeo, Gene W.

    2012-01-01

    SUMMARY Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, cross-linking and immunoprecipitation coupled with high-throughput sequencing, and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins, and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and auto-regulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells. PMID:22574288

  17. Genetic factors in nonsmokers with age-related macular degeneration revealed through genome-wide gene-environment interaction analysis.

    PubMed

    Naj, Adam C; Scott, William K; Courtenay, Monique D; Cade, William H; Schwartz, Stephen G; Kovach, Jaclyn L; Agarwal, Anita; Wang, Gaofeng; Haines, Jonathan L; Pericak-Vance, Margaret A

    2013-05-01

    Relatively little is known about the interaction between genes and environment in the complex etiology of age-related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene-smoking interactions in a genome-wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants' history of smoking at least 100 cigarettes lifetime was determined by a self-administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome-wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10(-30) ), ARMS2 (P = 1.94×10(-23) ), and RDBP/CFB/C2 (P = 4.37×10(-10) ), while joint effects analysis revealed three genomic regions with P < 10(-5) . Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10(-5) ), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.

  18. Genome-wide transcriptome analysis revealed organelle specific responses to temperature variations in algae

    PubMed Central

    Shin, HyeonSeok; Hong, Seong-Joo; Yoo, Chan; Han, Mi-Ae; Lee, Hookeun; Choi, Hyung-Kyoon; Cho, Suhyung; Lee, Choul-Gyun; Cho, Byung-Kwan

    2016-01-01

    Temperature is a critical environmental factor that affects microalgal growth. However, microalgal coping mechanisms for temperature variations are unclear. Here, we determined changes in transcriptome, total carbohydrate, total fatty acid methyl ester, and fatty acid composition of Tetraselmis sp. KCTC12432BP, a strain with a broad temperature tolerance range, to elucidate the tolerance mechanisms in response to large temperature variations. Owing to unavailability of genome sequence information, de novo transcriptome assembly coupled with BLAST analysis was performed using strand specific RNA-seq data. This resulted in 26,245 protein-coding transcripts, of which 83.7% could be annotated to putative functions. We identified more than 681 genes differentially expressed, suggesting an organelle-specific response to temperature variation. Among these, the genes related to the photosynthetic electron transfer chain, which are localized in the plastid thylakoid membrane, were upregulated at low temperature. However, the transcripts related to the electron transport chain and biosynthesis of phosphatidylethanolamine localized in mitochondria were upregulated at high temperature. These results show that the low energy uptake by repressed photosynthesis under low and high temperature conditions is compensated by different mechanisms, including photosystem I and mitochondrial oxidative phosphorylation, respectively. This study illustrates that microalgae tolerate different temperature conditions through organelle specific mechanisms. PMID:27883062

  19. Genome-Wide Analysis Reveals Selection for Important Traits in Domestic Horse Breeds

    PubMed Central

    Petersen, Jessica L.; Mickelson, James R.; Rendahl, Aaron K.; Valberg, Stephanie J.; Andersson, Lisa S.; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M.; Borges, Alexandre S.; Brama, Pieter; da Câmara Machado, Artur; Capomaccio, Stefano; Cappelli, Katia; Cothran, E. Gus; Distl, Ottmar; Fox-Clipsham, Laura; Graves, Kathryn T.; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A.; Mikko, Sofia; Orr, Nicholas; Penedo, M. Cecilia T.; Piercy, Richard J.; Raekallio, Marja; Rieder, Stefan; Røed, Knut H.; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M.; McCue, Molly E.

    2013-01-01

    Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an FST-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse. PMID:23349635

  20. Genome-wide analysis reveals selection for important traits in domestic horse breeds.

    PubMed

    Petersen, Jessica L; Mickelson, James R; Rendahl, Aaron K; Valberg, Stephanie J; Andersson, Lisa S; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M; Borges, Alexandre S; Brama, Pieter; da Câmara Machado, Artur; Capomaccio, Stefano; Cappelli, Katia; Cothran, E Gus; Distl, Ottmar; Fox-Clipsham, Laura; Graves, Kathryn T; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A; Mikko, Sofia; Orr, Nicholas; Penedo, M Cecilia T; Piercy, Richard J; Raekallio, Marja; Rieder, Stefan; Røed, Knut H; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M; McCue, Molly E

    2013-01-01

    Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse.

  1. Rumen Cellulosomics: Divergent Fiber-Degrading Strategies Revealed by Comparative Genome-Wide Analysis of Six Ruminococcal Strains

    PubMed Central

    Dassa, Bareket; Borovok, Ilya; Ruimy-Israeli, Vered; Lamed, Raphael; Flint, Harry J.; Duncan, Sylvia H.; Henrissat, Bernard; Coutinho, Pedro; Morrison, Mark; Mosoni, Pascale; Yeoman, Carl J.; White, Bryan A.; Bayer, Edward A.

    2014-01-01

    Background A complex community of microorganisms is responsible for efficient plant cell wall digestion by many herbivores, notably the ruminants. Understanding the different fibrolytic mechanisms utilized by these bacteria has been of great interest in agricultural and technological fields, reinforced more recently by current efforts to convert cellulosic biomass to biofuels. Methodology/Principal Findings Here, we have used a bioinformatics-based approach to explore the cellulosome-related components of six genomes from two of the primary fiber-degrading bacteria in the rumen: Ruminococcus flavefaciens (strains FD-1, 007c and 17) and Ruminococcus albus (strains 7, 8 and SY3). The genomes of two of these strains are reported for the first time herein. The data reveal that the three R. flavefaciens strains encode for an elaborate reservoir of cohesin- and dockerin-containing proteins, whereas the three R. albus strains are cohesin-deficient and encode mainly dockerins and a unique family of cell-anchoring carbohydrate-binding modules (family 37). Conclusions/Significance Our comparative genome-wide analysis pinpoints rare and novel strain-specific protein architectures and provides an exhaustive profile of their numerous lignocellulose-degrading enzymes. This work provides blueprints of the divergent cellulolytic systems in these two prominent fibrolytic rumen bacterial species, each of which reflects a distinct mechanistic model for efficient degradation of cellulosic biomass. PMID:24992679

  2. Genome-wide analysis reveals the ancient and recent admixture history of East African Shorthorn Zebu from Western Kenya

    PubMed Central

    Mbole-Kariuki, M N; Sonstegard, T; Orth, A; Thumbi, S M; Bronsvoort, B M de C; Kiara, H; Toye, P; Conradie, I; Jennings, A; Coetzer, K; Woolhouse, M E J; Hanotte, O; Tapio, M

    2014-01-01

    The Kenyan East African zebu cattle are valuable and widely used genetic resources. Previous studies using microsatellite loci revealed the complex history of these populations with the presence of taurine and zebu genetic backgrounds. Here, we estimate at genome-wide level the genetic composition and population structure of the East African Shorthorn Zebu (EASZ) of western Kenya. A total of 548 EASZ from 20 sub-locations were genotyped using the Illumina BovineSNP50 v. 1 beadchip. STRUCTURE analysis reveals admixture with Asian zebu, African and European taurine cattle. The EASZ were separated into three categories: substantial (⩾12.5%), moderate (1.56%

  3. Genome-wide direct target analysis reveals a role for SHORT-ROOT in root vascular patterning through cytokinin homeostasis.

    PubMed

    Cui, Hongchang; Hao, Yueling; Kovtun, Mikhail; Stolc, Viktor; Deng, Xing-Wang; Sakakibara, Hitoshi; Kojima, Mikiko

    2011-11-01

    SHORT-ROOT (SHR) is a key regulator of root growth and development in Arabidopsis (Arabidopsis thaliana). Made in the stele, the SHR protein moves into an adjacent cell layer, where it specifies endodermal cell fate; it is also essential for apical meristem maintenance, ground tissue patterning, vascular differentiation, and lateral root formation. Much has been learned about the mechanism by which SHR controls radial patterning, but how it regulates other aspects of root morphogenesis is still unclear. To dissect the SHR developmental pathway, we have determined the genome-wide locations of SHR direct targets using a chromatin immunoprecipitation followed by microarray analysis method. K-means clustering analysis not only identified additional quiescent center-specific SHR targets but also revealed a direct role for SHR in gene regulation in the pericycle and xylem. Using cell type-specific markers, we showed that in shr, the phloem and the phloem-associated pericycle expanded, whereas the xylem and xylem-associated pericycle diminished. Interestingly, we found that cytokinin level was elevated in shr and that exogenous cytokinin conferred a shr-like vascular patterning phenotype in wild-type root. By chromatin immunoprecipitation-polymerase chain reaction and reverse transcription-polymerase chain reaction assays, we showed that SHR regulates cytokinin homeostasis by directly controlling the transcription of cytokinin oxidase 3, a cytokinin catabolism enzyme preferentially expressed in the stele. Finally, overexpression of a cytokinin oxidase in shr alleviated its vascular patterning defect. On the basis of these results, we suggest that one mechanism by which SHR controls vascular patterning is the regulation of cytokinin homeostasis.

  4. Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes

    PubMed Central

    2011-01-01

    Background Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information. Results We have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like SOD1, APP, RUNX1 and DYRK1A as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under http://ds-geneminer.molgen.mpg.de/. Conclusions Our study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies. PMID:21569303

  5. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote

    PubMed Central

    Schübeler, Dirk; MacAlpine, David M.; Scalzo, David; Wirbelauer, Christiane; Kooperberg, Charles; van Leeuwen, Fred; Gottschling, Daniel E.; O'Neill, Laura P.; Turner, Bryan M.; Delrow, Jeffrey; Bell, Stephen P.; Groudine, Mark

    2004-01-01

    The covalent modification of nucleosomal histones has emerged as a major determinant of chromatin structure and gene activity. To understand the interplay between various histone modifications, including acetylation and methylation, we performed a genome-wide chromatin structure analysis in a higher eukaryote. We found a binary pattern of histone modifications among euchromatic genes, with active genes being hyperacetylated for H3 and H4 and hypermethylated at Lys 4 and Lys 79 of H3, and inactive genes being hypomethylated and deacetylated at the same residues. Furthermore, the degree of modification correlates with the level of transcription, and modifications are largely restricted to transcribed regions, suggesting that their regulation is tightly linked to polymerase activity. PMID:15175259

  6. Genome-wide analysis of the AP2/ERF family in Musa species reveals divergence and neofunctionalisation during evolution.

    PubMed

    Lakhwani, Deepika; Pandey, Ashutosh; Dhar, Yogeshwar Vikram; Bag, Sumit Kumar; Trivedi, Prabodh Kumar; Asif, Mehar Hasan

    2016-01-06

    AP2/ERF domain containing transcription factor super family is one of the important regulators in the plant kingdom. The involvement of AP2/ERF family members has been elucidated in various processes associated with plant growth, development as well as in response to hormones, biotic and abiotic stresses. In this study, we carried out genome-wide analysis to identify members of AP2/ERF family in Musa acuminata (A genome) and Musa balbisiana (B genome) and changes leading to neofunctionalisation of genes. Analysis identified 265 and 318 AP2/ERF encoding genes in M. acuminata and M. balbisiana respectively which were further classified into ERF, DREB, AP2, RAV and Soloist groups. Comparative analysis indicated that AP2/ERF family has undergone duplication, loss and divergence during evolution and speciation of the Musa A and B genomes. We identified nine genes which are up-regulated during fruit ripening and might be components of the regulatory machinery operating during ethylene-dependent ripening in banana. Tissue-specific expression analysis of the genes suggests that different regulatory mechanisms might be involved in peel and pulp ripening process through recruiting specific ERFs in these tissues. Analysis also suggests that MaRAV-6 and MaERF026 have structurally diverged from their M. balbisiana counterparts and have attained new functions during ripening.

  7. Genome-wide analysis of the AP2/ERF family in Musa species reveals divergence and neofunctionalisation during evolution

    PubMed Central

    Lakhwani, Deepika; Pandey, Ashutosh; Dhar, Yogeshwar Vikram; Bag, Sumit Kumar; Trivedi, Prabodh Kumar; Asif, Mehar Hasan

    2016-01-01

    AP2/ERF domain containing transcription factor super family is one of the important regulators in the plant kingdom. The involvement of AP2/ERF family members has been elucidated in various processes associated with plant growth, development as well as in response to hormones, biotic and abiotic stresses. In this study, we carried out genome-wide analysis to identify members of AP2/ERF family in Musa acuminata (A genome) and Musa balbisiana (B genome) and changes leading to neofunctionalisation of genes. Analysis identified 265 and 318 AP2/ERF encoding genes in M. acuminata and M. balbisiana respectively which were further classified into ERF, DREB, AP2, RAV and Soloist groups. Comparative analysis indicated that AP2/ERF family has undergone duplication, loss and divergence during evolution and speciation of the Musa A and B genomes. We identified nine genes which are up-regulated during fruit ripening and might be components of the regulatory machinery operating during ethylene-dependent ripening in banana. Tissue-specific expression analysis of the genes suggests that different regulatory mechanisms might be involved in peel and pulp ripening process through recruiting specific ERFs in these tissues. Analysis also suggests that MaRAV-6 and MaERF026 have structurally diverged from their M. balbisiana counterparts and have attained new functions during ripening. PMID:26733055

  8. Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci.

    PubMed

    Kelly, Tanika N; Takeuchi, Fumihiko; Tabara, Yasuharu; Edwards, Todd L; Kim, Young Jin; Chen, Peng; Li, Huaixing; Wu, Ying; Yang, Chi-Fan; Zhang, Yonghong; Gu, Dongfeng; Katsuya, Tomohiro; Ohkubo, Takayoshi; Gao, Yu-Tang; Go, Min Jin; Teo, Yik Ying; Lu, Ling; Lee, Nanette R; Chang, Li-Ching; Peng, Hao; Zhao, Qi; Nakashima, Eitaro; Kita, Yoshikuni; Shu, Xiao-Ou; Kim, Nam Hee; Tai, E Shyong; Wang, Yiqin; Adair, Linda S; Chen, Chien-Hsiun; Zhang, Shihiu; Li, Changwei; Nabika, Toru; Umemura, Satoshi; Cai, Qiuyin; Cho, Yoon Shin; Wong, Tien Yin; Zhu, Jingwen; Wu, Jer-Yuarn; Gao, Xin; Hixson, James E; Cai, Hui; Lee, Juyoung; Cheng, Ching-Yu; Rao, Dabeeru C; Xiang, Yong-Bing; Cho, Myeong-Chan; Han, Bok-Ghee; Wang, Aili; Tsai, Fuu-Jen; Mohlke, Karen; Lin, Xu; Ikram, Mohammad Kamran; Lee, Jong-Young; Zheng, Wei; Tetsuro, Miki; Kato, Norihiro; He, Jiang

    2013-11-01

    We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26,600 East Asian participants (stage 1) followed by replication study of up to 28,783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10(-8) in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10(-3). No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10(-15)), rs2681492 at ATP2B1 (P=3.4×10(-7)), rs11191593 at NT5C2 (1.1×10(-6)), rs3824755 at CYP17A1 (P=1.2×10(-6)), and rs13149993 at FGF5 (P=2.4×10(-4)). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10(-5)) and rs11191593 at NT5C2 (P=1.1×10(-3)), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10(-3)) and rs2681492 at ATP2B1 (P=9.0×10(-3)). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

  9. Genome-wide Computational Analysis Reveals Cardiomyocyte-specific Transcriptional Cis-regulatory Motifs That Enable Efficient Cardiac Gene Therapy

    PubMed Central

    Rincon, Melvin Y; Sarcar, Shilpita; Danso-Abeam, Dina; Keyaerts, Marleen; Matrai, Janka; Samara-Kuko, Ermira; Acosta-Sanchez, Abel; Athanasopoulos, Takis; Dickson, George; Lahoutte, Tony; De Bleser, Pieter; VandenDriessche, Thierry; Chuah, Marinee K

    2015-01-01

    Gene therapy is a promising emerging therapeutic modality for the treatment of cardiovascular diseases and hereditary diseases that afflict the heart. Hence, there is a need to develop robust cardiac-specific expression modules that allow for stable expression of the gene of interest in cardiomyocytes. We therefore explored a new approach based on a genome-wide bioinformatics strategy that revealed novel cardiac-specific cis-acting regulatory modules (CS-CRMs). These transcriptional modules contained evolutionary-conserved clusters of putative transcription factor binding sites that correspond to a “molecular signature” associated with robust gene expression in the heart. We then validated these CS-CRMs in vivo using an adeno-associated viral vector serotype 9 that drives a reporter gene from a quintessential cardiac-specific α-myosin heavy chain promoter. Most de novo designed CS-CRMs resulted in a >10-fold increase in cardiac gene expression. The most robust CRMs enhanced cardiac-specific transcription 70- to 100-fold. Expression was sustained and restricted to cardiomyocytes. We then combined the most potent CS-CRM4 with a synthetic heart and muscle-specific promoter (SPc5-12) and obtained a significant 20-fold increase in cardiac gene expression compared to the cytomegalovirus promoter. This study underscores the potential of rational vector design to improve the robustness of cardiac gene therapy. PMID:25195597

  10. Genome-wide computational analysis reveals cardiomyocyte-specific transcriptional Cis-regulatory motifs that enable efficient cardiac gene therapy.

    PubMed

    Rincon, Melvin Y; Sarcar, Shilpita; Danso-Abeam, Dina; Keyaerts, Marleen; Matrai, Janka; Samara-Kuko, Ermira; Acosta-Sanchez, Abel; Athanasopoulos, Takis; Dickson, George; Lahoutte, Tony; De Bleser, Pieter; VandenDriessche, Thierry; Chuah, Marinee K

    2015-01-01

    Gene therapy is a promising emerging therapeutic modality for the treatment of cardiovascular diseases and hereditary diseases that afflict the heart. Hence, there is a need to develop robust cardiac-specific expression modules that allow for stable expression of the gene of interest in cardiomyocytes. We therefore explored a new approach based on a genome-wide bioinformatics strategy that revealed novel cardiac-specific cis-acting regulatory modules (CS-CRMs). These transcriptional modules contained evolutionary-conserved clusters of putative transcription factor binding sites that correspond to a "molecular signature" associated with robust gene expression in the heart. We then validated these CS-CRMs in vivo using an adeno-associated viral vector serotype 9 that drives a reporter gene from a quintessential cardiac-specific α-myosin heavy chain promoter. Most de novo designed CS-CRMs resulted in a >10-fold increase in cardiac gene expression. The most robust CRMs enhanced cardiac-specific transcription 70- to 100-fold. Expression was sustained and restricted to cardiomyocytes. We then combined the most potent CS-CRM4 with a synthetic heart and muscle-specific promoter (SPc5-12) and obtained a significant 20-fold increase in cardiac gene expression compared to the cytomegalovirus promoter. This study underscores the potential of rational vector design to improve the robustness of cardiac gene therapy.

  11. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    MedlinePlus

    ... historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A team of international researchers supported by the ... when they divide and grow uncontrollably, develop into melanoma. Also, MITF activity is known to be amplified ...

  12. Genome-Wide Analysis Reveals Loci Encoding Anti-Macrophage Factors in the Human Pathogen Burkholderia pseudomallei K96243

    PubMed Central

    Dowling, Andrea J.; Wilkinson, Paul A.; Holden, Matthew T. G.; Quail, Michael A.; Bentley, Stephen D.; Reger, Julia; Waterfield, Nicholas R.; Titball, Richard W.; ffrench-Constant, Richard H.

    2010-01-01

    Burkholderia pseudomallei is an important human pathogen whose infection biology is still poorly understood. The bacterium is endemic to tropical regions, including South East Asia and Northern Australia, where it causes melioidosis, a serious disease associated with both high mortality and antibiotic resistance. B. pseudomallei is a Gram-negative facultative intracellular pathogen that is able to replicate in macrophages. However despite the critical nature of its interaction with macrophages, few anti-macrophage factors have been characterized to date. Here we perform a genome-wide gain of function screen of B. pseudomallei strain K96243 to identify loci encoding factors with anti-macrophage activity. We identify a total of 113 such loci scattered across both chromosomes, with positive gene clusters encoding transporters and secretion systems, enzymes/toxins, secondary metabolite, biofilm, adhesion and signal response related factors. Further phenotypic analysis of four of these regions shows that the encoded factors cause striking cellular phenotypes relevant to infection biology, including apoptosis, formation of actin ‘tails’ and multi-nucleation within treated macrophages. The detailed analysis of the remaining host of loci will facilitate genetic dissection of the interaction of this important pathogen with host macrophages and thus further elucidate this critical part of its infection cycle. PMID:21203527

  13. Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis

    PubMed Central

    Tengvall, Katarina; Kierczak, Marcin; Bergvall, Kerstin; Olsson, Mia; Frankowiack, Marcel; Farias, Fabiana H. G.; Pielberg, Gerli; Carlborg, Örjan; Leeb, Tosso; Andersson, Göran; Hammarström, Lennart; Hedhammar, Åke; Lindblad-Toh, Kerstin

    2013-01-01

    Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1×10−5) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0×10−9), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1×10−7, pgenome = 0.03). The total associated region was defined as a ∼1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ∼209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD. PMID:23671420

  14. Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

    PubMed

    Stuart, Philip E; Nair, Rajan P; Tsoi, Lam C; Tejasvi, Trilokraj; Das, Sayantan; Kang, Hyun Min; Ellinghaus, Eva; Chandran, Vinod; Callis-Duffin, Kristina; Ike, Robert; Li, Yanming; Wen, Xiaoquan; Enerbäck, Charlotta; Gudjonsson, Johann E; Kõks, Sulev; Kingo, Külli; Esko, Tõnu; Mrowietz, Ulrich; Reis, Andre; Wichmann, H Erich; Gieger, Christian; Hoffmann, Per; Nöthen, Markus M; Winkelmann, Juliane; Kunz, Manfred; Moreta, Elvia G; Mease, Philip J; Ritchlin, Christopher T; Bowcock, Anne M; Krueger, Gerald G; Lim, Henry W; Weidinger, Stephan; Weichenthal, Michael; Voorhees, John J; Rahman, Proton; Gregersen, Peter K; Franke, Andre; Gladman, Dafna D; Abecasis, Gonçalo R; Elder, James T

    2015-12-03

    Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

  15. Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture

    PubMed Central

    Stuart, Philip E.; Nair, Rajan P.; Tsoi, Lam C.; Tejasvi, Trilokraj; Das, Sayantan; Kang, Hyun Min; Ellinghaus, Eva; Chandran, Vinod; Callis-Duffin, Kristina; Ike, Robert; Li, Yanming; Wen, Xiaoquan; Enerbäck, Charlotta; Gudjonsson, Johann E.; Kõks, Sulev; Kingo, Külli; Esko, Tõnu; Mrowietz, Ulrich; Reis, Andre; Wichmann, H. Erich; Gieger, Christian; Hoffmann, Per; Nöthen, Markus M.; Winkelmann, Juliane; Kunz, Manfred; Moreta, Elvia G.; Mease, Philip J.; Ritchlin, Christopher T.; Bowcock, Anne M.; Krueger, Gerald G.; Lim, Henry W.; Weidinger, Stephan; Weichenthal, Michael; Voorhees, John J.; Rahman, Proton; Gregersen, Peter K.; Franke, Andre; Gladman, Dafna D.; Abecasis, Gonçalo R.; Elder, James T.

    2015-01-01

    Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10−11). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10−19; rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA. PMID:26626624

  16. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.

    PubMed

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D; Eeles, Rosalind A; Chatterjee, Nilanjan; Schumacher, Fredrick R; Schildkraut, Joellen M; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Amin Al Olama, Ali; Berndt, Sonja I; Giovannucci, Edward L; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir J; Stevens, Victoria L; Wiklund, Fredrik; Willett, Walter C; Goode, Ellen L; Permuth, Jennifer B; Risch, Harvey A; Reid, Brett M; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T; Chang-Claude, Jenny; Hudson, Thomas J; Kocarnik, Jonathan K; Newcomb, Polly A; Schoen, Robert E; Slattery, Martha L; White, Emily; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; Dos-Santos-Silva, Isabel; Eliassen, A Heather; Figueroa, Jonine D; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A; Nevanlinna, Heli; Peeters, Petra H; Peto, Julian; Prentice, Ross L; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F; Schmutzler, Rita K; Southey, Melissa C; Tamimi, Rulla; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Wang, Zhaoming; Whittemore, Alice S; Yang, Xiaohong R; Zheng, Wei; Buchanan, Daniel D; Casey, Graham; Conti, David V; Edlund, Christopher K; Gallinger, Steven; Haile, Robert W; Jenkins, Mark; Le Marchand, Loïc; Li, Li; Lindor, Noralene M; Schmit, Stephanie L; Thibodeau, Stephen N; Woods, Michael O; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N; Stefansson, Kari; Sulem, Patrick; Chen, Y Ann; Tyrer, Jonathan P; Christiani, David C; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma'en; Nickle, David; Timens, Wim; Freedman, Matthew L; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J; Gong, Jian; Peters, Ulrike; Gruber, Stephen B; Amos, Christopher I; Sellers, Thomas A; Easton, Douglas F; Hunter, David J; Haiman, Christopher A; Henderson, Brian E; Hung, Rayjean J

    2016-09-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

  17. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

    PubMed Central

    Fehringer, Gordon; Kraft, Peter; Pharoah, Paul D.; Eeles, Rosalind A.; Chatterjee, Nilanjan; Schumacher, Fred; Schildkraut, Joellen; Lindström, Sara; Brennan, Paul; Bickeböller, Heike; Houlston, Richard S.; Landi, Maria Teresa; Caporaso, Neil; Risch, Angela; Olama, Ali Amin Al; Berndt, Sonja I; Giovannucci, Edward; Grönberg, Henrik; Kote-Jarai, Zsofia; Ma, Jing; Muir, Kenneth; Stampfer, Meir; Stevens, Victoria L.; Wiklund, Fredrik; Willett, Walter; Goode, Ellen L.; Permuth, Jennifer; Risch, Harvey A.; Reid, Brett M.; Bezieau, Stephane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Hudson, Thomas J.; Kocarnik, Jonathan K.; Newcomb, Polly A.; Schoen, Robert E.; Slattery, Martha L.; White, Emily; Adank, Muriel A.; Ahsan, Habibul; Aittomäki, Kristiina; Baglietto, Laura; Blomquist, Carl; Canzian, Federico; Czene, Kamila; dos-Santos-Silva, Isabel; Eliassen, A. Heather; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Garcia-Closas, Montserrat; Gaudet, Mia M.; Johnson, Nichola; Hall, Per; Hazra, Aditi; Hein, Rebecca; Hofman, Albert; Hopper, John L.; Irwanto, Astrid; Johansson, Mattias; Kaaks, Rudolf; Kibriya, Muhammad G.; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Meindl, Alfons; Müller-Myhsok, Bertram; Muranen, Taru A.; Nevanlinna, Heli; Peeters, Petra H.; Peto, Julian; Prentice, Ross L.; Rahman, Nazneen; Sanchez, Maria Jose; Schmidt, Daniel F.; Schmutzler, Rita K.; Southey, Melissa C.; Tamimi, Rulla; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Wang, Zhaoming; Whittemore, Alice S.; Yang, Xiaohong R.; Zheng, Wei; Rafnar, Thorunn; Gudmundsson, Julius; Stacey, Simon N.; Stefansson, Kari; Sulem, Patrick; Chen, Y. Ann; Tyrer, Jonathan P.; Christiani, David C.; Wei, Yongyue; Shen, Hongbing; Hu, Zhibin; Shu, Xiao-Ou; Shiraishi, Kouya; Takahashi, Atsushi; Bossé, Yohan; Obeidat, Ma’en; Nickle, David; Timens, Wim; Freedman, Matthew L.; Li, Qiyuan; Seminara, Daniela; Chanock, Stephen J.; Gong, Jian; Peters, Ulrike; Gruber, Stephen B.; Amos, Christopher I.; Sellers, Thomas A.; Easton, Douglas F.; Hunter, David J.; Haiman, Christopher A.; Henderson, Brian E.; Hung, Rayjean J.

    2016-01-01

    Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. PMID:27197191

  18. Genome-Wide Analysis of PDZ Domain Binding Reveals Inherent Functional Overlap within the PDZ Interaction Network

    PubMed Central

    te Velthuis, Aartjan J. W.; Sakalis, Philippe A.; Fowler, Donald A.; Bagowski, Christoph P.

    2011-01-01

    Binding selectivity and cross-reactivity within one of the largest and most abundant interaction domain families, the PDZ family, has long been enigmatic. The complete human PDZ domain complement (the PDZome) consists of 267 domains and we applied here a Bayesian selectivity model to predict hundreds of human PDZ domain interactions, using target sequences of 22,997 non-redundant proteins. Subsequent analysis of these binding scores shows that PDZs can be divided into two genome-wide clusters that coincide well with the division between canonical class 1 and 2 PDZs. Within the class 1 PDZs we observed binding overlap at unprecedented levels, mediated by two residues at positions 1 and 5 of the second α-helix of the binding pocket. Eight PDZ domains were subsequently selected for experimental binding studies and to verify the basics of our predictions. Overall, the PDZ domain class 1 cross-reactivity identified here implies that auxiliary mechanisms must be in place to overcome this inherent functional overlap and to minimize cross-selectivity within the living cell. Indeed, when we superimpose PDZ domain binding affinities with gene ontologies, network topology data and the domain position within a PDZ superfamily protein, functional overlap is minimized and PDZ domains position optimally in the binding space. We therefore propose that PDZ domain selectivity is achieved through cellular context rather than inherent binding specificity. PMID:21283644

  19. Genome-Wide Analysis of the Expansin Gene Superfamily Reveals Grapevine-Specific Structural and Functional Characteristics

    PubMed Central

    Tornielli, Giovanni Battista; Fasoli, Marianna; Venturini, Luca; Pezzotti, Mario; Zenoni, Sara

    2013-01-01

    Background Expansins are proteins that loosen plant cell walls in a pH-dependent manner, probably by increasing the relative movement among polymers thus causing irreversible expansion. The expansin superfamily (EXP) comprises four distinct families: expansin A (EXPA), expansin B (EXPB), expansin-like A (EXLA) and expansin-like B (EXLB). There is experimental evidence that EXPA and EXPB proteins are required for cell expansion and developmental processes involving cell wall modification, whereas the exact functions of EXLA and EXLB remain unclear. The complete grapevine (Vitis vinifera) genome sequence has allowed the characterization of many gene families, but an exhaustive genome-wide analysis of expansin gene expression has not been attempted thus far. Methodology/Principal Findings We identified 29 EXP superfamily genes in the grapevine genome, representing all four EXP families. Members of the same EXP family shared the same exon–intron structure, and phylogenetic analysis confirmed a closer relationship between EXP genes from woody species, i.e. grapevine and poplar (Populus trichocarpa), compared to those from Arabidopsis thaliana and rice (Oryza sativa). We also identified grapevine-specific duplication events involving the EXLB family. Global gene expression analysis confirmed a strong correlation among EXP genes expressed in mature and green/vegetative samples, respectively, as reported for other gene families in the recently-published grapevine gene expression atlas. We also observed the specific co-expression of EXLB genes in woody organs, and the involvement of certain grapevine EXP genes in berry development and post-harvest withering. Conclusion Our comprehensive analysis of the grapevine EXP superfamily confirmed and extended current knowledge about the structural and functional characteristics of this gene family, and also identified properties that are currently unique to grapevine expansin genes. Our data provide a model for the functional

  20. Genome-wide regulatory analysis reveals T-bet controls Th17 lineage differentiation through direct suppression of IRF41

    PubMed Central

    Gökmen, M. Refik; Dong, Rong; Kanhere, Aditi; Powell, Nick; Perucha, Esperanza; Jackson, Ian; Howard, Jane K.; Hernandez-Fuentes, Maria; Jenner, Richard G.; Lord, Graham M.

    2013-01-01

    The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. It has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that mucosal Th17 responses were augmented in the absence of T-bet, and we have demonstrated that the role of T-bet in enforcing Th1 responses and suppressing Th17 responses are separable. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells. PMID:24249732

  1. Genome-wide analysis reveals artificial selection on coat colour and reproductive traits in Chinese domestic pigs.

    PubMed

    Wang, Chao; Wang, Hongyang; Zhang, Yu; Tang, Zhonglin; Li, Kui; Liu, Bang

    2015-03-01

    Pigs from Asia and Europe were independently domesticated from c. 9000 years ago. During this period, strong artificial selection has led to dramatic phenotypic changes in domestic pigs. However, the genetic basis underlying these morphological and behavioural adaptations is relatively unknown, particularly for indigenous Chinese pigs. Here, we performed a genome-wide analysis to screen 196 regions with selective sweep signals in Tongcheng pigs, which are a typical indigenous Chinese breed. Genes located in these regions have been found to be involved in lipid metabolism, melanocyte differentiation, neural development and other biological processes, which coincide with the evolutionary phenotypic changes in this breed. A synonymous substitution, c.669T>C, in ESR1, which colocalizes with a major quantitative trait locus for litter size, shows extreme differences in allele frequency between Tongcheng pigs and wild boars. Notably, the variant C allele in this locus exhibits high allele frequency in most Chinese populations, suggesting a consequence of positive selection. Five genes (PRM1, PRM2, TNP2, GPR149 and JMJD1C) related to reproductive traits were found to have high haplotype similarity in Chinese breeds. Two selected genes, MITF and EDNRB, are implied to shape the two-end black colour trait in Tongcheng pig. Subsequent SNP microarray studies of five Chinese white-spotted breeds displayed a concordant signature at both loci, suggesting that these two genes are responsible for colour variations in Chinese breeds. Utilizing massively parallel sequencing, we characterized the candidate sites that adapt to artificial and environmental selections during the Chinese pig domestication. This study provides fundamental proof for further research on the evolutionary adaptation of Chinese pigs.

  2. Genome-wide analysis of redox reactions reveals metabolic engineering targets for D-lactate overproduction in Escherichia coli.

    PubMed

    Kim, Hyun Ju; Hou, Bo Kyeng; Lee, Sung Gun; Kim, Joong Su; Lee, Dong-Woo; Lee, Sang Jun

    2013-07-01

    Most current metabolic engineering applications rely on the inactivation of unwanted reactions and the amplification of product-oriented reactions. All of the biochemical reactions involved with cellular metabolism are tightly coordinated with the electron flow, which depends on the cellular energy status. Thus, the cellular metabolic flux can be controlled either by modulation of the electron flow or the regulation of redox reactions. This study analyzed the genome-wide anaerobic fermentation products of 472 Escherichia coli single gene knockouts, which comprised mainly of dehydrogenases, oxidoreductases, and redox-related proteins. Many metabolic pathways that were located far from anaerobic mixed-acid fermentation significantly affected the profiles of lactic acid, succinic acid, acetic acid, formic acid, and ethanol. Unexpectedly, D-lactate overproduction was determined by a single gene deletion in dehydrogenases (e.g., guaB, pyrD, and serA) involved with nucleotide and amino acid metabolism. Furthermore, the combined knockouts of guaB, pyrD, serA, fnr, arcA, or arcB genes, which are involved with anaerobic transcription regulation, enhanced D-lactate overproduction. These results suggest that the anaerobic fermentation profiles of E. coli can be tuned via the disruption of peripheral dehydrogenases in anaerobic conditions.

  3. Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death.

    PubMed

    Pandyra, Aleksandra A; Mullen, Peter J; Goard, Carolyn A; Ericson, Elke; Sharma, Piyush; Kalkat, Manpreet; Yu, Rosemary; Pong, Janice T; Brown, Kevin R; Hart, Traver; Gebbia, Marinella; Lang, Karl S; Giaever, Guri; Nislow, Corey; Moffat, Jason; Penn, Linda Z

    2015-09-29

    The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy.

  4. Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death

    PubMed Central

    Pandyra, Aleksandra A.; Mullen, Peter J.; Goard, Carolyn A.; Ericson, Elke; Sharma, Piyush; Kalkat, Manpreet; Yu, Rosemary; Pong, Janice T.; Brown, Kevin R.; Hart, Traver; Gebbia, Marinella; Lang, Karl S.; Giaever, Guri; Nislow, Corey; Moffat, Jason; Penn, Linda Z.

    2015-01-01

    The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy. PMID:26353928

  5. Genome wide analysis reveals Zic3 interaction with distal regulatory elements of stage specific developmental genes in zebrafish.

    PubMed

    Winata, Cecilia L; Kondrychyn, Igor; Kumar, Vibhor; Srinivasan, Kandhadayar G; Orlov, Yuriy; Ravishankar, Ashwini; Prabhakar, Shyam; Stanton, Lawrence W; Korzh, Vladimir; Mathavan, Sinnakaruppan

    2013-10-01

    Zic3 regulates early embryonic patterning in vertebrates. Loss of Zic3 function is known to disrupt gastrulation, left-right patterning, and neurogenesis. However, molecular events downstream of this transcription factor are poorly characterized. Here we use the zebrafish as a model to study the developmental role of Zic3 in vivo, by applying a combination of two powerful genomics approaches--ChIP-seq and microarray. Besides confirming direct regulation of previously implicated Zic3 targets of the Nodal and canonical Wnt pathways, analysis of gastrula stage embryos uncovered a number of novel candidate target genes, among which were members of the non-canonical Wnt pathway and the neural pre-pattern genes. A similar analysis in zic3-expressing cells obtained by FACS at segmentation stage revealed a dramatic shift in Zic3 binding site locations and identified an entirely distinct set of target genes associated with later developmental functions such as neural development. We demonstrate cis-regulation of several of these target genes by Zic3 using in vivo enhancer assay. Analysis of Zic3 binding sites revealed a distribution biased towards distal intergenic regions, indicative of a long distance regulatory mechanism; some of these binding sites are highly conserved during evolution and act as functional enhancers. This demonstrated that Zic3 regulation of developmental genes is achieved predominantly through long distance regulatory mechanism and revealed that developmental transitions could be accompanied by dramatic changes in regulatory landscape.

  6. Genome Wide Analysis Reveals Zic3 Interaction with Distal Regulatory Elements of Stage Specific Developmental Genes in Zebrafish

    PubMed Central

    Kumar, Vibhor; Srinivasan, Kandhadayar G.; Orlov, Yuriy; Ravishankar, Ashwini; Prabhakar, Shyam; Stanton, Lawrence W.; Korzh, Vladimir; Mathavan, Sinnakaruppan

    2013-01-01

    Zic3 regulates early embryonic patterning in vertebrates. Loss of Zic3 function is known to disrupt gastrulation, left-right patterning, and neurogenesis. However, molecular events downstream of this transcription factor are poorly characterized. Here we use the zebrafish as a model to study the developmental role of Zic3 in vivo, by applying a combination of two powerful genomics approaches – ChIP-seq and microarray. Besides confirming direct regulation of previously implicated Zic3 targets of the Nodal and canonical Wnt pathways, analysis of gastrula stage embryos uncovered a number of novel candidate target genes, among which were members of the non-canonical Wnt pathway and the neural pre-pattern genes. A similar analysis in zic3-expressing cells obtained by FACS at segmentation stage revealed a dramatic shift in Zic3 binding site locations and identified an entirely distinct set of target genes associated with later developmental functions such as neural development. We demonstrate cis-regulation of several of these target genes by Zic3 using in vivo enhancer assay. Analysis of Zic3 binding sites revealed a distribution biased towards distal intergenic regions, indicative of a long distance regulatory mechanism; some of these binding sites are highly conserved during evolution and act as functional enhancers. This demonstrated that Zic3 regulation of developmental genes is achieved predominantly through long distance regulatory mechanism and revealed that developmental transitions could be accompanied by dramatic changes in regulatory landscape. PMID:24204288

  7. Genome-wide analysis of tandem repeats in Tribolium castaneum genome reveals abundant and highly dynamic tandem repeat families with satellite DNA features in euchromatic chromosomal arms.

    PubMed

    Pavlek, Martina; Gelfand, Yevgeniy; Plohl, Miroslav; Meštrović, Nevenka

    2015-12-01

    Although satellite DNAs are well-explored components of heterochromatin and centromeres, little is known about emergence, dispersal and possible impact of comparably structured tandem repeats (TRs) on the genome-wide scale. Our bioinformatics analysis of assembled Tribolium castaneum genome disclosed significant contribution of TRs in euchromatic chromosomal arms and clear predominance of satellite DNA-typical 170 bp monomers in arrays of ≥5 repeats. By applying different experimental approaches, we revealed that the nine most prominent TR families Cast1-Cast9 extracted from the assembly comprise ∼4.3% of the entire genome and reside almost exclusively in euchromatic regions. Among them, seven families that build ∼3.9% of the genome are based on ∼170 and ∼340 bp long monomers. Results of phylogenetic analyses of 2500 monomers originating from these families show high-sequence dynamics, evident by extensive exchanges between arrays on non-homologous chromosomes. In addition, our analysis shows that concerted evolution acts more efficiently on longer than on shorter arrays. Efficient genome-wide distribution of nine TR families implies the role of transposition only in expansion of the most dispersed family, and involvement of other mechanisms is anticipated. Despite similarities in sequence features, FISH experiments indicate high-level compartmentalization of centromeric and euchromatic tandem repeats.

  8. Genome-Wide Analysis of Arabidopsis Pentatricopeptide Repeat Proteins Reveals Their Essential Role in Organelle BiogenesisW⃞

    PubMed Central

    Lurin, Claire; Andrés, Charles; Aubourg, Sébastien; Bellaoui, Mohammed; Bitton, Frédérique; Bruyère, Clémence; Caboche, Michel; Debast, Cédrig; Gualberto, José; Hoffmann, Beate; Lecharny, Alain; Le Ret, Monique; Martin-Magniette, Marie-Laure; Mireau, Hakim; Peeters, Nemo; Renou, Jean-Pierre; Szurek, Boris; Taconnat, Ludivine; Small, Ian

    2004-01-01

    The complete sequence of the Arabidopsis thaliana genome revealed thousands of previously unsuspected genes, many of which cannot be ascribed even putative functions. One of the largest and most enigmatic gene families discovered in this way is characterized by tandem arrays of pentatricopeptide repeats (PPRs). We describe a detailed bioinformatic analysis of 441 members of the Arabidopsis PPR family plus genomic and genetic data on the expression (microarray data), localization (green fluorescent protein and red fluorescent protein fusions), and general function (insertion mutants and RNA binding assays) of many family members. The basic picture that arises from these studies is that PPR proteins play constitutive, often essential roles in mitochondria and chloroplasts, probably via binding to organellar transcripts. These results confirm, but massively extend, the very sparse observations previously obtained from detailed characterization of individual mutants in other organisms. PMID:15269332

  9. Genome-wide analysis of the Dof transcription factor gene family reveals soybean-specific duplicable and functional characteristics.

    PubMed

    Guo, Yong; Qiu, Li-Juan

    2013-01-01

    The Dof domain protein family is a classic plant-specific zinc-finger transcription factor family involved in a variety of biological processes. There is great diversity in the number of Dof genes in different plants. However, there are only very limited reports on the characterization of Dof transcription factors in soybean (Glycine max). In the present study, 78 putative Dof genes were identified from the whole-genome sequence of soybean. The predicted GmDof genes were non-randomly distributed within and across 19 out of 20 chromosomes and 97.4% (38 pairs) were preferentially retained duplicate paralogous genes located in duplicated regions of the genome. Soybean-specific segmental duplications contributed significantly to the expansion of the soybean Dof gene family. These Dof proteins were phylogenetically clustered into nine distinct subgroups among which the gene structure and motif compositions were considerably conserved. Comparative phylogenetic analysis of these Dof proteins revealed four major groups, similar to those reported for Arabidopsis and rice. Most of the GmDofs showed specific expression patterns based on RNA-seq data analyses. The expression patterns of some duplicate genes were partially redundant while others showed functional diversity, suggesting the occurrence of sub-functionalization during subsequent evolution. Comprehensive expression profile analysis also provided insights into the soybean-specific functional divergence among members of the Dof gene family. Cis-regulatory element analysis of these GmDof genes suggested diverse functions associated with different processes. Taken together, our results provide useful information for the functional characterization of soybean Dof genes by combining phylogenetic analysis with global gene-expression profiling.

  10. Genome-wide meta-analysis of maize heterosis reveals the potential role of additive gene expression at pericentromeric loci

    PubMed Central

    2014-01-01

    Background The identification of QTL involved in heterosis formation is one approach to unravel the not yet fully understood genetic basis of heterosis - the improved agronomic performance of hybrid F1 plants compared to their inbred parents. The identification of candidate genes underlying a QTL is important both for developing markers and determining the molecular genetic basis of a trait, but remains difficult owing to the large number of genes often contained within individual QTL. To address this problem in heterosis analysis, we applied a meta-analysis strategy for grain yield (GY) of Zea mays L. as example, incorporating QTL-, hybrid field-, and parental gene expression data. Results For the identification of genes underlying known heterotic QTL, we made use of tight associations between gene expression pattern and the trait of interest, identified by correlation analyses. Using this approach genes strongly associated with heterosis for GY were discovered to be clustered in pericentromeric regions of the complex maize genome. This suggests that expression differences of sequences in recombination-suppressed regions are important in the establishment of heterosis for GY in F1 hybrids and also in the conservation of heterosis for GY across genotypes. Importantly functional analysis of heterosis-associated genes from these genomic regions revealed over-representation of a number of functional classes, identifying key processes contributing to heterosis for GY. Based on the finding that the majority of the analyzed heterosis-associated genes were addtitively expressed, we propose a model referring to the influence of cis-regulatory variation on heterosis for GY by the compensation of fixed detrimental expression levels in parents. Conclusions The study highlights the utility of a meta-analysis approach that integrates phenotypic and multi-level molecular data to unravel complex traits in plants. It provides prospects for the identification of genes relevant for

  11. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes.

    PubMed

    Court, Franck; Martin-Trujillo, Alex; Romanelli, Valeria; Garin, Intza; Iglesias-Platas, Isabel; Salafsky, Ira; Guitart, Miriam; Perez de Nanclares, Guiomar; Lapunzina, Pablo; Monk, David

    2013-04-01

    Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance.

  12. High Differentiation among Eight Villages in a Secluded Area of Sardinia Revealed by Genome-Wide High Density SNPs Analysis

    PubMed Central

    Pirastu, Nicola; Persico, Ivana; Sassu, Alessandro; Picciau, Andrea; Prodi, Dionigio; Fraumene, Cristina; Mocci, Evelina; Manias, Maria Teresa; Atzeni, Rossano; Cosso, Massimiliano; Pirastu, Mario

    2009-01-01

    To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not “a priori” be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates. PMID:19247500

  13. Genome-wide expression analysis of soybean NF-Y genes reveals potential function in development and drought response.

    PubMed

    Quach, Truyen N; Nguyen, Hanh T M; Valliyodan, Babu; Joshi, Trupti; Xu, Dong; Nguyen, Henry T

    2015-06-01

    Nuclear factor-Y (NF-Y), a heterotrimeric transcription factor, is composed of NF-YA, NF-YB and NF-YC proteins. In plants, there are usually more than 10 genes for each family and their members have been identified to be key regulators in many developmental and physiological processes controlling gametogenesis, embryogenesis, nodule development, seed development, abscisic acid (ABA) signaling, flowering time, primary root elongation, blue light responses, endoplasmic reticulum (ER) stress response and drought tolerance. Taking the advantages of the recent soybean genome draft and information on functional characterizations of nuclear factor Y (NF-Y) transcription factor family in plants, we identified 21 GmNF-YA, 32 GmNF-YB, and 15 GmNF-YC genes in the soybean (Glycine max) genome. Phylogenetic analyses show that soybean's proteins share strong homology to Arabidopsis and many of them are closely related to functionally characterized NF-Y in plants. Expression analysis in various tissues of flower, leaf, root, seeds of different developmental stages, root hairs under rhizobium inoculation, and drought-treated roots and leaves revealed that certain groups of soybean NF-Y are likely involved in specific developmental and stress responses. This study provides extensive evaluation of the soybean NF-Y family and is particularly useful for further functional characterization of GmNF-Y proteins in seed development, nodulation and drought adaptation of soybean.

  14. A Genome-Wide Analysis Reveals Stress and Hormone Responsive Patterns of TIFY Family Genes in Brassica rapa

    PubMed Central

    Saha, Gopal; Park, Jong-In; Kayum, Md. Abdul; Nou, Ill-Sup

    2016-01-01

    The TIFY family is a plant-specific group of proteins with a diversity of functions and includes four subfamilies, viz. ZML, TIFY, PPD, and JASMONATE ZIM-domain (JAZ) proteins. TIFY family members, particularly JAZ subfamily proteins, play roles in biological processes such as development and stress and hormone responses in Arabidopsis, rice, chickpea, and grape. However, there is no information about this family in any Brassica crop. This study identifies 36 TIFY genes in Brassica rapa, an economically important crop species in the Brassicaceae. An extensive in silico analysis of phylogenetic grouping, protein motif organization and intron-exon distribution confirmed that there are four subfamilies of BrTIFY proteins. Out of 36 BrTIFY genes, we identified 21 in the JAZ subfamily, seven in the TIFY subfamily, six in ZML and two in PPD. Extensive expression profiling of 21 BrTIFY JAZs in various tissues, especially in floral organs and at different flower growth stages revealed constitutive expression patterns, which suggest that BrTIFY JAZ genes are important during growth and development of B. rapa flowers. A protein interaction network analysis also pointed to association of these proteins with fertility and defense processes of B. rapa. Using a low temperature-treated whole-genome microarray data set, most of the JAZ genes were found to have variable transcript abundance between the contrasting inbred lines Chiifu and Kenshin of B. rapa. Subsequently, the expression of all 21 BrTIFY JAZs in response to cold stress was characterized in the same two lines via qPCR, demonstrating that nine genes were up-regulated. Importantly, the BrTIFY JAZs showed strong and differential expression upon JA treatment, pointing to their probable involvement in JA-mediated growth regulatory functions, especially during flower development and stress responses. Additionally, BrTIFY JAZs were induced in response to salt, drought, Fusarium, ABA, and SA treatments, and six genes (BrTIFY3

  15. A Genome-Wide Analysis Reveals Stress and Hormone Responsive Patterns of TIFY Family Genes in Brassica rapa.

    PubMed

    Saha, Gopal; Park, Jong-In; Kayum, Md Abdul; Nou, Ill-Sup

    2016-01-01

    The TIFY family is a plant-specific group of proteins with a diversity of functions and includes four subfamilies, viz. ZML, TIFY, PPD, and JASMONATE ZIM-domain (JAZ) proteins. TIFY family members, particularly JAZ subfamily proteins, play roles in biological processes such as development and stress and hormone responses in Arabidopsis, rice, chickpea, and grape. However, there is no information about this family in any Brassica crop. This study identifies 36 TIFY genes in Brassica rapa, an economically important crop species in the Brassicaceae. An extensive in silico analysis of phylogenetic grouping, protein motif organization and intron-exon distribution confirmed that there are four subfamilies of BrTIFY proteins. Out of 36 BrTIFY genes, we identified 21 in the JAZ subfamily, seven in the TIFY subfamily, six in ZML and two in PPD. Extensive expression profiling of 21 BrTIFY JAZs in various tissues, especially in floral organs and at different flower growth stages revealed constitutive expression patterns, which suggest that BrTIFY JAZ genes are important during growth and development of B. rapa flowers. A protein interaction network analysis also pointed to association of these proteins with fertility and defense processes of B. rapa. Using a low temperature-treated whole-genome microarray data set, most of the JAZ genes were found to have variable transcript abundance between the contrasting inbred lines Chiifu and Kenshin of B. rapa. Subsequently, the expression of all 21 BrTIFY JAZs in response to cold stress was characterized in the same two lines via qPCR, demonstrating that nine genes were up-regulated. Importantly, the BrTIFY JAZs showed strong and differential expression upon JA treatment, pointing to their probable involvement in JA-mediated growth regulatory functions, especially during flower development and stress responses. Additionally, BrTIFY JAZs were induced in response to salt, drought, Fusarium, ABA, and SA treatments, and six genes (BrTIFY3

  16. Genome-wide analysis correlates Ayurveda Prakriti

    PubMed Central

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K.; Prasanna, B. V.; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S.; Dedge, Amrish P.; Bharadwaj, Ramachandra; Gangadharan, G. G.; Nair, Sreekumaran; Gopinath, Puthiya M.; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-01-01

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as “Prakriti”. To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10−5) were significantly different between Prakritis, without any confounding effect of stratification, after 106 permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India’s traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine. PMID:26511157

  17. Novel Comparative Pattern Count Analysis Reveals a Chronic Ethanol-Induced Dynamic Shift in Immediate Early NF-κB Genome-wide Promoter Binding During Liver Regeneration

    PubMed Central

    Kuttippurathu, Lakshmi; Patra, Biswanath; Hoek, Jan B; Vadigepalli, Rajanikanth

    2016-01-01

    Liver regeneration after partial hepatectomy is a clinically important process that is impaired by adaptation to chronic alcohol intake. We focused on the initial time points following partial hepatectomy (PHx) to analyze genome-wide binding activity of NF-κB, a key immediate early regulator. We investigated the effect of chronic alcohol intake on immediate early NF-κB genome-wide localization, in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found many ethanol-specific NF-κB binding target promoters in the ethanol-adapted state, corresponding to regulation of biosynthetic processes, oxidation-reduction and apoptosis. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns in ethanol and pair-fed control groups. The highest pattern count corresponded to promoters with NF-κB binding exclusively in the ethanol group at 1h post PHx. This set was associated with regulation of cell death, response to oxidative stress, histone modification, mitochondrial function, and metabolic processes. Integration with the global gene expression profiles to identify putative transcriptional consequences of NF-κB binding patterns revealed that several of ethanol-specific 1h binding targets showed ethanol-specific differential expression through 6h post PHx. Motif analysis yielded co-incident binding loci for STAT3, AP-1, CREB, C/EBP-β, PPAR-γ and C/EBP-α, likely participating in co-regulatory modules with NF-κB in shaping the immediate early response to PHx. We conclude that adaptation to chronic ethanol intake disrupts the NF-κB promoter binding landscape with consequences for the immediate early gene regulatory response to the acute challenge of PHx. PMID:26847025

  18. A genome wide dosage suppressor network reveals genomic robustness

    PubMed Central

    Patra, Biranchi; Kon, Yoshiko; Yadav, Gitanjali; Sevold, Anthony W.; Frumkin, Jesse P.; Vallabhajosyula, Ravishankar R.; Hintze, Arend; Østman, Bjørn; Schossau, Jory; Bhan, Ashish; Marzolf, Bruz; Tamashiro, Jenna K.; Kaur, Amardeep; Baliga, Nitin S.; Grayhack, Elizabeth J.; Adami, Christoph; Galas, David J.; Raval, Alpan; Phizicky, Eric M.; Ray, Animesh

    2017-01-01

    Genomic robustness is the extent to which an organism has evolved to withstand the effects of deleterious mutations. We explored the extent of genomic robustness in budding yeast by genome wide dosage suppressor analysis of 53 conditional lethal mutations in cell division cycle and RNA synthesis related genes, revealing 660 suppressor interactions of which 642 are novel. This collection has several distinctive features, including high co-occurrence of mutant-suppressor pairs within protein modules, highly correlated functions between the pairs and higher diversity of functions among the co-suppressors than previously observed. Dosage suppression of essential genes encoding RNA polymerase subunits and chromosome cohesion complex suggests a surprising degree of functional plasticity of macromolecular complexes, and the existence of numerous degenerate pathways for circumventing the effects of potentially lethal mutations. These results imply that organisms and cancer are likely able to exploit the genomic robustness properties, due the persistence of cryptic gene and pathway functions, to generate variation and adapt to selective pressures. PMID:27899637

  19. Genome-wide analysis of Dof transcription factors reveals functional characteristics during development and response to biotic stresses in pepper.

    PubMed

    Kang, Won-Hee; Kim, Seungill; Lee, Hyun-Ah; Choi, Doil; Yeom, Seon-In

    2016-09-22

    The DNA-binding with one zinc finger proteins (Dofs) are a plant-specific family of transcription factors. The Dofs are involved in a variety of biological processes such as phytohormone production, seed development, and environmental adaptation. Dofs have been previously identified in several plants, but not in pepper. We identified 33 putative Dof genes in pepper (CaDofs). To gain an overview of the CaDofs, we analyzed phylogenetic relationships, protein motifs, and evolutionary history. We divided the 33 CaDofs, containing 25 motifs, into four major groups distributed on eight chromosomes. We discovered an expansion of the CaDofs dated to a recent duplication event. Segmental duplication that occurred before the speciation of the Solanaceae lineages was predominant among the CaDofs. The global gene-expression profiling of the CaDofs by RNA-seq analysis showed distinct temporal and pathogen-specific variation during development and response to biotic stresses (two TMV strains, PepMoV, and Phytophthora capsici), suggesting functional diversity among the CaDofs. These results will provide the useful clues into the responses of Dofs in biotic stresses and promote a better understanding of their multiple function in pepper and other species.

  20. Genome-wide analysis of Dof transcription factors reveals functional characteristics during development and response to biotic stresses in pepper

    PubMed Central

    Kang, Won-Hee; Kim, Seungill; Lee, Hyun-Ah; Choi, Doil; Yeom, Seon-In

    2016-01-01

    The DNA-binding with one zinc finger proteins (Dofs) are a plant-specific family of transcription factors. The Dofs are involved in a variety of biological processes such as phytohormone production, seed development, and environmental adaptation. Dofs have been previously identified in several plants, but not in pepper. We identified 33 putative Dof genes in pepper (CaDofs). To gain an overview of the CaDofs, we analyzed phylogenetic relationships, protein motifs, and evolutionary history. We divided the 33 CaDofs, containing 25 motifs, into four major groups distributed on eight chromosomes. We discovered an expansion of the CaDofs dated to a recent duplication event. Segmental duplication that occurred before the speciation of the Solanaceae lineages was predominant among the CaDofs. The global gene-expression profiling of the CaDofs by RNA-seq analysis showed distinct temporal and pathogen-specific variation during development and response to biotic stresses (two TMV strains, PepMoV, and Phytophthora capsici), suggesting functional diversity among the CaDofs. These results will provide the useful clues into the responses of Dofs in biotic stresses and promote a better understanding of their multiple function in pepper and other species. PMID:27653666

  1. A genome-wide analysis of populations from European Russia reveals a new pole of genetic diversity in northern Europe.

    PubMed

    Khrunin, Andrey V; Khokhrin, Denis V; Filippova, Irina N; Esko, Tõnu; Nelis, Mari; Bebyakova, Natalia A; Bolotova, Natalia L; Klovins, Janis; Nikitina-Zake, Liene; Rehnström, Karola; Ripatti, Samuli; Schreiber, Stefan; Franke, Andre; Macek, Milan; Krulišová, Veronika; Lubinski, Jan; Metspalu, Andres; Limborska, Svetlana A

    2013-01-01

    Several studies examined the fine-scale structure of human genetic variation in Europe. However, the European sets analyzed represent mainly northern, western, central, and southern Europe. Here, we report an analysis of approximately 166,000 single nucleotide polymorphisms in populations from eastern (northeastern) Europe: four Russian populations from European Russia, and three populations from the northernmost Finno-Ugric ethnicities (Veps and two contrast groups of Komi people). These were compared with several reference European samples, including Finns, Estonians, Latvians, Poles, Czechs, Germans, and Italians. The results obtained demonstrated genetic heterogeneity of populations living in the region studied. Russians from the central part of European Russia (Tver, Murom, and Kursk) exhibited similarities with populations from central-eastern Europe, and were distant from Russian sample from the northern Russia (Mezen district, Archangelsk region). Komi samples, especially Izhemski Komi, were significantly different from all other populations studied. These can be considered as a second pole of genetic diversity in northern Europe (in addition to the pole, occupied by Finns), as they had a distinct ancestry component. Russians from Mezen and the Finnic-speaking Veps were positioned between the two poles, but differed from each other in the proportions of Komi and Finnic ancestries. In general, our data provides a more complete genetic map of Europe accounting for the diversity in its most eastern (northeastern) populations.

  2. Genome-wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation.

    PubMed

    Pai, Vaibhav P; Martyniuk, Christopher J; Echeverri, Karen; Sundelacruz, Sarah; Kaplan, David L; Levin, Michael

    2016-02-01

    Endogenous bioelectric signaling via changes in cellular resting potential (V mem) is a key regulator of patterning during regeneration and embryogenesis in numerous model systems. Depolarization of V mem has been functionally implicated in dedifferentiation, tumorigenesis, anatomical re-specification, and appendage regeneration. However, no unbiased analyses have been performed to understand genome-wide transcriptional responses to V mem change in vivo. Moreover, it is unknown which genes or gene networks represent conserved targets of bioelectrical signaling across different patterning contexts and species. Here, we use microarray analysis to comparatively analyze transcriptional responses to V mem depolarization. We compare the response of the transcriptome during embryogenesis (Xenopus development), regeneration (axolotl regeneration), and stem cell differentiation (human mesenchymal stem cells in culture) to identify common networks across model species that are associated with depolarization. Both subnetwork enrichment and PANTHER analyses identified a number of key genetic modules as targets of V mem change, and also revealed important (well-conserved) commonalities in bioelectric signal transduction, despite highly diverse experimental contexts and species. Depolarization regulates specific transcriptional networks across all three germ layers (ectoderm, mesoderm, and endoderm) such as cell differentiation and apoptosis, and this information will be used for developing mechanistic models of bioelectric regulation of patterning. Moreover, our analysis reveals that V mem change regulates transcripts related to important disease pathways such as cancer and neurodegeneration, which may represent novel targets for emerging electroceutical therapies.

  3. Genome-wide transcriptomic analysis reveals correlation between higher WRKY61 expression and reduced symptom severity in Turnip crinkle virus infected Arabidopsis thaliana

    PubMed Central

    Gao, Ruimin; Liu, Peng; Yong, Yuhan; Wong, Sek-Man

    2016-01-01

    Turnip crinkle virus (TCV) is a carmovirus that infects many Arabidopsis ecotypes. Most studies mainly focused on discovery of resistance genes against TCV infection, and there is no Next Generation Sequencing based comparative genome wide transcriptome analysis reported. In this study, RNA-seq based transcriptome analysis revealed that 238 (155 up-regulated and 83 down-regulated) significant differentially expressed genes with at least 15-fold change were determined. Fifteen genes (including upregulated, unchanged and downregulated) were selected for RNA-seq data validation using quantitative real-time PCR, which showed consistencies between these two sets of data. GO enrichment analysis showed that numerous terms such as stress, immunity, defence and chemical stimulus were affected in TCV-infected plants. One putative plant defence related gene named WRKY61 was selected for further investigation. It showed that WRKY61 overexpression plants displayed reduced symptoms and less virus accumulation, as compared to wild type (WT) and WRKY61 deficient lines, suggesting that higher WRKY61 expression level reduced TCV viral accumulation. In conclusion, our transcriptome analysis showed that global gene expression was detected in TCV-infected Arabidopsis thaliana. WRKY61 gene was shown to be negatively correlated with TCV infection and viral symptoms, which may be connected to plant immunity pathways. PMID:27086702

  4. Genome-wide SNP typing reveals signatures of population history.

    PubMed

    Hughes, Austin L; Welch, Robert; Puri, Vinita; Matthews, Casey; Haque, Kashif; Chanock, Stephen J; Yeager, Meredith

    2008-07-01

    Single-nucleotide polymorphism (SNP) arrays have become a popular technology for disease-association studies, but they also have potential for studying the genetic differentiation of human populations. Application of the Affymetrix GeneChip Human Mapping 500K Array Set to a population of 102 individuals representing the major ethnic groups in the United States (African, Asian, European, and Hispanic) revealed patterns of gene diversity and genetic distance that reflected population history. We analyzed allelic frequencies at 388,654 autosomal SNP sites that showed some variation in our study population and 10% or fewer missing values. Despite the small size (23-31 individuals) of each subpopulation, there were no fixed differences at any site between any two subpopulations. As expected from the African origin of modern humans, greater gene diversity was seen in Africans than in either Asians or Europeans, and the genetic distance between the Asian and the European populations was significantly lower than that between either of these two populations and Africans. Principal components analysis applied to a correlation matrix among individuals was able to separate completely the major continental groups of humans (Africans, Asians, and Europeans), while Hispanics overlapped all three of these groups. Genes containing two or more markers with extraordinarily high genetic distance between subpopulations were identified as candidate genes for health differences between subpopulations. The results show that, even with modest sample sizes, genome-wide SNP genotyping technologies have great promise for capturing signatures of gene frequency difference between human subpopulations, with applications in areas as diverse as forensics and the study of ethnic health disparities.

  5. Rank-based genome-wide analysis reveals the association of Ryanodine receptor-2 gene variants with childhood asthma among human populations

    PubMed Central

    2013-01-01

    Background The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database. Results Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value = 2.55 × 10−7) and was replicated in African (2.57 × 10−4) and Hispanic (1.18 × 10−3) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases. Conclusion Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top

  6. Genome-wide analysis of histone methylation reveals chromatin state-based complex regulation of differential gene transcription and function of CD8 memory T cells

    PubMed Central

    Araki, Yasuto; Wang, Zhibin; Zang, Chongzhi; Wood, William H.; Schones, Dustin; Cui, Kairong; Roh, Tae-Young; Lhotsky, Brad; Wersto, Robert P.; Peng, Weiqun; Becker, Kevin G.; Zhao, Keji; Weng, Nan-ping

    2009-01-01

    Summary Memory lymphocytes are characterized by their ability to exhibit a rapid response to the recall antigen, in which differential transcription plays a significant role, yet the underlying mechanism is not understood. We report here a genome-wide analysis of histone methylation on two histone H3 lysine residues (H3K4me3 and H3K27me3) and gene expression profiles in naïve and memory CD8 T cells. We found that a general correlation exists between the levels of gene expression and the levels of H3K4me3 (positive correlation) and H3K27me3 (negative correlation) across the gene body. These correlations display four distinct modes: repressive, active, poised, and bivalent, reflecting different functions of these genes. Furthermore, a permissive chromatin state of each gene is established by a combination of different histone modifications. Our findings reveal a complex regulation by histone methylation in differential gene expression and suggest that histone methylation may be responsible for memory CD8 T cell function. PMID:19523850

  7. Genome-Wide Analysis of Hydrogen Peroxide-Regulated Gene Expression in Arabidopsis Reveals a High Light-Induced Transcriptional Cluster Involved in Anthocyanin Biosynthesis1[w

    PubMed Central

    Vanderauwera, Sandy; Zimmermann, Philip; Rombauts, Stéphane; Vandenabeele, Steven; Langebartels, Christian; Gruissem, Wilhelm; Inzé, Dirk; Van Breusegem, Frank

    2005-01-01

    In plants, reactive oxygen species and, more particularly, hydrogen peroxide (H2O2) play a dual role as toxic by-products of normal cell metabolism and as regulatory molecules in stress perception and signal transduction. Peroxisomal catalases are an important sink for photorespiratory H2O2. Using ATH1 Affymetrix microarrays, expression profiles were compared between control and catalase-deficient Arabidopsis (Arabidopsis thaliana) plants. Reduced catalase levels already provoked differences in nuclear gene expression under ambient growth conditions, and these effects were amplified by high light exposure in a sun simulator for 3 and 8 h. This genome-wide expression analysis allowed us to reveal the expression characteristics of complete pathways and functional categories during H2O2 stress. In total, 349 transcripts were significantly up-regulated by high light in catalase-deficient plants and 88 were down-regulated. From this data set, H2O2 was inferred to play a key role in the transcriptional up-regulation of small heat shock proteins during high light stress. In addition, several transcription factors and candidate regulatory genes involved in H2O2 transcriptional gene networks were identified. Comparisons with other publicly available transcriptome data sets of abiotically stressed Arabidopsis revealed an important intersection with H2O2-deregulated genes, positioning elevated H2O2 levels as an important signal within abiotic stress-induced gene expression. Finally, analysis of transcriptional changes in a combination of a genetic (catalase deficiency) and an environmental (high light) perturbation identified a transcriptional cluster that was strongly and rapidly induced by high light in control plants, but impaired in catalase-deficient plants. This cluster comprises the complete known anthocyanin regulatory and biosynthetic pathway, together with genes encoding unknown proteins. PMID:16183842

  8. Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.

    PubMed

    Riechmann, J L; Heard, J; Martin, G; Reuber, L; Jiang, C; Keddie, J; Adam, L; Pineda, O; Ratcliffe, O J; Samaha, R R; Creelman, R; Pilgrim, M; Broun, P; Zhang, J Z; Ghandehari, D; Sherman, B K; Yu, G

    2000-12-15

    The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.

  9. Genome-Wide Analysis of the Phosphoinositide Kinome from Two Ciliates Reveals Novel Evolutionary Links for Phosphoinositide Kinases in Eukaryotic Cells

    PubMed Central

    Leondaritis, George; Siokos, John; Skaripa, Irini; Galanopoulou, Dia

    2013-01-01

    Background The complexity of phosphoinositide signaling in higher eukaryotes is partly due to expansion of specific families and types of phosphoinositide kinases (PIKs) that can generate all phosphoinositides via multiple routes. This is particularly evident in the PI3Ks and PIPKs, and it is considered an evolutionary trait associated with metazoan diversification. Yet, there are limited comprehensive studies on the PIK repertoire of free living unicellular organisms. Methodology/Principal Findings We undertook a genome-wide analysis of putative PIK genes in two free living ciliated cells, Tetrahymena and Paramecium. The Tetrahymena thermophila and Paramecium tetraurelia genomes were probed with representative kinases from all families and types. Putative homologs were verified by EST, microarray and deep RNA sequencing database searches and further characterized for domain structure, catalytic efficiency, expression patterns and phylogenetic relationships. In total, we identified and characterized 22 genes in the Tetrahymena thermophila genome and 62 highly homologues genes in Paramecium tetraurelia suggesting a tight evolutionary conservation in the ciliate lineage. Comparison to the kinome of fungi reveals a significant expansion of PIK genes in ciliates. Conclusions/Significance Our study highlights four important aspects concerning ciliate and other unicellular PIKs. First, ciliate-specific expansion of PI4KIII-like genes. Second, presence of class I PI3Ks which, at least in Tetrahymena, are associated with a metazoan-type machinery for PIP3 signaling. Third, expansion of divergent PIPK enzymes such as the recently described type IV transmembrane PIPKs. Fourth, presence of possible type II PIPKs and presumably inactive PIKs (hence, pseudo-PIKs) not previously described. Taken together, our results provide a solid framework for future investigation of the roles of PIKs in ciliates and indicate that novel functions and novel regulatory pathways of

  10. Genome-wide analysis of N1ICD/RBPJ targets in vivo reveals direct transcriptional regulation of Wnt, SHH, and hippo pathway effectors by Notch1.

    PubMed

    Li, Yaochen; Hibbs, Matthew Aaron; Gard, Ashley Lauren; Shylo, Natalia Aliakseeuna; Yun, Kyuson

    2012-04-01

    The Notch pathway plays a pivotal role in regulating cell fate decisions in many stem cell systems. However, the full repertoire of Notch target genes in vivo and the mechanisms through which this pathway activity is integrated with other signaling pathways are largely unknown. Here, we report a transgenic mouse in which the activation of the Notch pathway massively expands the neural stem cell (NSC) pool in a cell context-dependent manner. Using this in vivo system, we identify direct targets of RBPJ/N1ICD in cortical NSCs at a genome-wide level through combined ChIP-Seq and transcriptome analyses. Through a highly conservative analysis of these datasets, we identified 98 genes that are directly regulated by N1ICD/RPBJ in vivo. These include many transcription factors that are known to be critical for NSC self-renewal (Sox2, Pax6, Tlx, and Id4) and the transcriptional effectors of the Wnt, SHH, and Hippo pathways, TCF4, Gli2, Gli3, Yap1, and Tead2. Since little is known about the function of the Hippo-Yap pathway in NSCs, we analyzed Yap1 expression and function in NSCs. We show that Yap1 expression is restricted to the stem cell compartment in the developing forebrain and that its expression is sufficient to rescue Notch pathway inhibition in NSC self-renewal assays. Together, results of this study reveal a previously underappreciated complexity and breadth of Notch1 targets in vivo and show direct interaction between Notch and Hippo-Yap pathways in NSCs.

  11. Genome-wide analysis reveals NRP1 as a direct HIF1α-E2F7 target in the regulation of motorneuron guidance in vivo

    PubMed Central

    de Bruin, Alain; A. Cornelissen, Peter W.; Kirchmaier, Bettina C.; Mokry, Michal; Iich, Elhadi; Nirmala, Ella; Liang, Kuo-Hsuan; D. Végh, Anna M.; Scholman, Koen T.; Groot Koerkamp, Marian J.; Holstege, Frank C.; Cuppen, Edwin; Schulte-Merker, Stefan; Bakker, Walbert J.

    2016-01-01

    In this study, we explored the existence of a transcriptional network co-regulated by E2F7 and HIF1α, as we show that expression of E2F7, like HIF1α, is induced in hypoxia, and because of the previously reported ability of E2F7 to interact with HIF1α. Our genome-wide analysis uncovers a transcriptional network that is directly controlled by HIF1α and E2F7, and demonstrates both stimulatory and repressive functions of the HIF1α -E2F7 complex. Among this network we reveal Neuropilin 1 (NRP1) as a HIF1α-E2F7 repressed gene. By performing in vitro and in vivo reporter assays we demonstrate that the HIF1α-E2F7 mediated NRP1 repression depends on a 41 base pairs ‘E2F-binding site hub’, providing a molecular mechanism for a previously unanticipated role for HIF1α in transcriptional repression. To explore the biological significance of this regulation we performed in situ hybridizations and observed enhanced nrp1a expression in spinal motorneurons (MN) of zebrafish embryos, upon morpholino-inhibition of e2f7/8 or hif1α. Consistent with the chemo-repellent role of nrp1a, morpholino-inhibition of e2f7/8 or hif1α caused MN truncations, which was rescued in TALEN-induced nrp1ahu10012 mutants, and phenocopied in e2f7/8 mutant zebrafish. Therefore, we conclude that repression of NRP1 by the HIF1α-E2F7 complex regulates MN axon guidance in vivo. PMID:26681691

  12. Genome-wide binding analysis of the transcription activator ideal plant architecture1 reveals a complex network regulating rice plant architecture.

    PubMed

    Lu, Zefu; Yu, Hong; Xiong, Guosheng; Wang, Jing; Jiao, Yongqing; Liu, Guifu; Jing, Yanhui; Meng, Xiangbing; Hu, Xingming; Qian, Qian; Fu, Xiangdong; Wang, Yonghong; Li, Jiayang

    2013-10-01

    Ideal plant architecture1 (IPA1) is critical in regulating rice (Oryza sativa) plant architecture and substantially enhances grain yield. To elucidate its molecular basis, we first confirmed IPA1 as a functional transcription activator and then identified 1067 and 2185 genes associated with IPA1 binding sites in shoot apices and young panicles, respectively, through chromatin immunoprecipitation sequencing assays. The Squamosa promoter binding protein-box direct binding core motif GTAC was highly enriched in IPA1 binding peaks; interestingly, a previously uncharacterized indirect binding motif TGGGCC/T was found to be significantly enriched through the interaction of IPA1 with proliferating cell nuclear antigen promoter binding factor1 or promoter binding factor2. Genome-wide expression profiling by RNA sequencing revealed IPA1 roles in diverse pathways. Moreover, our results demonstrated that IPA1 could directly bind to the promoter of rice teosinte branched1, a negative regulator of tiller bud outgrowth, to suppress rice tillering, and directly and positively regulate dense and erect panicle1, an important gene regulating panicle architecture, to influence plant height and panicle length. The elucidation of target genes of IPA1 genome-wide will contribute to understanding the molecular mechanisms underlying plant architecture and to facilitating the breeding of elite varieties with ideal plant architecture.

  13. Genome-wide association interaction analysis for Alzheimer's disease

    PubMed Central

    Gusareva, Elena S.; Carrasquillo, Minerva M.; Bellenguez, Céline; Cuyvers, Elise; Colon, Samuel; Graff-Radford, Neill R.; Petersen, Ronald C.; Dickson, Dennis W.; Mahachie Johna, Jestinah M.; Bessonov, Kyrylo; Van Broeckhoven, Christine; Williams, Julie; Amouyel, Philippe; Sleegers, Kristel; Ertekin-Taner, Nilüfer; Lambert, Jean-Charles; Van Steen, Kristel

    2015-01-01

    We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = −0.19, p = 0.0006) and cerebellum (β = −0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. PMID:24958192

  14. High-resolution genome-wide analysis of irradiated (UV and γ-rays) diploid yeast cells reveals a high frequency of genomic loss of heterozygosity (LOH) events.

    PubMed

    St Charles, Jordan; Hazkani-Covo, Einat; Yin, Yi; Andersen, Sabrina L; Dietrich, Fred S; Greenwell, Patricia W; Malc, Ewa; Mieczkowski, Piotr; Petes, Thomas D

    2012-04-01

    In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote.

  15. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.

    PubMed

    Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson L S; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances M K; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

    2012-04-15

    Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

  16. Deep sequencing and genome-wide analysis reveals the expansion of MicroRNA genes in the gall midge Mayetiola destructor

    PubMed Central

    2013-01-01

    Background MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating post transcriptional gene expression. Gall midges encompass a large group of insects that are of economic importance and also possess fascinating biological traits. The gall midge Mayetiola destructor, commonly known as the Hessian fly, is a destructive pest of wheat and model organism for studying gall midge biology and insect – host plant interactions. Results In this study, we systematically analyzed miRNAs from the Hessian fly. Deep-sequencing a Hessian fly larval transcriptome led to the identification of 89 miRNA species that are either identical or very similar to known miRNAs from other insects, and 184 novel miRNAs that have not been reported from other species. A genome-wide search through a draft Hessian fly genome sequence identified a total of 611 putative miRNA-encoding genes based on sequence similarity and the existence of a stem-loop structure for miRNA precursors. Analysis of the 611 putative genes revealed a striking feature: the dramatic expansion of several miRNA gene families. The largest family contained 91 genes that encoded 20 different miRNAs. Microarray analyses revealed the expression of miRNA genes was strictly regulated during Hessian fly larval development and abundance of many miRNA genes were affected by host genotypes. Conclusion The identification of a large number of miRNAs for the first time from a gall midge provides a foundation for further studies of miRNA functions in gall midge biology and behavior. The dramatic expansion of identical or similar miRNAs provides a unique system to study functional relations among miRNA iso-genes as well as changes in sequence specificity due to small changes in miRNAs and in their mRNA targets. These results may also facilitate the identification of miRNA genes for potential pest control through transgenic approaches. PMID:23496979

  17. Genome-wide association and pathway analysis of feed efficiency in pigs reveal candidate genes and pathways for residual feed intake.

    PubMed

    Do, Duy N; Strathe, Anders B; Ostersen, Tage; Pant, Sameer D; Kadarmideen, Haja N

    2014-01-01

    Residual feed intake (RFI) is a complex trait that is economically important for livestock production; however, the genetic and biological mechanisms regulating RFI are largely unknown in pigs. Therefore, the study aimed to identify single nucleotide polymorphisms (SNPs), candidate genes and biological pathways involved in regulating RFI using Genome-wide association (GWA) and pathway analyses. A total of 596 Yorkshire boars with phenotypes for two different measures of RFI (RFI1 and 2) and 60k genotypic data was used. GWA analysis was performed using a univariate mixed model and 12 and 7 SNPs were found to be significantly associated with RFI1 and RFI2, respectively. Several genes such as xin actin-binding repeat-containing protein 2 (XIRP2),tetratricopeptide repeat domain 29 (TTC29),suppressor of glucose, autophagy associated 1 (SOGA1),MAS1,G-protein-coupled receptor (GPCR) kinase 5 (GRK5),prospero-homeobox protein 1 (PROX1),GPCR 155 (GPR155), and FYVE domain containing the 26 (ZFYVE26) were identified as putative candidates for RFI based on their genomic location in the vicinity of these SNPs. Genes located within 50 kbp of SNPs significantly associated with RFI and RFI2 (q-value ≤ 0.2) were subsequently used for pathway analyses. These analyses were performed by assigning genes to biological pathways and then testing the association of individual pathways with RFI using a Fisher's exact test. Metabolic pathway was significantly associated with both RFIs. Other biological pathways regulating phagosome, tight junctions, olfactory transduction, and insulin secretion were significantly associated with both RFI traits when relaxed threshold for cut-off p-value was used (p ≤ 0.05). These results implied porcine RFI is regulated by multiple biological mechanisms, although the metabolic processes might be the most important. Olfactory transduction pathway controlling the perception of feed via smell, insulin pathway controlling food intake might be important

  18. Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs.

    PubMed

    Lakhina, Vanisha; Arey, Rachel N; Kaletsky, Rachel; Kauffman, Amanda; Stein, Geneva; Keyes, William; Xu, Daniel; Murphy, Coleen T

    2015-01-21

    Induced CREB activity is a hallmark of long-term memory, but the full repertoire of CREB transcriptional targets required specifically for memory is not known in any system. To obtain a more complete picture of the mechanisms involved in memory, we combined memory training with genome-wide transcriptional analysis of C. elegans CREB mutants. This approach identified 757 significant CREB/memory-induced targets and confirmed the involvement of known memory genes from other organisms, but also suggested new mechanisms and novel components that may be conserved through mammals. CREB mediates distinct basal and memory transcriptional programs at least partially through spatial restriction of CREB activity: basal targets are regulated primarily in nonneuronal tissues, while memory targets are enriched for neuronal expression, emanating from CREB activity in AIM neurons. This suite of novel memory-associated genes will provide a platform for the discovery of orthologous mammalian long-term memory components.

  19. Genome-wide association analysis reveals variants on chromosome 19 that contribute to childhood risk of chronic otitis media with effusion

    PubMed Central

    Einarsdottir, Elisabet; Hafrén, Lena; Leinonen, Eira; Bhutta, Mahmood F.; Kentala, Erna; Kere, Juha; Mattila, Petri S.

    2016-01-01

    To identify genetic risk factors of childhood otitis media (OM), a genome-wide association study was performed on Finnish subjects, 829 affected children, and 2118 randomly selected controls. The most significant and validated finding was an association with an 80 kb region on chromosome 19. It includes the variants rs16974263 (P = 1.77 × 10−7, OR = 1.59), rs268662 (P = 1.564 × 10−6, OR = 1.54), and rs4150992 (P = 3.37 × 10−6, OR = 1.52), and harbors the genes PLD3, SERTAD1, SERTAD3, HIPK4, PRX, and BLVRB, all in strong linkage disequilibrium. In a sub-phenotype analysis of the 512 patients with chronic otitis media with effusion, one marker reached genome-wide significance (rs16974263, P = 2.92 × 10−8). The association to this locus was confirmed but with an association signal in the opposite direction, in a UK family cohort of 4860 subjects (rs16974263, P = 3.21 × 10−4, OR = 0.72; rs4150992, P = 1.62 × 10−4, OR = 0.71). Thus we hypothesize that this region is important for COME risk in both the Finnish and UK populations, although the precise risk variants or haplotype background remain unclear. Our study suggests that the identified region on chromosome 19 includes a novel and previously uncharacterized risk locus for OM. PMID:27632927

  20. Genome-wide analysis of copy number variations reveals that aging processes influence body fat distribution in Korea Associated Resource (KARE) cohorts.

    PubMed

    Lee, Bo-Young; Shin, Dong Hyun; Cho, Seoae; Seo, Kang-Seok; Kim, Heebal

    2012-11-01

    Many anthropometric measures, including body mass index (BMI), waist-to-hip ratio (WHR), and subcutaneous fat thickness, are used as indicators of nutritional status, fertility and predictors of future health outcomes. While BMI is currently the best available estimate of body adiposity, WHR and skinfold thickness at various sites (biceps, triceps, suprailiac, and subscapular) are used as indices of body fat distribution. Copy number variation (CNV) is an attractive emerging approach to the study of associations with various diseases. In this study, we investigated the dosage effect of genes in the CNV genome widely associated with fat distribution phenotypes in large cohorts. We used the Affymetrix genome-wide human SNP Array 5.0 data of 8,842 healthy unrelated adults in KARE cohorts and identified CNVs associated with BMI and fat distribution-related traits including WHR and subcutaneous skinfold thickness at suprailiac (SUP) and subscapular (SUB) sites. CNV segmentation of each chromosome was performed using Golden Helix SVS 7.0, and single regression analysis was used to identify CNVs associated with each phenotype. We found one CNV for BMI, 287 for WHR, 2,157 for SUP, and 2,102 for SUB at the 5% significance level after Holm-Bonferroni correction. Genes included in the CNV were used for the analysis of functional annotations using the Database for Annotation, Visualization and Integrated Discovery (DAVID v6.7b) tool. Functional gene classification analysis identified five significant gene clusters (metallothionein, ATP-binding proteins, ribosomal proteins, kinesin family members, and zinc finger proteins) for SUP, three (keratin-associated proteins, zinc finger proteins, keratins) for SUB, and one (protamines) for WHR. BMI was excluded from this analysis because the entire structure of no gene was identified in the CNV. Based on the analysis of genes enriched in the clusters, the fat distribution traits of KARE cohorts were related to the fat redistribution

  1. A novel statistic for genome-wide interaction analysis.

    PubMed

    Wu, Xuesen; Dong, Hua; Luo, Li; Zhu, Yun; Peng, Gang; Reveille, John D; Xiong, Momiao

    2010-09-23

    Although great progress in genome-wide association studies (GWAS) has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked). The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  2. Genome-wide SNP analysis reveals population structure and demographic history of the ryukyu islanders in the southern part of the Japanese archipelago.

    PubMed

    Sato, Takehiro; Nakagome, Shigeki; Watanabe, Chiaki; Yamaguchi, Kyoko; Kawaguchi, Akira; Koganebuchi, Kae; Haneji, Kuniaki; Yamaguchi, Tetsutaro; Hanihara, Tsunehiko; Yamamoto, Ken; Ishida, Hajime; Mano, Shuhei; Kimura, Ryosuke; Oota, Hiroki

    2014-11-01

    The Ryukyu Islands are located to the southwest of the Japanese archipelago. Archaeological evidence has revealed the existence of prehistoric cultural differentiation between the northern Ryukyu islands of Amami and Okinawa, and the southern Ryukyu islands of Miyako and Yaeyama. To examine a genetic subdivision in the Ryukyu Islands, we conducted genome-wide single nucleotide polymorphism typing of inhabitants from the Okinawa Islands, the Miyako Islands, and the Yaeyama Islands. Principal component and cluster analyses revealed genetic differentiation among the island groups, especially between Okinawa and Miyako. No genetic affinity was observed between aboriginal Taiwanese and any of the Ryukyu populations. The genetic differentiation observed between the inhabitants of the Okinawa Islands and the Miyako Islands is likely to have arisen due to genetic drift rather than admixture with people from neighboring regions. Based on the observed genetic differences, the divergence time between the inhabitants of Okinawa and Miyako islands was dated to the Holocene. These findings suggest that the Pleistocene inhabitants, whose bones have been found on the southern Ryukyu Islands, did not make a major genetic contribution, if any, to the present-day inhabitants of the southern Ryukyu Islands.

  3. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection

    PubMed Central

    Flavell, Steven W.; Kim, Tae-Kyung; Gray, Jesse M.; Harmin, David A.; Hemberg, Martin; Hong, Elizabeth J.; Markenscoff-Papadimitriou, Eirene; Bear, Daniel M.; Greenberg, Michael E.

    2009-01-01

    SUMMARY Although many transcription factors are known to control important aspects of neural development, the genome-wide programs that are directly regulated by these factors are not known. We have characterized the genetic program that is activated by MEF2, a key regulator of activity-dependent synapse development. These MEF2 target genes have diverse functions at synapses, revealing a broad role for MEF2 in synapse development. Several of the MEF2 targets are mutated in human neurological disorders including epilepsy and autism-spectrum disorders, suggesting that these disorders may be caused by disruption of an activity-dependent gene program that controls synapse development. Our analyses also reveal that neuronal activity promotes alternative polyadenylation site usage at many of the MEF2 target genes, leading to the production of truncated mRNAs that may have different functions than their full-length counterparts. Taken together, these analyses suggest that the ubiquitously expressed transcription factor MEF2 regulates an intricate transcriptional program in neurons that controls synapse development. PMID:19109909

  4. Genome-Wide Analysis of the Fasciclin-Like Arabinogalactan Protein Gene Family Reveals Differential Expression Patterns, Localization, and Salt Stress Response in Populus

    PubMed Central

    Zang, Lina; Zheng, Tangchun; Chu, Yanguang; Ding, Changjun; Zhang, Weixi; Huang, Qinjun; Su, Xiaohua

    2015-01-01

    Fasciclin-like arabinogalactan proteins (FLAs) are a subclass of arabinogalactan proteins (AGPs) involved in plant growth, development and response to abiotic stress. Although many studies have been performed to identify molecular functions of individual family members, little information is available on genome-wide identification and characterization of FLAs in the genus Populus. Based on genome-wide analysis, we have identified 35 Populus FLAs which were distributed on 16 chromosomes and phylogenetically clustered into four major groups. Gene structure and motif composition were relatively conserved in each group. All the members contained N-terminal signal peptide, 23 of which included predicted glycosylphosphatidylinositol (GPI) modification sites and were anchored to plasma membranes. Subcellular localization analysis showed that PtrFLA2/20/26 were localized in cell membrane and cytoplasm of protoplasts from Populus stem-differentiating xylem. The Ka/Ks ratios showed that purifying selection has played a leading role in the long-term evolutionary period which greatly maintained the function of this family. The expression profiles showed that 32 PtrFLAs were differentially expressed in four tissues at four seasons based on publicly available microarray data. 18 FLAs were further verified with qRT-PCR in different tissues, which indicated that PtrFLA1/2/3/7/11/12/20/21/22/24/26/30 were significantly expressed in male and female flowers, suggesting close correlations with the reproductive development. In addition, PtrFLA1/9/10/11/17/21/23/24/26/28 were highly expressed in the stems and differentiating xylem, which may be involved in stem development. To determine salt response of FLAs, qRT-PCR was performed to analyze the expression of 18 genes under salinity stress across two time points. Results demonstrated that all the 18 FLAs were expressed in root tissues; especially, PtrFLA2/12/20/21/24/30 were significantly induced at different time points. In summary

  5. A combination of genome-wide association and transcriptome analysis reveals candidate genes controlling harvest index-related traits in Brassica napus

    PubMed Central

    Lu, Kun; Xiao, Zhongchun; Jian, Hongju; Peng, Liu; Qu, Cunmin; Fu, Minglian; He, Bin; Tie, Linmei; Liang, Ying; Xu, Xingfu; Li, Jiana

    2016-01-01

    Harvest index (HI), the ratio of seed mass to total biomass of the aboveground plant parts, is an important trait for harvestable yield of crops. Unfortunately, HI of Brassica napus is lower than that of other economically important crops. To identify candidate genes associated with high HI, a genome-wide association study of HI and four HI-related traits was conducted with 520 B. napus accessions cultivated in both Yunnan and Chongqing. We detected 294 single nucleotide polymorphisms significantly associated with the abovementioned traits, including 79 SNPs that affected two or more traits. Differentially expressed genes between extremely high- and low-HI accessions were identified in 8 tissues at two cultivated regions. Combination of linkage disequilibrium and transcriptome analyses revealed 33 functional candidate genes located within the confidence intervals of significant SNPs associated with more than one trait, such as SHOOT GRAVITROPISM 5 (Bna.SGR5), ATP-CITRATE LYASE A-3 (Bna.ACLA-3) and CAROTENOID CLEAVAGE DIOXYGENASE 1 (Bna.CCD1), their orthologs in the Arabidopsis thaliana have been shown to play key roles in photosynthesis, inflorescence, and silique development. Our results provide insight into the molecular mechanisms underlying establishment of high-HI B. napus and lay a foundation for characterization of candidate genes aimed at developing high-HI B. napus varieties. PMID:27811979

  6. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment

    PubMed Central

    Court, Franck; Tayama, Chiharu; Romanelli, Valeria; Martin-Trujillo, Alex; Iglesias-Platas, Isabel; Okamura, Kohji; Sugahara, Naoko; Simón, Carlos; Moore, Harry; Harness, Julie V.; Keirstead, Hans; Sanchez-Mut, Jose Vicente; Kaneki, Eisuke; Lapunzina, Pablo; Soejima, Hidenobu; Wake, Norio; Esteller, Manel; Ogata, Tsutomu; Hata, Kenichiro; Nakabayashi, Kazuhiko; Monk, David

    2014-01-01

    Differential methylation between the two alleles of a gene has been observed in imprinted regions, where the methylation of one allele occurs on a parent-of-origin basis, the inactive X-chromosome in females, and at those loci whose methylation is driven by genetic variants. We have extensively characterized imprinted methylation in a substantial range of normal human tissues, reciprocal genome-wide uniparental disomies, and hydatidiform moles, using a combination of whole-genome bisulfite sequencing and high-density methylation microarrays. This approach allowed us to define methylation profiles at known imprinted domains at base-pair resolution, as well as to identify 21 novel loci harboring parent-of-origin methylation, 15 of which are restricted to the placenta. We observe that the extent of imprinted differentially methylated regions (DMRs) is extremely similar between tissues, with the exception of the placenta. This extra-embryonic tissue often adopts a different methylation profile compared to somatic tissues. Further, we profiled all imprinted DMRs in sperm and embryonic stem cells derived from parthenogenetically activated oocytes, individual blastomeres, and blastocysts, in order to identify primary DMRs and reveal the extent of reprogramming during preimplantation development. Intriguingly, we find that in contrast to ubiquitous imprints, the majority of placenta-specific imprinted DMRs are unmethylated in sperm and all human embryonic stem cells. Therefore, placental-specific imprinting provides evidence for an inheritable epigenetic state that is independent of DNA methylation and the existence of a novel imprinting mechanism at these loci. PMID:24402520

  7. Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome.

    PubMed

    Wu, Hao; Tao, Jifang; Chen, Pauline J; Shahab, Atif; Ge, Weihong; Hart, Ronald P; Ruan, Xiaoan; Ruan, Yijun; Sun, Yi E

    2010-10-19

    MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as posttranscriptional regulators of gene expression. Many miRNAs are expressed in the developing brain and regulate multiple aspects of neural development, including neurogenesis, dendritogenesis, and synapse formation. Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2). Although Mecp2 is known to act as a global transcriptional regulator, miRNAs that are directly regulated by Mecp2 in the brain are not known. Using massively parallel sequencing methods, we have identified miRNAs whose expression is altered in cerebella of Mecp2-null mice before and after the onset of severe neurological symptoms. In vivo genome-wide analyses indicate that promoter regions of a significant fraction of dysregulated miRNA transcripts, including a large polycistronic cluster of brain-specific miRNAs, are DNA-methylated and are bound directly by Mecp2. Functional analysis demonstrates that the 3' UTR of messenger RNA encoding Brain-derived neurotrophic factor (Bdnf) can be targeted by multiple miRNAs aberrantly up-regulated in the absence of Mecp2. Taken together, these results suggest that dysregulation of miRNAs may contribute to RTT pathoetiology and also may provide a valuable resource for further investigations of the role of miRNAs in RTT.

  8. Genome-wide location analysis reveals an important overlap between the targets of the yeast transcriptional regulators Rds2 and Adr1.

    PubMed

    Soontorngun, Nitnipa; Baramee, Sirilak; Tangsombatvichit, Chalinee; Thepnok, Piyasuda; Cheevadhanarak, Supapon; Robert, François; Turcotte, Bernard

    2012-07-13

    Upon glucose depletion, a massive reprogramming of gene expression occurs in the yeast Saccharomyces cerevisiae for the use of alternate carbon sources such as the nonfermentable compounds ethanol and glycerol. This process is mediated by the master kinase Snf1 that controls the activity of various targets including the transcriptional regulators Cat8, Sip4 and Adr1. We have recently identified Rds2 as an additional player in this pathway. Here, we have performed genome-wide location analysis of Rds2 in cells grown in the presence of glycerol. We show that Rds2 binds to promoters of genes involved in gluconeogenesis, the glyoxylate shunt, and the TCA cycle as well as some genes encoding mitochondrial components or some involved in the stress response. Interestingly, we also detected Rds2 at the promoters of SIP4, ADR1 and HAP4 which encodes the limiting subunit of the Hap2/3/4/5 complex, a regulator of respiration. Strikingly, we observed an important overlap between the targets of Rds2 and Adr1. Finally, we provide a model to account for the complex interplay among these transcriptional regulators.

  9. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

    PubMed Central

    Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

    2012-01-01

    Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420

  10. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course.

    PubMed

    Graff, Mariaelisa; Ngwa, Julius S; Workalemahu, Tsegaselassie; Homuth, Georg; Schipf, Sabine; Teumer, Alexander; Völzke, Henry; Wallaschofski, Henri; Abecasis, Goncalo R; Edward, Lakatta; Francesco, Cucca; Sanna, Serena; Scheet, Paul; Schlessinger, David; Sidore, Carlo; Xiao, Xiangjun; Wang, Zhaoming; Chanock, Stephen J; Jacobs, Kevin B; Hayes, Richard B; Hu, Frank; Van Dam, Rob M; Crout, Richard J; Marazita, Mary L; Shaffer, John R; Atwood, Larry D; Fox, Caroline S; Heard-Costa, Nancy L; White, Charles; Choh, Audrey C; Czerwinski, Stefan A; Demerath, Ellen W; Dyer, Thomas D; Towne, Bradford; Amin, Najaf; Oostra, Ben A; Van Duijn, Cornelia M; Zillikens, M Carola; Esko, Tõnu; Nelis, Mari; Nikopensius, Tit; Metspalu, Andres; Strachan, David P; Monda, Keri; Qi, Lu; North, Kari E; Cupples, L Adrienne; Gordon-Larsen, Penny; Berndt, Sonja I

    2013-09-01

    Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

  11. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

    PubMed Central

    Graff, Mariaelisa; Ngwa, Julius S.; Workalemahu, Tsegaselassie; Homuth, Georg; Schipf, Sabine; Teumer, Alexander; Völzke, Henry; Wallaschofski, Henri; Abecasis, Goncalo R.; Edward, Lakatta; Francesco, Cucca; Sanna, Serena; Scheet, Paul; Schlessinger, David; Sidore, Carlo; Xiao, Xiangjun; Wang, Zhaoming; Chanock, Stephen J.; Jacobs, Kevin B.; Hayes, Richard B.; Hu, Frank; Van Dam, Rob M.; Crout, Richard J.; Marazita, Mary L.; Shaffer, John R; Atwood, Larry D.; Fox, Caroline S.; Heard-Costa, Nancy L.; White, Charles; Choh, Audrey C.; Czerwinski, Stefan A.; Demerath, Ellen W.; Dyer, Thomas D.; Towne, Bradford; Amin, Najaf; Oostra, Ben A.; Van Duijn, Cornelia M.; Zillikens, M. Carola; Esko, Tõnu; Nelis, Mari; Nikopensius, Tit; Metspalu, Andres; Strachan, David P.; Monda, Keri; Qi, Lu; North, Kari E.; Cupples, L. Adrienne; Gordon-Larsen, Penny; Berndt, Sonja I.

    2013-01-01

    Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10−8) near FTO (P = 3.72 × 10−23), TMEM18 (P = 3.24 × 10−17), MC4R (P = 4.41 × 10−17), TNNI3K (P = 4.32 × 10−11), SEC16B (P = 6.24 × 10−9), GNPDA2 (P = 1.11 × 10−8) and POMC (P = 4.94 × 10−8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10−5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18–90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. PMID:23669352

  12. Genome-Wide Analysis of DNA Methylation in Human Amnion

    PubMed Central

    Kim, Jinsil; Pitlick, Mitchell M.; Christine, Paul J.; Schaefer, Amanda R.; Saleme, Cesar; Comas, Belén; Cosentino, Viviana; Gadow, Enrique; Murray, Jeffrey C.

    2013-01-01

    The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies. PMID:23533356

  13. Analysis of Heritability Using Genome-Wide Data.

    PubMed

    Hall, Jacob B; Bush, William S

    2016-10-11

    Most analyses of genome-wide association data consider each variant independently without considering or adjusting for the genetic background present in the rest of the genome. New approaches to genome analysis use representations of genomic sharing to better account for confounding factors like population stratification or to directly approximate heritability through the estimated sharing of individuals in a dataset. These approaches use mixed linear models, which relate genotypic sharing to phenotypic sharing, and rely on the efficient computation of genetic sharing among individuals in a dataset. This unit describes the principles and practical application of mixed models for the analysis of genome-wide association study data. © 2016 by John Wiley & Sons, Inc.

  14. Genome-wide functional analysis in Candida albicans.

    PubMed

    Motaung, Thabiso E; Ells, Ruan; Pohl, Carolina H; Albertyn, Jacobus; Tsilo, Toi J

    2017-02-08

    Candida albicans is an important etiological agent of superficial and life-threatening infections in individuals with compromised immune systems. To date, we know of several overlapping genetic networks that govern virulence attributes in this fungal pathogen. Classical use of deletion mutants has led to the discovery of numerous virulence factors over the years, and genome-wide functional analysis has propelled gene discovery at an even faster pace. Indeed, a number of recent studies using large-scale genetic screens followed by genome-wide functional analysis has allowed for the unbiased discovery of many new genes involved in C. albicans biology. Here we share our perspectives on the role of these studies in analyzing fundamental aspects of C. albicans virulence properties.

  15. A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM

    PubMed Central

    Weiss, Lauren A.; Arking, Dan E.

    2009-01-01

    Summary Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants. PMID:19812673

  16. Genome-Wide Analysis of Human Metapneumovirus Evolution

    PubMed Central

    Kim, Jin Il; Park, Sehee; Lee, Ilseob; Park, Kwang Sook; Kwak, Eun Jung; Moon, Kwang Mee; Lee, Chang Kyu; Bae, Joon-Yong; Park, Man-Seong; Song, Ki-Joon

    2016-01-01

    Human metapneumovirus (HMPV) has been described as an important etiologic agent of upper and lower respiratory tract infections, especially in young children and the elderly. Most of school-aged children might be introduced to HMPVs, and exacerbation with other viral or bacterial super-infection is common. However, our understanding of the molecular evolution of HMPVs remains limited. To address the comprehensive evolutionary dynamics of HMPVs, we report a genome-wide analysis of the eight genes (N, P, M, F, M2, SH, G, and L) using 103 complete genome sequences. Phylogenetic reconstruction revealed that the eight genes from one HMPV strain grouped into the same genetic group among the five distinct lineages (A1, A2a, A2b, B1, and B2). A few exceptions of phylogenetic incongruence might suggest past recombination events, and we detected possible recombination breakpoints in the F, SH, and G coding regions. The five genetic lineages of HMPVs shared quite remote common ancestors ranging more than 220 to 470 years of age with the most recent origins for the A2b sublineage. Purifying selection was common, but most protein genes except the F and M2-2 coding regions also appeared to experience episodic diversifying selection. Taken together, these suggest that the five lineages of HMPVs maintain their individual evolutionary dynamics and that recombination and selection forces might work on shaping the genetic diversity of HMPVs. PMID:27046055

  17. Genome-Wide Analysis of Human Metapneumovirus Evolution.

    PubMed

    Kim, Jin Il; Park, Sehee; Lee, Ilseob; Park, Kwang Sook; Kwak, Eun Jung; Moon, Kwang Mee; Lee, Chang Kyu; Bae, Joon-Yong; Park, Man-Seong; Song, Ki-Joon

    2016-01-01

    Human metapneumovirus (HMPV) has been described as an important etiologic agent of upper and lower respiratory tract infections, especially in young children and the elderly. Most of school-aged children might be introduced to HMPVs, and exacerbation with other viral or bacterial super-infection is common. However, our understanding of the molecular evolution of HMPVs remains limited. To address the comprehensive evolutionary dynamics of HMPVs, we report a genome-wide analysis of the eight genes (N, P, M, F, M2, SH, G, and L) using 103 complete genome sequences. Phylogenetic reconstruction revealed that the eight genes from one HMPV strain grouped into the same genetic group among the five distinct lineages (A1, A2a, A2b, B1, and B2). A few exceptions of phylogenetic incongruence might suggest past recombination events, and we detected possible recombination breakpoints in the F, SH, and G coding regions. The five genetic lineages of HMPVs shared quite remote common ancestors ranging more than 220 to 470 years of age with the most recent origins for the A2b sublineage. Purifying selection was common, but most protein genes except the F and M2-2 coding regions also appeared to experience episodic diversifying selection. Taken together, these suggest that the five lineages of HMPVs maintain their individual evolutionary dynamics and that recombination and selection forces might work on shaping the genetic diversity of HMPVs.

  18. The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes.

    PubMed

    Cusanovich, Darren A; Billstrand, Christine; Zhou, Xiang; Chavarria, Claudia; De Leon, Sherryl; Michelini, Katelyn; Pai, Athma A; Ober, Carole; Gilad, Yoav

    2012-05-01

    Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the 'missing heritability problem'. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility.

  19. Genome-wide analysis reveals diverged patterns of codon bias, gene expression, and rates of sequence evolution in picea gene families.

    PubMed

    De La Torre, Amanda R; Lin, Yao-Cheng; Van de Peer, Yves; Ingvarsson, Pär K

    2015-03-05

    The recent sequencing of several gymnosperm genomes has greatly facilitated studying the evolution of their genes and gene families. In this study, we examine the evidence for expression-mediated selection in the first two fully sequenced representatives of the gymnosperm plant clade (Picea abies and Picea glauca). We use genome-wide estimates of gene expression (>50,000 expressed genes) to study the relationship between gene expression, codon bias, rates of sequence divergence, protein length, and gene duplication. We found that gene expression is correlated with rates of sequence divergence and codon bias, suggesting that natural selection is acting on Picea protein-coding genes for translational efficiency. Gene expression, rates of sequence divergence, and codon bias are correlated with the size of gene families, with large multicopy gene families having, on average, a lower expression level and breadth, lower codon bias, and higher rates of sequence divergence than single-copy gene families. Tissue-specific patterns of gene expression were more common in large gene families with large gene expression divergence than in single-copy families. Recent family expansions combined with large gene expression variation in paralogs and increased rates of sequence evolution suggest that some Picea gene families are rapidly evolving to cope with biotic and abiotic stress. Our study highlights the importance of gene expression and natural selection in shaping the evolution of protein-coding genes in Picea species, and sets the ground for further studies investigating the evolution of individual gene families in gymnosperms.

  20. Genome-wide analysis of differential RNA editing in epilepsy

    PubMed Central

    Srivastava, Prashant Kumar; Bagnati, Marta; Delahaye-Duriez, Andree; Ko, Jeong-Hun; Rotival, Maxime; Langley, Sarah R.; Shkura, Kirill; Mazzuferi, Manuela; Danis, Bénédicte; van Eyll, Jonathan; Foerch, Patrik; Behmoaras, Jacques; Kaminski, Rafal M.; Petretto, Enrico; Johnson, Michael R.

    2017-01-01

    The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine–temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including “neuron projection” and “seizures.” Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures. PMID:28250018

  1. Genome-wide analysis of differential RNA editing in epilepsy.

    PubMed

    Srivastava, Prashant Kumar; Bagnati, Marta; Delahaye-Duriez, Andree; Ko, Jeong-Hun; Rotival, Maxime; Langley, Sarah R; Shkura, Kirill; Mazzuferi, Manuela; Danis, Bénédicte; van Eyll, Jonathan; Foerch, Patrik; Behmoaras, Jacques; Kaminski, Rafal M; Petretto, Enrico; Johnson, Michael R

    2017-03-01

    The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.

  2. Genome-Wide Ultrabithorax Binding Analysis Reveals Highly Targeted Genomic Loci at Developmental Regulators and a Potential Connection to Polycomb-Mediated Regulation

    PubMed Central

    Meireles-Filho, Antonio C. A.; Pagani, Michaela; Stark, Alexander

    2016-01-01

    Hox homeodomain transcription factors are key regulators of animal development. They specify the identity of segments along the anterior-posterior body axis in metazoans by controlling the expression of diverse downstream targets, including transcription factors and signaling pathway components. The Drosophila melanogaster Hox factor Ultrabithorax (Ubx) directs the development of thoracic and abdominal segments and appendages, and loss of Ubx function can lead for example to the transformation of third thoracic segment appendages (e.g. halters) into second thoracic segment appendages (e.g. wings), resulting in a characteristic four-wing phenotype. Here we present a Drosophila melanogaster strain with a V5-epitope tagged Ubx allele, which we employed to obtain a high quality genome-wide map of Ubx binding sites using ChIP-seq. We confirm the sensitivity of the V5 ChIP-seq by recovering 7/8 of well-studied Ubx-dependent cis-regulatory regions. Moreover, we show that Ubx binding is predictive of enhancer activity as suggested by comparison with a genome-scale resource of in vivo tested enhancer candidates. We observed densely clustered Ubx binding sites at 12 extended genomic loci that included ANTP-C, BX-C, Polycomb complex genes, and other regulators and the clustered binding sites were frequently active enhancers. Furthermore, Ubx binding was detected at known Polycomb response elements (PREs) and was associated with significant enrichments of Pc and Pho ChIP signals in contrast to binding sites of other developmental TFs. Together, our results show that Ubx targets developmental regulators via strongly clustered binding sites and allow us to hypothesize that regulation by Ubx might involve Polycomb group proteins to maintain specific regulatory states in cooperative or mutually exclusive fashion, an attractive model that combines two groups of proteins with prominent gene regulatory roles during animal development. PMID:27575958

  3. Genome-wide single nucleotide polymorphisms reveal population history and adaptive divergence in wild guppies.

    PubMed

    Willing, Eva-Maria; Bentzen, Paul; van Oosterhout, Cock; Hoffmann, Margarete; Cable, Joanne; Breden, Felix; Weigel, Detlef; Dreyer, Christine

    2010-03-01

    Adaptation of guppies (Poecilia reticulata) to contrasting upland and lowland habitats has been extensively studied with respect to behaviour, morphology and life history traits. Yet population history has not been studied at the whole-genome level. Although single nucleotide polymorphisms (SNPs) are the most abundant form of variation in many genomes and consequently very informative for a genome-wide picture of standing natural variation in populations, genome-wide SNP data are rarely available for wild vertebrates. Here we use genetically mapped SNP markers to comprehensively survey genetic variation within and among naturally occurring guppy populations from a wide geographic range in Trinidad and Venezuela. Results from three different clustering methods, Neighbor-net, principal component analysis (PCA) and Bayesian analysis show that the population substructure agrees with geographic separation and largely with previously hypothesized patterns of historical colonization. Within major drainages (Caroni, Oropouche and Northern), populations are genetically similar, but those in different geographic regions are highly divergent from one another, with some indications of ancient shared polymorphisms. Clear genomic signatures of a previous introduction experiment were seen, and we detected additional potential admixture events. Headwater populations were significantly less heterozygous than downstream populations. Pairwise F(ST) values revealed marked differences in allele frequencies among populations from different regions, and also among populations within the same region. F(ST) outlier methods indicated some regions of the genome as being under directional selection. Overall, this study demonstrates the power of a genome-wide SNP data set to inform for studies on natural variation, adaptation and evolution of wild populations.

  4. Signatures of positive selection in East African Shorthorn Zebu: a genome-wide SNP analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The small East African Shorthorn Zebu is the main indigenous cattle across East Africa. A recent genome wide SNPs analysis has revealed their ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signature of positive selection in their genome, with the aim...

  5. Development and application of a novel genome-wide SNP array reveals domestication history in soybean.

    PubMed

    Wang, Jiao; Chu, Shanshan; Zhang, Huairen; Zhu, Ying; Cheng, Hao; Yu, Deyue

    2016-02-09

    Domestication of soybeans occurred under the intense human-directed selections aimed at developing high-yielding lines. Tracing the domestication history and identifying the genes underlying soybean domestication require further exploration. Here, we developed a high-throughput NJAU 355 K SoySNP array and used this array to study the genetic variation patterns in 367 soybean accessions, including 105 wild soybeans and 262 cultivated soybeans. The population genetic analysis suggests that cultivated soybeans have tended to originate from northern and central China, from where they spread to other regions, accompanied with a gradual increase in seed weight. Genome-wide scanning for evidence of artificial selection revealed signs of selective sweeps involving genes controlling domestication-related agronomic traits including seed weight. To further identify genomic regions related to seed weight, a genome-wide association study (GWAS) was conducted across multiple environments in wild and cultivated soybeans. As a result, a strong linkage disequilibrium region on chromosome 20 was found to be significantly correlated with seed weight in cultivated soybeans. Collectively, these findings should provide an important basis for genomic-enabled breeding and advance the study of functional genomics in soybean.

  6. Genome-wide association study reveals sex-specific selection signals against autosomal nucleotide variants.

    PubMed

    Ryu, Dongchan; Ryu, Jihye; Lee, Chaeyoung

    2016-05-01

    A genome-wide association study (GWAS) was conducted to examine genetic associations of common autosomal nucleotide variants with sex in a Korean population with 4183 males and 4659 females. Nine genetic association signals were identified in four intragenic and five intergenic regions (P<5 × 10(-8)). Further analysis with an independent data set confirmed two intragenic association signals in the genes encoding protein phosphatase 1, regulatory subunit 12B (PPP1R12B, intron 12, rs1819043) and dynein, axonemal, heavy chain 11 (DNAH11, intron 61, rs10255013), which are directly involved in the reproductive system. This study revealed autosomal genetic variants associated with sex ratio by GWAS for the first time. This implies that genetic variants in proximity to the association signals may influence sex-specific selection and contribute to sex ratio variation. Further studies are required to reveal the mechanisms underlying sex-specific selection.

  7. Genome-Wide Transcriptome Analysis During Anthesis Reveals New Insights into the Molecular Basis of Heat Stress Responses in Tolerant and Sensitive Rice Varieties.

    PubMed

    González-Schain, Nahuel; Dreni, Ludovico; Lawas, Lovely M F; Galbiati, Massimo; Colombo, Lucia; Heuer, Sigrid; Jagadish, Krishna S V; Kater, Martin M

    2016-01-01

    Rice is one of the main food crops in the world. In the near future, yield is expected to be under pressure due to unfavorable climatic conditions, such as increasing temperatures. Therefore, improving rice germplasm in order to guarantee rice production under harsh environmental conditions is of top priority. Although many physiological studies have contributed to understanding heat responses during anthesis, the most heat-sensitive stage, molecular data are still largely lacking. In this study, an RNA-sequencing approach of heat- and control-treated reproductive tissues during anthesis was carried out using N22, one of the most heat-tolerant rice cultivars known to date. This analysis revealed that expression of genes encoding a number of transcription factor families, together with signal transduction and metabolic pathway genes, is repressed. On the other hand, expression of genes encoding heat shock factors and heat shock proteins was highly activated. Many of these genes are predominantly expressed at late stages of anther development. Further physiological experiments using heat-tolerant N22 and two sensitive cultivars suggest that reduced yield in heat-sensitive plants may be associated with poor pollen development or production in anthers prior to anthesis. In parallel, induction levels of a set of heat-responsive genes in these tissues correlated well with heat tolerance. Altogether, these findings suggest that proper expression of protective chaperones in anthers is needed before anthesis to overcome stress damage and to ensure fertilization. Genes putatively controlling this process were identified and are valuable candidates to consider for molecular breeding of highly productive heat-tolerant cultivars.

  8. Genome-wide search for eliminylating domains reveals novel function for BLES03-like proteins.

    PubMed

    Khater, Shradha; Mohanty, Debasisa

    2014-07-24

    Bacterial phosphothreonine lyases catalyze a novel posttranslational modification involving formation of dehydrobutyrine/dehyroalanine by β elimination of the phosphate group of phosphothreonine or phosphoserine residues in their substrate proteins. Though there is experimental evidence for presence of dehydro amino acids in human proteins, no eukaryotic homologs of these lyases have been identified as of today. A comprehensive genome-wide search for identifying phosphothreonine lyase homologs in eukaryotes was carried out. Our fold-based search revealed structural and catalytic site similarity between bacterial phosphothreonine lyases and BLES03 (basophilic leukemia-expressed protein 03), a human protein with unknown function. Ligand induced conformational changes similar to bacterial phosphothreonine lyases, and movement of crucial arginines in the loop region to the catalytic pocket upon binding of phosphothreonine-containing peptides was seen during docking and molecular dynamics studies. Genome-wide search for BLES03 homologs using sensitive profile-based methods revealed their presence not only in eukaryotic classes such as chordata and fungi but also in bacterial and archaebacterial classes. The synteny of these archaebacterial BLES03-like proteins was remarkably similar to that of type IV lantibiotic synthetases which harbor LanL-like phosphothreonine lyase domains. Hence, context-based analysis reinforced our earlier sequence/structure-based prediction of phosphothreonine lyase catalytic function for BLES03. Our in silico analysis has revealed that BLES03-like proteins with previously unknown function are novel eukaryotic phosphothreonine lyases involved in biosynthesis of dehydro amino acids, whereas their bacterial and archaebacterial counterparts might be involved in biosynthesis of natural products similar to lantibiotics.

  9. Weighted SNP set analysis in genome-wide association study.

    PubMed

    Dai, Hui; Zhao, Yang; Qian, Cheng; Cai, Min; Zhang, Ruyang; Chu, Minjie; Dai, Juncheng; Hu, Zhibin; Shen, Hongbing; Chen, Feng

    2013-01-01

    Genome-wide association studies (GWAS) are popular for identifying genetic variants which are associated with disease risk. Many approaches have been proposed to test multiple single nucleotide polymorphisms (SNPs) in a region simultaneously which considering disadvantages of methods in single locus association analysis. Kernel machine based SNP set analysis is more powerful than single locus analysis, which borrows information from SNPs correlated with causal or tag SNPs. Four types of kernel machine functions and principal component based approach (PCA) were also compared. However, given the loss of power caused by low minor allele frequencies (MAF), we conducted an extension work on PCA and used a new method called weighted PCA (wPCA). Comparative analysis was performed for weighted principal component analysis (wPCA), logistic kernel machine based test (LKM) and principal component analysis (PCA) based on SNP set in the case of different minor allele frequencies (MAF) and linkage disequilibrium (LD) structures. We also applied the three methods to analyze two SNP sets extracted from a real GWAS dataset of non-small cell lung cancer in Han Chinese population. Simulation results show that when the MAF of the causal SNP is low, weighted principal component and weighted IBS are more powerful than PCA and other kernel machine functions at different LD structures and different numbers of causal SNPs. Application of the three methods to a real GWAS dataset indicates that wPCA and wIBS have better performance than the linear kernel, IBS kernel and PCA.

  10. Genome-Wide Small RNA Analysis of Soybean Reveals Auxin-Responsive microRNAs that are Differentially Expressed in Response to Salt Stress in Root Apex

    PubMed Central

    Sun, Zhengxi; Wang, Youning; Mou, Fupeng; Tian, Yinping; Chen, Liang; Zhang, Senlei; Jiang, Qiong; Li, Xia

    2016-01-01

    Root growth and the architecture of the root system in Arabidopsis are largely determined by root meristematic activity. Legume roots show strong developmental plasticity in response to both abiotic and biotic stimuli, including symbiotic rhizobia. However, a global analysis of gene regulation in the root meristem of soybean plants is lacking. In this study, we performed a global analysis of the small RNA transcriptome of root tips from soybean seedlings grown under normal and salt stress conditions. In total, 71 miRNA candidates, including known and novel variants of 59 miRNA families, were identified. We found 66 salt-responsive miRNAs in the soybean root meristem; among them, 22 are novel miRNAs. Interestingly, we found auxin-responsive cis-elements in the promoters of many salt-responsive miRNAs, implying that these miRNAs may be regulated by auxin and auxin signaling plays a key role in regulating the plasticity of the miRNAome and root development in soybean. A functional analysis of miR399, a salt-responsive miRNA in the root meristem, indicates the crucial role of this miRNA in modulating soybean root developmental plasticity. Our data provide novel insight into the miRNAome-mediated regulatory mechanism in soybean root growth under salt stress. PMID:26834773

  11. Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells.

    PubMed

    Zhang, Xuesen; Gamble, Matthew J; Stadler, Sonja; Cherrington, Brian D; Causey, Corey P; Thompson, Paul R; Roberson, Mark S; Kraus, W Lee; Coonrod, Scott A

    2011-06-01

    Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found potential binding sites for Elk-1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites; and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. To better understand how PADI4 may facilitate gene transactivation, we then show that PADI4 interacts with Elk-1 at the c-Fos promoter and that, following Epidermal Growth Factor (EGF) stimulation, PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation. These results define a novel role for PADI4 as a transcription factor co-activator.

  12. Genome-wide analysis on Chlamydomonas reinhardtii reveals the impact of hydrogen peroxide on protein stress responses and overlap with other stress transcriptomes

    SciTech Connect

    Blaby, Ian K.; Blaby-Haas, Crysten E.; Pérez-Pérez, María Esther; Schmollinger, Stefan; Fitz-Gibbon, Sorel; Lemaire, Stéphane D.; Merchant, Sabeeha S.

    2015-12-07

    Reactive oxygen species (ROS) are produced by and have the potential to be damaging to all aerobic organisms. In photosynthetic organisms, they are an unavoidable byproduct of electron transfer in both the chloroplast and mitochondrion. Here, in this paper, we employ the reference unicellular green alga Chlamydomonas reinhardtii to identify the effect of H2O2 on gene expression by monitoring the changes in the transcriptome in a time-course experiment. Comparison of transcriptomes from cells sampled immediately prior to the addition of H2O2 and 0.5 and 1 h subsequently revealed 1278 differentially abundant transcripts. Of those transcripts that increase in abundance, many encode proteins involved in ROS detoxification, protein degradation and stress responses, whereas among those that decrease are transcripts encoding proteins involved in photosynthesis and central carbon metabolism. In addition to these transcriptomic adjustments, we observe that addition of H2O2 is followed by an accumulation and oxidation of the total intracellular glutathione pool, and a decrease in photosynthetic O2 output. Additionally, we analyze our transcriptomes in the context of changes in transcript abundance in response to singlet O2 (O2*), and relate our H2O2-induced transcripts to a diurnal transcriptome, where we demonstrate enrichments of H2O2-induced transcripts early in the light phase, late in the light phase and 2 h prior to light. In conclusion, on this basis several genes that are highlighted in this work may be involved in previously undiscovered stress remediation pathways or acclimation responses.

  13. Genome-wide analysis on Chlamydomonas reinhardtii reveals the impact of hydrogen peroxide on protein stress responses and overlap with other stress transcriptomes

    DOE PAGES

    Blaby, Ian K.; Blaby-Haas, Crysten E.; Pérez-Pérez, María Esther; ...

    2015-12-07

    Reactive oxygen species (ROS) are produced by and have the potential to be damaging to all aerobic organisms. In photosynthetic organisms, they are an unavoidable byproduct of electron transfer in both the chloroplast and mitochondrion. Here, in this paper, we employ the reference unicellular green alga Chlamydomonas reinhardtii to identify the effect of H2O2 on gene expression by monitoring the changes in the transcriptome in a time-course experiment. Comparison of transcriptomes from cells sampled immediately prior to the addition of H2O2 and 0.5 and 1 h subsequently revealed 1278 differentially abundant transcripts. Of those transcripts that increase in abundance, manymore » encode proteins involved in ROS detoxification, protein degradation and stress responses, whereas among those that decrease are transcripts encoding proteins involved in photosynthesis and central carbon metabolism. In addition to these transcriptomic adjustments, we observe that addition of H2O2 is followed by an accumulation and oxidation of the total intracellular glutathione pool, and a decrease in photosynthetic O2 output. Additionally, we analyze our transcriptomes in the context of changes in transcript abundance in response to singlet O2 (O2*), and relate our H2O2-induced transcripts to a diurnal transcriptome, where we demonstrate enrichments of H2O2-induced transcripts early in the light phase, late in the light phase and 2 h prior to light. In conclusion, on this basis several genes that are highlighted in this work may be involved in previously undiscovered stress remediation pathways or acclimation responses.« less

  14. Genome-wide array-CGH analysis reveals YRF1 gene copy number variation that modulates genetic stability in distillery yeasts.

    PubMed

    Deregowska, Anna; Skoneczny, Marek; Adamczyk, Jagoda; Kwiatkowska, Aleksandra; Rawska, Ewa; Skoneczna, Adrianna; Lewinska, Anna; Wnuk, Maciej

    2015-10-13

    Industrial yeasts, economically important microorganisms, are widely used in diverse biotechnological processes including brewing, winemaking and distilling. In contrast to a well-established genome of brewer's and wine yeast strains, the comprehensive evaluation of genomic features of distillery strains is lacking. In the present study, twenty two distillery yeast strains were subjected to electrophoretic karyotyping and array-based comparative genomic hybridization (array-CGH). The strains analyzed were assigned to the Saccharomyces sensu stricto complex and grouped into four species categories: S. bayanus, S. paradoxus, S. cerevisiae and S. kudriavzevii. The genomic diversity was mainly revealed within subtelomeric regions and the losses and/or gains of fragments of chromosomes I, III, VI and IX were the most frequently observed. Statistically significant differences in the gene copy number were documented in six functional gene categories: 1) telomere maintenance via recombination, DNA helicase activity or DNA binding, 2) maltose metabolism process, glucose transmembrane transporter activity; 3) asparagine catabolism, cellular response to nitrogen starvation, localized in cell wall-bounded periplasmic space, 4) siderophore transport, 5) response to copper ion, cadmium ion binding and 6) L-iditol 2- dehydrogenase activity. The losses of YRF1 genes (Y' element ATP-dependent helicase) were accompanied by decreased level of Y' sequences and an increase in DNA double and single strand breaks, and oxidative DNA damage in the S. paradoxus group compared to the S. bayanus group. We postulate that naturally occurring diversity in the YRF1 gene copy number may promote genetic stability in the S. bayanus group of distillery yeast strains.

  15. Genome-wide array-CGH analysis reveals YRF1 gene copy number variation that modulates genetic stability in distillery yeasts

    PubMed Central

    Adamczyk, Jagoda; Kwiatkowska, Aleksandra; Rawska, Ewa; Skoneczna, Adrianna

    2015-01-01

    Industrial yeasts, economically important microorganisms, are widely used in diverse biotechnological processes including brewing, winemaking and distilling. In contrast to a well-established genome of brewer's and wine yeast strains, the comprehensive evaluation of genomic features of distillery strains is lacking. In the present study, twenty two distillery yeast strains were subjected to electrophoretic karyotyping and array-based comparative genomic hybridization (array-CGH). The strains analyzed were assigned to the Saccharomyces sensu stricto complex and grouped into four species categories: S. bayanus, S. paradoxus, S. cerevisiae and S. kudriavzevii. The genomic diversity was mainly revealed within subtelomeric regions and the losses and/or gains of fragments of chromosomes I, III, VI and IX were the most frequently observed. Statistically significant differences in the gene copy number were documented in six functional gene categories: 1) telomere maintenance via recombination, DNA helicase activity or DNA binding, 2) maltose metabolism process, glucose transmembrane transporter activity; 3) asparagine catabolism, cellular response to nitrogen starvation, localized in cell wall-bounded periplasmic space, 4) siderophore transport, 5) response to copper ion, cadmium ion binding and 6) L-iditol 2- dehydrogenase activity. The losses of YRF1 genes (Y' element ATP-dependent helicase) were accompanied by decreased level of Y' sequences and an increase in DNA double and single strand breaks, and oxidative DNA damage in the S. paradoxus group compared to the S. bayanus group. We postulate that naturally occurring diversity in the YRF1 gene copy number may promote genetic stability in the S. bayanus group of distillery yeast strains. PMID:26384347

  16. Genome-wide analysis reveals the expansion of Cytochrome P450 genes associated with xenobiotic metabolism in rice striped stem borer, Chilo suppressalis.

    PubMed

    Wang, Baoju; Shahzad, Muhammad Faisal; Zhang, Zan; Sun, Haina; Han, Ping; Li, Fei; Han, Zhaojun

    2014-01-10

    The Cytochrome P450 (CYP) superfamily is a large group of ancient proteins with enzymatic activities involved in various physiological processes. The rice striped stem borer, Chilo suppressalis, is an important insect pest in rice production. Here, we report the identification and characterization of 77 CYP genes from rice striped stem borer (SSB) through genome and transcriptome sequence analyses. All these CYP genes were confirmed by RT-PCR and direct sequencing. Twenty-eight CYP transcripts have full open reading frame (ORF) and four additional transcripts have a nearly full length coding region. The SSB CYP genes were classified into four clans, the mitochondrial, CYP2, CYP3, and CYP4. Phylogenetic analysis indicated that there was an apparent expansion of the CYP3 clan in insects. The CYP6AB subfamily of the CYP3 clan had nine members in SSB. Evolutionary analysis showed that this subfamily was expanded only in lepidopteran insects. In this study, we identified a new P450 subfamily, CYP321F, which is unique to SSB and located in the genome as tandem repeats. Our work provided a foundation for future studies on the functions and mechanism of P450s in the destructive rice pest.

  17. Genome-wide analysis of AP2/ERF transcription factors in carrot (Daucus carota L.) reveals evolution and expression profiles under abiotic stress.

    PubMed

    Li, Meng-Yao; Xu, Zhi-Sheng; Huang, Ying; Tian, Chang; Wang, Feng; Xiong, Ai-Sheng

    2015-12-01

    AP2/ERF is a large transcription factor family that regulates plant physiological processes, such as plant development and stress response. Carrot (Daucus carota L.) is an important economical crop with a genome size of 480 Mb; the draft genome sequencing of this crop has been completed by our group. However, little is known about the AP2/ERF factors in carrot. In this study, a total of 267 putative AP2/ERF factors were identified from the whole-genome sequence of carrot. These AP2/ERF proteins were phylogenetically clustered into five subfamilies based on their similarity to the amino acid sequences from Arabidopsis. The distribution and comparative genome analysis of the AP2/ERF factors among plants showed the AP2/ERF factors had expansion during the evolutionary process, and the AP2 domain was highly conserved during evolution. The number of AP2/ERF factors in land plants expanded during their evolution. A total of 60 orthologous and 145 coorthologous AP2/ERF gene pairs between carrot and Arabidopsis were identified, and the interaction network of orthologous genes was constructed. The expression patterns of eight AP2/ERF family genes from each subfamily (DREB, ERF, AP2, and RAV) were related to abiotic stresses. Yeast one-hybrid and β-galactosidase activity assays confirmed the DRE and GCC box-binding activities of DREB subfamily genes. This study is the first to identify and characterize the AP2/ERF transcription factors in carrot using whole-genome analysis, and the findings may serve as references for future functional research on the transcription factors in carrot.

  18. Genome-wide transcriptome analysis reveals that a pleiotropic antibiotic regulator, AfsS, modulates nutritional stress response in Streptomyces coelicolor A3(2)

    PubMed Central

    Lian, Wei; Jayapal, Karthik P; Charaniya, Salim; Mehra, Sarika; Glod, Frank; Kyung, Yun-Seung; Sherman, David H; Hu, Wei-Shou

    2008-01-01

    Background A small "sigma-like" protein, AfsS, pleiotropically regulates antibiotic biosynthesis in Streptomyces coelicolor. Overexpression of afsS in S. coelicolor and certain related species causes antibiotic stimulatory effects in the host organism. Although recent studies have uncovered some of the upstream events activating this gene, the mechanisms through which this signal is relayed downstream leading to the eventual induction of antibiotic pathways remain unclear. Results In this study, we employed whole-genome DNA microarrays and quantitative PCRs to examine the transcriptome of an afsS disruption mutant that is completely deficient in the production of actinorhodin, a major S. coelicolor antibiotic. The production of undecylprodigiosin, another prominent antibiotic, was, however, perturbed only marginally in the mutant. Principal component analysis of temporal gene expression profiles identified two major gene classes each exhibiting a distinct coordinate differential expression pattern. Surprisingly, nearly 70% of the >117 differentially expressed genes were conspicuously associated with nutrient starvation response, particularly those of phosphate, nitrogen and sulfate. Furthermore, expression profiles of some transcriptional regulators including at least two sigma factors were perturbed in the mutant. In almost every case, the effect of afsS disruption was not observed until the onset of stationary phase. Conclusion Our data suggests a comprehensive role for S. coelicolor AfsS as a master regulator of both antibiotic synthesis and nutritional stress response, reminiscent of alternative sigma factors found in several bacteria. PMID:18230178

  19. Genome-Wide Analysis of Stowaway-Like MITEs in Wheat Reveals High Sequence Conservation, Gene Association, and Genomic Diversification1[C][W

    PubMed Central

    Yaakov, Beery; Ben-David, Smadar; Kashkush, Khalil

    2013-01-01

    The diversity and evolution of wheat (Triticum-Aegilops group) genomes is determined, in part, by the activity of transposable elements that constitute a large fraction of the genome (up to 90%). In this study, we retrieved sequences from publicly available wheat databases, including a 454-pyrosequencing database, and analyzed 18,217 insertions of 18 Stowaway-like miniature inverted-repeat transposable element (MITE) families previously characterized in wheat that together account for approximately 1.3 Mb of sequence. All 18 families showed high conservation in length, sequence, and target site preference. Furthermore, approximately 55% of the elements were inserted in transcribed regions, into or near known wheat genes. Notably, we observed significant correlation between the mean length of the MITEs and their copy number. In addition, the genomic composition of nine MITE families was studied by real-time quantitative polymerase chain reaction analysis in 40 accessions of Triticum spp. and Aegilops spp., including diploids, tetraploids, and hexaploids. The quantitative polymerase chain reaction data showed massive and significant intraspecific and interspecific variation as well as genome-specific proliferation and nonadditive quantities in the polyploids. We also observed significant differences in the methylation status of the insertion sites among MITE families. Our data thus suggest a possible role for MITEs in generating genome diversification and in the establishment of nascent polyploid species in wheat. PMID:23104862

  20. Genome-Wide Analysis of NBS-LRR Genes in Sorghum Genome Revealed Several Events Contributing to NBS-LRR Gene Evolution in Grass Species

    PubMed Central

    Yang, Xiping; Wang, Jianping

    2016-01-01

    The nucleotide-binding site (NBS)–leucine-rich repeat (LRR) gene family is crucially important for offering resistance to pathogens. To explore evolutionary conservation and variability of NBS-LRR genes across grass species, we identified 88, 107, 24, and 44 full-length NBS-LRR genes in sorghum, rice, maize, and Brachypodium, respectively. A comprehensive analysis was performed on classification, genome organization, evolution, expression, and regulation of these NBS-LRR genes using sorghum as a representative of grass species. In general, the full-length NBS-LRR genes are highly clustered and duplicated in sorghum genome mainly due to local duplications. NBS-LRR genes have basal expression levels and are highly potentially targeted by miRNA. The number of NBS-LRR genes in the four grass species is positively correlated with the gene clustering rate. The results provided a valuable genomic resource and insights for functional and evolutionary studies of NBS-LRR genes in grass species. PMID:26792976

  1. Genome-wide identification of citrus ATP-citrate lyase genes and their transcript analysis in fruits reveals their possible role in citrate utilization.

    PubMed

    Hu, Xiao-Mei; Shi, Cai-Yun; Liu, Xiao; Jin, Long-Fei; Liu, Yong-Zhong; Peng, Shu-Ang

    2015-02-01

    ATP-citrate lyase (ACL, EC4.1.3.8) catalyzes citrate to oxaloacetate and acetyl-CoA in the cell cytosol, and has important roles in normal plant growth and in the biosynthesis of some secondary metabolites. We identified three ACL genes, CitACLα1, CitACLα2, and CitACLβ1, in the citrus genome database. Both CitACLα1 and CitACLα2 encode putative ACL α subunits with 82.5 % amino acid identity, whereas CitACLβ1 encodes a putative ACL β subunit. Gene structure analysis showed that CitACLα1 and CitACLα2 had 12 exons and 11 introns, and CitACLβ1 had 16 exons and 15 introns. CitACLα1 and CitACLβ1 were predominantly expressed in flower, and CitACLα2 was predominantly expressed in stem and fibrous roots. As fruits ripen, the transcript levels of CitACLα1, CitACLβ1, and/or CitACLα2 in cultivars 'Niuher' and 'Owari' increased, accompanied by significant decreases in citrate content, while their transcript levels decreased significantly in 'Egan No. 1' and 'Iyokan', although citrate content also decreased. In 'HB pummelo', in which acid content increased as fruit ripened, and in acid-free pummelo, transcript levels of CitACLα2, CitACLβ1, and/or CitACLα1 increased. Moreover, mild drought stress and ABA treatment significantly increased citrate contents in fruits. Transcript levels of the three genes were significantly reduced by mild drought stress, and the transcript level of only CitACLβ1 was significantly reduced by ABA treatment. Taken together, these data indicate that the effects of ACL on citrate use during fruit ripening depends on the cultivar, and the reduction in ACL gene expression may be attributed to citrate increases under mild drought stress or ABA treatment.

  2. Genome-wide analysis of brain and gonad transcripts reveals changes of key sex reversal-related genes expression and signaling pathways in three stages of Monopterus albus

    PubMed Central

    Hu, Qing; Guo, Wei; Li, Dapeng

    2017-01-01

    Background The natural sex reversal severely affects the sex ratio and thus decreases the productivity of the rice field eel (Monopterus albus). How to understand and manipulate this process is one of the major issues for the rice field eel stocking. So far the genomics and transcriptomics data available for this species are still scarce. Here we provide a comprehensive study of transcriptomes of brain and gonad tissue in three sex stages (female, intersex and male) from the rice field eel to investigate changes in transcriptional level during the sex reversal process. Results Approximately 195 thousand unigenes were generated and over 44.4 thousand were functionally annotated. Comparative study between stages provided multiple differentially expressed genes in brain and gonad tissue. Overall 4668 genes were found to be of unequal abundance between gonad tissues, far more than that of the brain tissues (59 genes). These genes were enriched in several different signaling pathways. A number of 231 genes were found with different levels in gonad in each stage, with several reproduction-related genes included. A total of 19 candidate genes that could be most related to sex reversal were screened out, part of these genes’ expression patterns were validated by RT-qPCR. The expression of spef2, maats1, spag6 and dmc1 were abundant in testis, but was barely detected in females, while the 17β-hsd12, zpsbp3, gal3 and foxn5 were only expressed in ovary. Conclusion This study investigated the complexity of brain and gonad transcriptomes in three sex stages of the rice field eel. Integrated analysis of different gene expression and changes in signaling pathways, such as PI3K-Akt pathway, provided crucial data for further study of sex transformation mechanisms. PMID:28319194

  3. Comparative analysis of methods for genome-wide nucleosome cartography.

    PubMed

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use.

  4. Genome-wide transcriptome analysis of human epidermal melanocytes

    PubMed Central

    Haltaufderhyde, Kirk D.; Oancea, Elena

    2015-01-01

    Because human epidermal melanocytes (HEMs) provide critical protection against skin cancer, sunburn, and photoaging, a genome-wide perspective of gene expression in these cells is vital to understanding human skin physiology. In this study we performed high throughput sequencing of HEMs to obtain a complete data set of transcript sizes, abundances, and splicing. As expected, we found that melanocyte specific genes that function in pigmentation were among the highest expressed genes. We analyzed receptor, ion channel and transcription factor gene families to get a better understanding of the cell signalling pathways used by melanocytes. We also performed a comparative transcriptomic analysis of lightly versus darkly pigmented HEMs and found 16 genes differentially expressed in the two pigmentation phenotypes; of those, only one putative melanosomal transporter (SLC45A2) has known function in pigmentation. In addition, we found 166 genes with splice isoforms expressed exclusively in one pigmentation phenotype, 17 of which are genes involved in signal transduction. Our melanocyte transcriptome study provides a comprehensive view and may help identify novel pigmentation genes and potential pharmacological targets. PMID:25451175

  5. Genome-wide view of genetic diversity reveals paths of selection and cultivar differentiation in peach domestication

    PubMed Central

    Akagi, Takashi; Hanada, Toshio; Yaegaki, Hideaki; Gradziel, Thomas M.; Tao, Ryutaro

    2016-01-01

    Domestication and cultivar differentiation are requisite processes for establishing cultivated crops. These processes inherently involve substantial changes in population structure, including those from artificial selection of key genes. In this study, accessions of peach (Prunus persica) and its wild relatives were analysed genome-wide to identify changes in genetic structures and gene selections associated with their differentiation. Analysis of genome-wide informative single-nucleotide polymorphism loci revealed distinct changes in genetic structures and delineations among domesticated peach and its wild relatives and among peach landraces and modern fruit (F) and modern ornamental (O-A) cultivars. Indications of distinct changes in linkage disequilibrium extension/decay and of strong population bottlenecks or inbreeding were identified. Site frequency spectrum- and extended haplotype homozygosity-based evaluation of genome-wide genetic diversities supported selective sweeps distinguishing the domesticated peach from its wild relatives and each F/O-A cluster from the landrace clusters. The regions with strong selective sweeps harboured promising candidates for genes subjected to selection. Further sequence-based evaluation further defined the candidates and revealed their characteristics. All results suggest opportunities for identifying critical genes associated with each differentiation by analysing genome-wide genetic diversity in currently established populations. This approach obviates the special development of genetic populations, which is particularly difficult for long-lived tree crops. PMID:27085183

  6. Genome-wide view of genetic diversity reveals paths of selection and cultivar differentiation in peach domestication.

    PubMed

    Akagi, Takashi; Hanada, Toshio; Yaegaki, Hideaki; Gradziel, Thomas M; Tao, Ryutaro

    2016-06-01

    Domestication and cultivar differentiation are requisite processes for establishing cultivated crops. These processes inherently involve substantial changes in population structure, including those from artificial selection of key genes. In this study, accessions of peach (Prunus persica) and its wild relatives were analysed genome-wide to identify changes in genetic structures and gene selections associated with their differentiation. Analysis of genome-wide informative single-nucleotide polymorphism loci revealed distinct changes in genetic structures and delineations among domesticated peach and its wild relatives and among peach landraces and modern fruit (F) and modern ornamental (O-A) cultivars. Indications of distinct changes in linkage disequilibrium extension/decay and of strong population bottlenecks or inbreeding were identified. Site frequency spectrum- and extended haplotype homozygosity-based evaluation of genome-wide genetic diversities supported selective sweeps distinguishing the domesticated peach from its wild relatives and each F/O-A cluster from the landrace clusters. The regions with strong selective sweeps harboured promising candidates for genes subjected to selection. Further sequence-based evaluation further defined the candidates and revealed their characteristics. All results suggest opportunities for identifying critical genes associated with each differentiation by analysing genome-wide genetic diversity in currently established populations. This approach obviates the special development of genetic populations, which is particularly difficult for long-lived tree crops.

  7. Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.

    PubMed

    Kim, Sang Woo; Fishilevich, Elane; Arango-Argoty, Gustavo; Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.

  8. Genome-Wide Transcript Profiling Reveals Novel Breast Cancer-Associated Intronic Sense RNAs

    PubMed Central

    Lin, Yuefeng; Liu, Guodong; Li, Zhihua; Monaghan, A. Paula; Nichols, Mark; John, Bino

    2015-01-01

    Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer. PMID:25798919

  9. Genome-wide analysis of condensin binding in Caenorhabditis elegans

    PubMed Central

    2013-01-01

    Background Condensins are multi-subunit protein complexes that are essential for chromosome condensation during mitosis and meiosis, and play key roles in transcription regulation during interphase. Metazoans contain two condensins, I and II, which perform different functions and localize to different chromosomal regions. Caenorhabditis elegans contains a third condensin, IDC, that is targeted to and represses transcription of the X chromosome for dosage compensation. Results To understand condensin binding and function, we performed ChIP-seq analysis of C. elegans condensins in mixed developmental stage embryos, which contain predominantly interphase nuclei. Condensins bind to a subset of active promoters, tRNA genes and putative enhancers. Expression analysis in kle-2-mutant larvae suggests that the primary effect of condensin II on transcription is repression. A DNA sequence motif, GCGC, is enriched at condensin II binding sites. A sequence extension of this core motif, AGGG, creates the condensin IDC motif. In addition to differences in recruitment that result in X-enrichment of condensin IDC and condensin II binding to all chromosomes, we provide evidence for a shared recruitment mechanism, as condensin IDC recruiter SDC-2 also recruits condensin II to the condensin IDC recruitment sites on the X. In addition, we found that condensin sites overlap extensively with the cohesin loader SCC-2, and that SDC-2 also recruits SCC-2 to the condensin IDC recruitment sites. Conclusions Our results provide the first genome-wide view of metazoan condensin II binding in interphase, define putative recruitment motifs, and illustrate shared loading mechanisms for condensin IDC and condensin II. PMID:24125077

  10. Genome-Wide Divergence and Linkage Disequilibrium Analyses for Capsicum baccatum Revealed by Genome-Anchored Single Nucleotide Polymorphisms.

    PubMed

    Nimmakayala, Padma; Abburi, Venkata L; Saminathan, Thangasamy; Almeida, Aldo; Davenport, Brittany; Davidson, Joshua; Reddy, C V Chandra Mohan; Hankins, Gerald; Ebert, Andreas; Choi, Doil; Stommel, John; Reddy, Umesh K

    2016-01-01

    Principal component analysis (PCA) with 36,621 polymorphic genome-anchored single nucleotide polymorphisms (SNPs) identified collectively for Capsicum annuum and Capsicum baccatum was used to characterize population structure and species domestication of these two important incompatible cultivated pepper species. Estimated mean nucleotide diversity (π) and Tajima's D across various chromosomes revealed biased distribution toward negative values on all chromosomes (except for chromosome 4) in cultivated C. baccatum, indicating a population bottleneck during domestication of C. baccatum. In contrast, C. annuum chromosomes showed positive π and Tajima's D on all chromosomes except chromosome 8, which may be because of domestication at multiple sites contributing to wider genetic diversity. For C. baccatum, 13,129 SNPs were available, with minor allele frequency (MAF) ≥0.05; PCA of the SNPs revealed 283 C. baccatum accessions grouped into 3 distinct clusters, for strong population structure. The fixation index (FST ) between domesticated C. annuum and C. baccatum was 0.78, which indicates genome-wide divergence. We conducted extensive linkage disequilibrium (LD) analysis of C. baccatum var. pendulum cultivars on all adjacent SNP pairs within a chromosome to identify regions of high and low LD interspersed with a genome-wide average LD block size of 99.1 kb. We characterized 1742 haplotypes containing 4420 SNPs (range 9-2 SNPs per haplotype). Genome-wide association study (GWAS) of peduncle length, a trait that differentiates wild and domesticated C. baccatum types, revealed 36 significantly associated genome-wide SNPs. Population structure, identity by state (IBS) and LD patterns across the genome will be of potential use for future GWAS of economically important traits in C. baccatum peppers.

  11. Genome-Wide Divergence and Linkage Disequilibrium Analyses for Capsicum baccatum Revealed by Genome-Anchored Single Nucleotide Polymorphisms

    PubMed Central

    Nimmakayala, Padma; Abburi, Venkata L.; Saminathan, Thangasamy; Almeida, Aldo; Davenport, Brittany; Davidson, Joshua; Reddy, C. V. Chandra Mohan; Hankins, Gerald; Ebert, Andreas; Choi, Doil; Stommel, John; Reddy, Umesh K.

    2016-01-01

    Principal component analysis (PCA) with 36,621 polymorphic genome-anchored single nucleotide polymorphisms (SNPs) identified collectively for Capsicum annuum and Capsicum baccatum was used to characterize population structure and species domestication of these two important incompatible cultivated pepper species. Estimated mean nucleotide diversity (π) and Tajima's D across various chromosomes revealed biased distribution toward negative values on all chromosomes (except for chromosome 4) in cultivated C. baccatum, indicating a population bottleneck during domestication of C. baccatum. In contrast, C. annuum chromosomes showed positive π and Tajima's D on all chromosomes except chromosome 8, which may be because of domestication at multiple sites contributing to wider genetic diversity. For C. baccatum, 13,129 SNPs were available, with minor allele frequency (MAF) ≥0.05; PCA of the SNPs revealed 283 C. baccatum accessions grouped into 3 distinct clusters, for strong population structure. The fixation index (FST) between domesticated C. annuum and C. baccatum was 0.78, which indicates genome-wide divergence. We conducted extensive linkage disequilibrium (LD) analysis of C. baccatum var. pendulum cultivars on all adjacent SNP pairs within a chromosome to identify regions of high and low LD interspersed with a genome-wide average LD block size of 99.1 kb. We characterized 1742 haplotypes containing 4420 SNPs (range 9–2 SNPs per haplotype). Genome-wide association study (GWAS) of peduncle length, a trait that differentiates wild and domesticated C. baccatum types, revealed 36 significantly associated genome-wide SNPs. Population structure, identity by state (IBS) and LD patterns across the genome will be of potential use for future GWAS of economically important traits in C. baccatum peppers. PMID:27857720

  12. Genome-Wide Sequencing Reveals Two Major Sub-Lineages in the Genetically Monomorphic Pathogen Xanthomonas Campestris Pathovar Musacearum

    PubMed Central

    Wasukira, Arthur; Tayebwa, Johnbosco; Thwaites, Richard; Paszkiewicz, Konrad; Aritua, Valente; Kubiriba, Jerome; Smith, Julian; Grant, Murray; Studholme, David J.

    2012-01-01

    The bacterium Xanthomonas campestris pathovar musacearum (Xcm) is the causal agent of banana Xanthomonas wilt (BXW). This disease has devastated economies based on banana and plantain crops (Musa species) in East Africa. Here we use genome-wide sequencing to discover a set of single-nucleotide polymorphisms (SNPs) among East African isolates of Xcm. These SNPs have potential as molecular markers for phylogeographic studies of the epidemiology and spread of the pathogen. Our analysis reveals two major sub-lineages of the pathogen, suggesting that the current outbreaks of BXW on Musa species in the region may have more than one introductory event, perhaps from Ethiopia. Also, based on comparisons of genome-wide sequence data from multiple isolates of Xcm and multiple strains of X. vasicola pathovar vasculorum, we identify genes specific to Xcm that could be used to specifically detect Xcm by PCR-based methods. PMID:24704974

  13. Genome-wide sequencing reveals two major sub-lineages in the genetically monomorphic pathogen xanthomonas campestris pathovar musacearum.

    PubMed

    Wasukira, Arthur; Tayebwa, Johnbosco; Thwaites, Richard; Paszkiewicz, Konrad; Aritua, Valente; Kubiriba, Jerome; Smith, Julian; Grant, Murray; Studholme, David J

    2012-07-04

    The bacterium Xanthomonas campestris pathovar musacearum (Xcm) is the causal agent of banana Xanthomonas wilt (BXW). This disease has devastated economies based on banana and plantain crops (Musa species) in East Africa. Here we use genome-wide sequencing to discover a set of single-nucleotide polymorphisms (SNPs) among East African isolates of Xcm. These SNPs have potential as molecular markers for phylogeographic studies of the epidemiology and spread of the pathogen. Our analysis reveals two major sub-lineages of the pathogen, suggesting that the current outbreaks of BXW on Musa species in the region may have more than one introductory event, perhaps from Ethiopia. Also, based on comparisons of genome-wide sequence data from multiple isolates of Xcm and multiple strains of X. vasicola pathovar vasculorum, we identify genes specific to Xcm that could be used to specifically detect Xcm by PCR-based methods.

  14. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  15. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

    PubMed Central

    Fernandez, Christian A.; Smith, Colton; Yang, Wenjian; Mullighan, Charles G.; Qu, Chunxu; Larsen, Eric; Bowman, W. Paul; Liu, Chengcheng; Ramsey, Laura B.; Chang, Tamara; Karol, Seth E.; Loh, Mignon L.; Raetz, Elizabeth A.; Winick, Naomi J.; Hunger, Stephen P.; Carroll, William L.; Jeha, Sima; Pui, Ching-Hon; Evans, William E.; Devidas, Meenakshi

    2015-01-01

    Asparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a genome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children’s Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children’s Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 × 10−8; odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH ALL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 × 10−3 and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 × 10−6; OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response. PMID:25987655

  16. Genome-Wide Analysis of Polyadenylation Events in Schmidtea mediterranea

    PubMed Central

    Lakshmanan, Vairavan; Bansal, Dhiru; Kulkarni, Jahnavi; Poduval, Deepak; Krishna, Srikar; Sasidharan, Vidyanand; Anand, Praveen; Seshasayee, Aswin; Palakodeti, Dasaradhi

    2016-01-01

    In eukaryotes, 3′ untranslated regions (UTRs) play important roles in regulating posttranscriptional gene expression. The 3′UTR is defined by regulated cleavage/polyadenylation of the pre-mRNA. The advent of next-generation sequencing technology has now enabled us to identify these events on a genome-wide scale. In this study, we used poly(A)-position profiling by sequencing (3P-Seq) to capture all poly(A) sites across the genome of the freshwater planarian, Schmidtea mediterranea, an ideal model system for exploring the process of regeneration and stem cell function. We identified the 3′UTRs for ∼14,000 transcripts and thus improved the existing gene annotations. We found 97 transcripts, which are polyadenylated within an internal exon, resulting in the shrinking of the ORF and loss of a predicted protein domain. Around 40% of the transcripts in planaria were alternatively polyadenylated (ApA), resulting either in an altered 3′UTR or a change in coding sequence. We identified specific ApA transcript isoforms that were subjected to miRNA mediated gene regulation using degradome sequencing. In this study, we also confirmed a tissue-specific expression pattern for alternate polyadenylated transcripts. The insights from this study highlight the potential role of ApA in regulating the gene expression essential for planarian regeneration. PMID:27489207

  17. Genome-wide transcriptional profiling reveals molecular signatures of secondary xylem differentiation in Populus tomentosa.

    PubMed

    Yang, X H; Li, X G; Li, B L; Zhang, D Q

    2014-11-11

    Wood formation occurs via cell division, primary cell wall and secondary wall formation, and programmed cell death in the vascular cambium. Transcriptional profiling of secondary xylem differentiation is essential for understanding the molecular mechanisms underlying wood formation. Differential gene expression in secondary xylem differentiation of Populus has been previously investigated using cDNA microarray analysis. However, little is known about the molecular mechanisms from a genome-wide perspective. In this study, the Affymetrix poplar genome chips containing 61,413 probes were used to investigate the changes in the transcriptome during secondary xylem differentiation in Chinese white poplar (Populus tomentosa). Two xylem tissues (newly formed and lignified) were sampled for genome-wide transcriptional profiling. In total, 6843 genes (~11%) were identified with differential expression in the two xylem tissues. Many genes involved in cell division, primary wall modification, and cellulose synthesis were preferentially expressed in the newly formed xylem. In contrast, many genes, including 4-coumarate:cinnamate-4-hydroxylase (C4H), 4-coumarate:CoA ligase (4CL), cinnamyl alcohol dehydrogenase (CAD), and caffeoyl CoA 3-O-methyltransferase (CCoAOMT), associated with lignin biosynthesis were more transcribed in the lignified xylem. The two xylem tissues also showed differential expression of genes related to various hormones; thus, the secondary xylem differentiation could be regulated by hormone signaling. Furthermore, many transcription factor genes were preferentially expressed in the lignified xylem, suggesting that wood lignification involves extensive transcription regulation. The genome-wide transcriptional profiling of secondary xylem differentiation could provide additional insights into the molecular basis of wood formation in poplar species.

  18. Assessing statistical significance in multivariable genome wide association analysis

    PubMed Central

    Buzdugan, Laura; Kalisch, Markus; Navarro, Arcadi; Schunk, Daniel; Fehr, Ernst; Bühlmann, Peter

    2016-01-01

    Motivation: Although Genome Wide Association Studies (GWAS) genotype a very large number of single nucleotide polymorphisms (SNPs), the data are often analyzed one SNP at a time. The low predictive power of single SNPs, coupled with the high significance threshold needed to correct for multiple testing, greatly decreases the power of GWAS. Results: We propose a procedure in which all the SNPs are analyzed in a multiple generalized linear model, and we show its use for extremely high-dimensional datasets. Our method yields P-values for assessing significance of single SNPs or groups of SNPs while controlling for all other SNPs and the family wise error rate (FWER). Thus, our method tests whether or not a SNP carries any additional information about the phenotype beyond that available by all the other SNPs. This rules out spurious correlations between phenotypes and SNPs that can arise from marginal methods because the ‘spuriously correlated’ SNP merely happens to be correlated with the ‘truly causal’ SNP. In addition, the method offers a data driven approach to identifying and refining groups of SNPs that jointly contain informative signals about the phenotype. We demonstrate the value of our method by applying it to the seven diseases analyzed by the Wellcome Trust Case Control Consortium (WTCCC). We show, in particular, that our method is also capable of finding significant SNPs that were not identified in the original WTCCC study, but were replicated in other independent studies. Availability and implementation: Reproducibility of our research is supported by the open-source Bioconductor package hierGWAS. Contact: peter.buehlmann@stat.math.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153677

  19. Genome-wide analysis highlights genetic dilution in Algerian sheep.

    PubMed

    Gaouar, S B S; Lafri, M; Djaout, A; El-Bouyahiaoui, R; Bouri, A; Bouchatal, A; Maftah, A; Ciani, E; Da Silva, A B

    2017-03-01

    Algeria represents a reservoir of genetic diversity with local sheep breeds adapted to a large range of environments and showing specific features necessary to deal with harsh conditions. This remarkable diversity results from the traditional management of dryland by pastoralists over centuries. Most of these breeds are poorly productive, and the economic pressure leads farmers to realize anarchic cross-breeding (that is, not carried out in the framework of selection plans) with the hope to increase animal's conformation. In this study, eight of the nine local Algerian sheep breeds (D'men, Hamra, Ouled-Djellal, Rembi, Sidaoun, Tazegzawt, Berber and Barbarine) were investigated for the first time by genome-wide single-nucleotide polymorphism genotyping. At an international scale, Algerian sheep occupied an original position shaped by relations with African and European (particularly Italian) breeds. The strong genetic proximity with Caribbean and Brazilian breeds confirmed that the genetic make-up of these American breeds was largely influenced by the Atlantic slave trade. At a national scale, an alarming genetic dilution of the Berber (a primitive breed) and the Rembi was observed, as a consequence of uncontrolled mating practices with Ouled-Djellal. A similar, though less pronounced, phenomenon was also detected for the Barbarine, another ancestral breed. Genetic originality appeared to be better preserved in Tazegzawt, Hamra, D'men and Sidaoun. These breeds should be given high priority in the establishment of conservation plans to halt their progressive loss. For Berber and Barbarine that also occur in the bordering neighbor countries, urgent concerted transnational actions are needed.

  20. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    SciTech Connect

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMcahon, Katherine D.; Mamlstrom, Rex R.

    2014-05-12

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ecotype model? of diversification, but not previously observed in natural populations.

  1. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    SciTech Connect

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

    2014-06-18

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ‘ecotype model’ of diversification, but not previously observed in natural populations.

  2. Yeast genome-wide screen reveals dissimilar sets of host genes affecting replication of RNA viruses

    PubMed Central

    Panavas, Tadas; Serviene, Elena; Brasher, Jeremy; Nagy, Peter D.

    2005-01-01

    Viruses are devastating pathogens of humans, animals, and plants. To further our understanding of how viruses use the resources of infected cells, we systematically tested the yeast single-gene-knockout library for the effect of each host gene on the replication of tomato bushy stunt virus (TBSV), a positive-strand RNA virus of plants. The genome-wide screen identified 96 host genes whose absence either reduced or increased the accumulation of the TBSV replicon. The identified genes are involved in the metabolism of nucleic acids, lipids, proteins, and other compounds and in protein targeting/transport. Comparison with published genome-wide screens reveals that the replication of TBSV and brome mosaic virus (BMV), which belongs to a different supergroup among plus-strand RNA viruses, is affected by vastly different yeast genes. Moreover, a set of yeast genes involved in vacuolar targeting of proteins and vesicle-mediated transport both affected replication of the TBSV replicon and enhanced the cytotoxicity of the Parkinson's disease-related α-synuclein when this protein was expressed in yeast. In addition, a set of host genes involved in ubiquitin-dependent protein catabolism affected both TBSV replication and the cytotoxicity of a mutant huntingtin protein, a candidate agent in Huntington's disease. This finding suggests that virus infection and disease-causing proteins might use or alter similar host pathways and may suggest connections between chronic diseases and prior virus infection. PMID:15883361

  3. The complex genetics of gait speed: genome-wide meta-analysis approach

    PubMed Central

    Lunetta, Kathryn L.; Smith, Jennifer A.; Eicher, John D.; Vered, Rotem; Deelen, Joris; Arnold, Alice M.; Buchman, Aron S.; Tanaka, Toshiko; Faul, Jessica D.; Nethander, Maria; Fornage, Myriam; Adams, Hieab H.; Matteini, Amy M.; Callisaya, Michele L.; Smith, Albert V.; Yu, Lei; De Jager, Philip L.; Evans, Denis A.; Gudnason, Vilmundur; Hofman, Albert; Pattie, Alison; Corley, Janie; Launer, Lenore J.; Knopman, Davis S.; Parimi, Neeta; Turner, Stephen T.; Bandinelli, Stefania; Beekman, Marian; Gutman, Danielle; Sharvit, Lital; Mooijaart, Simon P.; Liewald, David C.; Houwing-Duistermaat, Jeanine J.; Ohlsson, Claes; Moed, Matthijs; Verlinden, Vincent J.; Mellström, Dan; van der Geest, Jos N.; Karlsson, Magnus; Hernandez, Dena; McWhirter, Rebekah; Liu, Yongmei; Thomson, Russell; Tranah, Gregory J.; Uitterlinden, Andre G.; Weir, David R.; Zhao, Wei; Starr, John M.; Johnson, Andrew D.; Ikram, M. Arfan; Bennett, David A.; Cummings, Steven R.; Deary, Ian J.; Harris, Tamara B.; Kardia, Sharon L. R.; Mosley, Thomas H.; Srikanth, Velandai K.; Windham, Beverly G.; Newman, Ann B.; Walston, Jeremy D.; Davies, Gail; Evans, Daniel S.; Slagboom, Eline P.; Ferrucci, Luigi; Kiel, Douglas P.; Murabito, Joanne M.; Atzmon, Gil

    2017-01-01

    Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. PMID:28077804

  4. Genome-wide genetic diversity, population structure and admixture analysis in African and Asian cattle breeds.

    PubMed

    Edea, Z; Bhuiyan, M S A; Dessie, T; Rothschild, M F; Dadi, H; Kim, K S

    2015-02-01

    Knowledge about genetic diversity and population structure is useful for designing effective strategies to improve the production, management and conservation of farm animal genetic resources. Here, we present a comprehensive genome-wide analysis of genetic diversity, population structure and admixture based on 244 animals sampled from 10 cattle populations in Asia and Africa and genotyped for 69,903 autosomal single-nucleotide polymorphisms (SNPs) mainly derived from the indicine breed. Principal component analysis, STRUCTURE and distance analysis from high-density SNP data clearly revealed that the largest genetic difference occurred between the two domestic lineages (taurine and indicine), whereas Ethiopian cattle populations represent a mosaic of the humped zebu and taurine. Estimation of the genetic influence of zebu and taurine revealed that Ethiopian cattle were characterized by considerable levels of introgression from South Asian zebu, whereas Bangladeshi populations shared very low taurine ancestry. The relationships among Ethiopian cattle populations reflect their history of origin and admixture rather than phenotype-based distinctions. The high within-individual genetic variability observed in Ethiopian cattle represents an untapped opportunity for adaptation to changing environments and for implementation of within-breed genetic improvement schemes. Our results provide a basis for future applications of genome-wide SNP data to exploit the unique genetic makeup of indigenous cattle breeds and to facilitate their improvement and conservation.

  5. Genome-Wide Association in Tomato Reveals 44 Candidate Loci for Fruit Metabolic Traits1[W

    PubMed Central

    Sauvage, Christopher; Segura, Vincent; Bauchet, Guillaume; Stevens, Rebecca; Do, Phuc Thi; Nikoloski, Zoran; Fernie, Alisdair R.; Causse, Mathilde

    2014-01-01

    Genome-wide association studies have been successful in identifying genes involved in polygenic traits and are valuable for crop improvement. Tomato (Solanum lycopersicum) is a major crop and is highly appreciated worldwide for its health value. We used a core collection of 163 tomato accessions composed of S. lycopersicum, S. lycopersicum var cerasiforme, and Solanum pimpinellifolium to map loci controlling variation in fruit metabolites. Fruits were phenotyped for a broad range of metabolites, including amino acids, sugars, and ascorbate. In parallel, the accessions were genotyped with 5,995 single-nucleotide polymorphism markers spread over the whole genome. Genome-wide association analysis was conducted on a large set of metabolic traits that were stable over 2 years using a multilocus mixed model as a general method for mapping complex traits in structured populations and applied to tomato. We detected a total of 44 loci that were significantly associated with a total of 19 traits, including sucrose, ascorbate, malate, and citrate levels. These results not only provide a list of candidate loci to be functionally validated but also a powerful analytical approach for finding genetic variants that can be directly used for crop improvement and deciphering the genetic architecture of complex traits. PMID:24894148

  6. A genome wide survey of SNP variation reveals the genetic structure of sheep breeds.

    PubMed

    Kijas, James W; Townley, David; Dalrymple, Brian P; Heaton, Michael P; Maddox, Jillian F; McGrath, Annette; Wilson, Peter; Ingersoll, Roxann G; McCulloch, Russell; McWilliam, Sean; Tang, Dave; McEwan, John; Cockett, Noelle; Oddy, V Hutton; Nicholas, Frank W; Raadsma, Herman

    2009-01-01

    The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identifying the first genome-wide set of SNP for sheep, we report on levels of genetic variability both within and between a diverse sample of ovine populations. Then, using cluster analysis and the partitioning of genetic variation, we demonstrate sheep are characterised by weak phylogeographic structure, overlapping genetic similarity and generally low differentiation which is consistent with their short evolutionary history. The degree of population substructure was, however, sufficient to cluster individuals based on geographic origin and known breed history. Specifically, African and Asian populations clustered separately from breeds of European origin sampled from Australia, New Zealand, Europe and North America. Furthermore, we demonstrate the presence of stratification within some, but not all, ovine breeds. The results emphasize that careful documentation of genetic structure will be an essential prerequisite when mapping the genetic basis of complex traits. Furthermore, the identification of a subset of SNP able to assign individuals into broad groupings demonstrates even a small panel of markers may be suitable for applications such as traceability.

  7. Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.

    PubMed

    Wexler, Eric M; Rosen, Ezra; Lu, Daning; Osborn, Gregory E; Martin, Elizabeth; Raybould, Helen; Geschwind, Daniel H

    2011-10-04

    Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.

  8. A genome-wide association study reveals a QTL influencing caudal supernumerary teats in Holstein cattle.

    PubMed

    Joerg, H; Meili, C; Ruprecht, O; Bangerter, E; Burren, A; Bigler, A

    2014-12-01

    Supernumerary teats represent a common abnormality of the bovine udder. A genome-wide association study was performed based on the proportion of the occurrence of supernumerary teats in the daughters of 1097 Holstein bulls. The heritability of caudal supernumerary teats without mammary gland in this study was 0.604. The largest proportion of the heritability was attributable to BTA 20. The strongest evidence for association was with five SNPs on chromosome 20, referred to as a QTL. The mode of inheritance at this QTL was dominant. These findings reveal that the occurrence of caudal supernumerary teats without mammary gland in Holstein cattle is influenced by a QTL on chromosome 20 and a polygenic part. The data support the high potential of the SNPs in the QTL region as markers for breeding against caudal supernumerary teats.

  9. Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation

    PubMed Central

    Díaz-Martínez, Laura A; Karamysheva, Zemfira N; Warrington, Ross; Li, Bing; Wei, Shuguang; Xie, Xian-Jin; Roth, Michael G; Yu, Hongtao

    2014-01-01

    The antimitotic anti-cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint-dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31comet actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro-apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest. PMID:25024437

  10. Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function

    PubMed Central

    Fuchsberger, Christian; 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; Hwang, Shih-Jen; Atkinson, Elizabeth J.; Lohman, Kurt; Cornelis, Marilyn C.; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G.; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y.; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; 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 B.; Demirkan, Ayse; Oostra, Ben A.; de Andrade, Mariza; Turner, Stephen T.; Ding, Jingzhong; Andrews, Jeanette S.; Freedman, Barry I.; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H.-Erich; Kolcic, Ivana; 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; Endlich, Karlhans; 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; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K.; Portas, Laura; Ford, Ian; Buckley, Brendan M.; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; 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; 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 C. M.; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M.; Goessling, Wolfram; Chasman, Daniel I.; Kao, W. H. Linda; Fox, Caroline S.

    2012-01-01

    Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. PMID:22479191

  11. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence

    PubMed Central

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Smith, G D; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-01-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case–control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence. PMID:26239293

  12. Genome-Wide Association Mapping for Intelligence in Military Working Dogs: Canine Cohort, Canine Intelligence Assessment Regimen, Genome-Wide Single Nucleotide Polymorphism (SNP) Typing, and Unsupervised Classification Algorithm for Genome-Wide Association Data Analysis

    DTIC Science & Technology

    2011-09-01

    were down-selected and successfully genotyped for whole genome (WG) single nucleotide polymorphism (SNP) markers by means of the Affymetrix Canine...SUBJECT TERMS Military working dog genome-wide association study genetic marker intelligence... marker , intelligence, Canine Intelligence Testing Protocol, classification technique, clustering analysis Technical Report: September 2011 2

  13. Graphic analysis of population structure on genome-wide rheumatoid arthritis data.

    PubMed

    Zhang, Jun; Weng, Chunhua; Niyogi, Partha

    2009-12-15

    Principal-component analysis (PCA) has been used for decades to summarize the human genetic variation across geographic regions and to infer population migration history. Reduction of spurious associations due to population structure is crucial for the success of disease association studies. Recently, PCA has also become a popular method for detecting population structure and correction of population stratification in disease association studies. Inspired by manifold learning, we propose a novel method based on spectral graph theory. Regarding each study subject as a node with suitably defined weights for its edges to close neighbors, one can form a weighted graph. We suggest using the spectrum of the associated graph Laplacian operator, namely, Laplacian eigenfunctions, to infer population structures instead of principal components (PCs). For the whole genome-wide association data for the North American Rheumatoid Arthritis Consortium (NARAC) provided by Genetic Workshop Analysis 16, Laplacian eigenfunctions revealed more meaningful structures of the underlying population than PCA. The proposed method has connection to PCA, and it naturally includes PCA as a special case. Our simple method is computationally fast and is suitable for disease studies at the genome-wide scale.

  14. Genome-wide association study of toxic metals and trace elements reveals novel associations.

    PubMed

    Ng, Esther; Lind, P Monica; Lindgren, Cecilia; Ingelsson, Erik; Mahajan, Anubha; Morris, Andrew; Lind, Lars

    2015-08-15

    The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10(-11), β = -0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10(-14), β = -0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10(-10), β = -1.2 and P = 1.8 × 10(-9), β = -1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity.

  15. Genome-wide association study of toxic metals and trace elements reveals novel associations

    PubMed Central

    Ng, Esther; Lind, P. Monica; Lindgren, Cecilia; Ingelsson, Erik; Mahajan, Anubha; Morris, Andrew; Lind, Lars

    2015-01-01

    The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10−11, β = −0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10−14, β = −0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10−10, β = −1.2 and P = 1.8 × 10−9, β = −1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity. PMID:26025379

  16. Genome-wide classification and expression analysis of MYB transcription factor families in rice and Arabidopsis

    PubMed Central

    2012-01-01

    Background The MYB gene family comprises one of the richest groups of transcription factors in plants. Plant MYB proteins are characterized by a highly conserved MYB DNA-binding domain. MYB proteins are classified into four major groups namely, 1R-MYB, 2R-MYB, 3R-MYB and 4R-MYB based on the number and position of MYB repeats. MYB transcription factors are involved in plant development, secondary metabolism, hormone signal transduction, disease resistance and abiotic stress tolerance. A comparative analysis of MYB family genes in rice and Arabidopsis will help reveal the evolution and function of MYB genes in plants. Results A genome-wide analysis identified at least 155 and 197 MYB genes in rice and Arabidopsis, respectively. Gene structure analysis revealed that MYB family genes possess relatively more number of introns in the middle as compared with C- and N-terminal regions of the predicted genes. Intronless MYB-genes are highly conserved both in rice and Arabidopsis. MYB genes encoding R2R3 repeat MYB proteins retained conserved gene structure with three exons and two introns, whereas genes encoding R1R2R3 repeat containing proteins consist of six exons and five introns. The splicing pattern is similar among R1R2R3 MYB genes in Arabidopsis. In contrast, variation in splicing pattern was observed among R1R2R3 MYB members of rice. Consensus motif analysis of 1kb upstream region (5′ to translation initiation codon) of MYB gene ORFs led to the identification of conserved and over-represented cis-motifs in both rice and Arabidopsis. Real-time quantitative RT-PCR analysis showed that several members of MYBs are up-regulated by various abiotic stresses both in rice and Arabidopsis. Conclusion A comprehensive genome-wide analysis of chromosomal distribution, tandem repeats and phylogenetic relationship of MYB family genes in rice and Arabidopsis suggested their evolution via duplication. Genome-wide comparative analysis of MYB genes and their expression analysis

  17. Genome-wide mRNA and miRNA analysis of peripheral blood mononuclear cells (PBMC) reveals different miRNAs regulating HIV/HCV co-infection.

    PubMed

    Gupta, P; Liu, B; Wu, J Q; Soriano, V; Vispo, E; Carroll, A P; Goldie, B J; Cairns, M J; Saksena, N K

    2014-02-01

    Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common due to shared transmission routes. The genomic basis of HIV/HCV co-infection and its regulation by microRNA (miRNA) is unknown. Therefore, our objective was to investigate genome-wide mRNA expression and its regulation by miRNA in primary PBMCs derived from 27 patients (5 HCV - mono-infected, 5 HIV-mono-infected, 12 HCV/HIV co-infected, and 5 healthy controls). This revealed 27 miRNAs and 476 mRNAs as differentially expressed (DE) in HCV/HIV co-infection when compared to controls (adj p<0.05). Our study shows the first evidence of miRNAs specific for co-infection, several of which are correlated with key gene targets demonstrating functional relationships to pathways in cancer, immune-function, and metabolism. Notable was the up regulation of HCV-specific miR-122 in co-infection (FC>50, p=4.02E-06), which may have clinical/biological implications.

  18. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

    PubMed

    Fox, Caroline S; Liu, Yongmei; White, Charles C; Feitosa, Mary; Smith, Albert V; Heard-Costa, Nancy; Lohman, Kurt; Johnson, Andrew D; Foster, Meredith C; Greenawalt, Danielle M; Griffin, Paula; Ding, Jinghong; Newman, Anne B; Tylavsky, Fran; Miljkovic, Iva; Kritchevsky, Stephen B; Launer, Lenore; Garcia, Melissa; Eiriksdottir, Gudny; Carr, J Jeffrey; Gudnason, Vilmunder; Harris, Tamara B; Cupples, L Adrienne; Borecki, Ingrid B

    2012-01-01

    Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for

  19. Genome-wide identification and expression analysis of MAPK and MAPKK gene family in Malus domestica.

    PubMed

    Zhang, Shizhong; Xu, Ruirui; Luo, Xiaocui; Jiang, Zesheng; Shu, Huairui

    2013-12-01

    MAPK signal transduction modules play crucial roles in regulating many biological processes in plants, which are composed of three classes of hierarchically organized protein kinases, namely MAPKKKs, MAPKKs, and MAPKs. Although genome-wide analysis of this family has been carried out in some species, little is known about MAPK and MAPKK genes in apple (Malus domestica). In this study, a total of 26 putative apple MAPK genes (MdMPKs) and 9 putative apple MAPKK genes (MdMKKs) have been identified and located within the apple genome. Phylogenetic analysis revealed that MdMAPKs and MdMAPKKs could be divided into 4 subfamilies (groups A, B, C and D), respectively. The predicted MdMAPKs and MdMAPKKs were distributed across 13 out of 17 chromosomes with different densities. In addition, analysis of exon-intron junctions and of intron phase inside the predicted coding region of each candidate gene has revealed high levels of conservation within and between phylogenetic groups. According to the microarray and expressed sequence tag (EST) analysis, the different expression patterns indicate that they may play different roles during fruit development and rootstock-scion interaction process. Moreover, MAPK and MAPKK genes were performed expression profile analyses in different tissues (root, stem, leaf, flower and fruit), and all of the selected genes were expressed in at least one of the tissues tested, indicating that the MAPKs and MAPKKs are involved in various aspects of physiological and developmental processes of apple. To our knowledge, this is the first report of a genome-wide analysis of the apple MAPK and MAPKK gene family. This study provides valuable information for understanding the classification and putative functions of the MAPK signal in apple.

  20. Genome Wide Copy Number Analysis of Paediatric Burkitt Lymphoma Using Formalin-Fixed Tissues Reveals a Subset with Gain of Chromosome 13q and Corresponding miRNA Over Expression

    PubMed Central

    Schiffman, Joshua D.; Lorimer, Patrick D.; Rodic, Vladimir; Jahromi, Mona S.; Downie, Jonathan M.; Bayerl, Michael G.; Sanmann, Jennifer N.; Althof, Pamela A.; Sanger, Warren G.; Barnette, Phillip; Perkins, Sherrie L.; Miles, Rodney R.

    2011-01-01

    SUMMARY The majority of paediatric Burkitt lymphoma (pBL) patients that relapse will die of disease, but markers for this high-risk subset are unknown. MYC translocations characterize pBL, but additional genetic changes may relate to prognosis and serve as potential biomarkers. We utilized a molecular inversion probe single nucleotide polymorphism assay to perform high resolution, genome-wide copy number analysis on archival formalin-fixed, paraffin-embedded pBL and germline tissues. We identified copy number abnormalities (CNAs) in 18/28 patients (64%) with a total of 62 CNAs that included 32 gains and 30 copy number losses. We identified 7 recurrent CNAs including 1q gain (7/28, 25%), 13q gain (3/28, 11%), and 17p loss (4/28, 14%). The minimum common amplified region on 13q was at 13q31 and included the MIR17HG (MIR17-92) locus. Samples with this gain had higher levels of MIR17 RNA and showed a tendency for early relapse. Tumour-specific uniparental disomy was identified in 32% of cases and usually was recurrent. These results demonstrate that high-resolution copy number analysis can be performed on archival lymphoma tissue specimens, which has significance for the study of rare diseases. PMID:21981616

  1. Genome-wide analysis of the MYB transcription factor superfamily in soybean

    PubMed Central

    2012-01-01

    Background The MYB superfamily constitutes one of the most abundant groups of transcription factors described in plants. Nevertheless, their functions appear to be highly diverse and remain rather unclear. To date, no genome-wide characterization of this gene family has been conducted in a legume species. Here we report the first genome-wide analysis of the whole MYB superfamily in a legume species, soybean (Glycine max), including the gene structures, phylogeny, chromosome locations, conserved motifs, and expression patterns, as well as a comparative genomic analysis with Arabidopsis. Results A total of 244 R2R3-MYB genes were identified and further classified into 48 subfamilies based on a phylogenetic comparative analysis with their putative orthologs, showed both gene loss and duplication events. The phylogenetic analysis showed that most characterized MYB genes with similar functions are clustered in the same subfamily, together with the identification of orthologs by synteny analysis, functional conservation among subgroups of MYB genes was strongly indicated. The phylogenetic relationships of each subgroup of MYB genes were well supported by the highly conserved intron/exon structures and motifs outside the MYB domain. Synonymous nucleotide substitution (dN/dS) analysis showed that the soybean MYB DNA-binding domain is under strong negative selection. The chromosome distribution pattern strongly indicated that genome-wide segmental and tandem duplication contribute to the expansion of soybean MYB genes. In addition, we found that ~ 4% of soybean R2R3-MYB genes had undergone alternative splicing events, producing a variety of transcripts from a single gene, which illustrated the extremely high complexity of transcriptome regulation. Comparative expression profile analysis of R2R3-MYB genes in soybean and Arabidopsis revealed that MYB genes play conserved and various roles in plants, which is indicative of a divergence in function. Conclusions In this

  2. A Genome Wide Survey of SNP Variation Reveals the Genetic Structure of Sheep Breeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identi...

  3. Human genome-wide RNAi screen reveals host factors required for enterovirus 71 replication

    PubMed Central

    Wu, Kan Xing; Phuektes, Patchara; Kumar, Pankaj; Goh, Germaine Yen Lin; Moreau, Dimitri; Chow, Vincent Tak Kwong; Bard, Frederic; Chu, Justin Jang Hann

    2016-01-01

    Enterovirus 71 (EV71) is a neurotropic enterovirus without antivirals or vaccine, and its host-pathogen interactions remain poorly understood. Here we use a human genome-wide RNAi screen to identify 256 host factors involved in EV71 replication in human rhabdomyosarcoma cells. Enrichment analyses reveal overrepresentation in processes like mitotic cell cycle and transcriptional regulation. We have carried out orthogonal experiments to characterize the roles of selected factors involved in cell cycle regulation and endoplasmatic reticulum-associated degradation. We demonstrate nuclear egress of CDK6 in EV71 infected cells, and identify CDK6 and AURKB as resistance factors. NGLY1, which co-localizes with EV71 replication complexes at the endoplasmatic reticulum, supports EV71 replication. We confirm importance of these factors for EV71 replication in a human neuronal cell line and for coxsackievirus A16 infection. A small molecule inhibitor of NGLY1 reduces EV71 replication. This study provides a comprehensive map of EV71 host factors and reveals potential antiviral targets. PMID:27748395

  4. Genome-Wide Transcriptome Analysis of Cadmium Stress in Rice

    PubMed Central

    Oono, Youko; Yazawa, Takayuki; Kanamori, Hiroyuki; Sasaki, Harumi; Mori, Satomi; Handa, Hirokazu; Matsumoto, Takashi

    2016-01-01

    Rice growth is severely affected by toxic concentrations of the nonessential heavy metal cadmium (Cd). To elucidate the molecular basis of the response to Cd stress, we performed mRNA sequencing of rice following our previous study on exposure to high concentrations of Cd (Oono et al., 2014). In this study, rice plants were hydroponically treated with low concentrations of Cd and approximately 211 million sequence reads were mapped onto the IRGSP-1.0 reference rice genome sequence. Many genes, including some identified under high Cd concentration exposure in our previous study, were found to be responsive to low Cd exposure, with an average of about 11,000 transcripts from each condition. However, genes expressed constitutively across the developmental course responded only slightly to low Cd concentrations, in contrast to their clear response to high Cd concentration, which causes fatal damage to rice seedlings according to phenotypic changes. The expression of metal ion transporter genes tended to correlate with Cd concentration, suggesting the potential of the RNA-Seq strategy to reveal novel Cd-responsive transporters by analyzing gene expression under different Cd concentrations. This study could help to develop novel strategies for improving tolerance to Cd exposure in rice and other cereal crops. PMID:27034955

  5. Genome-wide analysis of promoter architecture in Drosophila melanogaster

    SciTech Connect

    Hoskins, Roger A.; Landolin, Jane M.; Brown, James B.; Sandler, Jeremy E.; Takahashi, Hazuki; Lassmann, Timo; Yu, Charles; Booth, Benjamin W.; Zhang, Dayu; Wan, Kenneth H.; Yang, Li; Boley, Nathan; Andrews, Justen; Kaufman, Thomas C.; Graveley, Brenton R.; Bickel, Peter J.; Carninci, Piero; Carlson, Joseph W.; Celniker, Susan E.

    2010-10-20

    Core promoters are critical regions for gene regulation in higher eukaryotes. However, the boundaries of promoter regions, the relative rates of initiation at the transcription start sites (TSSs) distributed within them, and the functional significance of promoter architecture remain poorly understood. We produced a high-resolution map of promoters active in the Drosophila melanogaster embryo by integrating data from three independent and complementary methods: 21 million cap analysis of gene expression (CAGE) tags, 1.2 million RNA ligase mediated rapid amplification of cDNA ends (RLMRACE) reads, and 50,000 cap-trapped expressed sequence tags (ESTs). We defined 12,454 promoters of 8037 genes. Our analysis indicates that, due to non-promoter-associated RNA background signal, previous studies have likely overestimated the number of promoter-associated CAGE clusters by fivefold. We show that TSS distributions form a complex continuum of shapes, and that promoters active in the embryo and adult have highly similar shapes in 95% of cases. This suggests that these distributions are generally determined by static elements such as local DNA sequence and are not modulated by dynamic signals such as histone modifications. Transcription factor binding motifs are differentially enriched as a function of promoter shape, and peaked promoter shape is correlated with both temporal and spatial regulation of gene expression. Our results contribute to the emerging view that core promoters are functionally diverse and control patterning of gene expression in Drosophila and mammals.

  6. Genome-wide analysis of TCP family in tobacco.

    PubMed

    Chen, L; Chen, Y Q; Ding, A M; Chen, H; Xia, F; Wang, W F; Sun, Y H

    2016-05-23

    The TCP family is a transcription factor family, members of which are extensively involved in plant growth and development as well as in signal transduction in the response against many physiological and biochemical stimuli. In the present study, 61 TCP genes were identified in tobacco (Nicotiana tabacum) genome. Bioinformatic methods were employed for predicting and analyzing the gene structure, gene expression, phylogenetic analysis, and conserved domains of TCP proteins in tobacco. The 61 NtTCP genes were divided into three diverse groups, based on the division of TCP genes in tomato and Arabidopsis, and the results of the conserved domain and sequence analyses further confirmed the classification of the NtTCP genes. The expression pattern of NtTCP also demonstrated that majority of these genes play important roles in all the tissues, while some special genes exercise their functions only in specific tissues. In brief, the comprehensive and thorough study of the TCP family in other plants provides sufficient resources for studying the structure and functions of TCPs in tobacco.

  7. Genome-Wide Methylome Analyses Reveal Novel Epigenetic Regulation Patterns in Schizophrenia and Bipolar Disorder

    PubMed Central

    Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A.; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Jerez Magaña, Alvaro Antonio; Rubin, Lewis P.; Li, Xia; Xu, Chun

    2015-01-01

    Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3′-UTRs and 5′-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3′-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders. PMID:25734057

  8. Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.

    PubMed

    Li, Yongsheng; Camarillo, Cynthia; Xu, Juan; Arana, Tania Bedard; Xiao, Yun; Zhao, Zheng; Chen, Hong; Ramirez, Mercedes; Zavala, Juan; Escamilla, Michael A; Armas, Regina; Mendoza, Ricardo; Ontiveros, Alfonso; Nicolini, Humberto; Magaña, Alvaro Antonio Jerez; Rubin, Lewis P; Li, Xia; Xu, Chun

    2015-01-01

    Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

  9. Dynamics of oscillatory phenotypes in S. cerevisiae reveal a network of genome-wide transcriptional oscillators

    PubMed Central

    Chin, Shwe L.; Marcus, Ian M.; Klevecz, Robert R.; Li, Caroline M.

    2012-01-01

    Genetic and environmental factors are well-studied influences on phenotype; however, time is a variable that is rarely considered when studying changes in cellular phenotype. Time-resolved microarray data revealed genome-wide transcriptional oscillation in a yeast continuous culture system with ~2 and ~4 h periods. We mapped the global patterns of transcriptional oscillations into a 3D map to represent different cellular phenotypes of redox cycles. This map shows the dynamic nature of gene expression in that transcripts are ordered and coupled to each other through time and concentration space. Although cells differed in oscillation periods, transcripts involved in certain processes were conserved in a deterministic way. When oscillation period lengthened, the peak to trough ratio of transcripts increased and the fraction of cells in the unbudded (G0/G1) phase of the cell division cycle increased. Decreasing the glucose level in the culture media was one way to increase the redox cycle, possibly from changes in metabolic flux. The period may be responding to lower glucose levels by increasing the fraction of cells in G1 and reducing S-phase gating so that cells can spend more time in catabolic processes. Our results support that gene transcripts are coordinated with metabolic functions and the cell division cycle. PMID:22289124

  10. Genome-wide linkage analysis and association study identifies loci for polydactyly in chickens.

    PubMed

    Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie

    2014-04-21

    Polydactyly occurs in some chicken breeds, but the molecular mechanism remains incompletely understood. Combined genome-wide linkage analysis and association study (GWAS) for chicken polydactyly helps identify loci or candidate genes for the trait and potentially provides further mechanistic understanding of this phenotype in chickens and perhaps other species. The linkage analysis and GWAS for polydactyly was conducted using an F2 population derived from Beijing-You chickens and commercial broilers. The results identified two QTLs through linkage analysis and seven single-nucleotide polymorphisms (SNPs) through GWAS, associated with the polydactyly trait. One QTL located at 35 cM on the GGA2 was significant at the 1% genome-wise level and another QTL at the 1% chromosome-wide significance level was detected at 39 cM on GGA19. A total of seven SNPs, four of 5% genome-wide significance (P < 2.98 × 10(-6)) and three of suggestive significance (5.96 × 10(-5)) were identified, including two SNPs (GGaluGA132178 and Gga_rs14135036) in the QTL on GGA2. Of the identified SNPs, the eight nearest genes were sonic hedgehog (SHH), limb region 1 homolog (mouse) (LMBR1), dipeptidyl-peptidase 6, transcript variant 3 (DPP6), thyroid-stimulating hormone, beta (TSHB), sal-like 4 (Drosophila) (SALL4), par-6 partitioning defective 6 homolog beta (Caenorhabditis elegans) (PARD6B), coenzyme Q5 (COQ5), and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, etapolypeptide (YWHAH). The GWAS supports earlier reports of the importance of SHH and LMBR1 as regulating genes for polydactyly in chickens and other species, and identified others, most of which have not previously been associated with limb development. The genes and associated SNPs revealed here provide detailed information for further exploring the molecular and developmental mechanisms underlying polydactyly.

  11. Genome-wide association study reveals putative regulators of bioenergy traits in Populus deltoides

    DOE PAGES

    Fahrenkrog, Annette M.; Neves, Leandro G.; Resende, Jr., Marcio F. R.; ...

    2016-09-06

    Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genesmore » in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. Lastly, these polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.« less

  12. Genome-wide association study reveals putative regulators of bioenergy traits in Populus deltoides.

    PubMed

    Fahrenkrog, Annette M; Neves, Leandro G; Resende, Márcio F R; Vazquez, Ana I; de Los Campos, Gustavo; Dervinis, Christopher; Sykes, Robert; Davis, Mark; Davenport, Ruth; Barbazuk, William B; Kirst, Matias

    2017-01-01

    Genome-wide association studies (GWAS) have been used extensively to dissect the genetic regulation of complex traits in plants. These studies have focused largely on the analysis of common genetic variants despite the abundance of rare polymorphisms in several species, and their potential role in trait variation. Here, we conducted the first GWAS in Populus deltoides, a genetically diverse keystone forest species in North America and an important short rotation woody crop for the bioenergy industry. We searched for associations between eight growth and wood composition traits, and common and low-frequency single-nucleotide polymorphisms detected by targeted resequencing of 18 153 genes in a population of 391 unrelated individuals. To increase power to detect associations with low-frequency variants, multiple-marker association tests were used in combination with single-marker association tests. Significant associations were discovered for all phenotypes and are indicative that low-frequency polymorphisms contribute to phenotypic variance of several bioenergy traits. Our results suggest that both common and low-frequency variants need to be considered for a comprehensive understanding of the genetic regulation of complex traits, particularly in species that carry large numbers of rare polymorphisms. These polymorphisms may be critical for the development of specialized plant feedstocks for bioenergy.

  13. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders

    PubMed Central

    Miller, Frederick W.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy; Isenberg, David A.; Chinoy, Hector; Ollier, William E. R.; O’Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.

    2014-01-01

    Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID:23983088

  14. Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

    PubMed Central

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E.; Heath, Emma; Smedley, Damian P.; Estabel, Jeanne; Sunter, David; DiTommaso, Tia; White, Jacqueline K.; Ramirez-Solis, Ramiro; Smyth, Ian; Steel, Karen P.; Watt, Fiona M.

    2014-01-01

    Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. PMID:24721909

  15. Genome-wide efficient mixed-model analysis for association studies.

    PubMed

    Zhou, Xiang; Stephens, Matthew

    2012-06-17

    Linear mixed models have attracted considerable attention recently as a powerful and effective tool for accounting for population stratification and relatedness in genetic association tests. However, existing methods for exact computation of standard test statistics are computationally impractical for even moderate-sized genome-wide association studies. To address this issue, several approximate methods have been proposed. Here, we present an efficient exact method, which we refer to as genome-wide efficient mixed-model association (GEMMA), that makes approximations unnecessary in many contexts. This method is approximately n times faster than the widely used exact method known as efficient mixed-model association (EMMA), where n is the sample size, making exact genome-wide association analysis computationally practical for large numbers of individuals.

  16. Genome-Wide Analyses Reveal a Role for Peptide Hormones in Planarian Germline Development

    PubMed Central

    Collins, James J.; Hou, Xiaowen; Romanova, Elena V.; Lambrus, Bramwell G.; Miller, Claire M.; Saberi, Amir; Sweedler, Jonathan V.; Newmark, Phillip A.

    2010-01-01

    Bioactive peptides (i.e., neuropeptides or peptide hormones) represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites. PMID:20967238

  17. Genome-wide Identification and Structural, Functional and Evolutionary Analysis of WRKY Components of Mulberry

    PubMed Central

    Baranwal, Vinay Kumar; Negi, Nisha; Khurana, Paramjit

    2016-01-01

    Mulberry is known to be sensitive to several biotic and abiotic stresses, which in turn have a direct impact on the yield of silk, because it is the sole food source for the silk worm. WRKYs are a family of transcription factors, which play an important role in combating various biotic and abiotic stresses. In this study, we identified 54 genes with conserved WRKY motifs in the Morus notabilis genome. Motif searches coupled with a phylogenetic analysis revealed seven sub-groups as well as the absence of members of Group Ib in mulberry. Analyses of the 2K upstream region in addition to a gene ontology terms enrichment analysis revealed putative functions of mulberry WRKYs under biotic and abiotic stresses. An RNA-seq-based analysis showed that several of the identified WRKYs have shown preferential expression in the leaf, bark, root, male flower, and winter bud of M. notabilis. Finally, expression analysis by qPCR under different stress and hormone treatments revealed genotype-specific responses. Taken together, our results briefs about the genome-wide identification of WRKYs as well as their differential response to stresses and hormones. Importantly, these data can also be utilized to identify potential molecular targets for conferring tolerance to various stresses in mulberry. PMID:27477686

  18. Genome-wide Identification and Structural, Functional and Evolutionary Analysis of WRKY Components of Mulberry.

    PubMed

    Baranwal, Vinay Kumar; Negi, Nisha; Khurana, Paramjit

    2016-08-01

    Mulberry is known to be sensitive to several biotic and abiotic stresses, which in turn have a direct impact on the yield of silk, because it is the sole food source for the silk worm. WRKYs are a family of transcription factors, which play an important role in combating various biotic and abiotic stresses. In this study, we identified 54 genes with conserved WRKY motifs in the Morus notabilis genome. Motif searches coupled with a phylogenetic analysis revealed seven sub-groups as well as the absence of members of Group Ib in mulberry. Analyses of the 2K upstream region in addition to a gene ontology terms enrichment analysis revealed putative functions of mulberry WRKYs under biotic and abiotic stresses. An RNA-seq-based analysis showed that several of the identified WRKYs have shown preferential expression in the leaf, bark, root, male flower, and winter bud of M. notabilis. Finally, expression analysis by qPCR under different stress and hormone treatments revealed genotype-specific responses. Taken together, our results briefs about the genome-wide identification of WRKYs as well as their differential response to stresses and hormones. Importantly, these data can also be utilized to identify potential molecular targets for conferring tolerance to various stresses in mulberry.

  19. Sympatric speciation revealed by genome-wide divergence in the blind mole rat Spalax

    PubMed Central

    Li, Kexin; Hong, Wei; Jiao, Hengwu; Wang, Guo-Dong; Rodriguez, Karl A.; Buffenstein, Rochelle; Zhao, Yang; Nevo, Eviatar; Zhao, Huabin

    2015-01-01

    Sympatric speciation (SS), i.e., speciation within a freely breeding population or in contiguous populations, was first proposed by Darwin [Darwin C (1859) On the Origins of Species by Means of Natural Selection] and is still controversial despite theoretical support [Gavrilets S (2004) Fitness Landscapes and the Origin of Species (MPB-41)] and mounting empirical evidence. Speciation of subterranean mammals generally, including the genus Spalax, was considered hitherto allopatric, whereby new species arise primarily through geographic isolation. Here we show in Spalax a case of genome-wide divergence analysis in mammals, demonstrating that SS in continuous populations, with gene flow, encompasses multiple widespread genomic adaptive complexes, associated with the sharply divergent ecologies. The two abutting soil populations of S. galili in northern Israel habituate the ancestral Senonian chalk population and abutting derivative Plio-Pleistocene basalt population. Population divergence originated ∼0.2–0.4 Mya based on both nuclear and mitochondrial genome analyses. Population structure analysis displayed two distinctly divergent clusters of chalk and basalt populations. Natural selection has acted on 300+ genes across the genome, diverging Spalax chalk and basalt soil populations. Gene ontology enrichment analysis highlights strong but differential soil population adaptive complexes: in basalt, sensory perception, musculature, metabolism, and energetics, and in chalk, nutrition and neurogenetics are outstanding. Population differentiation of chemoreceptor genes suggests intersoil population's mate and habitat choice substantiating SS. Importantly, distinctions in protein degradation may also contribute to SS. Natural selection and natural genetic engineering [Shapiro JA (2011) Evolution: A View From the 21st Century] overrule gene flow, evolving divergent ecological adaptive complexes. Sharp ecological divergences abound in nature; therefore, SS appears to be

  20. Sympatric speciation revealed by genome-wide divergence in the blind mole rat Spalax.

    PubMed

    Li, Kexin; Hong, Wei; Jiao, Hengwu; Wang, Guo-Dong; Rodriguez, Karl A; Buffenstein, Rochelle; Zhao, Yang; Nevo, Eviatar; Zhao, Huabin

    2015-09-22

    Sympatric speciation (SS), i.e., speciation within a freely breeding population or in contiguous populations, was first proposed by Darwin [Darwin C (1859) On the Origins of Species by Means of Natural Selection] and is still controversial despite theoretical support [Gavrilets S (2004) Fitness Landscapes and the Origin of Species (MPB-41)] and mounting empirical evidence. Speciation of subterranean mammals generally, including the genus Spalax, was considered hitherto allopatric, whereby new species arise primarily through geographic isolation. Here we show in Spalax a case of genome-wide divergence analysis in mammals, demonstrating that SS in continuous populations, with gene flow, encompasses multiple widespread genomic adaptive complexes, associated with the sharply divergent ecologies. The two abutting soil populations of S. galili in northern Israel habituate the ancestral Senonian chalk population and abutting derivative Plio-Pleistocene basalt population. Population divergence originated ∼0.2-0.4 Mya based on both nuclear and mitochondrial genome analyses. Population structure analysis displayed two distinctly divergent clusters of chalk and basalt populations. Natural selection has acted on 300+ genes across the genome, diverging Spalax chalk and basalt soil populations. Gene ontology enrichment analysis highlights strong but differential soil population adaptive complexes: in basalt, sensory perception, musculature, metabolism, and energetics, and in chalk, nutrition and neurogenetics are outstanding. Population differentiation of chemoreceptor genes suggests intersoil population's mate and habitat choice substantiating SS. Importantly, distinctions in protein degradation may also contribute to SS. Natural selection and natural genetic engineering [Shapiro JA (2011) Evolution: A View From the 21st Century] overrule gene flow, evolving divergent ecological adaptive complexes. Sharp ecological divergences abound in nature; therefore, SS appears to be an

  1. 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

  2. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

    PubMed

    Ali Hassan, Nur Zarina; Mokhtar, Norfilza Mohd; Kok Sin, Teow; Mohamed Rose, Isa; Sagap, Ismail; Harun, Roslan; Jamal, Rahman

    2014-01-01

    Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV) and gene expression in colorectal cancer (CRC) samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  3. A genome-wide analysis of the expansin genes in Malus × Domestica.

    PubMed

    Zhang, Shizhong; Xu, Ruirui; Gao, Zheng; Chen, Changtian; Jiang, Zesheng; Shu, Huairui

    2014-04-01

    Expansins were first identified as cell wall-loosening proteins; they are involved in regulating cell expansion, fruits softening and many other physiological processes. However, our knowledge about the expansin family members and their evolutionary relationships in fruit trees, such as apple, is limited. In this study, we identified 41 members of the expansin gene family in the genome of apple (Malus × Domestica L. Borkh). Phylogenetic analysis revealed that expansin genes in apple could be divided into four subfamilies according to their gene structures and protein motifs. By phylogenetic analysis of the expansins in five plants (Arabidopsis, rice, poplar, grape and apple), the expansins were divided into 17 subgroups. Our gene duplication analysis revealed that whole-genome and chromosomal-segment duplications contributed to the expansion of Mdexpansins. The microarray and expressed sequence tag (EST) data showed that 34 Mdexpansin genes could be divided into five groups by the EST analysis; they may also play different roles during fruit development. An expression model for MdEXPA16 and MdEXPA20 showed their potential role in developing fruit. Overall, our study provides useful data and novel insights into the functions and regulatory mechanisms of the expansin genes in apple, as well as their evolution and divergence. As the first step towards genome-wide analysis of the expansin genes in apple, our results have established a solid foundation for future studies on the function of the expansin genes in fruit development.

  4. Genome-wide Association Analysis of Kernel Weight in Hard Winter Wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wheat kernel weight is an important and heritable component of wheat grain yield and a key predictor of flour extraction. Genome-wide association analysis was conducted to identify genomic regions associated with kernel weight and kernel weight environmental response in 8 trials of 299 hard winter ...

  5. Methods for meta-analysis of genome-wide association studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. For increasing N, results from different GWA can be combined in a meta-analysis (MA-...

  6. Meta-analysis of genome wide association studies for pork quality traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Given the importance of pork quality in the meat processing industry, genome-wide association studies were performed for eight meat quality traits and also, a meta-analysis (MA) of GWA was implemented combining independent results from pig populations. Data from three pig datasets (USMARC, Commercia...

  7. Combining Image Analysis, Genome Wide Association Studies and Different Field Trials to Reveal Stable Genetic Regions Related to Panicle Architecture and the Number of Spikelets per Panicle in Rice

    PubMed Central

    Rebolledo, Maria C.; Peña, Alexandra L.; Duitama, Jorge; Cruz, Daniel F.; Dingkuhn, Michael; Grenier, Cecile; Tohme, Joe

    2016-01-01

    Number of spikelets per panicle (NSP) is a key trait to increase yield potential in rice (O. sativa). The architecture of the rice inflorescence which is mainly determined by the length and number of primary (PBL and PBN) and secondary (SBL and SBN) branches can influence NSP. Although several genes controlling panicle architecture and NSP in rice have been identified, there is little evidence of (i) the genetic control of panicle architecture and NSP in different environments and (ii) the presence of stable genetic associations with panicle architecture across environments. This study combines image phenotyping of 225 accessions belonging to a genetic diversity array of indica rice grown under irrigated field condition in two different environments and Genome Wide Association Studies (GWAS) based on the genotyping of the diversity panel, providing 83,374 SNPs. Accessions sown under direct seeding in one environement had reduced Panicle Length (PL), NSP, PBN, PBL, SBN, and SBL compared to those established under transplanting in the second environment. Across environments, NSP was significantly and positively correlated with PBN, SBN and PBL. However, the length of branches (PBL and SBL) was not significantly correlated with variables related to number of branches (PBN and SBN), suggesting independent genetic control. Twenty- three GWAS sites were detected with P ≤ 1.0E-04 and 27 GWAS sites with p ≤ 5.9E−04. We found 17 GWAS sites related to NSP, 10 for PBN and 11 for SBN, 7 for PBL and 11 for SBL. This study revealed new regions related to NSP, but only three associations were related to both branching number (PBN and SBN) and NSP. Two GWAS sites associated with SBL and SBN were stable across contrasting environments and were not related to genes previously reported. The new regions reported in this study can help improving NSP in rice for both direct seeded and transplanted conditions. The integrated approach of high-throughput phenotyping, multi

  8. CNV-based genome wide association study reveals additional variants contributing to meat quality in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pork quality is important both to the meat processing industry and consumers’ purchasing attitudes. Copy number variation (CNV) is a burgeoning kind of variant that may influence meat quality. Herein, a genome-wide association study (GWAS) was performed between CNVs and meat quality traits in swine....

  9. Genome-Wide Binding of Posterior HOXA/D Transcription Factors Reveals Subgrouping and Association with CTCF

    PubMed Central

    Haas, Stefan; Janetzki, Catrin; González Navarrete, Irene; Mundlos, Stefan

    2017-01-01

    Homeotic genes code for key transcription factors (HOX-TFs) that pattern the animal body plan. During embryonic development, Hox genes are expressed in overlapping patterns and function in a partially redundant manner. In vitro biochemical screens probing the HOX-TF sequence specificity revealed largely overlapping sequence preferences, indicating that co-factors might modulate the biological function of HOX-TFs. However, due to their overlapping expression pattern, high protein homology, and insufficiently specific antibodies, little is known about their genome-wide binding preferences. In order to overcome this problem, we virally expressed tagged versions of limb-expressed posterior HOX genes (HOXA9-13, and HOXD9-13) in primary chicken mesenchymal limb progenitor cells (micromass). We determined the effect of each HOX-TF on cellular differentiation (chondrogenesis) and gene expression and found that groups of HOX-TFs induce distinct regulatory programs. We used ChIP-seq to determine their individual genome-wide binding profiles and identified between 12,721 and 28,572 binding sites for each of the nine HOX-TFs. Principal Component Analysis (PCA) of binding profiles revealed that the HOX-TFs are clustered in two subgroups (Group 1: HOXA/D9, HOXA/D10, HOXD12, and HOXA13 and Group 2: HOXA/D11 and HOXD13), which are characterized by differences in their sequence specificity and by the presence of cofactor motifs. Specifically, we identified CTCF binding sites in Group 1, indicating that this subgroup of HOX-proteins cooperates with CTCF. We confirmed this interaction by an independent biological assay (Proximity Ligation Assay) and demonstrated that CTCF is a novel HOX cofactor that specifically associates with Group 1 HOX-TFs, pointing towards a possible interplay between HOX-TFs and chromatin architecture. PMID:28103242

  10. On the analysis of a repeated measure design in genome-wide association analysis.

    PubMed

    Lee, Young; Park, Suyeon; Moon, Sanghoon; Lee, Juyoung; Elston, Robert C; Lee, Woojoo; Won, Sungho

    2014-11-28

    Longitudinal data enables detecting the effect of aging/time, and as a repeated measures design is statistically more efficient compared to cross-sectional data if the correlations between repeated measurements are not large. In particular, when genotyping cost is more expensive than phenotyping cost, the collection of longitudinal data can be an efficient strategy for genetic association analysis. However, in spite of these advantages, genome-wide association studies (GWAS) with longitudinal data have rarely been analyzed taking this into account. In this report, we calculate the required sample size to achieve 80% power at the genome-wide significance level for both longitudinal and cross-sectional data, and compare their statistical efficiency. Furthermore, we analyzed the GWAS of eight phenotypes with three observations on each individual in the Korean Association Resource (KARE). A linear mixed model allowing for the correlations between observations for each individual was applied to analyze the longitudinal data, and linear regression was used to analyze the first observation on each individual as cross-sectional data. We found 12 novel genome-wide significant disease susceptibility loci that were then confirmed in the Health Examination cohort, as well as some significant interactions between age/sex and SNPs.

  11. Genome-Wide Analysis of the Aquaporin Gene Family in Chickpea (Cicer arietinum L.).

    PubMed

    Deokar, Amit A; Tar'an, Bunyamin

    2016-01-01

    Aquaporins (AQPs) are essential membrane proteins that play critical role in the transport of water and many other solutes across cell membranes. In this study, a comprehensive genome-wide analysis identified 40 AQP genes in chickpea (Cicer arietinum L.). A complete overview of the chickpea AQP (CaAQP) gene family is presented, including their chromosomal locations, gene structure, phylogeny, gene duplication, conserved functional motifs, gene expression, and conserved promoter motifs. To understand AQP's evolution, a comparative analysis of chickpea AQPs with AQP orthologs from soybean, Medicago, common bean, and Arabidopsis was performed. The chickpea AQP genes were found on all of the chickpea chromosomes, except chromosome 7, with a maximum of six genes on chromosome 6, and a minimum of one gene on chromosome 5. Gene duplication analysis indicated that the expansion of chickpea AQP gene family might have been due to segmental and tandem duplications. CaAQPs were grouped into four subfamilies including 15 NOD26-like intrinsic proteins (NIPs), 13 tonoplast intrinsic proteins (TIPs), eight plasma membrane intrinsic proteins (PIPs), and four small basic intrinsic proteins (SIPs) based on sequence similarities and phylogenetic position. Gene structure analysis revealed a highly conserved exon-intron pattern within CaAQP subfamilies supporting the CaAQP family classification. Functional prediction based on conserved Ar/R selectivity filters, Froger's residues, and specificity-determining positions suggested wide differences in substrate specificity among the subfamilies of CaAQPs. Expression analysis of the AQP genes indicated that some of the genes are tissue-specific, whereas few other AQP genes showed differential expression in response to biotic and abiotic stresses. Promoter profiling of CaAQP genes for conserved cis-acting regulatory elements revealed enrichment of cis-elements involved in circadian control, light response, defense and stress responsiveness

  12. Genome-Wide Analysis of the Aquaporin Gene Family in Chickpea (Cicer arietinum L.)

    PubMed Central

    Deokar, Amit A.; Tar'an, Bunyamin

    2016-01-01

    Aquaporins (AQPs) are essential membrane proteins that play critical role in the transport of water and many other solutes across cell membranes. In this study, a comprehensive genome-wide analysis identified 40 AQP genes in chickpea (Cicer arietinum L.). A complete overview of the chickpea AQP (CaAQP) gene family is presented, including their chromosomal locations, gene structure, phylogeny, gene duplication, conserved functional motifs, gene expression, and conserved promoter motifs. To understand AQP's evolution, a comparative analysis of chickpea AQPs with AQP orthologs from soybean, Medicago, common bean, and Arabidopsis was performed. The chickpea AQP genes were found on all of the chickpea chromosomes, except chromosome 7, with a maximum of six genes on chromosome 6, and a minimum of one gene on chromosome 5. Gene duplication analysis indicated that the expansion of chickpea AQP gene family might have been due to segmental and tandem duplications. CaAQPs were grouped into four subfamilies including 15 NOD26-like intrinsic proteins (NIPs), 13 tonoplast intrinsic proteins (TIPs), eight plasma membrane intrinsic proteins (PIPs), and four small basic intrinsic proteins (SIPs) based on sequence similarities and phylogenetic position. Gene structure analysis revealed a highly conserved exon-intron pattern within CaAQP subfamilies supporting the CaAQP family classification. Functional prediction based on conserved Ar/R selectivity filters, Froger's residues, and specificity-determining positions suggested wide differences in substrate specificity among the subfamilies of CaAQPs. Expression analysis of the AQP genes indicated that some of the genes are tissue-specific, whereas few other AQP genes showed differential expression in response to biotic and abiotic stresses. Promoter profiling of CaAQP genes for conserved cis-acting regulatory elements revealed enrichment of cis-elements involved in circadian control, light response, defense and stress responsiveness

  13. Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

    PubMed Central

    Ludwig, Kerstin U.; Ahmed, Syeda Tasnim; Böhmer, Anne C.; Sangani, Nasim Bahram; Varghese, Sheryil; Klamt, Johanna; Schuenke, Hannah; Gültepe, Pinar; Hofmann, Andrea; Rubini, Michele; Aldhorae, Khalid Ahmed; Steegers-Theunissen, Regine P.; Rojas-Martinez, Augusto; Reiter, Rudolf; Borck, Guntram; Knapp, Michael; Nakatomi, Mitsushiro; Graf, Daniel; Mangold, Elisabeth; Peters, Heiko

    2016-01-01

    Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions. PMID:26968009

  14. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

    PubMed Central

    Zhang, Cathy R.; Adib-Samii, Poneh; Devan, William J.; Parsons, Owen E.; Lanfranconi, Silvia; Gregory, Sarah; Cloonan, Lisa; Falcone, Guido J.; Radmanesh, Farid; Fitzpatrick, Kaitlin; Kanakis, Allison; Barrick, Thomas R.; Moynihan, Barry; Lewis, Cathryn M.; Boncoraglio, Giorgio B.; Lemmens, Robin; Thijs, Vincent; Sudlow, Cathie; Wardlaw, Joanna; Rothwell, Peter M.; Meschia, James F.; Worrall, Bradford B.; Levi, Christopher; Bevan, Steve; Furie, Karen L.; Dichgans, Martin; Rosand, Jonathan; Markus, Hugh S.; Rost, Natalia

    2016-01-01

    Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10−6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10−8; rs941898 [EVL], p = 4.0 × 10−8; rs962888 [C1QL1], p = 1.1 × 10−8; rs9515201 [COL4A2], p = 6.9 × 10−9). Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease. PMID:26674333

  15. A genome-wide survey reveals a deletion polymorphism associated with resistance to gastrointestinal nematodes in Angus cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gastrointestinal (GI) nematode infections are a worldwide threat to animal health and production. In this study, we performed a genome-wide association study between copy number variations (CNV) and resistance to GI nematodes in an Angus cattle population. Using a linear regression analysis, we iden...

  16. Genome-wide analysis and expression profiling of the Solanum tuberosum aquaporins.

    PubMed

    Venkatesh, Jelli; Yu, Jae-Woong; Park, Se Won

    2013-12-01

    Aquaporins belongs to the major intrinsic proteins involved in the transcellular membrane transport of water and other small solutes. A comprehensive genome-wide search for the homologues of Solanum tuberosum major intrinsic protein (MIP) revealed 41 full-length potato aquaporin genes. All potato aquaporins are grouped into five subfamilies; plasma membrane intrinsic proteins (PIPs), tonoplast intrinsic proteins (TIPs), NOD26-like intrinsic proteins (NIPs), small basic intrinsic proteins (SIPs) and x-intrinsic proteins (XIPs). Functional predictions based on the aromatic/arginine (ar/R) selectivity filters and Froger's positions showed a remarkable difference in substrate transport specificity among subfamilies. The expression pattern of potato aquaporins, examined by qPCR analysis, showed distinct expression profiles in various organs and tuber developmental stages. Furthermore, qPCR analysis of potato plantlets, subjected to various abiotic stresses revealed the marked effect of stresses on expression levels of aquaporins. Taken together, the expression profiles of aquaporins imply that aquaporins play important roles in plant growth and development, in addition to maintaining water homeostasis in response to environmental stresses.

  17. Genome-wide characterization of transcriptional start sites in humans by integrative transcriptome analysis

    PubMed Central

    Yamashita, Riu; Sathira, Nuankanya P.; Kanai, Akinori; Tanimoto, Kousuke; Arauchi, Takako; Tanaka, Yoshiaki; Hashimoto, Shin-ichi; Sugano, Sumio; Nakai, Kenta; Suzuki, Yutaka

    2011-01-01

    We performed a genome-wide analysis of transcriptional start sites (TSSs) in human genes by multifaceted use of a massively parallel sequencer. By analyzing 800 million sequences that were obtained from various types of transcriptome analyses, we characterized 140 million TSS tags in 12 human cell types. Despite the large number of TSS clusters (TSCs), the number of TSCs was observed to decrease sharply with increasing expression levels. Highly expressed TSCs exhibited several characteristic features: Nucleosome-seq analysis revealed highly ordered nucleosome structures, ChIP-seq analysis detected clear RNA polymerase II binding signals in their surrounding regions, evaluations of previously sequenced and newly shotgun-sequenced complete cDNA sequences showed that they encode preferable transcripts for protein translation, and RNA-seq analysis of polysome-incorporated RNAs yielded direct evidence that those transcripts are actually translated into proteins. We also demonstrate that integrative interpretation of transcriptome data is essential for the selection of putative alternative promoter TSCs, two of which also have protein consequences. Furthermore, discriminative chromatin features that separate TSCs at different expression levels were found for both genic TSCs and intergenic TSCs. The collected integrative information should provide a useful basis for future biological characterization of TSCs. PMID:21372179

  18. Genome-Wide Analysis of Branched-Chain Amino Acid Levels in Arabidopsis Seeds[W

    PubMed Central

    Angelovici, Ruthie; Lipka, Alexander E.; Deason, Nicholas; Gonzalez-Jorge, Sabrina; Lin, Haining; Cepela, Jason; Buell, Robin; Gore, Michael A.; DellaPenna, Dean

    2013-01-01

    Branched-chain amino acids (BCAAs) are three of the nine essential amino acids in human and animal diets and are important for numerous processes in development and growth. However, seed BCAA levels in major crops are insufficient to meet dietary requirements, making genetic improvement for increased and balanced seed BCAAs an important nutritional target. Addressing this issue requires a better understanding of the genetics underlying seed BCAA content and composition. Here, a genome-wide association study and haplotype analysis for seed BCAA traits in Arabidopsis thaliana revealed a strong association with a chromosomal interval containing two BRANCHED-CHAIN AMINO ACID TRANSFERASES, BCAT1 and BCAT2. Linkage analysis, reverse genetic approaches, and molecular complementation analysis demonstrated that allelic variation at BCAT2 is responsible for the natural variation of seed BCAAs in this interval. Complementation analysis of a bcat2 null mutant with two significantly different alleles from accessions Bayreuth-0 and Shahdara is consistent with BCAT2 contributing to natural variation in BCAA levels, glutamate recycling, and free amino acid homeostasis in seeds in an allele-dependent manner. The seed-specific phenotype of bcat2 null alleles, its strong transcription induction during late seed development, and its subcellular localization to the mitochondria are consistent with a unique, catabolic role for BCAT2 in BCAA metabolism in seeds. PMID:24368787

  19. Genome-wide identification and phylogenetic analysis of the SBP-box gene family in melons.

    PubMed

    Ma, Y; Guo, J W; Bade, R; Men, Z H; Hasi, A

    2014-10-27

    The SBP-box gene family is specific to plants and encodes a class of zinc finger-containing transcription factors with a broad range of functions. Although SBP-box genes have been identified in numerous plants, including green algae, moss, silver birch, snapdragon, Arabidopsis, rice, and maize, there is little information concerning SBP-box genes, or the corresponding miR156/157, function in melon. Using the highly conserved sequence of the Arabidopsis thaliana SBP-box domain protein as a probe of information sequence, the genome-wide protein database of melon was explored to obtain 13 SBP-box protein sequences, which were further divided into 4 groups, based on phylogenetic analysis. A further analysis centered on the melon SBP-box genetic family's phylogenetic evolution, sequence similarities, gene structure, and miR156 target sequence was also conducted. Analysis of all the expression patterns of melon SBP-box family genes showed that the SBP-box genes were detected in 7 kinds of tissue, and fruit had the highest expression level. CmSBP11 tends to present its specific expression in melon fruit and root. CmSBP09 expression was the highest in flower. Overall, the molecular evolution and expression pattern of the melon SBP-box gene family, revealed by these results, suggest its function differentiation that followed gene duplication.

  20. Genome-wide association analysis for feed efficiency in Angus cattle

    PubMed Central

    Rolf, M M; Taylor, J F; Schnabel, R D; McKay, S D; McClure, M C; Northcutt, S L; Kerley, M S; Weaber, R L

    2012-01-01

    Estimated breeding values for average daily feed intake (AFI; kg/day), residual feed intake (RFI; kg/day) and average daily gain (ADG; kg/day) were generated using a mixed linear model incorporating genomic relationships for 698 Angus steers genotyped with the Illumina BovineSNP50 assay. Association analyses of estimated breeding values (EBVs) were performed for 41 028 single nucleotide polymorphisms (SNPs), and permutation analysis was used to empirically establish the genome-wide significance threshold (P < 0.05) for each trait. SNPs significantly associated with each trait were used in a forward selection algorithm to identify genomic regions putatively harbouring genes with effects on each trait. A total of 53, 66 and 68 SNPs explained 54.12% (24.10%), 62.69% (29.85%) and 55.13% (26.54%) of the additive genetic variation (when accounting for the genomic relationships) in steer breeding values for AFI, RFI and ADG, respectively, within this population. Evaluation by pathway analysis revealed that many of these SNPs are in genomic regions that harbour genes with metabolic functions. The presence of genetic correlations between traits resulted in 13.2% of SNPs selected for AFI and 4.5% of SNPs selected for RFI also being selected for ADG in the analysis of breeding values. While our study identifies panels of SNPs significant for efficiency traits in our population, validation of all SNPs in independent populations will be necessary before commercialization. PMID:22497295

  1. Genome-wide analysis of the MADS-box gene family in Brachypodium distachyon.

    PubMed

    Wei, Bo; Zhang, Rong-Zhi; Guo, Juan-Juan; Liu, Dan-Mei; Li, Ai-Li; Fan, Ren-Chun; Mao, Long; Zhang, Xiang-Qi

    2014-01-01

    MADS-box genes are important transcription factors for plant development, especially floral organogenesis. Brachypodium distachyon is a model for biofuel plants and temperate grasses such as wheat and barley, but a comprehensive analysis of MADS-box family proteins in Brachypodium is still missing. We report here a genome-wide analysis of the MADS-box gene family in Brachypodium distachyon. We identified 57 MADS-box genes and classified them into 32 MIKC(c)-type, 7 MIKC*-type, 9 Mα, 7 Mβ and 2 Mγ MADS-box genes according to their phylogenetic relationships to the Arabidopsis and rice MADS-box genes. Detailed gene structure and motif distribution were then studied. Investigation of their chromosomal localizations revealed that Brachypodium MADS-box genes distributed evenly across five chromosomes. In addition, five pairs of type II MADS-box genes were found on synteny blocks derived from whole genome duplication blocks. We then performed a systematic expression analysis of Brachypodium MADS-box genes in various tissues, particular floral organs. Further detection under salt, drought, and low-temperature conditions showed that some MADS-box genes may also be involved in abiotic stress responses, including type I genes. Comparative studies of MADS-box genes among Brachypodium, rice and Arabidopsis showed that Brachypodium had fewer gene duplication events. Taken together, this work provides useful data for further functional studies of MADS-box genes in Brachypodium distachyon.

  2. Genome-Wide Analysis of the Lysine Biosynthesis Pathway Network during Maize Seed Development

    PubMed Central

    Liu, Yuwei; Xie, Shaojun; Yu, Jingjuan

    2016-01-01

    Lysine is one of the most limiting essential amino acids for humans and livestock. The nutritional value of maize (Zea mays L.) is reduced by its poor lysine content. To better understand the lysine biosynthesis pathway in maize seed, we conducted a genome-wide analysis of the genes involved in lysine biosynthesis. We identified lysine biosynthesis pathway genes (LBPGs) and investigated whether a diaminopimelate pathway variant exists in maize. We analyzed two genes encoding the key enzyme dihydrodipicolinate synthase, and determined that they contribute differently to lysine synthesis during maize seed development. A coexpression network of LBPGs was constructed using RNA-sequencing data from 21 developmental stages of B73 maize seed. We found a large set of genes encoding ribosomal proteins, elongation factors and zein proteins that were coexpressed with LBPGs. The coexpressed genes were enriched in cellular metabolism terms and protein related terms. A phylogenetic analysis of the LBPGs from different plant species revealed different relationships. Additionally, six transcription factor (TF) families containing 13 TFs were identified as the Hub TFs of the LBPGs modules. Several expression quantitative trait loci of LBPGs were also identified. Our results should help to elucidate the lysine biosynthesis pathway network in maize seed. PMID:26829553

  3. Genome-wide identification and expression analysis of TCP transcription factors in Gossypium raimondii

    PubMed Central

    Ma, Jun; Wang, Qinglian; Sun, Runrun; Xie, Fuliang; Jones, Don C.; Zhang, Baohong

    2014-01-01

    Plant-specific TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play versatile functions in multiple aspects of plant growth and development. However, no systematical study has been performed in cotton. In this study, we performed for the first time the genome-wide identification and expression analysis of the TCP transcription factor family in Gossypium raimondii. A total of 38 non-redundant cotton TCP encoding genes were identified. The TCP transcription factors were divided into eleven subgroups based on phylogenetic analysis. Most TCP genes within the same subfamily demonstrated similar exon and intron organization and the motif structures were highly conserved among the subfamilies. Additionally, the chromosomal distribution pattern revealed that TCP genes were unevenly distributed across 11 out of the 13 chromosomes; segmental duplication is a predominant duplication event for TCP genes and the major contributor to the expansion of TCP gene family in G. raimondii. Moreover, the expression profiles of TCP genes shed light on their functional divergence. PMID:25322260

  4. Genome-wide identification and expression analysis of TCP transcription factors in Gossypium raimondii.

    PubMed

    Ma, Jun; Wang, Qinglian; Sun, Runrun; Xie, Fuliang; Jones, Don C; Zhang, Baohong

    2014-10-16

    Plant-specific TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play versatile functions in multiple aspects of plant growth and development. However, no systematical study has been performed in cotton. In this study, we performed for the first time the genome-wide identification and expression analysis of the TCP transcription factor family in Gossypium raimondii. A total of 38 non-redundant cotton TCP encoding genes were identified. The TCP transcription factors were divided into eleven subgroups based on phylogenetic analysis. Most TCP genes within the same subfamily demonstrated similar exon and intron organization and the motif structures were highly conserved among the subfamilies. Additionally, the chromosomal distribution pattern revealed that TCP genes were unevenly distributed across 11 out of the 13 chromosomes; segmental duplication is a predominant duplication event for TCP genes and the major contributor to the expansion of TCP gene family in G. raimondii. Moreover, the expression profiles of TCP genes shed light on their functional divergence.

  5. Pathway Analysis of Seven Common Diseases Assessed by Genome-Wide Association

    PubMed Central

    Torkamani, Ali; Topol, Eric J.; Schork, Nicholas J.

    2008-01-01

    Recent genome wide association studies (GWAS) have identified DNA sequence variations that exhibit unequivocal statistical associations with many common chronic diseases. However, the vast majority of these studies identified variations that explain only a very small fraction of disease burden in the population at large, suggesting that other factors, such as multiple rare or low-penetrance variations and interacting environmental factors, are major contributors to disease susceptibility. Identifying multiple low penetrance variations (or ‘polygenes’) contributing to disease susceptibility will be difficult. We present a pathway analysis approach to characterizing the likely polygenic basis of seven common diseases using the Wellcome Trust Case Control Consortium (WTCCC) GWAS results. We identify numerous pathways implicated in disease predisposition that would have not been revealed using standard single-locus GWAS statistical analysis criteria. Many of these pathways have long been assumed to contain polymorphic genes that lead to disease predisposition. Additionally, we analyze the genetic relationships between the seven diseases, and based upon similarities with respect to the associated genes and pathways affected in each, propose a new way of categorizing the diseases. PMID:18722519

  6. Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

    PubMed Central

    Chatonnet, Fabrice; Guyot, Romain; Benoît, Gérard; Flamant, Frederic

    2013-01-01

    TRα1 and TRβ1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3′,5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TRα1 or TRβ1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TRα1 and TRβ1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TRα1 and TRβ1 intrinsic properties contributes in a large part to the divergent evolution of the receptors’ function, at least during neurodevelopment. PMID:23382204

  7. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

    PubMed Central

    Raffensperger, Zachary D.; Heike, Carrie L.; Cunningham, Michael L.; Hecht, Jacqueline T.; Kau, Chung How; Moreno, Lina M.; Wehby, George L.; Murray, Jeffrey C.; Laurie, Cecelia A.; Laurie, Cathy C.; Santorico, Stephanie; Klein, Ophir; Feingold, Eleanor; Hallgrimsson, Benedikt; Spritz, Richard A.; Marazita, Mary L.; Weinberg, Seth M.

    2016-01-01

    Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis. PMID:27560520

  8. Genome-wide association study reveals novel variants for growth and egg traits in Dongxiang blue-shelled and White Leghorn chickens.

    PubMed

    Liao, R; Zhang, X; Chen, Q; Wang, Z; Wang, Q; Yang, C; Pan, Y

    2016-10-01

    This study was designed to investigate the genetic basis of growth and egg traits in Dongxiang blue-shelled chickens and White Leghorn chickens. In this study, we employed a reduced representation sequencing approach called genotyping by genome reducing and sequencing to detect genome-wide SNPs in 252 Dongxiang blue-shelled chickens and 252 White Leghorn chickens. The Dongxiang blue-shelled chicken breed has many specific traits and is characterized by blue-shelled eggs, black plumage, black skin, black bone and black organs. The White Leghorn chicken is an egg-type breed with high productivity. As multibreed genome-wide association studies (GWASs) can improve precision due to less linkage disequilibrium across breeds, a multibreed GWAS was performed with 156 575 SNPs to identify the associated variants underlying growth and egg traits within the two chicken breeds. The analysis revealed 32 SNPs exhibiting a significant genome-wide association with growth and egg traits. Some of the significant SNPs are located in genes that are known to impact growth and egg traits, but nearly half of the significant SNPs are located in genes with unclear functions in chickens. To our knowledge, this is the first multibreed genome-wide report for the genetics of growth and egg traits in the Dongxiang blue-shelled and White Leghorn chickens.

  9. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality

    PubMed Central

    Kamvar, Zhian N.; Brooks, Jonah C.; Grünwald, Niklaus J.

    2015-01-01

    To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies. PMID:26113860

  10. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

    PubMed

    Law, Matthew H; Bishop, D Timothy; Lee, Jeffrey E; Brossard, Myriam; Martin, Nicholas G; Moses, Eric K; Song, Fengju; Barrett, Jennifer H; Kumar, Rajiv; Easton, Douglas F; Pharoah, Paul D P; Swerdlow, Anthony J; Kypreou, Katerina P; Taylor, John C; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dȩbniak, Tadeusz; Duffy, David L; Elder, David E; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Chen, Wei V; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Mann, Graham J; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A; Radford-Smith, Graham L; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; Craig, Jamie E; Schadendorf, Dirk; Simms, Lisa A; Burdon, Kathryn P; Nyholt, Dale R; Pooley, Karen A; Orr, Nick; Stratigos, Alexander J; Cust, Anne E; Ward, Sarah V; Hayward, Nicholas K; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M; Bishop, Julia A Newton; Demenais, Florence; Amos, Christopher I; MacGregor, Stuart; Iles, Mark M

    2015-09-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

  11. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

    PubMed Central

    Law, Matthew H.; Bishop, D. Timothy; Martin, Nicholas G.; Moses, Eric K.; Song, Fengju; Barrett, Jennifer H.; Kumar, Rajiv; Easton, Douglas F.; Pharoah, Paul D. P.; Swerdlow, Anthony J.; Kypreou, Katerina P.; Taylor, John C.; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Duffy, David L.; Elder, David E.; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Chen, Wei V.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Mann, Graham J.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A.; Radford-Smith, Graham L.; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; Craig, Jamie E.; Schadendorf, Dirk; Simms, Lisa A.; Burdon, Kathryn P.; Nyholt, Dale R.; Pooley, Karen A.; Orr, Nick; Stratigos, Alexander J.; Cust, Anne E.; Ward, Sarah V.; Hayward, Nicholas K.; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M.; Bishop, Julia A. Newton; MacGregor, Stuart; Iles, Mark M.

    2015-01-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology. PMID:26237428

  12. Meta-analysis of sex-specific genome-wide association studies.

    PubMed

    Magi, Reedik; Lindgren, Cecilia M; Morris, Andrew P

    2010-12-01

    Despite the success of genome-wide association studies, much of the genetic contribution to complex human traits is still unexplained. One potential source of genetic variation that may contribute to this "missing heritability" is that which differs in magnitude and/or direction between males and females, which could result from sexual dimorphism in gene expression. Such sex-differentiated effects are common in model organisms, and are becoming increasingly evident in human complex traits through large-scale male- and female-specific meta-analyses. In this article, we review the methodology for meta-analysis of sex-specific genome-wide association studies, and propose a sex-differentiated test of association with quantitative or dichotomous traits, which allows for heterogeneity of allelic effects between males and females. We perform detailed simulations to compare the power of the proposed sex-differentiated meta-analysis with the more traditional "sex-combined" approach, which is ambivalent to gender. The results of this study highlight only a small loss in power for the sex-differentiated meta-analysis when the allelic effects of the causal variant are the same in males and females. However, over a range of models of heterogeneity in allelic effects between genders, our sex-differentiated meta-analysis strategy offers substantial gains in power, and thus has the potential to discover novel loci contributing effects to complex human traits with existing genome-wide association data.

  13. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping.

    PubMed

    Roh, Tae-Young; Cuddapah, Suresh; Zhao, Keji

    2005-03-01

    The identity and developmental potential of a human cell is specified by its epigenome that is largely defined by patterns of chromatin modifications including histone acetylation. Here we report high-resolution genome-wide mapping of diacetylation of histone H3 at Lys 9 and Lys 14 in resting and activated human T cells by genome-wide mapping technique (GMAT). Our data show that high levels of the H3 acetylation are detected in gene-rich regions. The chromatin accessibility and gene expression of a genetic domain is correlated with hyperacetylation of promoters and other regulatory elements but not with generally elevated acetylation of the entire domain. Islands of acetylation are identified in the intergenic and transcribed regions. The locations of the 46,813 acetylation islands identified in this study are significantly correlated with conserved noncoding sequences (CNSs) and many of them are colocalized with known regulatory elements in T cells. TCR signaling induces 4045 new acetylation loci that may mediate the global chromatin remodeling and gene activation. We propose that the acetylation islands are epigenetic marks that allow prediction of functional regulatory elements.

  14. Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping

    PubMed Central

    Roh, Tae-Young; Cuddapah, Suresh; Zhao, Keji

    2005-01-01

    The identity and developmental potential of a human cell is specified by its epigenome that is largely defined by patterns of chromatin modifications including histone acetylation. Here we report high-resolution genome-wide mapping of diacetylation of histone H3 at Lys 9 and Lys 14 in resting and activated human T cells by genome-wide mapping technique (GMAT). Our data show that high levels of the H3 acetylation are detected in gene-rich regions. The chromatin accessibility and gene expression of a genetic domain is correlated with hyperacetylation of promoters and other regulatory elements but not with generally elevated acetylation of the entire domain. Islands of acetylation are identified in the intergenic and transcribed regions. The locations of the 46,813 acetylation islands identified in this study are significantly correlated with conserved noncoding sequences (CNSs) and many of them are colocalized with known regulatory elements in T cells. TCR signaling induces 4045 new acetylation loci that may mediate the global chromatin remodeling and gene activation. We propose that the acetylation islands are epigenetic marks that allow prediction of functional regulatory elements. PMID:15706033

  15. Genome-wide association study reveals two new risk loci for bipolar disorder.

    PubMed

    Mühleisen, Thomas W; Leber, Markus; Schulze, Thomas G; Strohmaier, Jana; Degenhardt, Franziska; Treutlein, Jens; Mattheisen, Manuel; Forstner, Andreas J; Schumacher, Johannes; Breuer, René; Meier, Sandra; Herms, Stefan; Hoffmann, Per; Lacour, André; Witt, Stephanie H; Reif, Andreas; Müller-Myhsok, Bertram; Lucae, Susanne; Maier, Wolfgang; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Pfennig, Andrea; Bauer, Michael; Hautzinger, Martin; Moebus, Susanne; Priebe, Lutz; Czerski, Piotr M; Hauser, Joanna; Lissowska, Jolanta; Szeszenia-Dabrowska, Neonila; Brennan, Paul; McKay, James D; Wright, Adam; Mitchell, Philip B; Fullerton, Janice M; Schofield, Peter R; Montgomery, Grant W; Medland, Sarah E; Gordon, Scott D; Martin, Nicholas G; Krasnow, Valery; Chuchalin, Alexander; Babadjanova, Gulja; Pantelejeva, Galina; Abramova, Lilia I; Tiganov, Alexander S; Polonikov, Alexey; Khusnutdinova, Elza; Alda, Martin; Grof, Paul; Rouleau, Guy A; Turecki, Gustavo; Laprise, Catherine; Rivas, Fabio; Mayoral, Fermin; Kogevinas, Manolis; Grigoroiu-Serbanescu, Maria; Propping, Peter; Becker, Tim; Rietschel, Marcella; Nöthen, Markus M; Cichon, Sven

    2014-03-11

    Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

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

    PubMed

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

    2015-10-30

    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.

  17. 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

  18. Genome-wide analysis of glutathione reductase (GR) genes from rice and Arabidopsis.

    PubMed

    Trivedi, Dipesh Kumar; Gill, Sarvajeet Singh; Yadav, Sandep; Tuteja, Narendra

    2013-02-01

    Plant cells and tissues remain always on risk under abiotic and biotic stresses due to increased production of reactive oxygen species (ROS). Plants protect themselves against ROS induced oxidative damage by the upregulation of antioxidant machinery. Out of many components of antioxidant machinery, glutathione reductase (GR, EC 1.6.4.2) and glutathione (GSH, γ-Glu-Cys-Gly) play important role in the protection of cell against oxidative damage. In stress condition, the GR helps in maintaining the reduced glutathione pool for strengthening the antioxidative processes in plants. Present study investigates genome wide analysis of GR from rice and Arabidopsis. We were able to identify 3 rice GR genes (LOC_Os02 g56850, LOC_Os03 g06740, LOC_Os10 g28000) and 2 Arabidopsis GR genes (AT3G54660, AT3G24170) from their respective genomes on the basis of their annotation as well as the presence of pyridine nucleotide-disulphide oxidoreductases class-I active site. The evolutionary relationship of the GR genes from rice and Arabidopsis genomes was analyzed using the multiple sequence alignment and phylogenetic tree. This revealed evolutionary conserved pyridine nucleotide-disulphide oxidoreductases class-I active site among the GR protein in rice and Arabidopsis. This study should make an important contribution to our better understanding of the GR under normal and stress condition in plants.

  19. 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.

  20. The development of an Arabidopsis model system for genome-wide analysis of polyploidy effects

    PubMed Central

    JEFFREY CHEN, Z.; WANG, JIANLIN; TIAN, LU; LEE, HYEON-SE; WANG, JIYUAN J.; CHEN, MENG; LEE, JINSUK J.; JOSEFSSON, CAROLINE; MADLUNG, ANDREAS; WATSON, BRIAN; LIPPMAN, ZACH; VAUGHN, MATT; CHRIS PIRES, J.; COLOT, VINCENT; DOERGE, R. W.; MARTIENSSEN, ROBERT A.; COMAI, LUCA; OSBORN, THOMAS C.

    2007-01-01

    Arabidopsis is a model system not only for studying numerous aspects of plant biology, but also for understanding mechanisms of the rapid evolutionary process associated with genome duplication and polyploidization. Although in animals interspecific hybrids are often sterile and aneuploids are related to disease syndromes, both Arabidopsis autopolyploids and allopolyploids occur in nature and can be readily formed in the laboratory, providing an attractive system for comparing changes in gene expression and genome structure among relatively ‘young’ and ‘established’ or ‘ancient’ polyploids. Powerful reverse and forward genetics in Arabidopsis offer an exceptional means by which regulatory mechanisms of gene and genome duplication may be revealed. Moreover, the Arabidopsis genome is completely sequenced; both coding and non-coding sequences are available. We have developed spotted oligo-gene and chromosome microarrays using the complete Arabidopsis genome sequence. The oligo-gene microarray consists of ~26 000 70-mer oligonucleotides that are designed from all annotated genes in Arabidopsis, and the chromosome microarray contains 1 kb genomic tiling fragments amplified from a chromosomal region or the complete sequence of chromosome 4. We have demonstrated the utility of microarrays for genome-wide analysis of changes in gene expression, genome organization and chromatin structure in Arabidopsis polyploids and related species. PMID:18079994

  1. Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder.

    PubMed

    Belmonte Mahon, Pamela; Pirooznia, Mehdi; Goes, Fernando S; Seifuddin, Fayaz; Steele, Jo; Lee, Phil Hyoun; Huang, Jie; Hamshere, Marian L; Depaulo, J Raymond; Kelsoe, John R; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Purcell, Shaun; Smoller, Jordan W; Craddock, Nick; Schulze, Thomas G; McMahon, Francis J; Potash, James B; Zandi, Peter P

    2011-04-01

    Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles.

  2. A guide to genome-wide association analysis and post-analytic interrogation.

    PubMed

    Reed, Eric; Nunez, Sara; Kulp, David; Qian, Jing; Reilly, Muredach P; Foulkes, Andrea S

    2015-12-10

    This tutorial is a learning resource that outlines the basic process and provides specific software tools for implementing a complete genome-wide association analysis. Approaches to post-analytic visualization and interrogation of potentially novel findings are also presented. Applications are illustrated using the free and open-source R statistical computing and graphics software environment, Bioconductor software for bioinformatics and the UCSC Genome Browser. Complete genome-wide association data on 1401 individuals across 861,473 typed single nucleotide polymorphisms from the PennCATH study of coronary artery disease are used for illustration. All data and code, as well as additional instructional resources, are publicly available through the Open Resources in Statistical Genomics project: http://www.stat-gen.org.

  3. Genome-wide analysis of microRNA and mRNA expression signatures in cancer

    PubMed Central

    Li, Ming-hui; Fu, Sheng-bo; Xiao, Hua-sheng

    2015-01-01

    Cancer is an extremely diverse and complex disease that results from various genetic and epigenetic changes such as DNA copy-number variations, mutations, and aberrant mRNA and/or protein expression caused by abnormal transcriptional regulation. The expression profiles of certain microRNAs (miRNAs) and messenger RNAs (mRNAs) are closely related to cancer progression stages. In the past few decades, DNA microarray and next-generation sequencing techniques have been widely applied to identify miRNA and mRNA signatures for cancers on a genome-wide scale and have provided meaningful insights into cancer diagnosis, prognosis and personalized medicine. In this review, we summarize the progress in genome-wide analysis of miRNAs and mRNAs as cancer biomarkers, highlighting their diagnostic and prognostic roles. PMID:26299954

  4. Genome-wide association analysis identifies six new loci associated with forced vital capacity.

    PubMed

    Loth, Daan W; Soler Artigas, María; Gharib, Sina A; Wain, Louise V; Franceschini, Nora; Koch, Beate; Pottinger, Tess D; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P; James, Alan L; Huffman, Jennifer E; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kähönen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K; Fall, Tove; Viñuela, Ana; Launer, Lenore J; Loehr, Laura R; Fornage, Myriam; Li, Guo; Wilk, Jemma B; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B; North, Kari E; Rudnicka, Alicja R; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F; Hastie, Nicholas D; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A; Pietiläinen, Kirsi H; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M; Wojczynski, Mary; Pouta, Anneli; Johansson, Asa; Wild, Sarah H; Ingelsson, Erik; Rivadeneira, Fernando; Völzke, Henry; Hysi, Pirro G; Eiriksdottir, Gudny; Morrison, Alanna C; Rotter, Jerome I; Gao, Wei; Postma, Dirkje S; White, Wendy B; Rich, Stephen S; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J; Psaty, Bruce M; Lohman, Kurt; Burchard, Esteban G; Uitterlinden, André G; Garcia, Melissa; Joubert, Bonnie R; McArdle, Wendy L; Musk, A Bill; Hansel, Nadia; Heckbert, Susan R; Zgaga, Lina; van Meurs, Joyce B J; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah L; Zhao, Jing Hua; Rantanen, Taina; O'Connor, George T; Ripatti, Samuli; Scott, Rodney J; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C; Starr, John M; Wijmenga, Cisca; Minster, Ryan L; Lederer, David J; Pekkanen, Juha; Gyllensten, Ulf; Campbell, Harry; Morris, Andrew P; Gläser, Sven; Hammond, Christopher J; Burkart, Kristin M; Beilby, John; Kritchevsky, Stephen B; Gudnason, Vilmundur; Hancock, Dana B; Williams, O Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F; Wjst, Matthias; Kim, Woo Jin; Porteous, David J; Scotland, Generation; Smith, Blair H; Viljanen, Anne; Heliövaara, Markku; Attia, John R; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J; Boezen, H Marike; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F; Lind, Lars; Stricker, Bruno H; Teumer, Alexander; Spector, Timothy D; Melén, Erik; Peters, Marjolein J; Lange, Leslie A; Barr, R Graham; Bracke, Ken R; Verhamme, Fien M; Sung, Joohon; Hiemstra, Pieter S; Cassano, Patricia A; Sood, Akshay; Hayward, Caroline; Dupuis, Josée; Hall, Ian P; Brusselle, Guy G; Tobin, Martin D; London, Stephanie J

    2014-07-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

  5. Genome-wide association analysis identifies six new loci associated with forced vital capacity

    PubMed Central

    Loth, Daan W.; Artigas, María Soler; Gharib, Sina A.; Wain, Louise V.; Franceschini, Nora; Koch, Beate; Pottinger, Tess; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P.; James, Alan L.; Huffman, Jennifer E.; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J.; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kähönen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M.; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K.; Fall, Tove; Viňuela, Ana; Launer, Lenore J.; Loehr, Laura R.; Fornage, Myriam; Li, Guo; Wilk, Jemma B.; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B.; North, Kari E.; Rudnicka, Alicja R.; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F.; Hastie, Nicholas D.; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A.; Pietiläinen, Kirsi H.; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G.; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M.; Wojczynski, Mary; Pouta, Anneli; Johansson, Åsa; Wild, Sarah H.; Ingelsson, Erik; Rivadeneira, Fernando; Völzke, Henry; Hysi, Pirro G.; Eiriksdottir, Gudny; Morrison, Alanna C.; Rotter, Jerome I.; Gao, Wei; Postma, Dirkje S.; White, Wendy B.; Rich, Stephen S.; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J.; Psaty, Bruce M.; Lohman, Kurt; Burchard, Esteban G.; Uitterlinden, André G.; Garcia, Melissa; Joubert, Bonnie R.; McArdle, Wendy L.; Musk, A. Bill; Hansel, Nadia; Heckbert, Susan R.; Zgaga, Lina; van Meurs, Joyce B.J.; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah; Zhao, Jing Hua; Rantanen, Taina; O’Connor, George T.; Ripatti, Samuli; Scott, Rodney J.; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C.; Starr, John M.; Wijmenga, Cisca; Minster, Ryan L.; Lederer, David J.; Pekkanen, Juha; Gyllensten, Ulf; Campbell, Harry; Morris, Andrew P.; Gläser, Sven; Hammond, Christopher J.; Burkart, Kristin M.; Beilby, John; Kritchevsky, Stephen B.; Gudnason, Vilmundur; Hancock, Dana B.; Williams, O. Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F.; Wjst, Matthias; Kim, Woo Jin; Porteous, David J.; Scotland, Generation; Smith, Blair H.; Viljanen, Anne; Heliövaara, Markku; Attia, John R.; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J.; Boezen, H. Marike; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F.; Lind, Lars; Stricker, Bruno H.; Teumer, Alexander; Spector, Timothy D.; Melén, Erik; Peters, Marjolein J.; Lange, Leslie A.; Barr, R. Graham; Bracke, Ken R.; Verhamme, Fien M.; Sung, Joohon; Hiemstra, Pieter S.; Cassano, Patricia A.; Sood, Akshay; Hayward, Caroline; Dupuis, Josée; Hall, Ian P.; Brusselle, Guy G.; Tobin, Martin D.; London, Stephanie J.

    2014-01-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease. PMID:24929828

  6. Genome-Wide Association and Transcriptome Analyses Reveal Candidate Genes Underlying Yield-determining Traits in Brassica napus

    PubMed Central

    Lu, Kun; Peng, Liu; Zhang, Chao; Lu, Junhua; Yang, Bo; Xiao, Zhongchun; Liang, Ying; Xu, Xingfu; Qu, Cunmin; Zhang, Kai; Liu, Liezhao; Zhu, Qinlong; Fu, Minglian; Yuan, Xiaoyan; Li, Jiana

    2017-01-01

    Yield is one of the most important yet complex crop traits. To improve our understanding of the genetic basis of yield establishment, and to identify candidate genes responsible for yield improvement in Brassica napus, we performed genome-wide association studies (GWAS) for seven yield-determining traits [main inflorescence pod number (MIPN), branch pod number (BPN), pod number per plant (PNP), seed number per pod (SPP), thousand seed weight, main inflorescence yield (MIY), and branch yield], using data from 520 diverse B. napus accessions from two different yield environments. In total, we detected 128 significant single nucleotide polymorphisms (SNPs), 93 of which were revealed as novel by integrative analysis. A combination of GWAS and transcriptome sequencing on 21 haplotype blocks from samples pooled by four extremely high-yielding or low-yielding accessions revealed the differential expression of 14 crucial candiate genes (such as Bna.MYB83, Bna.SPL5, and Bna.ROP3) associated with multiple traits or containing multiple SNPs associated with the same trait. Functional annotation and expression pattern analyses further demonstrated that these 14 candiate genes might be important in developmental processes and biomass accumulation, thus affecting the yield establishment of B. napus. These results provide valuable information for understanding the genetic mechanisms underlying the establishment of high yield in B. napus, and lay the foundation for developing high-yielding B. napus varieties. PMID:28261256

  7. Genome-wide comparative analysis reveals similar types of NBS genes in hybrid Citrus sinensis genome and original Citrus clementine genome and provides new insights into non-TIR NBS genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, we identified and compared nucleotide-binding site (NBS) domain-containing genes from three Citrus genomes (C. clementina, C. sinensis from USA and C. sinensis from China). Phylogenetic analysis of all Citrus NBS genes across these three genomes revealed that there are three approxima...

  8. Five endometrial cancer risk loci identified through genome-wide association analysis.

    PubMed

    Cheng, Timothy H T; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica M J; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-06-01

    We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

  9. Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.

    PubMed

    Adkins, Daniel E; Clark, Shaunna L; Copeland, William E; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A; Silberg, Judy; Brown, Tyson H; Fergusson, David M; Horwood, L John; Eaves, Lindon; van den Oord, Edwin J C G; Sullivan, Patrick F; Costello, E J

    2015-08-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N=2,126, obs=12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and six others met our 'suggestive' criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies.

  10. Genome-wide gene-environment interaction analysis for asbestos exposure in lung cancer susceptibility.

    PubMed

    Wei, Sheng; Wang, Li-E; McHugh, Michelle K; Han, Younghun; Xiong, Momiao; Amos, Christopher I; Spitz, Margaret R; Wei, Qingyi Wei

    2012-08-01

    Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene-environment interactions. To determine gene-asbestos interactions in lung cancer risk, we conducted genome-wide gene-environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10(-6), which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10(-5)). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene-asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk.

  11. Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

    PubMed Central

    Nalls, Michael A.; Martinez, Maria; Schulte, Claudia; Holmans, Peter; Gasser, Thomas; Hardy, John; Singleton, Andrew B.; Wood, Nicholas W.; Brice, Alexis; Heutink, Peter; Williams, Nigel; Morris, Huw R.

    2012-01-01

    Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. PMID:22427796

  12. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

    PubMed Central

    2014-01-01

    Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the

  13. Genome-wide analysis of long-term evolutionary domestication in Drosophila melanogaster

    PubMed Central

    Phillips, Mark A.; Long, Anthony D.; Greenspan, Zachary S.; Greer, Lee F.; Burke, Molly K.; Villeponteau, Bryant; Matsagas, Kennedy C.; Rizza, Cristina L.; Mueller, Laurence D.; Rose, Michael R.

    2016-01-01

    Experimental evolutionary genomics now allows biologists to test fundamental theories concerning the genetic basis of adaptation. We have conducted one of the longest laboratory evolution experiments with any sexually-reproducing metazoan, Drosophila melanogaster. We used next-generation resequencing data from this experiment to examine genome-wide patterns of genetic variation over an evolutionary time-scale that approaches 1,000 generations. We also compared measures of variation within and differentiation between our populations to simulations based on a variety of evolutionary scenarios. Our analysis yielded no clear evidence of hard selective sweeps, whereby natural selection acts to increase the frequency of a newly-arising mutation in a population until it becomes fixed. We do find evidence for selection acting on standing genetic variation, as independent replicate populations exhibit similar population-genetic dynamics, without obvious fixation of candidate alleles under selection. A hidden-Markov model test for selection also found widespread evidence for selection. We found more genetic variation genome-wide, and less differentiation between replicate populations genome-wide, than arose in any of our simulated evolutionary scenarios. PMID:28004838

  14. Host cell factors in HIV replication: meta-analysis of genome-wide studies.

    PubMed

    Bushman, Frederic D; Malani, Nirav; Fernandes, Jason; D'Orso, Iván; Cagney, Gerard; Diamond, Tracy L; Zhou, Honglin; Hazuda, Daria J; Espeseth, Amy S; König, Renate; Bandyopadhyay, Sourav; Ideker, Trey; Goff, Stephen P; Krogan, Nevan J; Frankel, Alan D; Young, John A T; Chanda, Sumit K

    2009-05-01

    We have analyzed host cell genes linked to HIV replication that were identified in nine genome-wide studies, including three independent siRNA screens. Overlaps among the siRNA screens were very modest (<7% for any pairwise combination), and similarly, only modest overlaps were seen in pairwise comparisons with other types of genome-wide studies. Combining all genes from the genome-wide studies together with genes reported in the literature to affect HIV yields 2,410 protein-coding genes, or fully 9.5% of all human genes (though of course some of these are false positive calls). Here we report an "encyclopedia" of all overlaps between studies (available at http://www.hostpathogen.org), which yielded a more extensively corroborated set of host factors assisting HIV replication. We used these genes to calculate refined networks that specify cellular subsystems recruited by HIV to assist in replication, and present additional analysis specifying host cell genes that are attractive as potential therapeutic targets.

  15. Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

    PubMed Central

    Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L; Kähler, Anna K; Akterin, Susanne; Bergen, Sarah; Collins, Ann L; Crowley, James J; Fromer, Menachem; Kim, Yunjung; Lee, Sang Hong; Magnusson, Patrik KE; Sanchez, Nick; Stahl, Eli A; Williams, Stephanie; Wray, Naomi R; Xia, Kai; Bettella, Francesco; Børglum, Anders D; Bulik-Sullivan, Brendan K; Cormican, Paul; Craddock, Nick; de Leeuw, Christiaan; Durmishi, Naser; Gill, Michael; Golimbet, Vera; Hamshere, Marian L; Holmans, Peter; Hougaard, David M; Kendler, Kenneth S; Lin, Kuang; Morris, Derek W; Mors, Ole; Mortensen, Preben B; Neale, Benjamin M; O'Neill, Francis A; Owen, Michael J; Milovancevic, MilicaPejovic; Posthuma, Danielle; Powell, John; Richards, Alexander L; Riley, Brien P; Ruderfer, Douglas; Rujescu, Dan; Sigurdsson, Engilbert; Silagadze, Teimuraz; Smit, August B; Stefansson, Hreinn; Steinberg, Stacy; Suvisaari, Jaana; Tosato, Sarah; Verhage, Matthijs; Walters, James T; Bramon, Elvira; Corvin, Aiden P; O'Donovan, Michael C; Stefansson, Kari; Scolnick, Edward; Purcell, Shaun; McCarroll, Steve; Sklar, Pamela; Hultman, Christina M; Sullivan, Patrick F

    2013-01-01

    Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder. PMID:23974872

  16. Genome-Wide Binding of MBD2 Reveals Strong Preference for Highly Methylated Loci

    PubMed Central

    Menafra, Roberta; Brinkman, Arie B.; Matarese, Filomena; Franci, Gianluigi; Bartels, Stefanie J. J.; Nguyen, Luan; Shimbo, Takashi; Wade, Paul A.; Hubner, Nina C.; Stunnenberg, Hendrik G.

    2014-01-01

    MBD2 is a subunit of the NuRD complex that is postulated to mediate gene repression via recruitment of the complex to methylated DNA. In this study we adopted an MBD2 tagging-approach to study its genome wide binding characteristics. We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. Interestingly, MBD2 binds around 1 kb downstream of the transcription start site of a subset of ∼400 CpG island promoters that are characterized by the presence of active histone marks, RNA polymerase II (Pol2) and low to medium gene expression levels and H3K36me3 deposition. These tagged-MBD2 binding sites in MCF-7 show increased methylation in a cohort of primary breast cancers but not in normal breast samples, suggesting a putative role for MBD2 in breast cancer. PMID:24927503

  17. Genome-wide and parental allele-specific analysis of CTCF and cohesin DNA binding in mouse brain reveals a tissue-specific binding pattern and an association with imprinted differentially methylated regions.

    PubMed

    Prickett, Adam R; Barkas, Nikolaos; McCole, Ruth B; Hughes, Siobhan; Amante, Samuele M; Schulz, Reiner; Oakey, Rebecca J

    2013-10-01

    DNA binding factors are essential for regulating gene expression. CTCF and cohesin are DNA binding factors with central roles in chromatin organization and gene expression. We determined the sites of CTCF and cohesin binding to DNA in mouse brain, genome wide and in an allele-specific manner with high read-depth ChIP-seq. By comparing our results with existing data for mouse liver and embryonic stem (ES) cells, we investigated the tissue specificity of CTCF binding sites. ES cells have fewer unique CTCF binding sites occupied than liver and brain, consistent with a ground-state pattern of CTCF binding that is elaborated during differentiation. CTCF binding sites without the canonical consensus motif were highly tissue specific. In brain, a third of CTCF and cohesin binding sites coincide, consistent with the potential for many interactions between cohesin and CTCF but also many instances of independent action. In the context of genomic imprinting, CTCF and/or cohesin bind to a majority but not all differentially methylated regions, with preferential binding to the unmethylated parental allele. Whether the parental allele-specific methylation was established in the parental germlines or post-fertilization in the embryo is not a determinant in CTCF or cohesin binding. These findings link CTCF and cohesin with the control regions of a subset of imprinted genes, supporting the notion that imprinting control is mechanistically diverse.

  18. Genome-Wide and Paternal Diversity Reveal a Recent Origin of Human Populations in North Africa

    PubMed Central

    Martínez-Cruz, Begoña; Zalloua, Pierre; Benammar Elgaaied, Amel; Comas, David

    2013-01-01

    The geostrategic location of North Africa as a crossroad between three continents and as a stepping-stone outside Africa has evoked anthropological and genetic interest in this region. Numerous studies have described the genetic landscape of the human population in North Africa employing paternal, maternal, and biparental molecular markers. However, information from these markers which have different inheritance patterns has been mostly assessed independently, resulting in an incomplete description of the region. In this study, we analyze uniparental and genome-wide markers examining similarities or contrasts in the results and consequently provide a comprehensive description of the evolutionary history of North Africa populations. Our results show that both males and females in North Africa underwent a similar admixture history with slight differences in the proportions of admixture components. Consequently, genome-wide diversity show similar patterns with admixture tests suggesting North Africans are a mixture of ancestral populations related to current Africans and Eurasians with more affinity towards the out-of-Africa populations than to sub-Saharan Africans. We estimate from the paternal lineages that most North Africans emerged ∼15,000 years ago during the last glacial warming and that population splits started after the desiccation of the Sahara. Although most North Africans share a common admixture history, the Tunisian Berbers show long periods of genetic isolation and appear to have diverged from surrounding populations without subsequent mixture. On the other hand, continuous gene flow from the Middle East made Egyptians genetically closer to Eurasians than to other North Africans. We show that genetic diversity of today's North Africans mostly captures patterns from migrations post Last Glacial Maximum and therefore may be insufficient to inform on the initial population of the region during the Middle Paleolithic period. PMID:24312208

  19. Genome-wide and paternal diversity reveal a recent origin of human populations in North Africa.

    PubMed

    Fadhlaoui-Zid, Karima; Haber, Marc; Martínez-Cruz, Begoña; Zalloua, Pierre; Benammar Elgaaied, Amel; Comas, David

    2013-01-01

    The geostrategic location of North Africa as a crossroad between three continents and as a stepping-stone outside Africa has evoked anthropological and genetic interest in this region. Numerous studies have described the genetic landscape of the human population in North Africa employing paternal, maternal, and biparental molecular markers. However, information from these markers which have different inheritance patterns has been mostly assessed independently, resulting in an incomplete description of the region. In this study, we analyze uniparental and genome-wide markers examining similarities or contrasts in the results and consequently provide a comprehensive description of the evolutionary history of North Africa populations. Our results show that both males and females in North Africa underwent a similar admixture history with slight differences in the proportions of admixture components. Consequently, genome-wide diversity show similar patterns with admixture tests suggesting North Africans are a mixture of ancestral populations related to current Africans and Eurasians with more affinity towards the out-of-Africa populations than to sub-Saharan Africans. We estimate from the paternal lineages that most North Africans emerged ∼15,000 years ago during the last glacial warming and that population splits started after the desiccation of the Sahara. Although most North Africans share a common admixture history, the Tunisian Berbers show long periods of genetic isolation and appear to have diverged from surrounding populations without subsequent mixture. On the other hand, continuous gene flow from the Middle East made Egyptians genetically closer to Eurasians than to other North Africans. We show that genetic diversity of today's North Africans mostly captures patterns from migrations post Last Glacial Maximum and therefore may be insufficient to inform on the initial population of the region during the Middle Paleolithic period.

  20. 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.

  1. Genome-Wide Association Analysis of the Anthocyanin and Carotenoid Contents of Rose Petals

    PubMed Central

    Schulz, Dietmar F.; Schott, Rena T.; Voorrips, Roeland E.; Smulders, Marinus J. M.; Linde, Marcus; Debener, Thomas

    2016-01-01

    Petal color is one of the key characteristics determining the attractiveness and therefore the commercial value of an ornamental crop. Here, we present the first genome-wide association study for the important ornamental crop rose, focusing on the anthocyanin and carotenoid contents in petals of 96 diverse tetraploid garden rose genotypes. Cultivated roses display a vast phenotypic and genetic diversity and are therefore ideal targets for association genetics. For marker analysis, we used a recently designed Axiom SNP chip comprising 68,000 SNPs with additionally 281 SSRs, 400 AFLPs and 246 markers from candidate genes. An analysis of the structure of the rose population revealed three subpopulations with most of the genetic variation between individual genotypes rather than between clusters and with a high average proportion of heterozygous loci. The mapping of markers significantly associated with anthocyanin and carotenoid content to the related Fragaria and Prunus genomes revealed clusters of associated markers indicating five genomic regions associated with the total anthocyanin content and two large clusters associated with the carotenoid content. Among the marker clusters associated with the phenotypes, we found several candidate genes with known functions in either the anthocyanin or the carotenoid biosynthesis pathways. Among others, we identified a glutathione-S-transferase, 4CL, an auxin response factor and F3'H as candidate genes affecting anthocyanin concentration, and CCD4 and Zeaxanthine epoxidase as candidates affecting the concentration of carotenoids. These markers are starting points for future validation experiments in independent populations as well as for functional genomic studies to identify the causal factors for the observed color phenotypes. Furthermore, validated markers may be interesting tools for marker-assisted selection in commercial breeding programmes in that they provide the tools to identify superior parental combinations that

  2. 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.

  3. Genome wide transcriptome profiling of Fusarium oxysporum f sp. ciceris conidial germination reveals new insights into infection-related genes

    PubMed Central

    Sharma, Mamta; Sengupta, Anindita; Ghosh, Raju; Agarwal, Gaurav; Tarafdar, Avijit; Nagavardhini, A; Pande, Suresh; Varshney, Rajeev K

    2016-01-01

    Vascular wilt caused by Fusarium oxysporum f. sp. ciceris (Foc) is a serious disease of chickpea (Cicer arietinum L.) accounting for approximately 10–15% annual crop loss. The fungus invades the plant via roots, colonizes the xylem vessels and prevents the upward translocation of water and nutrients. Infection is initiated by conidia that invade the host tissue often by penetration of intact epidermal cells. Here, we report the characterization of the transcriptome of Foc sequenced using Illumina Hiseq technology during its conidial germination at different time points. Genome-wide expression profiling revealed that genes linked to fungal development are transcribed in successive ways. Analysis showed that Foc have large sets of germination-related genes and families of genes encoding secreted effectors, cell wall/pectin-degrading enzymes, metabolism related enzymes, transporters and peptidases. We found that metabolism related enzymes are up-regulated at early time point whereas most transporters and secondary metabolites important for tissue colonization and pathogenicity are up-regulated later as evident from the qRT-PCR. The study demonstrated that early conidial germination in Foc is accompanied by rapid shifts in gene expression that prepare the fungus for germ tube outgrowth, host cell invasion and pathogenesis. This work lays the foundation for facilitating further research towards understanding this host-pathogen interaction. PMID:27853284

  4. Experimental evolution reveals genome-wide spectrum and dynamics of mutations in the rice blast fungus, Magnaporthe oryzae.

    PubMed

    Jeon, Junhyun; Choi, Jaeyoung; Lee, Gir-Won; Dean, Ralph A; Lee, Yong-Hwan

    2013-01-01

    Knowledge on mutation processes is central to interpreting genetic analysis data as well as understanding the underlying nature of almost all evolutionary phenomena. However, studies on genome-wide mutational spectrum and dynamics in fungal pathogens are scarce, hindering our understanding of their evolution and biology. Here, we explored changes in the phenotypes and genome sequences of the rice blast fungus Magnaporthe oryzae during the forced in vitro evolution by weekly transfer of cultures on artificial media. Through combination of experimental evolution with high throughput sequencing technology, we found that mutations accumulate rapidly prior to visible phenotypic changes and that both genetic drift and selection seem to contribute to shaping mutational landscape, suggesting the buffering capacity of fungal genome against mutations. Inference of mutational effects on phenotypes through the use of T-DNA insertion mutants suggested that at least some of the DNA sequence mutations are likely associated with the observed phenotypic changes. Furthermore, our data suggest oxidative damages and UV as major sources of mutation during subcultures. Taken together, our work revealed important properties of original source of variation in the genome of the rice blast fungus. We believe that these results provide not only insights into stability of pathogenicity and genome evolution in plant pathogenic fungi but also a model in which evolution of fungal pathogens in natura can be comparatively investigated.

  5. Genome-Wide Comparison of Magnaporthe Species Reveals a Host-Specific Pattern of Secretory Proteins and Transposable Elements

    PubMed Central

    Gowda, Malali

    2016-01-01

    Blast disease caused by the Magnaporthe species is a major factor affecting the productivity of rice, wheat and millets. This study was aimed at generating genomic information for rice and non-rice Magnaporthe isolates to understand the extent of genetic variation. We have sequenced the whole genome of the Magnaporthe isolates, infecting rice (leaf and neck), finger millet (leaf and neck), foxtail millet (leaf) and buffel grass (leaf). Rice and finger millet isolates infecting both leaf and neck tissues were sequenced, since the damage and yield loss caused due to neck blast is much higher as compared to leaf blast. The genome-wide comparison was carried out to study the variability in gene content, candidate effectors, repeat element distribution, genes involved in carbohydrate metabolism and SNPs. The analysis of repeat element footprints revealed some genes such as naringenin, 2-oxoglutarate 3-dioxygenase being targeted by Pot2 and Occan, in isolates from different host species. Some repeat insertions were host-specific while other insertions were randomly shared between isolates. The distributions of repeat elements, secretory proteins, CAZymes and SNPs showed significant variation across host-specific lineages of Magnaporthe indicating an independent genome evolution orchestrated by multiple genomic factors. PMID:27658241

  6. A Genome-Wide Association Study Reveals Genes Associated with Fusarium Ear Rot Resistance in a Maize Core Diversity Panel

    PubMed Central

    Zila, Charles T.; Samayoa, L. Fernando; Santiago, Rogelio; Butrón, Ana; Holland, James B.

    2013-01-01

    Fusarium ear rot is a common disease of maize that affects food and feed quality globally. Resistance to the disease is highly quantitative, and maize breeders have difficulty incorporating polygenic resistance alleles from unadapted donor sources into elite breeding populations without having a negative impact on agronomic performance. Identification of specific allele variants contributing to improved resistance may be useful to breeders by allowing selection of resistance alleles in coupling phase linkage with favorable agronomic characteristics. We report the results of a genome-wide association study to detect allele variants associated with increased resistance to Fusarium ear rot in a maize core diversity panel of 267 inbred lines evaluated in two sets of environments. We performed association tests with 47,445 single-nucleotide polymorphisms (SNPs) while controlling for background genomic relationships with a mixed model and identified three marker loci significantly associated with disease resistance in at least one subset of environments. Each associated SNP locus had relatively small additive effects on disease resistance (±1.1% on a 0–100% scale), but nevertheless were associated with 3 to 12% of the genotypic variation within or across environment subsets. Two of three identified SNPs colocalized with genes that have been implicated with programmed cell death. An analysis of associated allele frequencies within the major maize subpopulations revealed enrichment for resistance alleles in the tropical/subtropical and popcorn subpopulations compared with other temperate breeding pools. PMID:24048647

  7. Transcriptome profiling of the demosponge Amphimedon queenslandica reveals genome-wide events that accompany major life cycle transitions

    PubMed Central

    2012-01-01

    Background The biphasic life cycle with pelagic larva and benthic adult stages is widely observed in the animal kingdom, including the Porifera (sponges), which are the earliest branching metazoans. The demosponge, Amphimedon queenslandica, undergoes metamorphosis from a free-swimming larva into a sessile adult that bears no morphological resemblance to other animals. While the genome of A. queenslandica contains an extensive repertoire of genes very similar to that of complex bilaterians, it is as yet unclear how this is drawn upon to coordinate changing morphological features and ecological demands throughout the sponge life cycle. Results To identify genome-wide events that accompany the pelagobenthic transition in A. queenslandica, we compared global gene expression profiles at four key developmental stages by sequencing the poly(A) transcriptome using SOLiD technology. Large-scale changes in transcription were observed as sponge larvae settled on the benthos and began metamorphosis. Although previous systematics suggest that the only clear homology between Porifera and other animals is in the embryonic and larval stages, we observed extensive use of genes involved in metazoan-associated cellular processes throughout the sponge life cycle. Sponge-specific transcripts are not over-represented in the morphologically distinct adult; rather, many genes that encode typical metazoan features, such as cell adhesion and immunity, are upregulated. Our analysis further revealed gene families with candidate roles in competence, settlement, and metamorphosis in the sponge, including transcription factors, G-protein coupled receptors and other signaling molecules. Conclusions This first genome-wide study of the developmental transcriptome in an early branching metazoan highlights major transcriptional events that accompany the pelagobenthic transition and point to a network of regulatory mechanisms that coordinate changes in morphology with shifting environmental demands

  8. Genome-wide analysis in endangered populations: a case study in Barbaresca sheep.

    PubMed

    Mastrangelo, S; Portolano, B; Di Gerlando, R; Ciampolini, R; Tolone, M; Sardina, M T

    2017-01-12

    Analysis of genomic data is becoming increasingly common in the livestock industry and the findings have been an invaluable resource for effective management of breeding programs in small and endangered populations. In this paper, with the goal of highlighting the potential of genomic analysis for small and endangered populations, genome-wide levels of linkage disequilibrium, measured as the squared correlation coefficient of allele frequencies at a pair of loci, effective population size, runs of homozygosity (ROH) and genetic diversity parameters, were estimated in Barbaresca sheep using Illumina OvineSNP50K array data. Moreover, the breed's genetic structure and its relationship with other breeds were investigated. Levels of pairwise linkage disequilibrium decreased with increasing distance between single nucleotide polymorphisms. An average correlation coefficient <0.25 was found for markers located up to 50 kb apart. Therefore, these results support the need to use denser single nucleotide polymorphism panels for high power association mapping and genomic selection efficiency in future breeding programs. The estimate of past effective population size ranged from 747 animals 250 generations ago to 28 animals five generations ago, whereas the contemporary effective population size was 25 animals. A total of 637 ROH were identified, most of which were short (67%) and ranged from 1 to 10 Mb. The genetic analyses revealed that the Barbaresca breed tended to display lower variability than other Sicilian breeds. Recent inbreeding was evident, according to the ROH analysis. All the investigated parameters showed a comparatively narrow genetic base and indicated an endangered status for Barbaresca. Multidimensional scaling, model-based clustering, measurement of population differentiation, neighbor networks and haplotype sharing distinguished Barbaresca from other breeds, showed a low level of admixture with the other breeds considered in this study, and indicated

  9. Genome-wide investigation reveals high evolutionary rates in annual model plants

    PubMed Central

    2010-01-01

    Background Rates of molecular evolution vary widely among species. While significant deviations from molecular clock have been found in many taxa, effects of life histories on molecular evolution are not fully understood. In plants, annual/perennial life history traits have long been suspected to influence the evolutionary rates at the molecular level. To date, however, the number of genes investigated on this subject is limited and the conclusions are mixed. To evaluate the possible heterogeneity in evolutionary rates between annual and perennial plants at the genomic level, we investigated 85 nuclear housekeeping genes, 10 non-housekeeping families, and 34 chloroplast genes using the genomic data from model plants including Arabidopsis thaliana and Medicago truncatula for annuals and grape (Vitis vinifera) and popular (Populus trichocarpa) for perennials. Results According to the cross-comparisons among the four species, 74-82% of the nuclear genes and 71-97% of the chloroplast genes suggested higher rates of molecular evolution in the two annuals than those in the two perennials. The significant heterogeneity in evolutionary rate between annuals and perennials was consistently found both in nonsynonymous sites and synonymous sites. While a linear correlation of evolutionary rates in orthologous genes between species was observed in nonsynonymous sites, the correlation was weak or invisible in synonymous sites. This tendency was clearer in nuclear genes than in chloroplast genes, in which the overall evolutionary rate was small. The slope of the regression line was consistently lower than unity, further confirming the higher evolutionary rate in annuals at the genomic level. Conclusions The higher evolutionary rate in annuals than in perennials appears to be a universal phenomenon both in nuclear and chloroplast genomes in the four dicot model plants we investigated. Therefore, such heterogeneity in evolutionary rate should result from factors that have genome-wide

  10. Genome-Wide Analysis of Polycistronic MicroRNAs in Cultivated and Wild Rice

    PubMed Central

    Baldrich, Patricia; Hsing, Yue-Ie Caroline; San Segundo, Blanca

    2016-01-01

    MicroRNAs (miRNAs) are small noncoding RNAs that direct posttranscriptional gene silencing in eukaryotes. They are frequently clustered in the genomes of animals and can be independently transcribed or simultaneously transcribed into single polycistronic transcripts. Only a few miRNA clusters have been described in plants, and most of them are generated from independent transcriptional units. Here, we used a combination of bioinformatic tools and experimental analyses to discover new polycistronic miRNAs in rice. A genome-wide analysis of clustering patterns of MIRNA loci in the rice genome was carried out using a criterion of 3 kb as the maximal distance between two miRNAs. This analysis revealed 28 loci with the ability to form the typical hairpin structure of miRNA precursors in which 2 or more mature miRNAs mapped along the same structure. RT-PCR provided evidence for the polycistronic nature of seven miRNA precursors containing homologous or nonhomologous miRNA species. Polycistronic miRNAs and candidate polycistronic miRNAs are located across different rice chromosomes, except chromosome 12, and resided in both duplicated and nonduplicated chromosomal regions. Finally, most polycistronic and candidate polycistronic miRNAs showed a pattern of conservation in the genome of rice species with an AA genome. The diversity in the organization of MIR genes that are transcribed as polycistrons suggests a versatile mechanism for the control of gene expression in different biological processes and supports additional levels of complexity in miRNA functioning in plants. PMID:27190137

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

    PubMed

    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.

  12. Genome-wide SNP analysis of the Systemic Capillary Leak Syndrome (Clarkson disease)

    PubMed Central

    Xie, Zhihui; Nagarajan, Vijayaraj; Sturdevant, Daniel E; Iwaki, Shoko; Chan, Eunice; Wisch, Laura; Young, Michael; Nelson, Celeste M; Porcella, Stephen F; Druey, Kirk M

    2013-01-01

    The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles, and is frequently erroneously diagnosed as, systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flanking CAV3 (3p25.3) as well as SNP clusters in PON1 (7q21.3), PSORS1C1 (6p21.3), and CHCHD3 (7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterized LOC100130480 gene (rs6417039, rs2004296). Top case-associated SNPs were observed in BTRC (rs12355803, 3rs4436485), ARHGEF18 (rs11668246), CDH13 (rs4782779), and EDG2 (rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. 61 SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS. PMID:24808988

  13. Genome-Wide Identification and Analysis of the TIFY Gene Family in Grape

    PubMed Central

    Zhang, Yucheng; Gao, Min; Singer, Stacy D.; Fei, Zhangjun; Wang, Hua; Wang, Xiping

    2012-01-01

    Background The TIFY gene family constitutes a plant-specific group of genes with a broad range of functions. This family encodes four subfamilies of proteins, including ZML, TIFY, PPD and JASMONATE ZIM-Domain (JAZ) proteins. JAZ proteins are targets of the SCFCOI1 complex, and function as negative regulators in the JA signaling pathway. Recently, it has been reported in both Arabidopsis and rice that TIFY genes, and especially JAZ genes, may be involved in plant defense against insect feeding, wounding, pathogens and abiotic stresses. Nonetheless, knowledge concerning the specific expression patterns and evolutionary history of plant TIFY family members is limited, especially in a woody species such as grape. Methodology/Principal Findings A total of two TIFY, four ZML, two PPD and 11 JAZ genes were identified in the Vitis vinifera genome. Phylogenetic analysis of TIFY protein sequences from grape, Arabidopsis and rice indicated that the grape TIFY proteins are more closely related to those of Arabidopsis than those of rice. Both segmental and tandem duplication events have been major contributors to the expansion of the grape TIFY family. In addition, synteny analysis between grape and Arabidopsis demonstrated that homologues of several grape TIFY genes were found in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the divergence of lineages that led to grape and Arabidopsis. Analyses of microarray and quantitative real-time RT-PCR expression data revealed that grape TIFY genes are not a major player in the defense against biotrophic pathogens or viruses. However, many of these genes were responsive to JA and ABA, but not SA or ET. Conclusion The genome-wide identification, evolutionary and expression analyses of grape TIFY genes should facilitate further research of this gene family and provide new insights regarding their evolutionary history and regulatory control. PMID:22984514

  14. Genome-Wide Analysis of miRNA targets in Brachypodium and Biomass Energy Crops

    SciTech Connect

    Green, Pamela J.

    2015-08-11

    MicroRNAs (miRNAs) contribute to the control of numerous biological processes through the regulation of specific target mRNAs. Although the identities of these targets are essential to elucidate miRNA function, the targets are much more difficult to identify than the small RNAs themselves. Before this work, we pioneered the genome-wide identification of the targets of Arabidopsis miRNAs using an approach called PARE (German et al., Nature Biotech. 2008; Nature Protocols, 2009). Under this project, we applied PARE to Brachypodium distachyon (Brachypodium), a model plant in the Poaceae family, which includes the major food grain and bioenergy crops. Through in-depth global analysis and examination of specific examples, this research greatly expanded our knowledge of miRNAs and target RNAs of Brachypodium. New regulation in response to environmental stress or tissue type was found, and many new miRNAs were discovered. More than 260 targets of new and known miRNAs with PARE sequences at the precise sites of miRNA-guided cleavage were identified and characterized. Combining PARE data with the small RNA data also identified the miRNAs responsible for initiating approximately 500 phased loci, including one of the novel miRNAs. PARE analysis also revealed that differentially expressed miRNAs in the same family guide specific target RNA cleavage in a correspondingly tissue-preferential manner. The project included generation of small RNA and PARE resources for bioenergy crops, to facilitate ongoing discovery of conserved miRNA-target RNA regulation. By associating specific miRNA-target RNA pairs with known physiological functions, the research provides insights about gene regulation in different tissues and in response to environmental stress. This, and release of new PARE and small RNA data sets should contribute basic knowledge to enhance breeding and may suggest new strategies for improvement of biomass energy crops.

  15. 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. PMID:27630648

  16. 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

  17. Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.

    PubMed

    Herold, C; Hooli, B V; Mullin, K; Liu, T; Roehr, J T; Mattheisen, M; Parrado, A R; Bertram, L; Lange, C; Tanzi, R E

    2016-11-01

    The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10(-8)), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10(-8)), and rs1513625 near PDCL3 (P-value=4.28 × 10(-8)). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10(-7)) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10(-7); rs62400067, P-value=3.54 × 10(-7)). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.

  18. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  19. Genome-wide identification and comparative expression analysis reveal a rapid expansion and functional divergence of duplicated genes in the WRKY gene family of cabbage, Brassica oleracea var. capitata.

    PubMed

    Yao, Qiu-Yang; Xia, En-Hua; Liu, Fei-Hu; Gao, Li-Zhi

    2015-02-15

    WRKY transcription factors (TFs), one of the ten largest TF families in higher plants, play important roles in regulating plant development and resistance. To date, little is known about the WRKY TF family in Brassica oleracea. Recently, the completed genome sequence of cabbage (B. oleracea var. capitata) allows us to systematically analyze WRKY genes in this species. A total of 148 WRKY genes were characterized and classified into seven subgroups that belong to three major groups. Phylogenetic and synteny analyses revealed that the repertoire of cabbage WRKY genes was derived from a common ancestor shared with Arabidopsis thaliana. The B. oleracea WRKY genes were found to be preferentially retained after the whole-genome triplication (WGT) event in its recent ancestor, suggesting that the WGT event had largely contributed to a rapid expansion of the WRKY gene family in B. oleracea. The analysis of RNA-Seq data from various tissues (i.e., roots, stems, leaves, buds, flowers and siliques) revealed that most of the identified WRKY genes were positively expressed in cabbage, and a large portion of them exhibited patterns of differential and tissue-specific expression, demonstrating that these gene members might play essential roles in plant developmental processes. Comparative analysis of the expression level among duplicated genes showed that gene expression divergence was evidently presented among cabbage WRKY paralogs, indicating functional divergence of these duplicated WRKY genes.

  20. Genome-wide comparison of African-ancestry populations from CARe and other cohorts reveals signals of natural selection.

    PubMed

    Bhatia, Gaurav; Patterson, Nick; Pasaniuc, Bogdan; Zaitlen, Noah; Genovese, Giulio; Pollack, Samuela; Mallick, Swapan; Myers, Simon; Tandon, Arti; Spencer, Chris; Palmer, Cameron D; Adeyemo, Adebowale A; Akylbekova, Ermeg L; Cupples, L Adrienne; Divers, Jasmin; Fornage, Myriam; Kao, W H Linda; Lange, Leslie; Li, Mingyao; Musani, Solomon; Mychaleckyj, Josyf C; Ogunniyi, Adesola; Papanicolaou, George; Rotimi, Charles N; Rotter, Jerome I; Ruczinski, Ingo; Salako, Babatunde; Siscovick, David S; Tayo, Bamidele O; Yang, Qiong; McCarroll, Steve; Sabeti, Pardis; Lettre, Guillaume; De Jager, Phil; Hirschhorn, Joel; Zhu, Xiaofeng; Cooper, Richard; Reich, David; Wilson, James G; Price, Alkes L

    2011-09-09

    The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better understand the population level response to environmental pressures including infectious disease. Our study examines unusual population differentiation between three large data sets to detect natural selection. The populations examined, African Americans, Nigerians, and Gambians, are genetically close to one another (F(ST) < 0.01 for all pairs), allowing us to detect selection even with moderate changes in allele frequency. We also develop a tree-based method to pinpoint the population in which selection occurred, incorporating information across populations. Our genome-wide significant results corroborate loci previously reported to be under selection in Africans including HBB and CD36. At the HLA locus on chromosome 6, results suggest the existence of multiple, independent targets of population-specific selective pressure. In addition, we report a genome-wide significant (p = 1.36 × 10(-11)) signal of selection in the prostate stem cell antigen (PSCA) gene. The most significantly differentiated marker in our analysis, rs2920283, is highly differentiated in both Africa and East Asia and has prior genome-wide significant associations to bladder and gastric cancers.

  1. Genome-wide quantification of homeolog expression ratio revealed nonstochastic gene regulation in synthetic allopolyploid Arabidopsis

    PubMed Central

    Akama, Satoru; Shimizu-Inatsugi, Rie; Shimizu, Kentaro K.; Sese, Jun

    2014-01-01

    Genome duplication with hybridization, or allopolyploidization, occurs commonly in plants, and is considered to be a strong force for generating new species. However, genome-wide quantification of homeolog expression ratios was technically hindered because of the high homology between homeologous gene pairs. To quantify the homeolog expression ratio using RNA-seq obtained from polyploids, a new method named HomeoRoq was developed, in which the genomic origin of sequencing reads was estimated using mismatches between the read and each parental genome. To verify this method, we first assembled the two diploid parental genomes of Arabidopsis halleri subsp. gemmifera and Arabidopsis lyrata subsp. petraea (Arabidopsis petraea subsp. umbrosa), then generated a synthetic allotetraploid, mimicking the natural allopolyploid Arabidopsis kamchatica. The quantified ratios corresponded well to those obtained by Pyrosequencing. We found that the ratios of homeologs before and after cold stress treatment were highly correlated (r = 0.870). This highlights the presence of nonstochastic polyploid gene regulation despite previous research identifying stochastic variation in expression. Moreover, our new statistical test incorporating overdispersion identified 226 homeologs (1.11% of 20 369 expressed homeologs) with significant ratio changes, many of which were related to stress responses. HomeoRoq would contribute to the study of the genes responsible for polyploid-specific environmental responses. PMID:24423873

  2. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication.

    PubMed

    Vonholdt, Bridgett M; Pollinger, John P; Lohmueller, Kirk E; Han, Eunjung; Parker, Heidi G; Quignon, Pascale; Degenhardt, Jeremiah D; Boyko, Adam R; Earl, Dent A; Auton, Adam; Reynolds, Andy; Bryc, Kasia; Brisbin, Abra; Knowles, James C; Mosher, Dana S; Spady, Tyrone C; Elkahloun, Abdel; Geffen, Eli; Pilot, Malgorzata; Jedrzejewski, Wlodzimierz; Greco, Claudia; Randi, Ettore; Bannasch, Danika; Wilton, Alan; Shearman, Jeremy; Musiani, Marco; Cargill, Michelle; Jones, Paul G; Qian, Zuwei; Huang, Wei; Ding, Zhao-Li; Zhang, Ya-Ping; Bustamante, Carlos D; Ostrander, Elaine A; Novembre, John; Wayne, Robert K

    2010-04-08

    Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.

  3. Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication

    PubMed Central

    vonHoldt, Bridgett M.; Pollinger, John P.; Lohmueller, Kirk E.; Han, Eunjung; Parker, Heidi G.; Quignon, Pascale; Degenhardt, Jeremiah D.; Boyko, Adam R.; Earl, Dent A.; Auton, Adam; Reynolds, Andy; Bryc, Kasia; Brisbin, Abra; Knowles, James C.; Mosher, Dana S.; Spady, Tyrone C.; Elkahloun, Abdel; Geffen, Eli; Pilot, Malgorzata; Jedrzejewski, Wlodzimierz; Greco, Claudia; Randi, Ettore; Bannasch, Danika; Wilton, Alan; Shearman, Jeremy; Musiani, Marco; Cargill, Michelle; Jones, Paul G.; Qian, Zuwei; Huang, Wei; Ding, Zhao-Li; Zhang, Ya-ping; Bustamante, Carlos D.; Ostrander, Elaine A.; Novembre, John; Wayne, Robert K.

    2010-01-01

    Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication1,2. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data3. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity. PMID:20237475

  4. Genome-Wide Association Study Reveals the Genetic Basis of Stalk Cell Wall Components in Maize

    PubMed Central

    Hu, Xiaojiao; Liu, Zhifang; Wu, Yujin; Huang, Changling

    2016-01-01

    Lignin, cellulose and hemicellulose are the three main components of the plant cell wall and can impact stalk quality by affecting cell wall structure and strength. In this study, we evaluated the lignin (LIG), cellulose (CEL) and hemicellulose (HC) contents in maize using an association mapping panel that included 368 inbred lines in seven environments. A genome-wide association study using approximately 0.56 million SNPs with a minor allele frequency of 0.05 identified 22, 18 and 24 loci significantly associated with LIG, CEL and HC at P < 1.0×10−4, respectively. The allelic variation of each significant association contributed 4 to 7% of the phenotypic variation. Candidate genes identified by GWAS mainly encode enzymes involved in cell wall metabolism, transcription factors, protein kinase and protein related to other biological processes. Among the association signals, six candidate genes had pleiotropic effects on lignin and cellulose content. These results provide valuable information for better understanding the genetic basis of stalk cell wall components in maize. PMID:27479588

  5. Genome-Wide Crossover Distribution in Arabidopsis thaliana Meiosis Reveals Sex-Specific Patterns along Chromosomes

    PubMed Central

    Drouaud, Jan; Pereira, Lucie; Martin, Olivier C.; Mézard, Christine

    2011-01-01

    In most species, crossovers (COs) are essential for the accurate segregation of homologous chromosomes at the first meiotic division. Their number and location are tightly regulated. Here, we report a detailed, genome-wide characterization of the rate and localization of COs in Arabidopsis thaliana, in male and female meiosis. We observed dramatic differences between male and female meiosis which included: (i) genetic map length; 575 cM versus 332 cM respectively; (ii) CO distribution patterns: male CO rates were very high at both ends of each chromosome, whereas female CO rates were very low; (iii) correlations between CO rates and various chromosome features: female CO rates correlated strongly and negatively with GC content and gene density but positively with transposable elements (TEs) density, whereas male CO rates correlated positively with the CpG ratio. However, except for CpG, the correlations could be explained by the unequal repartition of these sequences along the Arabidopsis chromosome. For both male and female meiosis, the number of COs per chromosome correlates with chromosome size expressed either in base pairs or as synaptonemal complex length. Finally, we show that interference modulates the CO distribution both in male and female meiosis. PMID:22072983

  6. Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

    PubMed Central

    Kraehling, Jan R.; Chidlow, John H.; Rajagopal, Chitra; Sugiyama, Michael G.; Fowler, Joseph W.; Lee, Monica Y.; Zhang, Xinbo; Ramírez, Cristina M.; Park, Eon Joo; Tao, Bo; Chen, Keyang; Kuruvilla, Leena; Larriveé, Bruno; Folta-Stogniew, Ewa; Ola, Roxana; Rotllan, Noemi; Zhou, Wenping; Nagle, Michael W.; Herz, Joachim; Williams, Kevin Jon; Eichmann, Anne; Lee, Warren L.; Fernández-Hernando, Carlos; Sessa, William C.

    2016-01-01

    In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL. PMID:27869117

  7. Genome-Wide Transcriptional Analysis Reveals the Protection against Hypoxia-Induced Oxidative Injury in the Intestine of Tibetans via the Inhibition of GRB2/EGFR/PTPN11 Pathways

    PubMed Central

    Gesang, Luobu; Dan, Zeng; Gusang, Lamu

    2016-01-01

    The molecular mechanisms for hypoxic environment causing the injury of intestinal mucosal barrier (IMB) are widely unknown. To address the issue, Han Chinese from 100 m altitude and Tibetans from high altitude (more than 3650 m) were recruited. Histological and transcriptome analyses were performed. The results showed intestinal villi were reduced and appeared irregular, and glandular epithelium was destroyed in the IMB of Tibetans when compared with Han Chinese. Transcriptome analysis revealed 2573 genes with altered expression. The levels of 1137 genes increased and 1436 genes decreased in Tibetans when compared with Han Chinese. Gene ontology (GO) analysis indicated most immunological responses were reduced in the IMB of Tibetans when compared with Han Chinese. Gene microarray showed that there were 25-, 22-, and 18-fold downregulation for growth factor receptor-bound protein 2 (GRB2), epidermal growth factor receptor (EGFR), and tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) in the IMB of Tibetans when compared with Han Chinese. The downregulation of EGFR, GRB2, and PTPN11 will reduce the production of reactive oxygen species and protect against oxidative stress-induced injury for intestine. Thus, the transcriptome analysis showed the protecting functions of IMB patients against hypoxia-induced oxidative injury in the intestine of Tibetans via affecting GRB2/EGFR/PTPN11 pathways. PMID:27594973

  8. Genome wide analysis of transcript levels after perturbation of the EGFR pathway in the Drosophila ovary.

    PubMed

    Jordan, Katherine C; Hatfield, Steven D; Tworoger, Michael; Ward, Ellen J; Fischer, Karin A; Bowers, Stuart; Ruohola-Baker, Hannele

    2005-03-01

    Defects in the epidermal growth factor receptor (EGFR) pathway can lead to aggressive tumor formation. Activation of this pathway during normal development produces multiple outcomes at the cellular level, leading to cellular differentiation and cell cycle activation. To elucidate the downstream events induced by this pathway, we used genome-wide cDNA microarray technology to identify potential EGFR targets in Drosophila oogenesis. We focused on genes for which the transcriptional responses due to EGFR pathway activation and inactivation were in opposite directions, as this is expected for genes that are directly regulated by the pathway in this tissue type. We perturbed the EGFR pathway in epithelial follicle cells using seven different genetic backgrounds. To activate the pathway, we overexpressed an activated form of the EGFR (UAS-caEGFR), and an activated form of the signal transducer Raf (UAS-caRaf); we also over- or ectopically expressed the downstream homeobox transcription factor Mirror (UAS-mirr) and the ligand-activating serine protease Rhomboid (UAS-rho). To reduce pathway activity we used loss-of-function mutations in the ligand (gurken) and receptor (torpedo). From microarrays containing 6,255 genes, we found 454 genes that responded in an opposite manner in gain-of-function and loss-of-function conditions among which are many Wingless signaling pathway components. Further analysis of two such components, sugarless and pangolin, revealed a function for these genes in late follicle cell patterning. Of interest, components of other signaling pathways were also enriched in the EGFR target group, suggesting that one reason for the pleiotropic effects seen with EGFR activity in cancer progression and development may be its ability to regulate many other signaling pathways.

  9. Genome-wide analysis of WRKY transcription factors in Solanum lycopersicum.

    PubMed

    Huang, Shengxiong; Gao, Yongfeng; Liu, Jikai; Peng, Xiaoli; Niu, Xiangli; Fei, Zhangjun; Cao, Shuqing; Liu, Yongsheng

    2012-06-01

    The WRKY transcription factors have been implicated in multiple biological processes in plants, especially in regulating defense against biotic and abiotic stresses. However, little information is available about the WRKYs in tomato (Solanum lycopersicum). The recent release of the whole-genome sequence of tomato allowed us to perform a genome-wide investigation for tomato WRKY proteins, and to compare these positively identified proteins with their orthologs in model plants, such as Arabidopsis and rice. In the present study, based on the recently released tomato whole-genome sequences, we identified 81 SlWRKY genes that were classified into three main groups, with the second group further divided into five subgroups. Depending on WRKY domains' sequences derived from tomato, Arabidopsis and rice, construction of a phylogenetic tree demonstrated distinct clustering and unique gene expansion of WRKY genes among the three species. Genome mapping analysis revealed that tomato WRKY genes were enriched on several chromosomes, especially on chromosome 5, and 16 % of the family members were tandemly duplicated genes. The tomato WRKYs from each group were shown to share similar motif compositions. Furthermore, tomato WRKY genes showed distinct temporal and spatial expression patterns in different developmental processes and in response to various biotic and abiotic stresses. The expression of 18 selected tomato WRKY genes in response to drought and salt stresses and Pseudomonas syringae invasion, respectively, was validated by quantitative RT-PCR. Our results will provide a platform for functional identification and molecular breeding study of WRKY genes in tomato and probably other Solanaceae plants.

  10. Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients

    PubMed Central

    Yue, Weihua; Cheng, Weiqiu; Liu, Zhaorui; Tang, Yi; Lu, Tianlan; Zhang, Dai; Tang, Muni; Huang, Yueqin

    2016-01-01

    Literatures have suggested that not only genetic but also environmental factors, interactively accounted for susceptibility of obsessive-compulsive disorder (OCD). DNA methylation may regulate expression of genes as the heritable epigenetic modification. The examination for genome-wide DNA methylation was performed on blood samples from 65 patients with OCD, as well as 96 healthy control subjects. The DNA methylation was examined at over 485,000 CpG sites using the Illumina Infinium Human Methylation450 BeadChip. As a result, 8,417 probes corresponding to 2,190 unique genes were found to be differentially methylated between OCD and healthy control subjects. Of those genes, 4,013 loci were located in CpG islands and 2,478 were in promoter regions. These included BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc., which have previously been reported to be associated with OCD. Pathway analyses indicated that regulation of actin cytoskeleton, cell adhesion molecules (CAMs), actin binding, transcription regulator activity, and other pathways might be further associated with risk of OCD. Unsupervised clustering analysis of the top 3,000 most variable probes revealed two distinct groups with significantly more people with OCD in cluster one compared with controls (67.74% of cases v.s. 27.13% of controls, Chi-square = 26.011, df = 1, P = 3.41E-07). These results strongly suggested that differential DNA methylation might play an important role in etiology of OCD. PMID:27527274

  11. Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients.

    PubMed

    Yue, Weihua; Cheng, Weiqiu; Liu, Zhaorui; Tang, Yi; Lu, Tianlan; Zhang, Dai; Tang, Muni; Huang, Yueqin

    2016-08-16

    Literatures have suggested that not only genetic but also environmental factors, interactively accounted for susceptibility of obsessive-compulsive disorder (OCD). DNA methylation may regulate expression of genes as the heritable epigenetic modification. The examination for genome-wide DNA methylation was performed on blood samples from 65 patients with OCD, as well as 96 healthy control subjects. The DNA methylation was examined at over 485,000 CpG sites using the Illumina Infinium Human Methylation450 BeadChip. As a result, 8,417 probes corresponding to 2,190 unique genes were found to be differentially methylated between OCD and healthy control subjects. Of those genes, 4,013 loci were located in CpG islands and 2,478 were in promoter regions. These included BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc., which have previously been reported to be associated with OCD. Pathway analyses indicated that regulation of actin cytoskeleton, cell adhesion molecules (CAMs), actin binding, transcription regulator activity, and other pathways might be further associated with risk of OCD. Unsupervised clustering analysis of the top 3,000 most variable probes revealed two distinct groups with significantly more people with OCD in cluster one compared with controls (67.74% of cases v.s. 27.13% of controls, Chi-square = 26.011, df = 1, P = 3.41E-07). These results strongly suggested that differential DNA methylation might play an important role in etiology of OCD.

  12. Power comparison of admixture mapping and direct association analysis in genome-wide association studies.

    PubMed

    Qin, Huaizhen; Zhu, Xiaofeng

    2012-04-01

    When dense markers are available, one can interrogate almost every common variant across the genome via imputation and single nucleotide polymorphism (SNP) test, which has become a routine in current genome-wide association studies (GWASs). As a complement, admixture mapping exploits the long-range linkage disequilibrium (LD) generated by admixture between genetically distinct ancestral populations. It is then questionable whether admixture mapping analysis is still necessary in detecting the disease associated variants in admixed populations. We argue that admixture mapping is able to reduce the burden of massive comparisons in GWASs; it therefore can be a powerful tool to locate the disease variants with substantial allele frequency differences between ancestral populations. In this report we studied a two-stage approach, where candidate regions are defined by conducting admixture mapping at stage 1, and single SNP association tests are followed at stage 2 within the candidate regions defined at stage 1. We first established the genome-wide significance levels corresponding to the criteria to define the candidate regions at stage 1 by simulations. We next compared the power of the two-stage approach with direct association analysis. Our simulations suggest that the two-stage approach can be more powerful than the standard genome-wide association analysis when the allele frequency difference of a causal variant in ancestral populations, is larger than 0.4. Our conclusion is consistent with a theoretical prediction by Risch and Tang ([2006] Am J Hum Genet 79:S254). Surprisingly, our study also suggests that power can be improved when we use less strict criteria to define the candidate regions at stage 1.

  13. Meta-analysis of genome-wide association studies of anxiety disorders

    PubMed Central

    Otowa, Takeshi; Hek, Karin; Lee, Minyoung; Byrne, Enda M.; Mirza, Saira S.; Nivard, Michel G.; Bigdeli, Timothy; Aggen, Steven H.; Adkins, Daniel; Wolen, Aaron; Fanous, Ayman; Keller, Matthew C.; Castelao, Enrique; Kutalik, Zoltan; Van der Auwera, Sandra; Homuth, Georg; Nauck, Matthias; Teumer, Alexander; Milaneschi, Yuri; Hottenga, Jouke-Jan; Direk, Nese; Hofman, Albert; Uitterlinden, Andre; Mulder, Cornelis L.; Henders, Anjali K.; Medland, Sarah E.; Gordon, Scott; Heath, Andrew C.; Madden, Pamela A.F.; Pergadia, Michelle; van der Most, Peter J.; Nolte, Ilja M.; van Oort, Floor V.A.; Hartman, Catharina A.; Oldehinkel, Albertine J.; Preisig, Martin; Grabe, Hans Jörgen; Middeldorp, Christel M.; Penninx, Brenda WJH; Boomsma, Dorret; Martin, Nicholas G.; Montgomery, Grant; Maher, Brion S.; van den Oord, Edwin J.; Wray, Naomi R.; Tiemeier, Henning; Hettema, John M.

    2015-01-01

    Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders. PMID:26754954

  14. Principal components analysis corrects for stratification in genome-wide association studies.

    PubMed

    Price, Alkes L; Patterson, Nick J; Plenge, Robert M; Weinblatt, Michael E; Shadick, Nancy A; Reich, David

    2006-08-01

    Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.

  15. MAVEN: a tool for visualization and functional analysis of genome-wide association results

    PubMed Central

    Narayanan, Kanchana; Li, Jing

    2010-01-01

    Summary: We describe the features and implementation of a web application tool named MAVEN—for Management, Analysis, Visualization and rEsults shariNg of genome-wide association data using cutting edge technologies. Main capabilities include user data uploading and management, queries using a variety of criteria, visualization of results, interactive selections and seamless integration of users' data with databases at the National Center for Biotechnology Information (NCBI) for functional annotations of single nucleotide polymorphisms (SNPs) and genes. Availability: http://cbc.case.edu/maven Contact: jingli@case.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19933166

  16. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

    PubMed

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A; Barnes, Michael R; Li, Xiaohui; Warren, Helen R; Chasman, Daniel I; Zhou, Kaixin; Arsenault, Benoit J; Donnelly, Louise A; Wiggins, Kerri L; Avery, Christy L; Griffin, Paula; Feng, QiPing; Taylor, Kent D; Li, Guo; Evans, Daniel S; Smith, Albert V; de Keyser, Catherine E; Johnson, Andrew D; de Craen, Anton J M; Stott, David J; Buckley, Brendan M; Ford, Ian; Westendorp, Rudi G J; Slagboom, P Eline; Sattar, Naveed; Munroe, Patricia B; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y-D Ida; Nickerson, Deborah A; Smith, Joshua D; Dubé, Marie Pierre; Boekholdt, S Matthijs; Hovingh, G Kees; Kastelein, John J P; McKeigue, Paul M; Betteridge, John; Neil, Andrew; Durrington, Paul N; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C; Rice, Kenneth; Smith, Nicholas L; Lumley, Thomas; Whitsel, Eric A; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S; O'Donnell, Christopher J; Vasan, Ramachandran S; Wei, Wei-Qi; Wilke, Russell A; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M; Stafford, Jeanette M; Ding, Jingzhong; Herrington, David M; Kritchevsky, Stephen B; Eiriksdottir, Gudny; Launer, Leonore J; Harris, Tamara B; Chu, Audrey Y; Giulianini, Franco; MacFadyen, Jean G; Barratt, Bryan J; Nyberg, Fredrik; Stricker, Bruno H; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H; Ridker, Paul M; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C; Ballantyne, Christie M; Rotter, Jerome I; Adrienne Cupples, L; Psaty, Bruce M; Palmer, Colin N A; Tardif, Jean-Claude; Colhoun, Helen M; Hitman, Graham; Krauss, Ronald M; Wouter Jukema, J; Caulfield, Mark J

    2014-10-28

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

  17. Genome-wide linkage analysis of blood pressure under locus heterogeneity

    PubMed Central

    Yang, Xinqun; Wang, Kai; Huang, Jian; Vieland, Veronica J

    2003-01-01

    We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals. PMID:14975146

  18. Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling

    PubMed Central

    Robbins, Scott H; Walzer, Thierry; Dembélé, Doulaye; Thibault, Christelle; Defays, Axel; Bessou, Gilles; Xu, Huichun; Vivier, Eric; Sellars, MacLean; Pierre, Philippe; Sharp, Franck R; Chan, Susan; Kastner, Philippe; Dalod, Marc

    2008-01-01

    Background Dendritic cells (DCs) are a complex group of cells that play a critical role in vertebrate immunity. Lymph-node resident DCs (LN-DCs) are subdivided into conventional DC (cDC) subsets (CD11b and CD8α in mouse; BDCA1 and BDCA3 in human) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To gain novel insights into these questions, we sought conserved genetic signatures for LN-DCs and in vitro derived granulocyte-macrophage colony stimulating factor (GM-CSF) DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes. Results We show through clustering analysis that all LN-DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionarily conserved in all LN-DC subsets. Moreover, we identify a large gene expression program shared between mouse and human pDCs, and smaller conserved profiles shared between mouse and human LN-cDC subsets. Importantly, most of these genes have not been previously associated with DC function and many have unknown functions. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs, lin-CD16+HLA-DR+ cells and in vitro derived GM-CSF DCs, and show that these cells are more closely linked to natural killer and myeloid cells, respectively. Conclusion Our study provides a unique database resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs. PMID:18218067

  19. Genome-Wide Collation of the Plasmodium falciparum WDR Protein Superfamily Reveals Malarial Parasite-Specific Features

    PubMed Central

    Chahar, Priyanka; Kaushik, Manjeri; Gill, Sarvajeet Singh; Gakhar, Surendra Kumar; Gopalan, Natrajan; Datt, Manish; Sharma, Amit; Gill, Ritu

    2015-01-01

    Despite a significant drop in malaria deaths during the past decade, malaria continues to be one of the biggest health problems around the globe. WD40 repeats (WDRs) containing proteins comprise one of the largest and functionally diverse protein superfamily in eukaryotes, acting as scaffolds for assembling large protein complexes. In the present study, we report an extensive in silico analysis of the WDR gene family in human malaria parasite Plasmodium falciparum. Our genome-wide identification has revealed 80 putative WDR genes in P. falciparum (PfWDRs). Five distinct domain compositions were discovered in Plasmodium as compared to the human host. Notably, 31 PfWDRs were annotated/re-annotated on the basis of their orthologs in other species. Interestingly, most PfWDRs were larger as compared to their human homologs highlighting the presence of parasite-specific insertions. Fifteen PfWDRs appeared specific to the Plasmodium with no assigned orthologs. Expression profiling of PfWDRs revealed a mixture of linear and nonlinear relationships between transcriptome and proteome, and only nine PfWDRs were found to be stage-specific. Homology modeling identified conservation of major binding sites in PfCAF-1 and PfRACK. Protein-protein interaction network analyses suggested that PfWDRs are highly connected proteins with ~1928 potential interactions, supporting their role as hubs in cellular networks. The present study highlights the roles and relevance of the WDR family in P. falciparum, and identifies unique features that lay a foundation for further experimental dissection of PfWDRs. PMID:26043001

  20. Genome-Wide Collation of the Plasmodium falciparum WDR Protein Superfamily Reveals Malarial Parasite-Specific Features.

    PubMed

    Chahar, Priyanka; Kaushik, Manjeri; Gill, Sarvajeet Singh; Gakhar, Surendra Kumar; Gopalan, Natrajan; Datt, Manish; Sharma, Amit; Gill, Ritu

    2015-01-01

    Despite a significant drop in malaria deaths during the past decade, malaria continues to be one of the biggest health problems around the globe. WD40 repeats (WDRs) containing proteins comprise one of the largest and functionally diverse protein superfamily in eukaryotes, acting as scaffolds for assembling large protein complexes. In the present study, we report an extensive in silico analysis of the WDR gene family in human malaria parasite Plasmodium falciparum. Our genome-wide identification has revealed 80 putative WDR genes in P. falciparum (PfWDRs). Five distinct domain compositions were discovered in Plasmodium as compared to the human host. Notably, 31 PfWDRs were annotated/re-annotated on the basis of their orthologs in other species. Interestingly, most PfWDRs were larger as compared to their human homologs highlighting the presence of parasite-specific insertions. Fifteen PfWDRs appeared specific to the Plasmodium with no assigned orthologs. Expression profiling of PfWDRs revealed a mixture of linear and nonlinear relationships between transcriptome and proteome, and only nine PfWDRs were found to be stage-specific. Homology modeling identified conservation of major binding sites in PfCAF-1 and PfRACK. Protein-protein interaction network analyses suggested that PfWDRs are highly connected proteins with ~1928 potential interactions, supporting their role as hubs in cellular networks. The present study highlights the roles and relevance of the WDR family in P. falciparum, and identifies unique features that lay a foundation for further experimental dissection of PfWDRs.

  1. Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays.

    PubMed

    Honkela, Antti; Peltonen, Jaakko; Topa, Hande; Charapitsa, Iryna; Matarese, Filomena; Grote, Korbinian; Stunnenberg, Hendrik G; Reid, George; Lawrence, Neil D; Rattray, Magnus

    2015-10-20

    Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcription time, degradation rate, and RNA-processing kinetics. Recent studies have shown that a splicing-associated RNA production delay can be significant. To investigate this issue more generally, it is useful to develop methods applicable to genome-wide datasets. We introduce a joint model of transcriptional activation and mRNA accumulation that can be used for inference of transcription rate, RNA production delay, and degradation rate given data from high-throughput sequencing time course experiments. We combine a mechanistic differential equation model with a nonparametric statistical modeling approach allowing us to capture a broad range of activation kinetics, and we use Bayesian parameter estimation to quantify the uncertainty in estimates of the kinetic parameters. We apply the model to data from estrogen receptor α activation in the MCF-7 breast cancer cell line. We use RNA polymerase II ChIP-Seq time course data to characterize transcriptional activation and mRNA-Seq time course data to quantify mature transcripts. We find that 11% of genes with a good signal in the data display a delay of more than 20 min between completing transcription and mature mRNA production. The genes displaying these long delays are significantly more likely to be short. We also find a statistical association between high delay and late intron retention in pre-mRNA data, indicating significant splicing-associated production delays in many genes.

  2. Genome-Wide Diversity in the Levant Reveals Recent Structuring by Culture

    PubMed Central

    Haber, Marc; Gauguier, Dominique; Youhanna, Sonia; Patterson, Nick; Moorjani, Priya; Botigué, Laura R.; Platt, Daniel E.; Matisoo-Smith, Elizabeth; Soria-Hernanz, David F.; Wells, R. Spencer; Bertranpetit, Jaume; Tyler-Smith, Chris

    2013-01-01

    The Levant is a region in the Near East with an impressive record of continuous human existence and major cultural developments since the Paleolithic period. Genetic and archeological studies present solid evidence placing the Middle East and the Arabian Peninsula as the first stepping-stone outside Africa. There is, however, little understanding of demographic changes in the Middle East, particularly the Levant, after the first Out-of-Africa expansion and how the Levantine peoples relate genetically to each other and to their neighbors. In this study we analyze more than 500,000 genome-wide SNPs in 1,341 new samples from the Levant and compare them to samples from 48 populations worldwide. Our results show recent genetic stratifications in the Levant are driven by the religious affiliations of the populations within the region. Cultural changes within the last two millennia appear to have facilitated/maintained admixture between culturally similar populations from the Levant, Arabian Peninsula, and Africa. The same cultural changes seem to have resulted in genetic isolation of other groups by limiting admixture with culturally different neighboring populations. Consequently, Levant populations today fall into two main groups: one sharing more genetic characteristics with modern-day Europeans and Central Asians, and the other with closer genetic affinities to other Middle Easterners and Africans. Finally, we identify a putative Levantine ancestral component that diverged from other Middle Easterners ∼23,700–15,500 years ago during the last glacial period, and diverged from Europeans ∼15,900–9,100 years ago between the last glacial warming and the start of the Neolithic. PMID:23468648

  3. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

    PubMed

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang; Wilson, Robert S; De Jager, Philip L; Yu, Lei; Singleton, Andrew B; Harris, Tamara; Mosley, Thomas H; Pinto, Jayant M; Bennett, David A; Chen, Honglei

    2015-11-01

    Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.

  4. Genome-Wide Comparative Analysis Reveals Similar Types of NBS Genes in Hybrid Citrus sinensis Genome and Original Citrus clementine Genome and Provides New Insights into Non-TIR NBS Genes

    PubMed Central

    Wang, Yunsheng; Zhou, Lijuan; Li, Dazhi; Dai, Liangying; Lawton-Rauh, Amy; Srimani, Pradip K.; Duan, Yongping; Luo, Feng

    2015-01-01

    In this study, we identified and compared nucleotide-binding site (NBS) domain-containing genes from three Citrus genomes (C. clementina, C. sinensis from USA and C. sinensis from China). Phylogenetic analysis of all Citrus NBS genes across these three genomes revealed that there are three approximately evenly numbered groups: one group contains the Toll-Interleukin receptor (TIR) domain and two different Non-TIR groups in which most of proteins contain the Coiled Coil (CC) domain. Motif analysis confirmed that the two groups of CC-containing NBS genes are from different evolutionary origins. We partitioned NBS genes into clades using NBS domain sequence distances and found most clades include NBS genes from all three Citrus genomes. This suggests that three Citrus genomes have similar numbers and types of NBS genes. We also mapped the re-sequenced reads of three pomelo and three mandarin genomes onto the C. sinensis genome. We found that most NBS genes of the hybrid C. sinensis genome have corresponding homologous genes in both pomelo and mandarin genomes. The homologous NBS genes in pomelo and mandarin suggest that the parental species of C. sinensis may contain similar types of NBS genes. This explains why the hybrid C. sinensis and original C. clementina have similar types of NBS genes in this study. Furthermore, we found that sequence variation amongst Citrus NBS genes were shaped by multiple independent and shared accelerated mutation accumulation events among different groups of NBS genes and in different Citrus genomes. Our comparative analyses yield valuable insight into the structure, organization and evolution of NBS genes in Citrus genomes. Furthermore, our comprehensive analysis showed that the non-TIR NBS genes can be divided into two groups that come from different evolutionary origins. This provides new insights into non-TIR genes, which have not received much attention. PMID:25811466

  5. Genome-wide comparative analysis reveals similar types of NBS genes in hybrid Citrus sinensis genome and original Citrus clementine genome and provides new insights into non-TIR NBS genes.

    PubMed

    Wang, Yunsheng; Zhou, Lijuan; Li, Dazhi; Dai, Liangying; Lawton-Rauh, Amy; Srimani, Pradip K; Duan, Yongping; Luo, Feng

    2015-01-01

    In this study, we identified and compared nucleotide-binding site (NBS) domain-containing genes from three Citrus genomes (C. clementina, C. sinensis from USA and C. sinensis from China). Phylogenetic analysis of all Citrus NBS genes across these three genomes revealed that there are three approximately evenly numbered groups: one group contains the Toll-Interleukin receptor (TIR) domain and two different Non-TIR groups in which most of proteins contain the Coiled Coil (CC) domain. Motif analysis confirmed that the two groups of CC-containing NBS genes are from different evolutionary origins. We partitioned NBS genes into clades using NBS domain sequence distances and found most clades include NBS genes from all three Citrus genomes. This suggests that three Citrus genomes have similar numbers and types of NBS genes. We also mapped the re-sequenced reads of three pomelo and three mandarin genomes onto the C. sinensis genome. We found that most NBS genes of the hybrid C. sinensis genome have corresponding homologous genes in both pomelo and mandarin genomes. The homologous NBS genes in pomelo and mandarin suggest that the parental species of C. sinensis may contain similar types of NBS genes. This explains why the hybrid C. sinensis and original C. clementina have similar types of NBS genes in this study. Furthermore, we found that sequence variation amongst Citrus NBS genes were shaped by multiple independent and shared accelerated mutation accumulation events among different groups of NBS genes and in different Citrus genomes. Our comparative analyses yield valuable insight into the structure, organization and evolution of NBS genes in Citrus genomes. Furthermore, our comprehensive analysis showed that the non-TIR NBS genes can be divided into two groups that come from different evolutionary origins. This provides new insights into non-TIR genes, which have not received much attention.

  6. Genome-wide analysis of alternative splicing during human heart development

    NASA Astrophysics Data System (ADS)

    Wang, He; Chen, Yanmei; Li, Xinzhong; Chen, Guojun; Zhong, Lintao; Chen, Gangbing; Liao, Yulin; Liao, Wangjun; Bin, Jianping

    2016-10-01

    Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA). A significant difference of AS patterns was found between foetal and adult hearts. The predicted difference in AS events was further confirmed using quantitative reverse transcription-polymerase chain reaction analysis of human heart samples. Functional foetal-specific AS event analysis showed enrichment associated with cell proliferation-related pathways including cell cycle, whereas adult-specific AS events were associated with protein synthesis. Furthermore, 42.6% of foetal-specific AS events showed significant changes in gene expression levels between foetal and adult hearts. Genes exhibiting both foetal-specific AS and differential expression were highly enriched in cell cycle-associated functions. In conclusion, we provided a genome-wide profiling of AS transitions between foetal and adult hearts and proposed that AS transitions and deferential gene expression may play determinative roles in human heart development.

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

    PubMed

    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.

  8. Genome-wide analysis of zygotic linkage disequilibrium and its components in crossbred cattle

    PubMed Central

    2012-01-01

    Background Linkage disequilibrium (LD) between genes at linked or independent loci can occur at gametic and zygotic levels known asgametic LD and zygotic LD, respectively. Gametic LD is well known for its roles in fine-scale mapping of quantitative trait loci, genomic selection and evolutionary inference. The less-well studied is the zygotic LD and its components that can be also estimated directly from the unphased SNPs. Results This study was set up to investigate the genome-wide extent and patterns of zygotic LD and its components in a crossbred cattle population using the genomic data from the Illumina BovineSNP50 beadchip. The animal population arose from repeated crossbreeding of multiple breeds and selection for growth and cow reproduction. The study showed that similar genomic structures in gametic and zygotic LD were observed, with zygotic LD decaying faster than gametic LD over marker distance. The trigenic and quadrigenic disequilibria were generally two- to three-fold smaller than the usual digenic disequilibria (gametic or composite LD). There was less power of testing for these high-order genic disequilibria than for the digenic disequilibria. The power estimates decreased with the marker distance between markers though the decay trend is more obvious for the digenic disequilibria than for high-order disequilibria. Conclusions This study is the first major genome-wide survey of all non-allelic associations between pairs of SNPs in a cattle population. Such analysis allows us to assess the relative importance of gametic LD vs. all other non-allelic genic LDs regardless of whether or not the population is in HWE. The observed predominance of digenic LD (gametic or composite LD) coupled with insignificant high-order trigenic and quadrigenic disequilibria supports the current intensive focus on the use of high-density SNP markers for genome-wide association studies and genomic selection activities in the cattle population. PMID:22827586

  9. Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease

    PubMed Central

    Keller, Margaux F.; Saad, Mohamad; Bras, Jose; Bettella, Francesco; Nicolaou, Nayia; Simón-Sánchez, Javier; Mittag, Florian; Büchel, Finja; Sharma, Manu; Gibbs, J. Raphael; Schulte, Claudia; Moskvina, Valentina; Durr, Alexandra; Holmans, Peter; Kilarski, Laura L.; Guerreiro, Rita; Hernandez, Dena G.; Brice, Alexis; Ylikotila, Pauli; Stefánsson, Hreinn; Majamaa, Kari; Morris, Huw R.; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nicholas W.; Hardy, John; Martinez, Maria; Singleton, Andrew B.; Nalls, Michael A.

    2012-01-01

    Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17–38, P = 8.08E − 08) phenotypic variance associated with all types of PD, 15% (95% CI −0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17–44, P = 1.34E − 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered. PMID:22892372

  10. Genome-wide analysis of PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE (PDAT) genes in plants reveals the eudicot-wide PDAT gene expansion and altered selective pressures acting on the core eudicot PDAT paralogs.

    PubMed

    Pan, Xue; Peng, Fred Y; Weselake, Randall J

    2015-03-01

    PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE (PDAT) is an enzyme that catalyzes the transfer of a fatty acyl moiety from the sn-2 position of a phospholipid to the sn-3-position of sn-1,2-diacylglyerol, thus forming triacylglycerol and a lysophospholipid. Although the importance of PDAT in triacylglycerol biosynthesis has been illustrated in some previous studies, the evolutionary relationship of plant PDATs has not been studied in detail. In this study, we investigated the evolutionary relationship of the PDAT gene family across the green plants using a comparative phylogenetic framework. We found that the PDAT candidate genes are present in all examined green plants, including algae, lowland plants (a moss and a lycophyte), monocots, and eudicots. Phylogenetic analysis revealed the evolutionary division of the PDAT gene family into seven major clades. The separation is supported by the conservation and variation in the gene structure, protein properties, motif patterns, and/or selection constraints. We further demonstrated that there is a eudicot-wide PDAT gene expansion, which appears to have been mainly caused by the eudicot-shared ancient gene duplication and subsequent species-specific segmental duplications. In addition, selection pressure analyses showed that different selection constraints have acted on three core eudicot clades, which might enable paleoduplicated PDAT paralogs to either become nonfunctionalized or develop divergent expression patterns during evolution. Overall, our study provides important insights into the evolution of the plant PDAT gene family and explores the evolutionary mechanism underlying the functional diversification among the core eudicot PDAT paralogs.

  11. Genome-Wide Analysis of Homeobox Gene Family in Legumes: Identification, Gene Duplication and Expression Profiling

    PubMed Central

    Garg, Rohini; Jain, Mukesh

    2015-01-01

    Homeobox genes encode transcription factors that are known to play a major role in different aspects of plant growth and development. In the present study, we identified homeobox genes belonging to 14 different classes in five legume species, including chickpea, soybean, Medicago, Lotus and pigeonpea. The characteristic differences within homeodomain sequences among various classes of homeobox gene family were quite evident. Genome-wide expression analysis using publicly available datasets (RNA-seq and microarray) indicated that homeobox genes are differentially expressed in various tissues/developmental stages and under stress conditions in different legumes. We validated the differential expression of selected chickpea homeobox genes via quantitative reverse transcription polymerase chain reaction. Genome duplication analysis in soybean indicated that segmental duplication has significantly contributed in the expansion of homeobox gene family. The Ka/Ks ratio of duplicated homeobox genes in soybean showed that several members of this family have undergone purifying selection. Moreover, expression profiling indicated that duplicated genes might have been retained due to sub-functionalization. The genome-wide identification and comprehensive gene expression profiling of homeobox gene family members in legumes will provide opportunities for functional analysis to unravel their exact role in plant growth and development. PMID:25745864

  12. Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment

    PubMed Central

    Fransen, Erik; Bonneux, Sarah; Corneveaux, Jason J; Schrauwen, Isabelle; Di Berardino, Federica; White, Cory H; Ohmen, Jeffrey D; Van de Heyning, Paul; Ambrosetti, Umberto; Huentelman, Matthew J; Van Camp, Guy; Friedman, Rick A

    2015-01-01

    We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of the genetic architecture indicates for the first time that ARHI is highly polygenic in nature, with probably no major genes involved. The phenotype depends on the aggregated effect of a large number of SNPs, of which the individual effects are undetectable in a modestly powered GWAS. We estimated that 22% of the variance in our data set can be explained by the collective effect of all genotyped SNPs. A score analysis showed a modest enrichment in causative SNPs among the SNPs with a P-value below 0.01. PMID:24939585

  13. Genome-wide analysis of homeobox gene family in legumes: identification, gene duplication and expression profiling.

    PubMed

    Bhattacharjee, Annapurna; Ghangal, Rajesh; Garg, Rohini; Jain, Mukesh

    2015-01-01

    Homeobox genes encode transcription factors that are known to play a major role in different aspects of plant growth and development. In the present study, we identified homeobox genes belonging to 14 different classes in five legume species, including chickpea, soybean, Medicago, Lotus and pigeonpea. The characteristic differences within homeodomain sequences among various classes of homeobox gene family were quite evident. Genome-wide expression analysis using publicly available datasets (RNA-seq and microarray) indicated that homeobox genes are differentially expressed in various tissues/developmental stages and under stress conditions in different legumes. We validated the differential expression of selected chickpea homeobox genes via quantitative reverse transcription polymerase chain reaction. Genome duplication analysis in soybean indicated that segmental duplication has significantly contributed in the expansion of homeobox gene family. The Ka/Ks ratio of duplicated homeobox genes in soybean showed that several members of this family have undergone purifying selection. Moreover, expression profiling indicated that duplicated genes might have been retained due to sub-functionalization. The genome-wide identification and comprehensive gene expression profiling of homeobox gene family members in legumes will provide opportunities for functional analysis to unravel their exact role in plant growth and development.

  14. [Analysis of population stratification using random SNPs in genome-wide association studies].

    PubMed

    Cao, Zong-Fu; Ma, Chuan-Xiang; Wang, Lei; Cai, Bin

    2010-09-01

    Since population genetic STRUCTURE can increase false-positive rate in genome-wide association studies (GWAS) for complex diseases, the effect of population stratification should be taken into account in GWAS. However, the effect of randomly selected SNPs in population stratification analysis is underdetermined. In this study, based on the genotype data generated on Genome-Wide Human SNP Array 6.0 from unrelated individuals of HapMap Phase2, we randomly selected SNPs that were evenly distributed across the whole-genome, and acquired Ancestry Informative Markers (AIMs) by the method of f value and allelic Fisher exact test. F-statistics and STRUCTURE analysis based on the select different sets of SNPs were used to evaluate the effect of distinguishing the populations from HapMap Phase3. We found that randomly selected SNPs that were evenly distributed across the whole-genome were able to be used to identify the population structure. This study further indicated that more than 3 000 randomly selected SNPs that were evenly distributed across the whole-genome were substituted for AIMs in population stratification analysis, when there were no available AIMs for spe-cific populations.

  15. Genome-Wide Analysis of Phosphorylated PhoP Binding to Chromosomal DNA Reveals Several Novel Features of the PhoPR-Mediated Phosphate Limitation Response in Bacillus subtilis

    PubMed Central

    Salzberg, Letal I.; Botella, Eric; Hokamp, Karsten; Antelmann, Haike; Maaß, Sandra; Becher, Dörte; Noone, David

    2015-01-01

    ABSTRACT The PhoPR two-component signal transduction system controls one of three responses activated by Bacillus subtilis to adapt to phosphate-limiting conditions (PHO response). The response involves the production of enzymes and transporters that scavenge for phosphate in the environment and assimilate it into the cell. However, in B. subtilis and some other Firmicutes bacteria, cell wall metabolism is also part of the PHO response due to the high phosphate content of the teichoic acids attached either to peptidoglycan (wall teichoic acid) or to the cytoplasmic membrane (lipoteichoic acid). Prompted by our observation that the phosphorylated WalR (WalR∼P) response regulator binds to more chromosomal loci than are revealed by transcriptome analysis, we established the PhoP∼P bindome in phosphate-limited cells. Here, we show that PhoP∼P binds to the chromosome at 25 loci: 12 are within the promoters of previously identified PhoPR regulon genes, while 13 are newly identified. We extend the role of PhoPR in cell wall metabolism showing that PhoP∼P binds to the promoters of four cell wall-associated operons (ggaAB, yqgS, wapA, and dacA), although none show PhoPR-dependent expression under the conditions of this study. We also show that positive autoregulation of phoPR expression and full induction of the PHO response upon phosphate limitation require PhoP∼P binding to the 3′ end of the phoPR operon. IMPORTANCE The PhoPR two-component system controls one of three responses mounted by B. subtilis to adapt to phosphate limitation (PHO response). Here, establishment of the phosphorylated PhoP (PhoP∼P) bindome enhances our understanding of the PHO response in two important ways. First, PhoPR plays a more extensive role in adaptation to phosphate-limiting conditions than was deduced from transcriptome analyses. Among 13 newly identified binding sites, 4 are cell wall associated (ggaAB, yqgS, wapA, and dacA), revealing that PhoPR has an extended involvement

  16. Quantifying the heritability of glioma using genome-wide complex trait analysis

    PubMed Central

    Kinnersley, Ben; Mitchell, Jonathan S.; Gousias, Konstantinos; Schramm, Johannes; Idbaih, Ahmed; Labussière, Marianne; Marie, Yannick; Rahimian, Amithys; Wichmann, H.-Erich; Schreiber, Stefan; Hoang-Xuan, Khe; Delattre, Jean-Yves; Nöthen, Markus M.; Mokhtari, Karima; Lathrop, Mark; Bondy, Melissa; Simon, Matthias; Sanson, Marc; Houlston, Richard S.

    2015-01-01

    Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20–31%, P = 1.15 × 10−17) for all forms of glioma - 26% (95% CI: 17–35%, P = 1.05 × 10−8) for glioblastoma multiforme (GBM) and 25% (95% CI: 17–32%, P = 1.26 × 10−10) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified. PMID:26625949

  17. Genome-wide identification and analysis of the MADS-box gene family in apple.

    PubMed

    Tian, Yi; Dong, Qinglong; Ji, Zhirui; Chi, Fumei; Cong, Peihua; Zhou, Zongshan

    2015-01-25

    The MADS-box gene family is one of the most widely studied families in plants and has diverse developmental roles in flower pattern formation, gametophyte cell division and fruit differentiation. Although the genome-wide analysis of this family has been performed in some species, little is known regarding MADS-box genes in apple (Malus domestica). In this study, 146 MADS-box genes were identified in the apple genome and were phylogenetically clustered into six subgroups (MIKC(c), MIKC*, Mα, Mβ, Mγ and Mδ) with the MADS-box genes from Arabidopsis and rice. The predicted apple MADS-box genes were distributed across all 17 chromosomes at different densities. Additionally, the MADS-box domain, exon length, gene structure and motif compositions of the apple MADS-box genes were analysed. Moreover, the expression of all of the apple MADS-box genes was analysed in the root, stem, leaf, flower tissues and five stages of fruit development. All of the apple MADS-box genes, with the exception of some genes in each group, were expressed in at least one of the tissues tested, which indicates that the MADS-box genes are involved in various aspects of the physiological and developmental processes of the apple. To the best of our knowledge, this report describes the first genome-wide analysis of the apple MADS-box gene family, and the results should provide valuable information for understanding the classification, cloning and putative functions of this family.

  18. Genome Wide Analysis of Fatty Acid Desaturation and Its Response to Temperature1[OPEN

    PubMed Central

    Menard, Guillaume N.; Moreno, Jose Martin; Bryant, Fiona M.; Munoz-Azcarate, Olaya; Hassani-Pak, Keywan; Kurup, Smita

    2017-01-01

    Plants modify the polyunsaturated fatty acid content of their membrane and storage lipids in order to adapt to changes in temperature. In developing seeds, this response is largely controlled by the activities of the microsomal ω-6 and ω-3 fatty acid desaturases, FAD2 and FAD3. Although temperature regulation of desaturation has been studied at the molecular and biochemical levels, the genetic control of this trait is poorly understood. Here, we have characterized the response of Arabidopsis (Arabidopsis thaliana) seed lipids to variation in ambient temperature and found that heat inhibits both ω-6 and ω-3 desaturation in phosphatidylcholine, leading to a proportional change in triacylglycerol composition. Analysis of the 19 parental accessions of the multiparent advanced generation intercross (MAGIC) population showed that significant natural variation exists in the temperature responsiveness of ω-6 desaturation. A combination of quantitative trait locus (QTL) analysis and genome-wide association studies (GWAS) using the MAGIC population suggests that ω-6 desaturation is largely controlled by cis-acting sequence variants in the FAD2 5′ untranslated region intron that determine the expression level of the gene. However, the temperature responsiveness of ω-6 desaturation is controlled by a separate QTL on chromosome 2. The identity of this locus is unknown, but genome-wide association studies identified potentially causal sequence variants within ∼40 genes in an ∼450-kb region of the QTL. PMID:28108698

  19. Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

    PubMed Central

    Baurecht, Hansjörg; Hotze, Melanie; Brand, Stephan; Büning, Carsten; Cormican, Paul; Corvin, Aiden; Ellinghaus, David; Ellinghaus, Eva; Esparza-Gordillo, Jorge; Fölster-Holst, Regina; Franke, Andre; Gieger, Christian; Hubner, Norbert; Illig, Thomas; Irvine, Alan D.; Kabesch, Michael; Lee, Young A.E.; Lieb, Wolfgang; Marenholz, Ingo; McLean, W.H. Irwin; Morris, Derek W.; Mrowietz, Ulrich; Nair, Rajan; Nöthen, Markus M.; Novak, Natalija; O’Regan, Grainne M.; Schreiber, Stefan; Smith, Catherine; Strauch, Konstantin; Stuart, Philip E.; Trembath, Richard; Tsoi, Lam C.; Weichenthal, Michael; Barker, Jonathan; Elder, James T.; Weidinger, Stephan; Cordell, Heather J.; Brown, Sara J.

    2015-01-01

    Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21–22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features. PMID:25574825

  20. Five endometrial cancer risk loci identified through genome-wide association analysis

    PubMed Central

    O’Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica MJ; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Consortium, CHIBCHA; Jun Li, Mulin; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-01-01

    We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. PMID:27135401

  1. Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms.

    PubMed

    Baurecht, Hansjörg; Hotze, Melanie; Brand, Stephan; Büning, Carsten; Cormican, Paul; Corvin, Aiden; Ellinghaus, David; Ellinghaus, Eva; Esparza-Gordillo, Jorge; Fölster-Holst, Regina; Franke, Andre; Gieger, Christian; Hubner, Norbert; Illig, Thomas; Irvine, Alan D; Kabesch, Michael; Lee, Young A E; Lieb, Wolfgang; Marenholz, Ingo; McLean, W H Irwin; Morris, Derek W; Mrowietz, Ulrich; Nair, Rajan; Nöthen, Markus M; Novak, Natalija; O'Regan, Grainne M; Schreiber, Stefan; Smith, Catherine; Strauch, Konstantin; Stuart, Philip E; Trembath, Richard; Tsoi, Lam C; Weichenthal, Michael; Barker, Jonathan; Elder, James T; Weidinger, Stephan; Cordell, Heather J; Brown, Sara J

    2015-01-08

    Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.

  2. Genome-wide identification of polycomb target genes reveals a functional association of Pho with Scm in Bombyx mori.

    PubMed

    Li, Zhiqing; Cheng, Daojun; Mon, Hiroaki; Tatsuke, Tsuneyuki; Zhu, Li; Xu, Jian; Lee, Jae Man; Xia, Qingyou; Kusakabe, Takahiro

    2012-01-01

    Polycomb group (PcG) proteins are evolutionarily conserved chromatin modifiers and act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2), and Pleiohomeotic repressive complex (PhoRC), to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori with holocentric centromere using genome-wide expression screening based on the knockdown of BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, the expressions of 29 genes were up-regulated after knocking down 4 PcG genes. Particularly, there is a significant overlap between targets of BmPho (331 out of 524) and BmScm (331 out of 532), and among these, 190 genes function as regulator factors playing important roles in development. We also found that BmPho, as well as BmScm, can interact with other Polycomb components examined in this study. Further detailed analysis revealed that the C-terminus of BmPho containing zinc finger domain is involved in the interaction between BmPho and BmScm. Moreover, the zinc finger domain in BmPho contributes to its inhibitory function and ectopic overexpression of BmScm is able to promote transcriptional repression by Gal4-Pho fusions including BmScm-interacting domain. Loss of BmPho expression causes relocalization of BmScm into the cytoplasm. Collectively, we provide evidence of a functional link between BmPho and BmScm, and propose two Polycomb-related repression mechanisms requiring only BmPho associated with BmScm or a whole set of PcG complexes.

  3. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder.

    PubMed

    Zhao, Z; Xu, J; Chen, J; Kim, S; Reimers, M; Bacanu, S-A; Yu, H; Liu, C; Sun, J; Wang, Q; Jia, P; Xu, F; Zhang, Y; Kendler, K S; Peng, Z; Chen, X

    2015-05-01

    Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10(-7)) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.

  4. 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

  5. A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

    PubMed

    Lamina, Claudia; Friedel, Salome; Coassin, Stefan; Rueedi, Rico; Yousri, Noha A; Seppälä, Ilkka; Gieger, Christian; Schönherr, Sebastian; Forer, Lukas; Erhart, Gertraud; Kollerits, Barbara; Marques-Vidal, Pedro; Ried, Janina; Waeber, Gerard; Bergmann, Sven; Dähnhardt, Doreen; Stöckl, Andrea; Kiechl, Stefan; Raitakari, Olli T; Kähönen, Mika; Willeit, Johann; Kedenko, Ludmilla; Paulweber, Bernhard; Peters, Annette; Meitinger, Thomas; Strauch, Konstantin; Study Group, Kora; Lehtimäki, Terho; Hunt, Steven C; Vollenweider, Peter; Kronenberg, Florian

    2016-08-15

    Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 (-)  (44)), rs5104 in APOA4 (P = 1.79 × 10(-)(24)) and rs4241819 in KLKB1 (P = 5.6 × 10(-)(14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 (-)  (07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10(-)(05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

  6. 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.

  7. A genome-wide association meta-analysis on apolipoprotein A-IV concentrations

    PubMed Central

    Lamina, Claudia; Friedel, Salome; Coassin, Stefan; Rueedi, Rico; Yousri, Noha A.; Seppälä, Ilkka; Gieger, Christian; Schönherr, Sebastian; Forer, Lukas; Erhart, Gertraud; Kollerits, Barbara; Marques-Vidal, Pedro; Ried, Janina; Waeber, Gerard; Bergmann, Sven; Dähnhardt, Doreen; Stöckl, Andrea; Kiechl, Stefan; Raitakari, Olli T.; Kähönen, Mika; Willeit, Johann; Kedenko, Ludmilla; Paulweber, Bernhard; Peters, Annette; Meitinger, Thomas; Strauch, Konstantin; Study Group, KORA; Lehtimäki, Terho; Hunt, Steven C.; Vollenweider, Peter; Kronenberg, Florian

    2016-01-01

    Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 − 44), rs5104 in APOA4 (P = 1.79 × 10−24) and rs4241819 in KLKB1 (P = 5.6 × 10−14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 − 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10−05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1. The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations. PMID

  8. CONAN: copy number variation analysis software for genome-wide association studies

    PubMed Central

    2010-01-01

    Background Genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs) promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs. Results CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data. Conclusions CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at. PMID:20546565

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

    DOE PAGES

    Yurchenko, Olga P.; Park, Sunjung; Ilut, Daniel C.; ...

    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

  10. The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.

    PubMed

    van Leeuwen, Elisabeth M; Smouter, Françoise A S; Kam-Thong, Tony; Karbalai, Nazanin; Smith, Albert V; Harris, Tamara B; Launer, Lenore J; Sitlani, Colleen M; Li, Guo; Brody, Jennifer A; Bis, Joshua C; White, Charles C; Jaiswal, Alok; Oostra, Ben A; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G; Boerwinkle, Eric; Ballantyne, Christie M; Gudnason, Vilmundur; Psaty, Bruce M; Cupples, L Adrienne; Järvelin, Marjo-Riitta; Ripatti, Samuli; Isaacs, Aaron; Müller-Myhsok, Bertram; Karssen, Lennart C; van Duijn, Cornelia M

    2014-01-01

    Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

  11. The Challenges of Genome-Wide Interaction Studies: Lessons to Learn from the Analysis of HDL Blood Levels

    PubMed Central

    van Leeuwen, Elisabeth M.; Smouter, Françoise A. S.; Kam-Thong, Tony; Karbalai, Nazanin; Smith, Albert V.; Harris, Tamara B.; Launer, Lenore J.; Sitlani, Colleen M.; Li, Guo; Brody, Jennifer A.; Bis, Joshua C.; White, Charles C.; Jaiswal, Alok; Oostra, Ben A.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Boerwinkle, Eric; Ballantyne, Christie M.; Gudnason, Vilmundur; Psaty, Bruce M.; Cupples, L. Adrienne; Järvelin, Marjo-Riitta; Ripatti, Samuli; Isaacs, Aaron; Müller-Myhsok, Bertram; Karssen, Lennart C.; van Duijn, Cornelia M.

    2014-01-01

    Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-value<1 · 10−8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011) when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098) and rs12442098 in SPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS. PMID:25329471

  12. Genome-Wide Analysis of Promoters: Clustering by Alignment and Analysis of Regular Patterns

    PubMed Central

    Pettinato, Lucia; Calistri, Elisa; Di Patti, Francesca; Livi, Roberto; Luccioli, Stefano

    2014-01-01

    In this paper we perform a genome-wide analysis of H. sapiens promoters. To this aim, we developed and combined two mathematical methods that allow us to (i) classify promoters into groups characterized by specific global structural features, and (ii) recover, in full generality, any regular sequence in the different classes of promoters. One of the main findings of this analysis is that H. sapiens promoters can be classified into three main groups. Two of them are distinguished by the prevalence of weak or strong nucleotides and are characterized by short compositionally biased sequences, while the most frequent regular sequences in the third group are strongly correlated with transposons. Taking advantage of the generality of these mathematical procedures, we have compared the promoter database of H. sapiens with those of other species. We have found that the above-mentioned features characterize also the evolutionary content appearing in mammalian promoters, at variance with ancestral species in the phylogenetic tree, that exhibit a definitely lower level of differentiation among promoters. PMID:24465517

  13. Stepwise Evolution of Coral Biomineralization Revealed with Genome-Wide Proteomics and Transcriptomics

    PubMed Central

    Sawada, Hitoshi; Satoh, Noriyuki

    2016-01-01

    Despite the importance of stony corals in many research fields related to global issues, such as marine ecology, climate change, paleoclimatogy, and metazoan evolution, very little is known about the evolutionary origin of coral skeleton formation. In order to investigate the evolution of coral biomineralization, we have identified skeletal organic matrix proteins (SOMPs) in the skeletal proteome of the scleractinian coral, Acropora digitifera, for which large genomic and transcriptomic datasets are available. Scrupulous gene annotation was conducted based on comparisons of functional domain structures among metazoans. We found that SOMPs include not only coral-specific proteins, but also protein families that are widely conserved among cnidarians and other metazoans. We also identified several conserved transmembrane proteins in the skeletal proteome. Gene expression analysis revealed that expression of these conserved genes continues throughout development. Therefore, these genes are involved not only skeleton formation, but also in basic cellular functions, such as cell-cell interaction and signaling. On the other hand, genes encoding coral-specific proteins, including extracellular matrix domain-containing proteins, galaxins, and acidic proteins, were prominently expressed in post-settlement stages, indicating their role in skeleton formation. Taken together, the process of coral skeleton formation is hypothesized as: 1) formation of initial extracellular matrix between epithelial cells and substrate, employing pre-existing transmembrane proteins; 2) additional extracellular matrix formation using novel proteins that have emerged by domain shuffling and rapid molecular evolution and; 3) calcification controlled by coral-specific SOMPs. PMID:27253604

  14. Genome-wide computational analysis of the secretome of brown algae (Phaeophyceae).

    PubMed

    Terauchi, Makoto; Yamagishi, Takahiro; Hanyuda, Takeaki; Kawai, Hiroshi

    2017-04-01

    Brown algae have evolved complex multicellularity in the heterokont lineage. They are phylogenetically distant to land plants, fungi and animals. Especially, the members of Laminariales (so-called kelps) have developed highly differentiated tissues. Extracellular matrix (ECM) plays pivotal roles in a number of essential processes in multicellular organisms, such as cell adhesion, cell and tissue differentiations, cell-to-cell communication, and responses to environmental stimuli. In these processes, a set of extracellular secreted proteins called the secretome operates remodeling of the physicochemical nature of ECM and signal transduction by interacting with cell surface proteins and signaling molecules. Characterization of the secretome is a critical step to clarify the contributions of ECM to the multicellularity of brown algae. However, the identity of the brown algal secretome has been poorly understood. In order to reveal the repertory of the brown algal secretome and its involvement in the evolution of Laminariales, we conducted a genome-wide analysis of the brown algal secretome utilizing the published complete genome data of Ectocarpus siliculosus and Saccharina japonica as well as newly obtained RNA-seq data of seven laminarialean species (Agarum clathratum, Alaria crassifolia, Aureophycus aleuticus, Costaria costata, Pseudochorda nagaii, Saccharina angustata and Undaria pinnatifida) largely covering the laminarialean families. We established the in silico pipeline to systematically and accurately detect the secretome by combining multiple prediction algorithms for the N-terminal signal peptide and transmembrane domain within the protein sequence. From 16,189 proteins of E. siliculosus and 18,733 proteins of S. japonica, 552 and 964 proteins respectively were predicted to be classified as the secretome. Conserved domain analysis showed that the domain repertory were very similar to each other, and that of the brown algal secretome was partially common

  15. Analysis of Genome-Wide Association Studies with Multiple Outcomes Using Penalization

    PubMed Central

    Liu, Jin; Huang, Jian; Ma, Shuangge

    2012-01-01

    Genome-wide association studies have been extensively conducted, searching for markers for biologically meaningful outcomes and phenotypes. Penalization methods have been adopted in the analysis of the joint effects of a large number of SNPs (single nucleotide polymorphisms) and marker identification. This study is partly motivated by the analysis of heterogeneous stock mice dataset, in which multiple correlated phenotypes and a large number of SNPs are available. Existing penalization methods designed to analyze a single response variable cannot accommodate the correlation among multiple response variables. With multiple response variables sharing the same set of markers, joint modeling is first employed to accommodate the correlation. The group Lasso approach is adopted to select markers associated with all the outcome variables. An efficient computational algorithm is developed. Simulation study and analysis of the heterogeneous stock mice dataset show that the proposed method can outperform existing penalization methods. PMID:23272092

  16. Meta-analysis of New Genome-wide Association Studies of Colorectal Cancer Risk

    PubMed Central

    Peters, Ulrike; Hutter, Carolyn M.; Hsu, Li; Schumacher, Fredrick R.; Conti, David V.; Carlson, Christopher S.; Edlund, Christopher K.; Haile, Robert W.; Gallinger, Steven; Zanke, Brent W.; Lemire, Mathieu; Rangrej, Jagadish; Vijayaraghavan, Raakhee; Chan, Andrew T.; Hazra, Aditi; Hunter, David J.; Ma, Jing; Fuchs, Charles S.; Giovannucci, Edward L.; Kraft, Peter; Liu, Yan; Chen, Lin; Jiao, Shuo; Makar, Karen W.; Taverna, Darin; Gruber, Stephen B.; Rennert, Gad; Moreno, Victor; Ulrich, Cornelia M.; Woods, Michael O.; Green, Roger C.; Parfrey, Patrick S.; Prentice, Ross L.; Kooperberg, Charles; Jackson, Rebecca D.; LaCroix, Andrea Z.; Caan, Bette J.; Hayes, Richard B.; Berndt, Sonja I.; Chanock, Stephen J.; Schoen, Robert E.; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; Frank, Bernd; Bézieau, Stéphane; Küry, Sébastien; Slattery, Martha L.; Hopper, John L.; Jenkins, Mark A.; Le Marchand, Loic; Lindor, Noralane M.; Newcomb, Polly A.; Seminara, Daniela; Hudson, Thomas J.; Duggan, David J.; Potter, John D.; Casey, Graham

    2011-01-01

    Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow-up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for genome-wide association studies (GWAS) of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using 10 independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured 10 SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p-value range: 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p<0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p-value 0.03; combined p-value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant

  17. Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis

    PubMed Central

    Dix, Andreas; Czakai, Kristin; Springer, Jan; Fliesser, Mirjam; Bonin, Michael; Guthke, Reinhard; Schmitt, Anna L.; Einsele, Hermann; Linde, Jörg; Löffler, Jürgen

    2016-01-01

    Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis. PMID:27047454

  18. Genome-wide comparison of cowpox viruses reveals a new clade related to Variola virus.

    PubMed

    Dabrowski, Piotr Wojtek; Radonić, Aleksandar; Kurth, Andreas; Nitsche, Andreas

    2013-01-01

    Zoonotic infections caused by several orthopoxviruses (OPV) like monkeypox virus or vaccinia virus have a significant impact on human health. In Europe, the number of diagnosed infections with cowpox viruses (CPXV) is increasing in animals as well as in humans. CPXV used to be enzootic in cattle; however, such infections were not being diagnosed over the last decades. Instead, individual cases of cowpox are being found in cats or exotic zoo animals that transmit the infection to humans. Both animals and humans reveal local exanthema on arms and legs or on the face. Although cowpox is generally regarded as a self-limiting disease, immunosuppressed patients can develop a lethal systemic disease resembling smallpox. To date, only limited information on the complex and, compared to other OPV, sparsely conserved CPXV genomes is available. Since CPXV displays the widest host range of all OPV known, it seems important to comprehend the genetic repertoire of CPXV which in turn may help elucidate specific mechanisms of CPXV pathogenesis and origin. Therefore, 22 genomes of independent CPXV strains from clinical cases, involving ten humans, four rats, two cats, two jaguarundis, one beaver, one elephant, one marah and one mongoose, were sequenced by using massive parallel pyrosequencing. The extensive phylogenetic analysis showed that the CPXV strains sequenced clearly cluster into several distinct clades, some of which are closely related to Vaccinia viruses while others represent different clades in a CPXV cluster. Particularly one CPXV clade is more closely related to Camelpox virus, Taterapox virus and Variola virus than to any other known OPV. These results support and extend recent data from other groups who postulate that CPXV does not form a monophyletic clade and should be divided into multiple lineages.

  19. Genome-wide association analysis of anti-TNF drug response in rheumatoid arthritis patients

    PubMed Central

    Mirkov, Maša Umiċeviċ; Cui, Jing; Vermeulen, Sita H; Stahl, Eli A.; Toonen, Erik JM; Makkinje, Remco R; Lee, Annette T; Huizinga, Tom WJ; Allaart, Renee; Barton, Anne; Mariette, Xavier; Miceli-Richard, Corinne; Criswell, Lindsey A; Tak, Paul P; de Vries, Niek; Saevarsdottir, Saedis; Padyukov, Leonid; Bridges, S. Louis; van Schaardenburg, Dirk-Jan; Jansen, Tim; Dutmer, Ellen AJ; van de Laar, Mart; Barrera, Pilar; Radstake, Timothy RDJ; van Riel, Piet LCM; Scheffer, Hans; Franke, Barbara; Brunner, Han G; Plenge, Robert M; Gregersen, Peter K; Guchelaar, Henk-Jan; Coenen, Marieke JH

    2014-01-01

    Background Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently there are no means of identifying these patients prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach. Methods We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity. Results Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. Conclusion Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections. PMID:23233654

  20. Genome-wide copy number profiling of single cells in S-phase reveals DNA-replication domains.

    PubMed

    Van der Aa, Niels; Cheng, Jiqiu; Mateiu, Ligia; Zamani Esteki, Masoud; Kumar, Parveen; Dimitriadou, Eftychia; Vanneste, Evelyne; Moreau, Yves; Vermeesch, Joris Robert; Voet, Thierry

    2013-04-01

    Single-cell genomics is revolutionizing basic genome research and clinical genetic diagnosis. However, none of the current research or clinical methods for single-cell analysis distinguishes between the analysis of a cell in G1-, S- or G2/M-phase of the cell cycle. Here, we demonstrate by means of array comparative genomic hybridization that charting the DNA copy number landscape of a cell in S-phase requires conceptually different approaches to that of a cell in G1- or G2/M-phase. Remarkably, despite single-cell whole-genome amplification artifacts, the log2 intensity ratios of single S-phase cells oscillate according to early and late replication domains, which in turn leads to the detection of significantly more DNA imbalances when compared with a cell in G1- or G2/M-phase. Although these DNA imbalances may, on the one hand, be falsely interpreted as genuine structural aberrations in the S-phase cell's copy number profile and hence lead to misdiagnosis, on the other hand, the ability to detect replication domains genome wide in one cell has important applications in DNA-replication research. Genome-wide cell-type-specific early and late replicating domains have been identified by analyses of DNA from populations of cells, but cell-to-cell differences in DNA replication may be important in genome stability, disease aetiology and various other cellular processes.

  1. Genome-wide meta-analysis identifies new susceptibility loci for migraine.

    PubMed

    Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E; Todt, Unda; McArdle, Wendy L; Quaye, Lydia; Koiranen, Markku; Ikram, M Arfan; Lehtimäki, Terho; Stam, Anine H; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M; Palta, Priit; Hamalainen, Eija; Schürks, Markus; Rose, Lynda M; Buring, Julie E; Ridker, Paul M; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A; Evans, David M; Ring, Susan M; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari A; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R; Pelzer, Nadine; Weller, Claudia M; Zielman, Ronald; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant W; Martin, Nicholas G; Borck, Guntram; Göbel, Hartmut; Heinze, Axel; Heinze-Kuhn, Katja; Williams, Frances M K; Hartikainen, Anna-Liisa; Pouta, Anneli; van den Ende, Joyce; Uitterlinden, Andre G; Hofman, Albert; Amin, Najaf; Hottenga, Jouke-Jan; Vink, Jacqueline M; Heikkilä, Kauko; Alexander, Michael; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G; Traynor, Bryan J; Trabzuni, Daniah; Rossin, Elizabeth; Lage, Kasper; Jacobs, Suzanne B R; Gibbs, J Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W; Boomsma, Dorret I; van Duijn, Cornelia; Raitakari, Olli; Jarvelin, Marjo-Riitta; Zwart, John-Anker; Cherkas, Lynn; Strachan, David P; Kubisch, Christian; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefansson, Kari; Daly, Mark J; Nyholt, Dale R; Chasman, Daniel I; Palotie, Aarno

    2013-08-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

  2. Genome-Wide Association Study Reveals Four Loci for Lipid Ratios in the Korean Population and the Constitutional Subgroup

    PubMed Central

    Kim, Taehyeung; Park, Ah Yeon; Baek, Younghwa

    2017-01-01

    Circulating lipid ratios are considered predictors of cardiovascular risks and metabolic syndrome, which cause coronary heart diseases. One constitutional type of Korean medicine prone to weight accumulation, the Tae-Eum type, predisposes the consumers to metabolic syndrome, hypertension, diabetes mellitus, etc. Here, we aimed to identify genetic variants for lipid ratios using a genome-wide association study (GWAS) and followed replication analysis in Koreans and constitutional subgroups. GWASs in 5,292 individuals of the Korean Genome and Epidemiology Study and replication analyses in 2,567 subjects of the Korea medicine Data Center were performed to identify genetic variants associated with triglyceride (TG) to HDL cholesterol (HDLC), LDL cholesterol (LDLC) to HDLC, and non-HDLC to HDLC ratios. For subgroup analysis, a computer-based constitution analysis tool was used to categorize the constitutional types of the subjects. In the discovery stage, seven variants in four loci, three variants in three loci, and two variants in one locus were associated with the ratios of log-transformed TG:HDLC (log[TG]:HDLC), LDLC:HDLC, and non-HDLC:HDLC, respectively. The associations of the GWAS variants with lipid ratios were replicated in the validation stage: for the log[TG]:HDLC ratio, rs6589566 near APOA5 and rs4244457 and rs6586891 near LPL; for the LDLC:HDLC ratio, rs4420638 near APOC1 and rs17445774 near C2orf47; and for the non-HDLC:HDLC ratio, rs6589566 near APOA5. Five of these six variants are known to be associated with TG, LDLC, and/or HDLC, but rs17445774 was newly identified to be involved in lipid level changes in this study. Constitutional subgroup analysis revealed effects of variants associated with log[TG]:HDLC and non-HDLC:HDLC ratios in both the Tae-Eum and non-Tae-Eum types, whereas the effect of the LDLC:HDLC ratio-associated variants remained only in the Tae-Eum type. In conclusion, we identified three log[TG]:HDLC ratio-associated variants, two LDLC

  3. Genome-Wide Linkage Analysis Identifies Loci for Physical Appearance Traits in Chickens.

    PubMed

    Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie

    2015-08-06

    Physical appearance traits, such as feather-crested head, comb size and type, beard, wattles size, and feathered feet, are used to distinguish between breeds of chicken and also may be associated with economic traits. In this study, a genome-wide linkage analysis was used to identify candidate regions and genes for physical appearance traits and to potentially provide further knowledge of the molecular mechanisms that underlie these traits. The linkage analysis was conducted with an F2 population derived from Beijing-You chickens and a commercial broiler line. Single-nucleotide polymorphisms were analyzed using the Illumina 60K Chicken SNP Beadchip. The data were used to map quantitative trait loci and genes for six physical appearance traits. A 10-cM/0.51-Mb region (0.0-10.0 cM/0.00-0.51 Mb) with 1% genome-wide significant level on LGE22C19W28_E50C23 linkage group (LGE22) for crest trait was identified, which is likely very closely linked to the HOXC8. A QTL with 5% chromosome-wide significant level for comb weight, which partly overlaps with a region identified in a previous study, was identified at 74 cM/25.55 Mb on chicken (Gallus gallus; GG) chromosome 3 (i.e., GGA3). For beard and wattles traits, an identical region 11 cM/2.23 Mb (0.0-11.0 cM/0.00-2.23 Mb) including WNT3 and GH genes on GGA27 was identified. Two QTL with 1% genome-wide significant level for feathered feet trait, one 9-cM/2.80-Mb (48.0-57.0/13.40-16.20 Mb) region on GGA13, and another 12-cM/1.45-Mb (41.0-53.0 cM/11.37-12.82 Mb) region on GGA15 were identified. These candidate regions and genes provide important genetic information for the physical appearance traits in chicken.

  4. Genome-Wide Linkage Analysis Identifies Loci for Physical Appearance Traits in Chickens

    PubMed Central

    Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie

    2015-01-01

    Physical appearance traits, such as feather-crested head, comb size and type, beard, wattles size, and feathered feet, are used to distinguish between breeds of chicken and also may be associated with economic traits. In this study, a genome-wide linkage analysis was used to identify candidate regions and genes for physical appearance traits and to potentially provide further knowledge of the molecular mechanisms that underlie these traits. The linkage analysis was conducted with an F2 population derived from Beijing-You chickens and a commercial broiler line. Single-nucleotide polymorphisms were analyzed using the Illumina 60K Chicken SNP Beadchip. The data were used to map quantitative trait loci and genes for six physical appearance traits. A 10-cM/0.51-Mb region (0.0−10.0 cM/0.00−0.51 Mb) with 1% genome-wide significant level on LGE22C19W28_E50C23 linkage group (LGE22) for crest trait was identified, which is likely very closely linked to the HOXC8. A QTL with 5% chromosome-wide significant level for comb weight, which partly overlaps with a region identified in a previous study, was identified at 74 cM/25.55 Mb on chicken (Gallus gallus; GG) chromosome 3 (i.e., GGA3). For beard and wattles traits, an identical region 11 cM/2.23 Mb (0.0−11.0 cM/0.00−2.23 Mb) including WNT3 and GH genes on GGA27 was identified. Two QTL with 1% genome-wide significant level for feathered feet trait, one 9-cM/2.80-Mb (48.0-57.0/13.40-16.20 Mb) region on GGA13, and another 12-cM/1.45-Mb (41.0−53.0 cM/11.37−12.82 Mb) region on GGA15 were identified. These candidate regions and genes provide important genetic information for the physical appearance traits in chicken. PMID:26248982

  5. Genome-wide interaction-based association analysis identified multiple new susceptibility Loci for common diseases.

    PubMed

    Liu, Yang; Xu, Haiming; Chen, Suchao; Chen, Xianfeng; Zhang, Zhenguo; Zhu, Zhihong; Qin, Xueying; Hu, Landian; Zhu, Jun; Zhao, Guo-Ping; Kong, Xiangyin

    2011-03-01

    Genome-wide interaction-based association (GWIBA) analysis has the potential to identify novel susceptibility loci. These interaction effects could be missed with the prevailing approaches in genome-wide association studies (GWAS). However, no convincing loci have been discovered exclusively from GWIBA methods, and the intensive computation involved is a major barrier for application. Here, we developed a fast, multi-thread/parallel program named "pair-wise interaction-based association mapping" (PIAM) for exhaustive two-locus searches. With this program, we performed a complete GWIBA analysis on seven diseases with stringent control for false positives, and we validated the results for three of these diseases. We identified one pair-wise interaction between a previously identified locus, C1orf106, and one new locus, TEC, that was specific for Crohn's disease, with a Bonferroni corrected P < 0.05 (P = 0.039). This interaction was replicated with a pair of proxy linked loci (P = 0.013) on an independent dataset. Five other interactions had corrected P < 0.5. We identified the allelic effect of a locus close to SLC7A13 for coronary artery disease. This was replicated with a linked locus on an independent dataset (P = 1.09 × 10⁻⁷). Through a local validation analysis that evaluated association signals, rather than locus-based associations, we found that several other regions showed association/interaction signals with nominal P < 0.05. In conclusion, this study demonstrated that the GWIBA approach was successful for identifying novel loci, and the results provide new insights into the genetic architecture of common diseases. In addition, our PIAM program was capable of handling very large GWAS datasets that are likely to be produced in the future.

  6. MPE-seq, a new method for the genome-wide analysis of chromatin structure

    PubMed Central

    Ishii, Haruhiko; Kadonaga, James T.; Ren, Bing

    2015-01-01

    The analysis of chromatin structure is essential for the understanding of transcriptional regulation in eukaryotes. Here we describe methidiumpropyl-EDTA sequencing (MPE-seq), a method for the genome-wide characterization of chromatin that involves the digestion of nuclei withMPE-Fe(II) followed by massively parallel sequencing. Like micrococcal nuclease (MNase), MPE-Fe(II) preferentially cleaves the linker DNA between nucleosomes. However, there are differences in the cleavage of nuclear chromatin by MPE-Fe(II) relative to MNase. Most notably, immediately upstream of the transcription start site of active promoters, we frequently observed nucleosome-sized (141–190 bp) and subnucleosome-sized (such as 101–140 bp) peaks of digested chromatin fragments with MPE-seq but not with MNase-seq. These peaks also correlate with the presence of core histones and could thus be due, at least in part, to noncanonical chromatin structures such as labile nucleosome-like particles that have been observed in other contexts. The subnucleosome-sized MPE-seq peaks exhibit a particularly distinct association with active promoters. In addition, unlike MNase, MPE-Fe(II) cleaves nuclear DNA with little sequence bias. In this regard, we found that DNA sequences at RNA splice sites are hypersensitive to digestion by MNase but not by MPE-Fe(II). This phenomenon may have affected the analysis of nucleosome occupancy over exons. These findings collectively indicate that MPE-seq provides a unique and straightforward means for the genome-wide analysis of chromatin structure with minimal DNA sequence bias. In particular, the combined use of MPE-seq and MNase-seq enables the identification of noncanonical chromatin structures that are likely to be important for the regulation of gene expression. PMID:26080409

  7. Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis.

    PubMed

    Skwark, Marcin J; Croucher, Nicholas J; Puranen, Santeri; Chewapreecha, Claire; Pesonen, Maiju; Xu, Ying Ying; Turner, Paul; Harris, Simon R; Beres, Stephen B; Musser, James M; Parkhill, Julian; Bentley, Stephen D; Aurell, Erik; Corander, Jukka

    2017-02-01

    Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein-protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly

  8. A genome-wide 20 K citrus microarray for gene expression analysis

    PubMed Central

    Martinez-Godoy, M Angeles; Mauri, Nuria; Juarez, Jose; Marques, M Carmen; Santiago, Julia; Forment, Javier; Gadea, Jose

    2008-01-01

    Background Understanding of genetic elements that contribute to key aspects of citrus biology will impact future improvements in this economically important crop. Global gene expression analysis demands microarray platforms with a high genome coverage. In the last years, genome-wide EST collections have been generated in citrus, opening the possibility to create new tools for functional genomics in this crop plant. Results We have designed and constructed a publicly available genome-wide cDNA microarray that include 21,081 putative unigenes of citrus. As a functional companion to the microarray, a web-browsable database [1] was created and populated with information about the unigenes represented in the microarray, including cDNA libraries, isolated clones, raw and processed nucleotide and protein sequences, and results of all the structural and functional annotation of the unigenes, like general description, BLAST hits, putative Arabidopsis orthologs, microsatellites, putative SNPs, GO classification and PFAM domains. We have performed a Gene Ontology comparison with the full set of Arabidopsis proteins to estimate the genome coverage of the microarray. We have also performed microarray hybridizations to check its usability. Conclusion This new cDNA microarray replaces the first 7K microarray generated two years ago and allows gene expression analysis at a more global scale. We have followed a rational design to minimize cross-hybridization while maintaining its utility for different citrus species. Furthermore, we also provide access to a website with full structural and functional annotation of the unigenes represented in the microarray, along with the ability to use this site to directly perform gene expression analysis using standard tools at different publicly available servers. Furthermore, we show how this microarray offers a good representation of the citrus genome and present the usefulness of this genomic tool for global studies in citrus by using it to

  9. Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis

    PubMed Central

    Pesonen, Maiju; Musser, James M.; Bentley, Stephen D.; Aurell, Erik; Corander, Jukka

    2017-01-01

    Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein-protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly

  10. A genome-wide survey reveals a deletion polymorphism associated with resistance to gastrointestinal nematodes in Angus cattle.

    PubMed

    Xu, Lingyang; Hou, Yali; Bickhart, Derek M; Song, Jiuzhou; Van Tassell, Curtis P; Sonstegard, Tad S; Liu, George E

    2014-06-01

    Gastrointestinal (GI) nematode infections are a worldwide threat to human health and animal production. In this study, we performed a genome-wide association study between copy number variations (CNVs) and resistance to GI nematodes in an Angus cattle population. Using a linear regression analysis, we identified one deletion CNV which reaches genome-wide significance after Bonferroni correction. With multiple mapped human olfactory receptor genes but no annotated bovine genes in the region, this significantly associated CNV displays high population frequencies (58.26 %) with a length of 104.8 kb on chr7. We further investigated the linkage disequilibrium (LD) relationships between this CNV and its nearby single nucleotide polymorphisms (SNPs) and genes. The underlining haplotype blocks contain immune-related genes such as ZNF496 and NLRP3. As this CNV co-segregates with linked SNPs and associated genes, we suspect that it could contribute to the detected variations in gene expression and thus differences in host parasite resistance.

  11. A high definition look at the NF-Y regulome reveals genome-wide associations with selected transcription factors

    PubMed Central

    Dolfini, Diletta; Zambelli, Federico; Pedrazzoli, Maurizio; Mantovani, Roberto; Pavesi, Giulio

    2016-01-01

    NF-Y is a trimeric transcription factor (TF), binding the CCAAT box element, for which several results suggest a pioneering role in activation of transcription. In this work, we integrated 380 ENCODE ChIP-Seq experiments for 154 TFs and cofactors with sequence analysis, protein–protein interactions and RNA profiling data, in order to identify genome-wide regulatory modules resulting from the co-association of NF-Y with other TFs. We identified three main degrees of co-association with NF-Y for sequence-specific TFs. In the most relevant one, we found TFs having a significant overlap with NF-Y in their DNA binding loci, some with a precise spacing of binding sites with respect to the CCAAT box, others (FOS, Sp1/2, RFX5, IRF3, PBX3) mostly lacking their canonical binding site and bound to arrays of well spaced CCAAT boxes. As expected, NF-Y binding also correlates with RNA Pol II General TFs and with subunits of complexes involved in the control of H3K4 methylations. Co-association patterns are confirmed by protein–protein interactions, and correspond to specific functional categorizations and expression level changes of target genes following NF-Y inactivation. These data define genome-wide rules for the organization of NF-Y-centered regulatory modules, supporting a model of distinct categorization and synergy with well defined sets of TFs. PMID:26896797

  12. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

    PubMed Central

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

    2014-01-01

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

  13. A genome-wide resource for the analysis of protein localisation in Drosophila.

    PubMed

    Sarov, Mihail; Barz, Christiane; Jambor, Helena; Hein, Marco Y; Schmied, Christopher; Suchold, Dana; Stender, Bettina; Janosch, Stephan; K J, Vinay Vikas; Krishnan, R T; Krishnamoorthy, Aishwarya; Ferreira, Irene R S; Ejsmont, Radoslaw K; Finkl, Katja; Hasse, Susanne; Kämpfer, Philipp; Plewka, Nicole; Vinis, Elisabeth; Schloissnig, Siegfried; Knust, Elisabeth; Hartenstein, Volker; Mann, Matthias; Ramaswami, Mani; VijayRaghavan, K; Tomancak, Pavel; Schnorrer, Frank

    2016-02-20

    The Drosophila genome contains >13000 protein-coding genes, the majority of which remain poorly investigated. Important reasons include the lack of antibodies or reporter constructs to visualise these proteins. Here, we present a genome-wide fosmid library of 10000 GFP-tagged clones, comprising tagged genes and most of their regulatory information. For 880 tagged proteins, we created transgenic lines, and for a total of 207 lines, we assessed protein expression and localisation in ovaries, embryos, pupae or adults by stainings and live imaging approaches. Importantly, we visualised many proteins at endogenous expression levels and found a large fraction of them localising to subcellular compartments. By applying genetic complementation tests, we estimate that about two-thirds of the tagged proteins are functional. Moreover, these tagged proteins enable interaction proteomics from developing pupae and adult flies. Taken together, this resource will boost systematic analysis of protein expression and localisation in various cellular and developmental contexts.

  14. Moving toward System Genetics through Multiple Trait Analysis in Genome-Wide Association Studies

    PubMed Central

    Shriner, Daniel

    2011-01-01

    Association studies are a staple of genotype–phenotype mapping studies, whether they are based on single markers, haplotypes, candidate genes, genome-wide genotypes, or whole genome sequences. Although genetic epidemiological studies typically contain data collected on multiple traits which themselves are often correlated, most analyses have been performed on single traits. Here, I review several methods that have been developed to perform multiple trait analysis. These methods range from traditional multivariate models for systems of equations to recently developed graphical approaches based on network theory. The application of network theory to genetics is termed systems genetics and has the potential to address long-standing questions in genetics about complex processes such as coordinate regulation, homeostasis, and pleiotropy. PMID:22303408

  15. Genome-wide Analysis of RNA Polymerase II Termination at Protein-Coding Genes.

    PubMed

    Baejen, Carlo; Andreani, Jessica; Torkler, Phillipp; Battaglia, Sofia; Schwalb, Bjoern; Lidschreiber, Michael; Maier, Kerstin C; Boltendahl, Andrea; Rus, Petra; Esslinger, Stephanie; Söding, Johannes; Cramer, Patrick

    2017-03-06

    At the end of protein-coding genes, RNA polymerase (Pol) II undergoes a concerted transition that involves 3'-processing of the pre-mRNA and transcription termination. Here, we present a genome-wide analysis of the 3'-transition in budding yeast. We find that the 3'-transition globally requires the Pol II elongation factor Spt5 and factors involved in the recognition of the polyadenylation (pA) site and in endonucleolytic RNA cleavage. Pol II release from DNA occurs in a narrow termination window downstream of the pA site and requires the "torpedo" exonuclease Rat1 (XRN2 in human). The Rat1-interacting factor Rai1 contributes to RNA degradation downstream of the pA site. Defects in the 3'-transition can result in increased transcription at downstream genes.

  16. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis

    PubMed Central

    Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R.; Hutter, Carolyn M.; Aragaki, Aaron K.; Baron, John A.; Berndt, Sonja I.; Bézieau, Stéphane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Lin S.; Coetzee, Gerhard A.; Coetzee, Simon G.; Conti, David V.; Curtis, Keith R.; Duggan, David; Edwards, Todd; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Gogarten, Stephanie M.; Gruber, Stephen B.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Hunter, David J.; Jackson, Rebecca D.; Jee, Sun Ha; Jenkins, Mark A.; Jia, Wei-Hua; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; Lacroix, Andrea Z.; Laurie, Cathy C.; Laurie, Cecelia A.; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane M.; Liu, Yan; Ma, Jing; Makar, Karen W.; Matsuo, Keitaro; Newcomb, Polly A.; Potter, John D.; Prentice, Ross L.; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A.; Schoen, Robert E.; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao-Ou; Slattery, Martha L.; Taverna, Darin; Thibodeau, Stephen N.; Ulrich, Cornelia M.; White, Emily; Xiang, Yongbing; Zanke, Brent W.; Zeng, Yi-Xin; Zhang, Ben; Zheng, Wei; Hsu, Li

    2013-01-01

    BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products

  17. Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

    PubMed

    Hellwege, Jacklyn N; Palmer, Nicholette D; Dimitrov, Latchezar; Keaton, Jacob M; Tabb, Keri L; Sajuthi, Satria; Taylor, Kent D; Ng, Maggie C Y; Speliotes, Elizabeth K; Hawkins, Gregory A; Long, Jirong; Ida Chen, Yii-Der; Lorenzo, Carlos; Norris, Jill M; Rotter, Jerome I; Langefeld, Carl D; Wagenknecht, Lynne E; Bowden, Donald W

    2017-02-01

    Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.

  18. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

    PubMed

    Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire; van der Valk, Ralf J P; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Møller, Eskil; Mahajan, Anubha; Pitkänen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M; Cousminer, Diana L; Marsh, Julie A; Lehtimäki, Terho; Curtin, John A; Vioque, Jesus; Ahluwalia, Tarunveer S; Myhre, Ronny; Price, Thomas S; Vilor-Tejedor, Natalia; Yengo, Loïc; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M A; Hirschhorn, Joel N; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N; Kähönen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A; Lewin, Alexandra M; Liang, Liming; Lyytikäinen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E; McMahon, George; Mentch, Frank D; Middeldorp, Christel M; Murray, Clare S; Pahkala, Katja; Pers, Tune H; Pfäffle, Roland; Postma, Dirkje S; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M T; Torrent, Maties; Uitterlinden, André G; van Meurs, Joyce B; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S; Dedoussis, George V; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R; Custovic, Adnan; Raitakari, Olli T; Pennell, Craig E; Widén, Elisabeth; Boomsma, Dorret I; Koppelman, Gerard H; Sebert, Sylvain; Järvelin, Marjo-Riitta; Hyppönen, Elina; McCarthy, Mark I; Lindi, Virpi; Harri, Niinikoski; Körner, Antje; Bønnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M; Smith, George Davey; Sørensen, Thorkild I A; Timpson, Nicholas J; Grant, Struan F A; Jaddoe, Vincent W V

    2016-01-15

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

  19. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    PubMed Central

    Felix, Janine F.; Bradfield, Jonathan P.; Monnereau, Claire; van der Valk, Ralf J.P.; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Møller, Eskil; Mahajan, Anubha; Pitkänen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M.; Cousminer, Diana L.; Marsh, Julie A.; Lehtimäki, Terho; Curtin, John A.; Vioque, Jesus; Ahluwalia, Tarunveer S.; Myhre, Ronny; Price, Thomas S.; Vilor-Tejedor, Natalia; Yengo, Loïc; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I.; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M.A.; Hirschhorn, Joel N.; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N.; Kähönen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A.; Lewin, Alexandra M.; Liang, Liming; Lyytikäinen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E.; McMahon, George; Mentch, Frank D.; Middeldorp, Christel M.; Murray, Clare S.; Pahkala, Katja; Pers, Tune H.; Pfäffle, Roland; Postma, Dirkje S.; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M. T.; Torrent, Maties; Uitterlinden, André G.; van Meurs, Joyce B.; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S.; Dedoussis, George V.; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R.; Custovic, Adnan; Raitakari, Olli T.; Pennell, Craig E.; Widén, Elisabeth; Boomsma, Dorret I.; Koppelman, Gerard H.; Sebert, Sylvain; Järvelin, Marjo-Riitta; Hyppönen, Elina; McCarthy, Mark I.; Lindi, Virpi; Harri, Niinikoski; Körner, Antje; Bønnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M.; Smith, George Davey; Sørensen, Thorkild I.A.; Timpson, Nicholas J.; Grant, Struan F.A.; Jaddoe, Vincent W.V.

    2016-01-01

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. PMID:26604143

  20. Genome-Wide Analysis of A-to-I RNA Editing.

    PubMed

    Savva, Yiannis A; Laurent, Georges St; Reenan, Robert A

    2016-01-01

    Adenosine (A)-to-inosine (I) RNA editing is a fundamental posttranscriptional modification that ensures the deamination of A-to-I in double-stranded (ds) RNA molecules. Intriguingly, the A-to-I RNA editing system is particularly active in the nervous system of higher eukaryotes, altering a plethora of noncoding and coding sequences. Abnormal RNA editing is highly associated with many neurological phenotypes and neurodevelopmental disorders. However, the molecular mechanisms underlying RNA editing-mediated pathogenesis still remain enigmatic and have attracted increasing attention from researchers. Over the last decade, methods available to perform genome-wide transcriptome analysis, have evolved rapidly. Within the RNA editing field researchers have adopted next-generation sequencing technologies to identify RNA-editing sites within genomes and to elucidate the underlying process. However, technical challenges associated with editing site discovery have hindered efforts to uncover comprehensive editing site datasets, resulting in the general perception that the collections of annotated editing sites represent only a small minority of the total number of sites in a given organism, tissue, or cell type of interest. Additionally to doubts about sensitivity, existing RNA-editing site lists often contain high percentages of false positives, leading to uncertainty about their validity and usefulness in downstream studies. An accurate investigation of A-to-I editing requires properly validated datasets of editing sites with demonstrated and transparent levels of sensitivity and specificity. Here, we describe a high signal-to-noise method for RNA-editing site detection using single-molecule sequencing (SMS). With this method, authentic RNA-editing sites may be differentiated from artifacts. Machine learning approaches provide a procedure to improve upon and experimentally validate sequencing outcomes through use of computationally predicted, iterative feedback loops

  1. Genome-wide meta-analysis of common variant differences between men and women

    PubMed Central

    Boraska, Vesna; Jerončić, Ana; Colonna, Vincenza; Southam, Lorraine; Nyholt, Dale R.; William Rayner, Nigel; Perry, John R.B.; Toniolo, Daniela; Albrecht, Eva; Ang, Wei; Bandinelli, Stefania; Barbalic, Maja; Barroso, Inês; Beckmann, Jacques S.; Biffar, Reiner; Boomsma, Dorret; Campbell, Harry; Corre, Tanguy; Erdmann, Jeanette; Esko, Tõnu; Fischer, Krista; Franceschini, Nora; Frayling, Timothy M.; Girotto, Giorgia; Gonzalez, Juan R.; Harris, Tamara B.; Heath, Andrew C.; Heid, Iris M.; Hoffmann, Wolfgang; Hofman, Albert; Horikoshi, Momoko; Hua Zhao, Jing; Jackson, Anne U.; Hottenga, Jouke-Jan; Jula, Antti; Kähönen, Mika; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Klopp, Norman; Kutalik, Zoltán; Lagou, Vasiliki; Launer, Lenore J.; Lehtimäki, Terho; Lemire, Mathieu; Lokki, Marja-Liisa; Loley, Christina; Luan, Jian'an; Mangino, Massimo; Mateo Leach, Irene; Medland, Sarah E.; Mihailov, Evelin; Montgomery, Grant W.; Navis, Gerjan; Newnham, John; Nieminen, Markku S.; Palotie, Aarno; Panoutsopoulou, Kalliope; Peters, Annette; Pirastu, Nicola; Polašek, Ozren; Rehnström, Karola; Ripatti, Samuli; Ritchie, Graham R.S.; Rivadeneira, Fernando; Robino, Antonietta; Samani, Nilesh J.; Shin, So-Youn; Sinisalo, Juha; Smit, Johannes H.; Soranzo, Nicole; Stolk, Lisette; Swinkels, Dorine W.; Tanaka, Toshiko; Teumer, Alexander; Tönjes, Anke; Traglia, Michela; Tuomilehto, Jaakko; Valsesia, Armand; van Gilst, Wiek H.; van Meurs, Joyce B.J.; Smith, Albert Vernon; Viikari, Jorma; Vink, Jacqueline M.; Waeber, Gerard; Warrington, Nicole M.; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F.; Zanke, Brent W.; Zgaga, Lina; Boehnke, Michael; d'Adamo, Adamo Pio; de Geus, Eco; Demerath, Ellen W.; den Heijer, Martin; Eriksson, Johan G.; Ferrucci, Luigi; Gieger, Christian; Gudnason, Vilmundur; Hayward, Caroline; Hengstenberg, Christian; Hudson, Thomas J.; Järvelin, Marjo-Riitta; Kogevinas, Manolis; Loos, Ruth J.F.; Martin, Nicholas G.; Metspalu, Andres; Pennell, Craig E.; Penninx, Brenda W.; Perola, Markus; Raitakari, Olli; Salomaa, Veikko; Schreiber, Stefan; Schunkert, Heribert; Spector, Tim D.; Stumvoll, Michael; Uitterlinden, André G.; Ulivi, Sheila; van der Harst, Pim; Vollenweider, Peter; Völzke, Henry; Wareham, Nicholas J.; Wichmann, H.-Erich; Wilson, James F.; Rudan, Igor; Xue, Yali; Zeggini, Eleftheria

    2012-01-01

    The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genome-wide significant (P < 5 × 10−8) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits. PMID:22843499

  2. Genome-wide Linkage and Association Analysis of Cardiometabolic Phenotypes in Hispanic Americans

    PubMed Central

    Hellwege, Jacklyn N.; Palmer, Nicholette D.; Dimitrov, Latchezar; Keaton, Jacob M.; Tabb, Keri L.; Sajuthi, Satria; Taylor, Kent D.; Ng, Maggie C.Y.; Speliotes, Elizabeth K.; Hawkins, Gregory A.; Long, Jirong; Chen, Yii-Der Ida; Lorenzo, Carlos; Norris, Jill M.; Rotter, Jerome I.; Langefeld, Carl D.; Wagenknecht, Lynne E.; Bowden, Donald W.

    2016-01-01

    Linkage studies of complex genetic diseases have been largely replaced by Genome-Wide Association studies (GWAS), due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates reexamination of family-based methods. In this study we investigated the performance of two-point linkage analysis for over 1.6 million SNPs combined with single variant association analysis to identify high impact variants which are both strongly linked and associated with cardiometabolic traits in up to 1 414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD scores with 9 214 LOD scores ≥ 3.0, 845 ≥ 4.0, and 89 ≥ 5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for TNFα receptor 2). Twenty-seven variants were associated with p < 0.005 as well as having a LOD score > 4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31Mb) on chromosome 1q with acute insulin response (max LOD = 5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes. PMID:27535031

  3. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis

    PubMed Central

    Whiffin, Nicola; Hosking, Fay J.; Farrington, Susan M.; Palles, Claire; Dobbins, Sara E.; Zgaga, Lina; Lloyd, Amy; Kinnersley, Ben; Gorman, Maggie; Tenesa, Albert; Broderick, Peter; Wang, Yufei; Barclay, Ella; Hayward, Caroline; Martin, Lynn; Buchanan, Daniel D.; Win, Aung Ko; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Liu, Tao; Campbell, Harry; Lindblom, Annika; Houlston, Richard S.; Tomlinson, Ian P.; Dunlop, Malcolm G.

    2014-01-01

    To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10−11]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10−10) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10−8). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. PMID:24737748

  4. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology.

    PubMed

    Matarin, Mar; Salih, Dervis A; Yasvoina, Marina; Cummings, Damian M; Guelfi, Sebastian; Liu, Wenfei; Nahaboo Solim, Muzammil A; Moens, Thomas G; Paublete, Rocio Moreno; Ali, Shabinah S; Perona, Marina; Desai, Roshni; Smith, Kenneth J; Latcham, Judy; Fulleylove, Michael; Richardson, Jill C; Hardy, John; Edwards, Frances A

    2015-02-03

    We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.

  5. Genome-Wide Analysis of Seed Acid Detergent Lignin (ADL) and Hull Content in Rapeseed (Brassica napus L.).

    PubMed

    Wang, Jia; Jian, Hongju; Wei, Lijuan; Qu, Cunmin; Xu, Xinfu; Lu, Kun; Qian, Wei; Li, Jiana; Li, Maoteng; Liu, Liezhao

    2015-01-01

    A stable yellow-seeded variety is the breeding goal for obtaining the ideal rapeseed (Brassica napus L.) plant, and the amount of acid detergent lignin (ADL) in the seeds and the hull content (HC) are often used as yellow-seeded rapeseed screening indices. In this study, a genome-wide association analysis of 520 accessions was performed using the Q + K model with a total of 31,839 single-nucleotide polymorphism (SNP) sites. As a result, three significant associations on the B. napus chromosomes A05, A09, and C05 were detected for seed ADL content. The peak SNPs were within 9.27, 14.22, and 20.86 kb of the key genes BnaA.PAL4, BnaA.CAD2/BnaA.CAD3, and BnaC.CCR1, respectively. Further analyses were performed on the major locus of A05, which was also detected in the seed HC examination. A comparison of our genome-wide association study (GWAS) results and previous linkage mappings revealed a common chromosomal region on A09, which indicates that GWAS can be used as a powerful complementary strategy for dissecting complex traits in B. napus. Genomic selection (GS) utilizing the significant SNP markers based on the GWAS results exhibited increased predictive ability, indicating that the predictive ability of a given model can be substantially improved by using GWAS and GS.

  6. Genome-wide recombination and chromosome segregation in human oocytes and embryos reveal selection for maternal recombination rates”

    PubMed Central

    Natesan, Senthilkumar A.; Joshi, Hrishikesh A.; Cimadomo, Danilo; Griffin, Darren K.; Sage, Karen; Summers, Michael C.; Thornhill, Alan R.; Housworth, Elizabeth; Herbert, Alex D.; Rienzi, Laura; Ubaldi, Filippo M.; Handyside, Alan H.; Hoffmann, Eva R.

    2015-01-01

    Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Here, we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses. Genotyping > 4 million informative single-nucleotide polymorphisms (SNPs) from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns of 529 chromosome pairs. We uncover a novel reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germline by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings reveal that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II. PMID:25985139

  7. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.

    PubMed

    Plagnol, Vincent; Howson, Joanna M M; Smyth, Deborah J; Walker, Neil; Hafler, Jason P; Wallace, Chris; Stevens, Helen; Jackson, Laura; Simmonds, Matthew J; Bingley, Polly J; Gough, Stephen C; Todd, John A

    2011-08-01

    The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).

  8. Genome-Wide Association Mapping for Intelligence in Military Working Dogs: Development of Advanced Classification Algorithm for Genome-Wide Single Nucleotide Polymorphism (SNP) Data Analysis

    DTIC Science & Technology

    2011-04-01

    distribution unlimited. QC – quality control QTL – quantitative trait loci SNP – single nucleotide polymorphism TE – Tris + EDTA TBE – Tris + Boric Acid + EDTA WGSA – whole genome sampling assay ...canine intelligence testing protocol EDTA – ethylenediaminetetraacetic acid GWAS – genome-wide association study LD – linkage disequilibrium MWD

  9. Genome-wide sequencing data reveals virulence factors implicated in banana Xanthomonas wilt.

    PubMed

    Studholme, David J; Kemen, Eric; MacLean, Daniel; Schornack, Sebastian; Aritua, Valente; Thwaites, Richard; Grant, Murray; Smith, Julian; Jones, Jonathan D G

    2010-09-01

    Banana Xanthomonas wilt is a newly emerging disease that is currently threatening the livelihoods of millions of farmers in East Africa. The causative agent is Xanthomonas campestris pathovar musacearum (Xcm), but previous work suggests that this pathogen is much more closely related to species Xanthomonas vasicola than to X. campestris. We have generated draft genome sequences for a banana-pathogenic strain of Xcm isolated in Uganda and for a very closely related strain of X. vasicola pathovar vasculorum, originally isolated from sugarcane, that is nonpathogenic on banana. The draft sequences revealed overlapping but distinct repertoires of candidate virulence effectors in the two strains. Both strains encode homologues of the Pseudomonas syringae effectors HopW, HopAF1 and RipT from Ralstonia solanacearum. The banana-pathogenic and non-banana-pathogenic strains also differed with respect to lipopolysaccharide synthesis and type-IV pili, and in at least several thousand single-nucleotide polymorphisms in the core conserved genome. We found evidence of horizontal transfer between X. vasicola and very distantly related bacteria, including members of other divisions of the Proteobacteria. The availability of these draft genomes will be an invaluable tool for further studies aimed at understanding and combating this important disease.

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

    PubMed Central

    Tan, Shengjun; Zhong, Yan; Wang, Ling; Gu, Longjiang; Chen, Jian-Qun; Pan, Qinghua; Bergelson, Joy; Tian, Dacheng

    2015-01-01

    Summary 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 whose composite behavior is yet to be characterized? Here, we survey 332 NBS-LRR genes cloned from 5 resistant 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

  11. 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.

  12. Genome-Wide Sequencing Reveals MicroRNAs Downregulated in Cerebral Cavernous Malformations.

    PubMed

    Kar, Souvik; Bali, Kiran Kumar; Baisantry, Arpita; Geffers, Robert; Samii, Amir; Bertalanffy, Helmut

    2017-02-01

    Cerebral cavernous malformations (CCM) are vascular lesions associated with loss-of-function mutations in one of the three genes encoding KRIT1 (CCM1), CCM2, and PDCD10. Recent understanding of the molecular mechanisms that lead to CCM development is limited. The role of microRNAs (miRNAs) has been demonstrated in vascular pathologies resulting in loss of tight junction proteins, increased vascular permeability and endothelial cell dysfunction. Since the relevance of miRNAs in CCM pathophysiology has not been elucidated, the primary aim of the study was to identify the miRNA-mRNA expression network associated with CCM. Using small RNA sequencing, we identified a total of 764 matured miRNAs expressed in CCM patients compared to the healthy brains. The expression of the selected miRNAs was validated by qRT-PCR, and the results were found to be consistent with the sequencing data. Upon application of additional statistical stringency, five miRNAs (let-7b-5p, miR-361-5p, miR-370-3p, miR-181a-2-3p, and miR-95-3p) were prioritized to be top CCM-relevant miRNAs. Further in silico analyses revealed that the prioritized miRNAs have a direct functional relation with mRNAs, such as MIB1, HIF1A, PDCD10, TJP1, OCLN, HES1, MAPK1, VEGFA, EGFL7, NF1, and ENG, which are previously characterized as key regulators of CCM pathology. To date, this is the first study to investigate the role of miRNAs in CCM pathology. By employing cutting edge molecular and in silico analyses on clinical samples, the current study reports global miRNA expression changes in CCM patients and provides a rich source of data set to understand detailed molecular machinery involved in CCM pathophysiology.

  13. Systematic genome-wide annotation of spliceosomal proteins reveals differential gene family expansion

    PubMed Central

    Barbosa-Morais, Nuno L.; Carmo-Fonseca, Maria; Aparício, Samuel

    2006-01-01

    Although more than 200 human spliceosomal and splicing-associated proteins are known, the evolution of the splicing machinery has not been studied extensively. The recent near-complete sequencing and annotation of distant vertebrate and chordate genomes provides the opportunity for an exhaustive comparative analysis of splicing factors across eukaryotes. We describe here our semiautomated computational pipeline to identify and annotate splicing factors in representative species of eukaryotes. We focused on protein families whose role in splicing is confirmed by experimental evidence. We visually inspected 1894 proteins and manually curated 224 of them. Our analysis shows a general conservation of the core spliceosomal proteins across the eukaryotic lineage, contrasting with selective expansions of protein families known to play a role in the regulation of splicing, most notably of SR proteins in metazoans and of heterogeneous nuclear ribonucleoproteins (hnRNP) in vertebrates. We also observed vertebrate-specific expansion of the CLK and SRPK kinases (which phosphorylate SR proteins), and the CUG-BP/CELF family of splicing regulators. Furthermore, we report several intronless genes amongst splicing proteins in mammals, suggesting that retrotransposition contributed to the complexity of the mammalian splicing apparatus. PMID:16344558

  14. Transcription factors expressed in olfactory bulb local progenitor cells revealed by genome-wide transcriptome profiling

    PubMed Central

    Campbell, Gordon R. O.; Baudhuin, Ariane; Vranizan, Karen; Ngai, John

    2011-01-01

    The local progenitor population in the olfactory bulb (OB) gives rise to mitral and tufted projection neurons during embryonic development. In contrast, OB interneurons are derived from sources outside the bulb where neurogenesis continues throughout life. While many of the genes involved in OB interneuron development have been characterized, the genetic pathways driving local progenitor cell differentiation in this tissue are largely unknown. To better understand this process, we used transcriptional profiling to monitor gene expression of whole OB at daily intervals from embryonic day 11 through birth, generating a compendium of gene expression encompassing the major developmental events of this tissue. Through hierarchical clustering, bioinformatics analysis, and validation by RNA in situ hybridizations, we identified a large number of transcription factors, DNA binding proteins, and cell cycle-related genes expressed by the local neural progenitor cells (NPCs) of the embryonic OB. Further in silico analysis of transcription factor binding sites identified an enrichment of genes regulated by the E2F-Rb pathway among those expressed in the local NPC population. Together these results provide initial insights into the molecular identity of the OB local NPC population and the transcription factor networks that may regulate their function. PMID:21194568

  15. Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome

    PubMed Central

    Shim, Unjin; Kim, Han-Na; Lee, Hyejin; Oh, Jee-Young

    2015-01-01

    Background Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is affected by both environmental and genetic factors. Although the genetic component of PCOS is evident, studies aiming to identify susceptibility genes have shown controversial results. This study conducted a pathway-based analysis using a dataset obtained through a genome-wide association study (GWAS) to elucidate the biological pathways that contribute to PCOS susceptibility and the associated genes. Methods We used GWAS data on 636,797 autosomal single nucleotide polymorphisms (SNPs) from 1,221 individuals (432 PCOS patients and 789 controls) for analysis. A pathway analysis was conducted using meta-analysis gene-set enrichment of variant associations (MAGENTA). Top-ranking pathways or gene sets associated with PCOS were identified, and significant genes within the pathways were analyzed. Results The pathway analysis of the GWAS dataset identified significant pathways related to oocyte meiosis and the regulation of insulin secretion by acetylcholine and free fatty acids (all nominal gene-set enrichment analysis (GSEA) P-values < 0.05). In addition, INS, GNAQ, STXBP1, PLCB3, PLCB2, SMC3 and PLCZ1 were significant genes observed within the biological pathways (all gene P-values < 0.05). Conclusions By applying MAGENTA pathway analysis to PCOS GWAS data, we identified significant pathways and candidate genes involved in PCOS. Our findings may provide new leads for understanding the mechanisms underlying the development of PCOS. PMID:26308735

  16. Genome-wide profiling of DNA methylation reveals preferred sequences of DNMTs in hepatocellular carcinoma cells.

    PubMed

    Fan, Hong; Zhao, Zhujiang; Cheng, Yuchao; Cui, He; Qiao, Fengchang; Wang, Ling; Hu, Jiaojiao; Wu, Huzhang; Song, Wei

    2016-01-01

    Aberrant DNA methylation of CpG site is among the earliest and most frequent alterations in developmental process and diseases including cancer. To elucidate the functional preferred site of DNMTs, we analyzed the feature of distinct methylated sequences and established the defined relationship between DNMTs and preference genomic DNA sequences. Small interfering RNA (siRNA) construct of DNTM1, DNMT3A, and DNMT3B was transfected into the human hepatocellular carcinoma cell line SMMC-7721, respectively. Distinguishing methylated fragments pool was enriched by SHH method in cells which is knocked down DNMT1, DNMT3A, DNMT3B, separately. The defined binding transcription factors (TFs) containing of 5'CpG islands were obtained with bioinformatics software and website. In SMMC-7721 hepatocellular carcinoma (HCC) cell line, DNMT1, DNMT3A, and DNMT3B were specific suppressed by their corresponding siRNA construct, separately. A 46, 42, 67 distinctive methylated fragments from three different DNMTs were evaluated according to genomic DNA database. Those separated fragments were distributed among genomic DNA regions of all chromosome complements, including coding genes, repeat sequences, and genes with unknown function. The majority of coding genes contain CpG islands in their promoter region. Cluster analysis demonstrated all of preference sequences identified by three DNMTs shares their own conserved sequences. In depleting of different DNMTs cells, 80 % of 103 upregulation genes induced by DNMT1 knock-down contain CpG sites; 76 % of 25 upregulation genes induced by DNMT3A knock-down contain CpG sites; 63 % of 126 upregulation genes induced by DNMT3B knock-down contain CpG sites. Our findings suggested that distinctive DNMTs targeted DNA methylation site to their preference sequences, and this targeting might be associated with diverse roles of DNMTs in tumorigenesis. Meanwhile, the analysis of preference sequences provides an alternative way to find out the individual

  17. Family-based Association Analyses of Imputed Genotypes Reveal Genome-Wide Significant Association of Alzheimer’s disease with OSBPL6, PTPRG and PDCL3

    PubMed Central

    Herold, Christine; Hooli, Basavaraj V.; Mullin, Kristina; Liu, Tian; Roehr, Johannes T; Mattheisen, Manuel; Parrado, Antonio R.; Bertram, Lars; Lange, Christoph; Tanzi, Rudolph E.

    2015-01-01

    The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1 and PSEN2 cause a subset of early-onset familial Alzheimer's disease (EOFAD). On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ε4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3,500 subjects from 1,070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value = 3.98·10−08), rs1347297 in the gene OSBPL6 (P-value = 4.53·10−08), and rs1513625 near PDCL3 (P-value = 4.28·10−08). In addition, rs72953347 in OSBPL6 (P-value = 6.36·10−07) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value: 4.76·10−07; rs62400067, P-value: 3.54·10−07). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance. PMID:26830138

  18. Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens.

    PubMed

    Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O

    2012-07-01

    Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r(2) ≥ 0.3) in both traditional and village chickens at pairwise marker distances of ~10 Kb; while haplotype block analysis indicates a median block size of 11-12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55-38.89 Mb) and rose comb (Gga 7:18.41-22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25-67.28 Mb, Gga 1:67.28-67.32 Mb) totalling ~75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions.

  19. Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens

    PubMed Central

    Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O

    2012-01-01

    Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r2⩾0.3) in both traditional and village chickens at pairwise marker distances of ∼10 Kb; while haplotype block analysis indicates a median block size of 11–12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55–38.89 Mb) and rose comb (Gga 7:18.41–22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25–67.28 Mb, Gga 1:67.28–67.32 Mb) totalling ∼75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions. PMID:22395157

  20. Genome-wide DNA methylation profiling reveals parity-associated hypermethylation of FOXA1.

    PubMed

    Ghosh, Sagar; Gu, Fei; Wang, Chou-Miin; Lin, Chun-Lin; Liu, Joseph; Wang, Howard; Ravdin, Peter; Hu, Yanfen; Huang, Tim H M; Li, Rong

    2014-10-01

    Early pregnancy in women by the age of 20 is known to have a profound effect on reduction of lifelong breast cancer risk as compared to their nulliparous counterparts. Additional pregnancies further enhance the protection against breast cancer development. Nationwide trend of delayed pregnancy may contribute to the recently reported increase in the incidence of advanced breast cancer among young women in this country. The underlying mechanism for the parity-associated reduction of breast cancer risk is not clearly understood. The purpose of the current study is to use whole-genome DNA methylation profiling to explore a potential association between parity and epigenetic changes in breast tissue from women with early parity and nulliparity. Breast tissue was collected from age-matched cancer-free women with early parity (age < 20; n = 15) or nulliparity (n = 13). The methyl-CpG binding domain-based capture-sequencing technology was used for whole-genome DNA methylation profiling. Potential parity-associated hypermethylated genes were further verified by locus-specific pyrosequencing, using an expanded cohort of parous (n = 19) and nulliparous (n = 16) women that included the initial samples used in the global analysis. Our study identified six genes that are hypermethylated in the parous group (P < 0.05). Pyrosequencing confirmed parity-associated hypermethylation at multiple CpG islands of the FOXA1 gene, which encodes a pioneer factor that facilitates chromatin binding of estrogen receptor α. Our work identifies several potential methylation biomarkers for parity-associated breast cancer risk assessment. In addition, the results are consistent with the notion that parity-associated epigenetic silencing of FOXA1 contributes to long-term attenuation of the estrogenic impact on breast cancer development.

  1. A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.

    PubMed

    Wang, Ke-Sheng; Liu, Xue-Feng; Aragam, Nagesh

    2010-12-01

    Schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder.

  2. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium.

    PubMed

    Li, Qing; Wojciechowski, Robert; Simpson, Claire L; Hysi, Pirro G; Verhoeven, Virginie J M; Ikram, Mohammad Kamran; Höhn, René; Vitart, Veronique; Hewitt, Alex W; Oexle, Konrad; Mäkelä, Kari-Matti; MacGregor, Stuart; Pirastu, Mario; Fan, Qiao; Cheng, Ching-Yu; St Pourcain, Beaté; McMahon, George; Kemp, John P; Northstone, Kate; Rahi, Jugnoo S; Cumberland, Phillippa M; Martin, Nicholas G; Sanfilippo, Paul G; Lu, Yi; Wang, Ya Xing; Hayward, Caroline; Polašek, Ozren; Campbell, Harry; Bencic, Goran; Wright, Alan F; Wedenoja, Juho; Zeller, Tanja; Schillert, Arne; Mirshahi, Alireza; Lackner, Karl; Yip, Shea Ping; Yap, Maurice K H; Ried, Janina S; Gieger, Christian; Murgia, Federico; Wilson, James F; Fleck, Brian; Yazar, Seyhan; Vingerling, Johannes R; Hofman, Albert; Uitterlinden, André; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart; Oostra, Ben A; Zhou, Xin; Teo, Yik-Ying; Tai, E Shyong; Vithana, Eranga; Barathi, Veluchamy; Zheng, Yingfeng; Siantar, Rosalynn Grace; Neelam, Kumari; Shin, Youchan; Lam, Janice; Yonova-Doing, Ekaterina; Venturini, Cristina; Hosseini, S Mohsen; Wong, Hoi-Suen; Lehtimäki, Terho; Kähönen, Mika; Raitakari, Olli; Timpson, Nicholas J; Evans, David M; Khor, Chiea-Chuen; Aung, Tin; Young, Terri L; Mitchell, Paul; Klein, Barbara; van Duijn, Cornelia M; Meitinger, Thomas; Jonas, Jost B; Baird, Paul N; Mackey, David A; Wong, Tien Yin; Saw, Seang-Mei; Pärssinen, Olavi; Stambolian, Dwight; Hammond, Christopher J; Klaver, Caroline C W; Williams, Cathy; Paterson, Andrew D; Bailey-Wilson, Joan E; Guggenheim, Jeremy A

    2015-02-01

    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

  3. Identification of proprotein convertase substrates using genome-wide expression correlation analysis

    PubMed Central

    2011-01-01

    Background Subtilisin/kexin-like proprotein convertase (PCSK) enzymes have important regulatory function in a wide variety of biological processes. PCSKs proteolytically process at a target sequence that contains basic amino acids arginine and lysine, which results in functional maturation of the target protein. In vitro assays have showed significant biochemical redundancy between the seven family members, but the phenotypes of PCSK deficient mice and patients carrying an inactive PCSK allele argue for a specific biological function. Modeling the structures of individual PCSK enzymes has offered little insights into the specificity determinants. However, previous studies have shown that there can be a coordinated expression between a PCSK and its target molecule. Here, we have surveyed the putative PCSK target proteins using genome-wide expression correlation analysis and cleavage site prediction algorithms. Results We first performed a gene expression correlation analysis over the whole genome for all PCSK enzymes. PCSKs were found to cluster differently based on the strength of correlations. The screen for putative PCSK target proteins showed a significant enrichment (p-values from 1.2e-4 to < 1.0e-10) of putative targets among the most positively correlating genes for most PCSKs. Interestingly, there was no enrichment in putative targets among the genes that correlated positively with the biologically redundant PCSK7, whereas PCSK5 showed an inverse correlation. PCSKs also showed a highly variable degree of shared target genes that were identified by expression correlation and cleavage site prediction. Multiple alignments were used to evaluate the putative targets to pinpoint the important residues for the substrate recognition. Finally, we validated our approach and identified biochemically PAPPA1 and ADAMTS6 as novel targets for FURIN proteolytic activity. Conclusions Most PCSK enzymes display strong positive expression correlation with predicted target

  4. Pathway analysis of genome-wide association datasets of personality traits.

    PubMed

    Kim, H-N; Kim, B-H; Cho, J; Ryu, S; Shin, H; Sung, J; Shin, C; Cho, N H; Sung, Y A; Choi, B-O; Kim, H-L

    2015-04-01

    Although several genome-wide association (GWA) studies of human personality have been recently published, genetic variants that are highly associated with certain personality traits remain unknown, due to difficulty reproducing results. To further investigate these genetic variants, we assessed biological pathways using GWA datasets. Pathway analysis using GWA data was performed on 1089 Korean women whose personality traits were measured with the Revised NEO Personality Inventory for the 5-factor model of personality. A total of 1042 pathways containing 8297 genes were included in our study. Of these, 14 pathways were highly enriched with association signals that were validated in 1490 independent samples. These pathways include association of: Neuroticism with axon guidance [L1 cell adhesion molecule (L1CAM) interactions]; Extraversion with neuronal system and voltage-gated potassium channels; Agreeableness with L1CAM interaction, neurotransmitter receptor binding and downstream transmission in postsynaptic cells; and Conscientiousness with the interferon-gamma and platelet-derived growth factor receptor beta polypeptide pathways. Several genes that contribute to top-ranked pathways in this study were previously identified in GWA studies or by pathway analysis in schizophrenia or other neuropsychiatric disorders. Here we report the first pathway analysis of all five personality traits. Importantly, our analysis identified novel pathways that contribute to understanding the etiology of personality traits.

  5. Genome-Wide Comparative Analyses Reveal the Dynamic Evolution of Nucleotide-Binding Leucine-Rich Repeat Gene Family among Solanaceae Plants.

    PubMed

    Seo, Eunyoung; Kim, Seungill; Yeom, Seon-In; Choi, Doil

    2016-01-01

    Plants have evolved an elaborate innate immune system against invading pathogens. Within this system, intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors are known play critical roles in effector-triggered immunity (ETI) plant defense. We performed genome-wide identification and classification of NLR-coding sequences from the genomes of pepper, tomato, and potato using fixed criteria. We then compared genomic duplication and evolution features. We identified intact 267, 443, and 755 NLR-encoding genes in tomato, potato, and pepper genomes, respectively. Phylogenetic analysis and classification of Solanaceae NLRs revealed that the majority of NLR super family members fell into 14 subgroups, including a TIR-NLR (TNL) subgroup and 13 non-TNL subgroups. Specific subgroups have expanded in each genome, with the expansion in pepper showing subgroup-specific physical clusters. Comparative analysis of duplications showed distinct duplication patterns within pepper and among Solanaceae plants suggesting subgroup- or species-specific gene duplication events after speciation, resulting in divergent evolution. Taken together, genome-wide analysis of NLR family members provide insights into their evolutionary history in Solanaceae. These findings also provide important foundational knowledge for understanding NLR evolution and will empower broader characterization of disease resistance genes to be used for crop breeding.

  6. Genome-Wide Comparative Analyses Reveal the Dynamic Evolution of Nucleotide-Binding Leucine-Rich Repeat Gene Family among Solanaceae Plants

    PubMed Central

    Seo, Eunyoung; Kim, Seungill; Yeom, Seon-In; Choi, Doil

    2016-01-01

    Plants have evolved an elaborate innate immune system against invading pathogens. Within this system, intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors are known play critical roles in effector-triggered immunity (ETI) plant defense. We performed genome-wide identification and classification of NLR-coding sequences from the genomes of pepper, tomato, and potato using fixed criteria. We then compared genomic duplication and evolution features. We identified intact 267, 443, and 755 NLR-encoding genes in tomato, potato, and pepper genomes, respectively. Phylogenetic analysis and classification of Solanaceae NLRs revealed that the majority of NLR super family members fell into 14 subgroups, including a TIR-NLR (TNL) subgroup and 13 non-TNL subgroups. Specific subgroups have expanded in each genome, with the expansion in pepper showing subgroup-specific physical clusters. Comparative analysis of duplications showed distinct duplication patterns within pepper and among Solanaceae plants suggesting subgroup- or species-specific gene duplication events after speciation, resulting in divergent evolution. Taken together, genome-wide analysis of NLR family members provide insights into their evolutionary history in Solanaceae. These findings also provide important foundational knowledge for understanding NLR evolution and will empower broader characterization of disease resistance genes to be used for crop breeding. PMID:27559340

  7. Genome-Wide Meta-Analysis of Sciatica in Finnish Population

    PubMed Central

    Lemmelä, Susanna; Solovieva, Svetlana; Shiri, Rahman; Benner, Christian; Heliövaara, Markku; Kettunen, Johannes; Anttila, Verneri; Ripatti, Samuli; Perola, Markus; Seppälä, Ilkka; Juonala, Markus; Kähönen, Mika; Salomaa, Veikko; Viikari, Jorma; Raitakari, Olli T.; Lehtimäki, Terho; Palotie, Aarno; Viikari-Juntura, Eira; Husgafvel-Pursiainen, Kirsti

    2016-01-01

    Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6–7%) than in other European populations (1–2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate. PMID:27764105

  8. Genome-wide characterisation and expression profile of the grapevine ATL ubiquitin ligase family reveal biotic and abiotic stress-responsive and development-related members

    PubMed Central

    Ariani, Pietro; Regaiolo, Alice; Lovato, Arianna; Giorgetti, Alejandro; Porceddu, Andrea; Camiolo, Salvatore; Wong, Darren; Castellarin, Simone; Vandelle, Elodie; Polverari, Annalisa

    2016-01-01

    The Arabidopsis Tóxicos en Levadura (ATL) protein family is a class of E3 ubiquitin ligases with a characteristic RING-H2 Zn-finger structure that mediates diverse physiological processes and stress responses in plants. We carried out a genome-wide survey of grapevine (Vitis vinifera L.) ATL genes and retrieved 96 sequences containing the canonical ATL RING-H2 domain. We analysed their genomic organisation, gene structure and evolution, protein domains and phylogenetic relationships. Clustering revealed several clades, as already reported in Arabidopsis thaliana and rice (Oryza sativa), with an expanded subgroup of grapevine-specific genes. Most of the grapevine ATL genes lacked introns and were scattered among the 19 chromosomes, with a high level of duplication retention. Expression profiling revealed that some ATL genes are expressed specifically during early or late development and may participate in the juvenile to mature plant transition, whereas others may play a role in pathogen and/or abiotic stress responses, making them key candidates for further functional analysis. Our data offer the first genome-wide overview and annotation of the grapevine ATL family, and provide a basis for investigating the roles of specific family members in grapevine physiology and stress responses, as well as potential biotechnological applications. PMID:27910910

  9. Genome-wide characterisation and expression profile of the grapevine ATL ubiquitin ligase family reveal biotic and abiotic stress-responsive and development-related members.

    PubMed

    Ariani, Pietro; Regaiolo, Alice; Lovato, Arianna; Giorgetti, Alejandro; Porceddu, Andrea; Camiolo, Salvatore; Wong, Darren; Castellarin, Simone; Vandelle, Elodie; Polverari, Annalisa

    2016-12-02

    The Arabidopsis Tóxicos en Levadura (ATL) protein family is a class of E3 ubiquitin ligases with a characteristic RING-H2 Zn-finger structure that mediates diverse physiological processes and stress responses in plants. We carried out a genome-wide survey of grapevine (Vitis vinifera L.) ATL genes and retrieved 96 sequences containing the canonical ATL RING-H2 domain. We analysed their genomic organisation, gene structure and evolution, protein domains and phylogenetic relationships. Clustering revealed several clades, as already reported in Arabidopsis thaliana and rice (Oryza sativa), with an expanded subgroup of grapevine-specific genes. Most of the grapevine ATL genes lacked introns and were scattered among the 19 chromosomes, with a high level of duplication retention. Expression profiling revealed that some ATL genes are expressed specifically during early or late development and may participate in the juvenile to mature plant transition, whereas others may play a role in pathogen and/or abiotic stress responses, making them key candidates for further functional analysis. Our data offer the first genome-wide overview and annotation of the grapevine ATL family, and provide a basis for investigating the roles of specific family members in grapevine physiology and stress responses, as well as potential biotechnological applications.

  10. Genome-Wide Identification and Expression Analysis of Calcium-dependent Protein Kinase in Tomato

    PubMed Central

    Hu, Zhangjian; Lv, Xiangzhang; Xia, Xiaojian; Zhou, Jie; Shi, Kai; Yu, Jingquan; Zhou, Yanhong

    2016-01-01

    Calcium-dependent protein kinases (CDPKs) play critical roles in regulating growth, development and stress response in plants. Information about CDPKs in tomato, however, remains obscure although it is one of the most important model crops in the world. In this study, we performed a bioinformatics analysis of the entire tomato genome and identified 29 CDPK genes. These CDPK genes are found to be located in 12 chromosomes, and could be divided into four groups. Analysis of the gene structure and splicing site reflected high structure conservation within different CDPK gene groups both in the exon-intron pattern and mRNA splicing. Transcripts of most CDPK genes varied with plant organs and developmental stages and their transcripts could be differentially induced by abscisic acid (ABA), brassinosteroids (BRs), methyl jasmonate (MeJA), and salicylic acid (SA), as well as after exposure to heat, cold, and drought, respectively. To our knowledge, this is the first report about the genome-wide analysis of the CDPK gene family in tomato, and the findings obtained offer a clue to the elaborated regulatory role of CDPKs in plant growth, development and stress response in tomato. PMID:27092168

  11. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies.

    PubMed

    Kar, S P; Seldin, M F; Chen, W; Lu, E; Hirschfield, G M; Invernizzi, P; Heathcote, J; Cusi, D; Gershwin, M E; Siminovitch, K A; Amos, C I

    2013-04-01

    Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10⁻⁴, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.

  12. Genome-wide analysis of plant-specific Dof transcription factor family in tomato.

    PubMed

    Cai, Xiaofeng; Zhang, Yuyang; Zhang, Chanjuan; Zhang, Tingyan; Hu, Tixu; Ye, Jie; Zhang, Junhong; Wang, Taotao; Li, Hanxia; Ye, Zhibiao

    2013-06-01

    The Dof (DNA binding with One Finger) family encoding single zinc finger proteins has been known as a family of plant-specific transcription factors. These transcription factors are involved in a variety of functions of importance for different biological processes in plants. In the current study, we identified 34 Dof family genes in tomato, distributed on 11 chromosomes. A complete overview of SlDof genes in tomato is presented, including the gene structures, chromosome locations, phylogeny, protein motifs and evolution pattern. Phylogenetic analysis of 34 SlDof proteins resulted in four classes constituting six clusters. In addition, a comparative analysis between these genes in tomato, Arabidopsis and rice was also performed. The tomato Dof family expansion has been dated to recent duplication events, and segmental duplication is predominant for the SlDof genes. Furthermore, the SlDof genes displayed differential expression either in their transcript abundance or in their expression patterns under normal growth conditions. This is the first step towards genome-wide analyses of the Dof genes in tomato. Our study provides a very useful reference for cloning and functional analysis of the members of this gene family in tomato and other species.

  13. Genome-Wide DNA Methylation Analysis and Epigenetic Variations Associated with Congenital Aortic Valve Stenosis (AVS)

    PubMed Central

    Radhakrishna, Uppala; Albayrak, Samet; Alpay-Savasan, Zeynep; Zeb, Amna; Turkoglu, Onur; Sobolewski, Paul; Bahado-Singh, Ray O.

    2016-01-01

    Congenital heart defect (CHD) is the most common cause of death from congenital anomaly. Among several candidate epigenetic mechanisms, DNA methylation may play an important role in the etiology of CHDs. We conducted a genome-wide DNA methylation analysis using an Illumina Infinium 450k human methylation assay in a cohort of 24 newborns who had aortic valve stenosis (AVS), with gestational-age matched controls. The study identified significantly-altered CpG methylation at 59 sites in 52 genes in AVS subjects as compared to controls (either hypermethylated or demethylated). Gene Ontology analysis identified biological processes and functions for these genes including positive regulation of receptor-mediated endocytosis. Consistent with prior clinical data, the molecular function categories as determined using DAVID identified low-density lipoprotein receptor binding, lipoprotein receptor binding and identical protein binding to be over-represented in the AVS group. A significant epigenetic change in the APOA5 and PCSK9 genes known to be involved in AVS was also observed. A large number CpG methylation sites individually demonstrated good to excellent diagnostic accuracy for the prediction of AVS status, thus raising possibility of molecular screening markers for this disorder. Using epigenetic analysis we were able to identify genes significantly involved in the pathogenesis of AVS. PMID:27152866

  14. Pathway Analysis for Genome-Wide Association Study of Lung Cancer in Han Chinese Population

    PubMed Central

    Wu, Chen; Jin, Guangfu; Dai, Juncheng; Wang, Cheng; Hu, Lingmin; Gou, Jianwei; Qian, Chen; Bai, Jianling; Wu, Tangchun; Hu, Zhibin; Lin, Dongxin; Shen, Hongbing; Chen, Feng

    2013-01-01

    Genome-wide association studies (GWAS) have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA) method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls) and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls). We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) were consistently significant in both studies and the P values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer. PMID:23469231

  15. Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

    PubMed Central

    Kar, SP; Seldin, MF; Chen, W; Lu, E; Hirschfield, GM; Invernizzi, P; Heathcote, J; Cusi, D; Gershwin, ME; Siminovitch, KA; Amos, CI

    2013-01-01

    Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P < 0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR < 0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P = 7.38 × 10−4, FDR = 0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P < 0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P < 0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P < 0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that on further independent replication and functional validation, may provide fresh insights into PBC etiology. PMID:23392275

  16. A genome-wide transcription analysis of a fungal riboflavin overproducer.

    PubMed

    Karos, Marvin; Vilariño, Cristina; Bollschweiler, Claus; Revuelta, Jose Luis

    2004-09-30

    The production of many fine chemicals such as vitamins and amino acids is carried out in bioreactors using microorganisms. Usually, these strains are developed from wild-type organisms by classical mutation and selection. After several generations of strain improvement, no further enhancement can be achieved. Therefore, metabolic engineering (ME) is a rational approach to optimise such producer organisms beyond this point, or for starting all over from the beginning. Metabolic Engineering involves detailed analysis of the organism's metabolic and genetic properties, leading to the identification of new target genes. The fungal riboflavin overproducer Ashbya gossypii converts vegetable oil to vitamin B2 in a "one-step reaction". The productivity and selectivity of this microorganism have been optimised significantly over the years, first following a classical approach and now a rational one. The improvement is based on our understanding of vitamin B2 metabolism. We have been able to selectively enhance the pathways that are necessary for the formation of riboflavin and to inhibit those leading to unwanted side products. New targets for further improvements of this process have been found using a genome-wide transcript expression analysis; namely massive parallel signature sequencing (MPSS). With this analysis even completely unknown genes can be used for strain improvement.

  17. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

    PubMed

    Smith, D J; Escott-Price, V; Davies, G; Bailey, M E S; Colodro-Conde, L; Ward, J; Vedernikov, A; Marioni, R; Cullen, B; Lyall, D; Hagenaars, S P; Liewald, D C M; Luciano, M; Gale, C R; Ritchie, S J; Hayward, C; Nicholl, B; Bulik-Sullivan, B; Adams, M; Couvy-Duchesne, B; Graham, N; Mackay, D; Evans, J; Smith, B H; Porteous, D J; Medland, S E; Martin, N G; Holmans, P; McIntosh, A M; Pell, J P; Deary, I J; O'Donovan, M C

    2016-06-01

    Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured

  18. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

    PubMed Central

    Smith, D J; Escott-Price, V; Davies, G; Bailey, M E S; Colodro-Conde, L; Ward, J; Vedernikov, A; Marioni, R; Cullen, B; Lyall, D; Hagenaars, S P; Liewald, D C M; Luciano, M; Gale, C R; Ritchie, S J; Hayward, C; Nicholl, B; Bulik-Sullivan, B; Adams, M; Couvy-Duchesne, B; Graham, N; Mackay, D; Evans, J; Smith, B H; Porteous, D J; Medland, S E; Martin, N G; Holmans, P; McIntosh, A M; Pell, J P; Deary, I J; O'Donovan, M C

    2016-01-01

    Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured

  19. Genome Wide Association Studies

    NASA Astrophysics Data System (ADS)

    Sebastiani, Paola; Solovieff, Nadia

    The availability of high throughput technology for parallel genotyping has opened the field of genetics to genome-wide association studies (GWAS). These studies generate massive amount of genetic data that challenge investigators with issues related to data management, statistical analysis of large data sets, visualization, and annotation of results. We will review the common approach to analysis of GWAS data and then discuss options to learn more from these data.

  20. Genome-wide methylation analysis identified sexually dimorphic methylated regions in hybrid tilapia

    PubMed Central

    Wan, Zi Yi; Xia, Jun Hong; Lin, Grace; Wang, Le; Lin, Valerie C. L.; Yue, Gen Hua

    2016-01-01

    Sexual dimorphism is an interesting biological phenomenon. Previous studies showed that DNA methylation might play a role in sexual dimorphism. However, the overall picture of the genome-wide methylation landscape in sexually dimorphic species remains unclear. We analyzed the DNA methylation landscape and transcriptome in hybrid tilapia (Oreochromis spp.) using whole genome bisulfite sequencing (WGBS) and RNA-sequencing (RNA-seq). We found 4,757 sexually dimorphic differentially methylated regions (DMRs), with significant clusters of DMRs located on chromosomal regions associated with sex determination. CpG methylation in promoter regions was negatively correlated with the gene expression level. MAPK/ERK pathway was upregulated in male tilapia. We also inferred active cis-regulatory regions (ACRs) in skeletal muscle tissues from WGBS datasets, revealing sexually dimorphic cis-regulatory regions. These results suggest that DNA methylation contribute to sex-specific phenotypes and serve as resources for further investigation to analyze the functions of these regions and their contributions towards sexual dimorphisms. PMID:27782217

  1. An across-breed genome wide association analysis of susceptibility to paratuberculosis in dairy cattle.

    PubMed

    Sallam, Ahmed M; Zare, Yalda; Alpay, Fazli; Shook, George E; Collins, Michael T; Alsheikh, Samir; Sharaby, Mahmoud; Kirkpatrick, Brian W

    2017-02-01

    Paratuberculosis is a chronic disease of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). It occurs worldwide and causes a significant loss in the animal production industry. There is no cure for MAP infection and vaccination is problematic. Identification of genetics of susceptibility could be a useful adjunct for programs that focus on management, testing and culling of diseased animals. A case-control, genome-wide association study (GWAS) was conducted using Holstein and Jersey cattle in a combined analysis in order to identify markers and chromosomal regions associated with susceptibility to MAP infection across-breed. A mixed-model method (GRAMMAR-GC) implemented in the GenABEL R package and a Bayes C analysis implemented in GenSel software were used as alternative approaches to conduct GWAS analysis focused on single SNPs and chromosomal segments, respectively. After conducting quality control, 22 406 SNPs from 2157 individuals were available for the GRAMMAR-GC (Bayes C) analysis and 45 640 SNPs from 2199 individuals were available for the Bayes C analysis. One SNP located on BTA27 (8·6 Mb) was identified as moderately associated (P < 5 × 10-5, FDR = 0·44) in the GRAMMAR-GC analysis of the combined breed data. Nine 1 Mb windows located on BTA 2, 3 (3 windows), 6, 8, 25, 27 and 29 each explained ≥1% of the total proportion of genetic variance in the Bayes C analysis. In an analysis ignoring differences in linkage phase, two moderately significantly associated SNPs were identified; ARS-BFGL-NGS-19381 on BTA23 (32 Mb) and Hapmap40994-BTA-46361 on BTA19 (61 Mb). New common genomic regions and candidate genes have been identified from the across-breed analysis that might be involved in the immune response and susceptibility to MAP infection.

  2. A genome-wide association meta-analysis identifies new childhood obesity loci.

    PubMed

    Bradfield, Jonathan P; Taal, H Rob; Timpson, Nicholas J; Scherag, André; Lecoeur, Cecile; Warrington, Nicole M; Hypponen, Elina; Holst, Claus; Valcarcel, Beatriz; Thiering, Elisabeth; Salem, Rany M; Schumacher, Fredrick R; Cousminer, Diana L; Sleiman, Patrick M A; Zhao, Jianhua; Berkowitz, Robert I; Vimaleswaran, Karani S; Jarick, Ivonne; Pennell, Craig E; Evans, David M; St Pourcain, Beate; Berry, Diane J; Mook-Kanamori, Dennis O; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; van Duijn, Cornelia M; van der Valk, Ralf J P; de Jongste, Johan C; Postma, Dirkje S; Boomsma, Dorret I; Gauderman, W James; Hassanein, Mohamed T; Lindgren, Cecilia M; Mägi, Reedik; Boreham, Colin A G; Neville, Charlotte E; Moreno, Luis A; Elliott, Paul; Pouta, Anneli; Hartikainen, Anna-Liisa; Li, Mingyao; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G; Palotie, Aarno; Dallongeville, Jean; Das, Shikta; Deloukas, Panos; McMahon, George; Ring, Susan M; Kemp, John P; Buxton, Jessica L; Blakemore, Alexandra I F; Bustamante, Mariona; Guxens, Mònica; Hirschhorn, Joel N; Gillman, Matthew W; Kreiner-Møller, Eskil; Bisgaard, Hans; Gilliland, Frank D; Heinrich, Joachim; Wheeler, Eleanor; Barroso, Inês; O'Rahilly, Stephen; Meirhaeghe, Aline; Sørensen, Thorkild I A; Power, Chris; Palmer, Lyle J; Hinney, Anke; Widen, Elisabeth; Farooqi, I Sadaf; McCarthy, Mark I; Froguel, Philippe; Meyre, David; Hebebrand, Johannes; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W V; Smith, George Davey; Hakonarson, Hakon; Grant, Struan F A

    2012-05-01

    Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).

  3. Genome-wide Analysis of the Homeobox C6 Transcriptional Network in Prostate Cancer

    PubMed Central

    McCabe, Colleen D.; Spyropoulos, Demetri D.; Martin, David; Moreno, Carlos S.

    2008-01-01

    Homeobox (HOX) transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of BMP7, FGFR2, IGFBP3, and PDGFRA in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment. PMID:18339881

  4. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

    PubMed Central

    Braggio, Esteban; Van Wier, Scott; Ojha, Juhi; McPhail, Ellen; Asmann, Yan W.; Egan, Jan; da Silva, Jackline Ayres; Schiff, David; Lopes, M Beatriz; Decker, Paul A; Valdez, Riccardo; Tibes, Raoul; Eckloff, Bruce; Witzig, Thomas E.; Stewart, A Keith; Fonseca, Rafael; O’Neill, Brian Patrick

    2015-01-01

    Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas. PMID:25991819

  5. A genome-wide association meta-analysis identifies new childhood obesity loci

    PubMed Central

    Bradfield, Jonathan P.; Taal, H. Rob; Timpson, Nicholas J.; Scherag, André; Lecoeur, Cecile; Warrington, Nicole M.; Hypponen, Elina; Holst, Claus; Valcarcel, Beatriz; Thiering, Elisabeth; Salem, Rany M.; Schumacher, Fredrick R.; Cousminer, Diana L.; Sleiman, Patrick M.A.; Zhao, Jianhua; Berkowitz, Robert I.; Vimaleswaran, Karani S.; Jarick, Ivonne; Pennell, Craig E.; Evans, David M.; St. Pourcain, Beate; Berry, Diane J.; Mook-Kanamori, Dennis O; Hofman, Albert; Rivadeinera, Fernando; Uitterlinden, André G.; van Duijn, Cornelia M.; van der Valk, Ralf J.P.; de Jongste, Johan C.; Postma, Dirkje S.; Boomsma, Dorret I.; Gauderman, William J.; Hassanein, Mohamed T.; Lindgren, Cecilia M.; Mägi, Reedik; Boreham, Colin A.G.; Neville, Charlotte E.; Moreno, Luis A.; Elliott, Paul; Pouta, Anneli; Hartikainen, Anna-Liisa; Li, Mingyao; Raitakari, Olli; Lehtimäki, Terho; Eriksson, Johan G.; Palotie, Aarno; Dallongeville, Jean; Das, Shikta; Deloukas, Panos; McMahon, George; Ring, Susan M.; Kemp, John P.; Buxton, Jessica L.; Blakemore, Alexandra I.F.; Bustamante, Mariona; Guxens, Mònica; Hirschhorn, Joel N.; Gillman, Matthew W.; Kreiner-Møller, Eskil; Bisgaard, Hans; Gilliland, Frank D.; Heinrich, Joachim; Wheeler, Eleanor; Barroso, Inês; O'Rahilly, Stephen; Meirhaeghe, Aline; Sørensen, Thorkild I.A.; Power, Chris; Palmer, Lyle J.; Hinney, Anke; Widen, Elisabeth; Farooqi, I. Sadaf; McCarthy, Mark I.; Froguel, Philippe; Meyre, David; Hebebrand, Johannes; Jarvelin, Marjo-Riitta; Jaddoe, Vincent W.V.; Smith, George Davey; Hakonarson, Hakon; Grant, Struan F.A.

    2012-01-01

    Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made to establish genetic influences on common early-onset obesity. We performed a North American-Australian-European collaborative meta-analysis of fourteen studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight novel signals yielding association with P < 5×10−6 in to nine independent datasets (n = 2,818 cases and 4,083 controls) we observed two loci that yielded a genome wide significant combined P-value, namely near OLFM4 on 13q14 (rs9568856; P=1.82×10−9; OR=1.22) and within HOXB5 on 17q21 (rs9299; P=3.54×10−9; OR=1.14). Both loci continued to show association when including two extreme childhood obesity cohorts (n = 2,214 cases and 2,674 controls). Finally, these two loci yielded directionally consistent associations in the GIANT meta-analysis of adult BMI1. PMID:22484627

  6. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    PubMed Central

    Berndt, Sonja I.; Camp, Nicola J.; Skibola, Christine F.; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S.; Smedby, Karin E.; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S.; Lan, Qing; Teras, Lauren R.; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R.; Hartge, Patricia; Purdue, Mark P.; Birmann, Brenda M.; Vajdic, Claire M.; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G.; Shanafelt, Tait D.; Novak, Anne J.; Kay, Neil E.; Liebow, Mark; Cunningham, Julie M.; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T.; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A.; Diver, W Ryan; Link, Brian K.; Weiner, George J.; Conde, Lucia; Bracci, Paige M.; Riby, Jacques; Arnett, Donna K.; Zhi, Degui; Leach, Justin M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G.; Achenbach, Sara J.; Vachon, Celine M.; Goldin, Lynn R.; Strom, Sara S.; Leis, Jose F.; Weinberg, J. Brice; Caporaso, Neil E.; Norman, Aaron D.; De Roos, Anneclaire J.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María- Dolores; Vermeulen, Roel C. H.; Travis, Ruth C.; Southey, Melissa C.; Milne, Roger L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R.; Villano, Danylo J.; Maria, Ann; Spinelli, John J.; Gascoyne, Randy D.; Connors, Joseph M.; Bertrand, Kimberly A.; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M.; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E.; Snowden, John A.; Wright, Josh; Fraumeni, Joseph F.; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R.; Chanock, Stephen J.; Rothman, Nathaniel; Slager, Susan L.

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  7. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

    PubMed

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-03-09

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

  8. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

    PubMed Central

    Legge, Sophie E; Hamshere, Marian L; Ripke, Stephan; Pardinas, Antonio F; Goldstein, Jacqueline I; Rees, Elliott; Richards, Alexander L; Leonenko, Ganna; Jorskog, L Fredrik; Chambert, Kimberly D; Collier, David A; Genovese, Giulio; Giegling, Ina; Holmans, Peter; Jonasdottir, Adalbjorg; Kirov, George; McCarroll, Steven A; MacCabe, James H; Mantripragada, Kiran; Moran, Jennifer L; Neale, Benjamin M; Stefansson, Hreinn; Rujescu, Dan; Daly, Mark J; Sullivan, Patrick F; Owen, Michael J; O’Donovan, Michael C; Walters, James T R

    2016-01-01

    The antipsychotic clozapine is uniquely effective in the management of schizophrenia, but its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown although genetic factors play an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed HLA alleles, exome array, and copy number variation analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (OR=4.32, P=1.79×10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P = 0.015, positive predictive value = 35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect. PMID:27400856

  9. 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

    2015-10-05

    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.

  10. Genome-wide identification of Fas/CD95 alternative splicing regulators reveals links with iron homeostasis.

    PubMed

    Tejedor, J Ramón; Papasaikas, Panagiotis; Valcárcel, Juan

    2015-01-08

    Alternative splicing of Fas/CD95 exon 6 generates either a membrane-bound receptor that promotes, or a soluble isoform that inhibits, apoptosis. Using an automatized genome-wide siRNA screening for alternative splicing regulators of endogenous transcripts in mammalian cells, we identified 200 genes whose knockdown modulates the ratio between Fas/CD95 isoforms. These include classical splicing regulators; core spliceosome components; and factors implicated in transcription and chromatin remodeling, RNA transport, intracellular signaling, and metabolic control. Coherent effects of genes involved in iron homeostasis and pharmacological modulation of iron levels revealed a link between intracellular iron and Fas/CD95 exon 6 inclusion. A splicing regulatory network linked iron levels with reduced activity of the Zinc-finger-containing splicing regulator SRSF7, and in vivo and in vitro assays revealed that iron inhibits SRSF7 RNA binding. Our results uncover numerous links between cellular pathways and RNA processing and a mechanism by which iron homeostasis can influence alternative splicing.

  11. Genome-wide mapping of transcription factor binding reveals developmental process integration and a fresh look at evolutionary dynamics.

    PubMed

    Yant, Levi

    2012-02-01

    How does evolution forge adaptive responses? Are many changes required or few? Just how complex are the transcriptional networks that control development? Diverse questions like these are being newly addressed by next-generation sequencing-based techniques. Facilitating a mechanistic understanding, these approaches reveal the direct in vivo interactions between transcription factors and their physical targets, combined with genome-scale readouts to comprehensively map adaptive gene regulatory networks (GRNs). Here I focus on pioneering work from the last 3 years that has leveraged these data to investigate diverse aspects of GRN circuitry controlling the reproductive transition in plants. These approaches have revealed surprising new functions for long-investigated key players in developmental programs and laid bare the basis for pleiotropy in many others, suggesting widespread process integration at the transcriptional level. Evolutionary questions begged by the recent deluge of GRN mapping data are being assessed anew, both by emerging work outside Arabidopsis thaliana and novel analyses within. These studies have swiftly exposed the distinctive power and adaptability of genome-wide GRN mapping and illustrate that this unique data type holds tremendous promise for plant biology.

  12. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

    PubMed

    Law, Philip J; Berndt, Sonja I; Speedy, Helen E; Camp, Nicola J; Sava, Georgina P; Skibola, Christine F; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R; Clot, Guillem; Teras, Lauren R; Quintela, Inés; Birmann, Brenda M; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R; Hall, Andrew G; Purdue, Mark P; Mainou-Fowler, Tryfonia; Vajdic, Claire M; Jackson, Graham H; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G; Lawrence, Charles; Call, Timothy G; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K; Conde, Lucia; Bracci, Paige M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C H; Southey, Melissa C; Milne, Roger L; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M; Harris, Robert J; Miligi, Lucia; Pettitt, Andrew R; North, Kari E; Allsup, David J; Fraumeni, Joseph F; Bailey, James R; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J S; Catovsky, Daniel; Campo, Elias; Cerhan, James R; Allan, James M; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-02-06

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10(-13)), 1q42.13 (rs41271473, P=1.06 × 10(-10)), 4q24 (rs71597109, P=1.37 × 10(-10)), 4q35.1 (rs57214277, P=3.69 × 10(-8)), 6p21.31 (rs3800461, P=1.97 × 10(-8)), 11q23.2 (rs61904987, P=2.64 × 10(-11)), 18q21.1 (rs1036935, P=3.27 × 10(-8)), 19p13.3 (rs7254272, P=4.67 × 10(-8)) and 22q13.33 (rs140522, P=2.70 × 10(-9)). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

  13. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes.

    PubMed

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-03-16

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat.

  14. Analysis of binary responses with outcome-specific misclassification probability in genome-wide association studies

    PubMed Central

    Rekaya, Romdhane; Smith, Shannon; Hay, El Hamidi; Farhat, Nourhene; Aggrey, Samuel E

    2016-01-01

    Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS). A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case–control) were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs) and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the proposed method. Additionally, truly misclassified binary records were identified with high probability using the proposed method. The superiority of the proposed method was maintained across different simulation parameters (misclassification rates and odds ratios) attesting to its robustness. PMID:27942229

  15. Genome-wide Promoter Analysis of the SOX4 Transcriptional Network in Prostate Cancer Cells

    PubMed Central

    Scharer, Christopher D.; McCabe, Colleen D.; Ali-Seyed, Mohamed; Berger, Michael F.; Bulyk, Martha L.; Moreno, Carlos S.

    2008-01-01

    SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the exact role of SOX4 in cancer progression is not well understood. Here we have identified the direct transcriptional targets of SOX4 using a combination of genome-wide localization ChIP-chip analysis and transient overexpression followed by expression profiling in a prostate cancer model cell line. We have also used protein-binding microarrays to derive a novel SOX4-specific position-weight matrix and determined that SOX4 binding sites are enriched in SOX4-bound promoter regions. Direct transcriptional targets of SOX4 include several key cellular regulators such as EGFR, HSP70, Tenascin C, Frizzled-5, Patched-1, and Delta-like 1 We also show that SOX4 targets 23 transcription factors such as MLL, FOXA1, ZNF281, and NKX3-1 In addition, SOX4 directly regulates expression of three components of the RNA-induced silencing complex (RISC), namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 impacts developmental signaling pathways and how these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, the TGFβ, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis. PMID:19147588

  16. Genome-wide linkage analysis in families with infantile hypertrophic pyloric stenosis indicates novel susceptibility loci.

    PubMed

    Svenningsson, Anna; Söderhäll, Cilla; Persson, Sofia; Lundberg, Fredrik; Luthman, Holger; Chung, Eddie; Gardiner, Mark; Kockum, Ingrid; Nordenskjöld, Agneta

    2012-02-01

    Infantile hypertrophic pyloric stenosis (IHPS) is a common cause of upper gastrointestinal obstruction during infancy. A multifactorial background of the disease is well established. Multiple susceptibility loci including the neuronal nitric oxide synthase (NOS1) gene have previously been linked to IHPS, but contradictory results of linkage studies in different materials indicate genetic heterogeneity. To identify IHPS susceptibility loci, we conducted a genome-wide linkage analysis in 37 Swedish families. In regions where the Swedish material showed most evidence in favor of linkage, 31 additional British IHPS families were analyzed. Evidence in favor of significant linkage was observed in the Swedish material to two loci on chromosome 2q24 (non-parametric linkage (NPL) =3.77) and 7p21 (NPL=4.55). In addition, evidence of suggestive linkage was found to two loci on chromosome 6p21 (NPL=2.97) and 12q24 (NPL=2.63). Extending the material with British samples did not enhance the level of significance. Regions with linkage harbor interesting candidate genes, such as glucagon-like peptide-2 (GLP-2 encoded by the glucagon gene GCG), NOS1, motilin (MLN) and neuropeptide Y (NPY). The coding exons for GLP-2, and NPY were screened for mutations with negative results. In conclusion, we could confirm suggestive linkage to the region harboring the NOS1 gene and detected additional novel susceptibility loci for IHPS.

  17. The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing

    PubMed Central

    Gorbunova, Anna; Evsyukov, Igor; Rayko, Michael; Gapon, Svetlana; Bozhokina, Ekaterina; Shishkin, Alexander; O’Brien, Stephen J.

    2016-01-01

    Сarcinoembryonic antigen (CEA, CEACAM5, CD66) is a promoter of metastasis in epithelial cancers that is widely used as a prognostic clinical marker of metastasis. The aim of this study is to identify the network of genes that are associated with CEA-induced colorectal cancer liver metastasis. We compared the genome-wide transcriptomic profiles of CEA positive (MIP101 clone 8) and CEA negative (MIP 101) colorectal cancer cell lines with different metastatic potential in vivo. The CEA-producing cells displayed quantitative changes in the level of expression for 100 genes (over-expressed or down-regulated). They were confirmed by quantitative RT-PCR. The KEGG pathway analysis identified 4 significantly enriched pathways: cytokine-cytokine receptor interaction, MAPK signaling pathway, TGF-beta signaling pathway and pyrimidine metabolism. Our results suggest that CEA production by colorectal cancer cells triggers colorectal cancer progression by inducing the epithelial- mesenchymal transition, increasing tumor cell invasiveness into the surrounding tissues and suppressing stress and apoptotic signaling. The novel gene expression distinctions establish the relationships between the existing cancer markers and implicate new potential biomarkers for colorectal cancer hepatic metastasis. PMID:27583792

  18. Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

    PubMed Central

    Qi, Lu; Speliotes, Elizabeth K.; Thorleifsson, Gudmar; Willer, Cristen J.; Herrera, Blanca M.; Jackson, Anne U.; Lim, Noha; Scheet, Paul; Soranzo, Nicole; Amin, Najaf; Aulchenko, Yurii S.; Chambers, John C.; Drong, Alexander; Luan, Jian'an; Lyon, Helen N.; Rivadeneira, Fernando; Sanna, Serena; Timpson, Nicholas J.; Zillikens, M. Carola; Zhao, Jing Hua; Almgren, Peter; Bandinelli, Stefania; Bennett, Amanda J.; Bergman, Richard N.; Bonnycastle, Lori L.; Bumpstead, Suzannah J.; Chanock, Stephen J.; Cherkas, Lynn; Chines, Peter; Coin, Lachlan; Cooper, Cyrus; Crawford, Gabriel; Doering, Angela; Dominiczak, Anna; Doney, Alex S. F.; Ebrahim, Shah; Elliott, Paul; Erdos, Michael R.; Estrada, Karol; Ferrucci, Luigi; Fischer, Guido; Forouhi, Nita G.; Gieger, Christian; Grallert, Harald; Groves, Christopher J.; Grundy, Scott; Guiducci, Candace; Hadley, David; Hamsten, Anders; Havulinna, Aki S.; Hofman, Albert; Holle, Rolf; Holloway, John W.; Illig, Thomas; Isomaa, Bo; Jacobs, Leonie C.; Jameson, Karen; Jousilahti, Pekka; Karpe, Fredrik; Kuusisto, Johanna; Laitinen, Jaana; Lathrop, G. Mark; Lawlor, Debbie A.; Mangino, Massimo; McArdle, Wendy L.; Meitinger, Thomas; Morken, Mario A.; Morris, Andrew P.; Munroe, Patricia; Narisu, Narisu; Nordström, Anna; Nordström, Peter; Oostra, Ben A.; Palmer, Colin N. A.; Payne, Felicity; Peden, John F.; Prokopenko, Inga; Renström, Frida; Ruokonen, Aimo; Salomaa, Veikko; Sandhu, Manjinder S.; Scott, Laura J.; Scuteri, Angelo; Silander, Kaisa; Song, Kijoung; Yuan, Xin; Stringham, Heather M.; Swift, Amy J.; Tuomi, Tiinamaija; Uda, Manuela; Vollenweider, Peter; Waeber, Gerard; Wallace, Chris; Walters, G. Bragi; Weedon, Michael N.; Witteman, Jacqueline C. M.; Zhang, Cuilin; Zhang, Weihua; Caulfield, Mark J.; Collins, Francis S.; Davey Smith, George; Day, Ian N. M.; Franks, Paul W.; Hattersley, Andrew T.; Hu, Frank B.; Jarvelin, Marjo-Riitta; Kong, Augustine; Kooner, Jaspal S.; Laakso, Markku; Lakatta, Edward; Mooser, Vincent; Morris, Andrew D.; Peltonen, Leena; Samani, Nilesh J.; Spector, Timothy D.; Strachan, David P.; Tanaka, Toshiko; Tuomilehto, Jaakko; Uitterlinden, André G.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Watkins for the PROCARDIS consortia, Hugh; Waterworth, Dawn M.; Boehnke, Michael; Deloukas, Panos; Groop, Leif; Hunter, David J.; Thorsteinsdottir, Unnur; Schlessinger, David; Wichmann, H.-Erich; Frayling, Timothy M.; Abecasis, Gonçalo R.; Hirschhorn, Joel N.; Loos, Ruth J. F.; Stefansson, Kari; Mohlke, Karen L.; Barroso, Inês; McCarthy for the GIANT consortium, Mark I.

    2009-01-01

    To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity. PMID:19557161

  19. Pooled Genome-Wide Analysis to Identify Novel Risk Loci for Pediatric Allergic Asthma

    PubMed Central

    Ricci, Giampaolo; Astolfi, Annalisa; Remondini, Daniel; Cipriani, Francesca; Formica, Serena; Dondi, Arianna; Pession, Andrea

    2011-01-01

    Background Genome-wide association studies of pooled DNA samples were shown to be a valuable tool to identify candidate SNPs associated to a phenotype. No such study was up to now applied to childhood allergic asthma, even if the very high complexity of asthma genetics is an appropriate field to explore the potential of pooled GWAS approach. Methodology/Principal Findings We performed a pooled GWAS and individual genotyping in 269 children with allergic respiratory diseases comparing allergic children with and without asthma. We used a modular approach to identify the most significant loci associated with asthma by combining silhouette statistics and physical distance method with cluster-adapted thresholding. We found 97% concordance between pooled GWAS and individual genotyping, with 36 out of 37 top-scoring SNPs significant at individual genotyping level. The most significant SNP is located inside the coding sequence of C5, an already identified asthma susceptibility gene, while the other loci regulate functions that are relevant to bronchial physiopathology, as immune- or inflammation-mediated mechanisms and airway smooth muscle contraction. Integration with gene expression data showed that almost half of the putative susceptibility genes are differentially expressed in experimental asthma mouse models. Conclusion/Significance Combined silhouette statistics and cluster-adapted physical distance threshold analysis of pooled GWAS data is an efficient method to identify candidate SNP associated to asthma development in an allergic pediatric population. PMID:21359210

  20. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    PubMed Central

    Law, Philip J.; Berndt, Sonja I.; Speedy, Helen E.; Camp, Nicola J.; Sava, Georgina P.; Skibola, Christine F.; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J.; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R.; Clot, Guillem; Teras, Lauren R.; Quintela, Inés; Birmann, Brenda M.; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E.; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R.; Hall, Andrew G.; Purdue, Mark P.; Mainou-Fowler, Tryfonia; Vajdic, Claire M.; Jackson, Graham H.; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G.; Lawrence, Charles; Call, Timothy G.; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K.; Conde, Lucia; Bracci, Paige M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C. H.; Southey, Melissa C.; Milne, Roger L.; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J.; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M.; Harris, Robert J.; Miligi, Lucia; Pettitt, Andrew R.; North, Kari E.; Allsup, David J.; Fraumeni, Joseph F.; Bailey, James R.; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J.; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J. S.; Catovsky, Daniel; Campo, Elias; Cerhan, James R.; Allan, James M.; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. PMID:28165464

  1. Mammalian NET-seq analysis defines nascent RNA profiles and associated RNA processing genome-wide

    PubMed Central

    Nojima, Takayuki; Gomes, Tomás; Carmo-Fonseca, Maria; Proudfoot, Nicholas J

    2016-01-01

    The transcription cycle of RNA polymerase II (Pol II) correlates with changes to the phosphorylation state of its large subunit C-terminal domain (CTD). We recently developed Native Elongation Transcript sequencing using mammalian cells (mNET-seq), which generates single-nucleotide–resolution genome-wide profiles of nascent RNA and co-transcriptional RNA processing that are associated with different CTD phosphorylation states. Here we provide a detailed protocol for mNET-seq. First, Pol II elongation complexes are isolated with specific phospho-CTD antibodies from chromatin solubilized by micrococcal nuclease digestion. Next, RNA derived from within the Pol II complex is size fractionated and Illumina sequenced. using mNET-seq, we have previously shown that Pol II pauses at both ends of protein-coding genes but with different CTD phosphorylation patterns, and we have also detected phosphorylation at serine 5 (Ser5-P) CTD-specific splicing intermediates and Pol II accumulation over co-transcriptionally spliced exons. With moderate biochemical and bioinformatic skills, mNET-seq can be completed in ~6 d, not including sequencing and data analysis. PMID:26844429

  2. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    PubMed Central

    2011-01-01

    Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

  3. Genome-wide identification, classification and transcriptional analysis of nitrate and ammonium transporters in Coffea.

    PubMed

    Santos, Tiago Benedito Dos; Lima, Joni Esrom; Felicio, Mariane Silva; Soares, João Danillo Moura; Domingues, Douglas Silva

    2017-04-10

    Nitrogen (N) is quantitatively the main nutrient required by coffee plants, with acquisition mainly by the roots and mostly exported to coffee beans. Nitrate (NO3-) and ammonium (NH4+) are the most important inorganic sources for N uptake. Several N transporters encoded by different gene families mediate the uptake of these compounds. They have an important role in source preference for N uptake in the root system. In this study, we performed a genome-wide analysis, including in silico expression and phylogenetic analyses of AMT1, AMT2, NRT1/PTR, and NRT2 transporters in the recently sequenced Coffea canephora genome. We analyzed the expression of six selected transporters in Coffea arabica roots submitted to N deficiency. N source preference was also analyzed in C. arabica using isotopes. C. canephora N transporters follow the patterns observed for most eudicots, where each member of the AMT and NRT families has a particular role in N mobilization, and where some of these are modulated by N deficiency. Despite the prevalence of putative nitrate transporters in the Coffea genome, ammonium was the preferential inorganic N source for N-starved C. arabica roots. This data provides an important basis for fundamental and applied studies to depict molecular mechanisms involved in N uptake in coffee trees.

  4. A genome-wide resource for the analysis of protein localisation in Drosophila

    PubMed Central

    Sarov, Mihail; Barz, Christiane; Jambor, Helena; Hein, Marco Y; Schmied, Christopher; Suchold, Dana; Stender, Bettina; Janosch, Stephan; KJ, Vinay Vikas; Krishnan, RT; Krishnamoorthy, Aishwarya; Ferreira, Irene RS; Ejsmont, Radoslaw K; Finkl, Katja; Hasse, Susanne; Kämpfer, Philipp; Plewka, Nicole; Vinis, Elisabeth; Schloissnig, Siegfried; Knust, Elisabeth; Hartenstein, Volker; Mann, Matthias; Ramaswami, Mani; VijayRaghavan, K; Tomancak, Pavel; Schnorrer, Frank

    2016-01-01

    The Drosophila genome contains >13000 protein-coding genes, the majority of which remain poorly investigated. Important reasons include the lack of antibodies or reporter constructs to visualise these proteins. Here, we present a genome-wide fosmid library of 10000 GFP-tagged clones, comprising tagged genes and most of their regulatory information. For 880 tagged proteins, we created transgenic lines, and for a total of 207 lines, we assessed protein expression and localisation in ovaries, embryos, pupae or adults by stainings and live imaging approaches. Importantly, we visualised many proteins at endogenous expression levels and found a large fraction of them localising to subcellular compartments. By applying genetic complementation tests, we estimate that about two-thirds of the tagged proteins are functional. Moreover, these tagged proteins enable interaction proteomics from developing pupae and adult flies. Taken together, this resource will boost systematic analysis of protein expression and localisation in various cellular and developmental contexts. DOI: http://dx.doi.org/10.7554/eLife.12068.001 PMID:26896675

  5. A molecular scheme for Yersinia enterocolitica patho-serotyping derived from genome-wide analysis.

    PubMed

    Garzetti, Debora; Susen, Rosa; Fruth, Angelika; Tietze, Erhard; Heesemann, Jürgen; Rakin, Alexander

    2014-05-01

    Yersinia enterocolitica is a food-borne, gastro-intestinal pathogen with world-wide distribution. Only 11 serotypes have been isolated from patients, with O:3, O:9, O:8 and O:5,27 being the serotypes most commonly associated with human yersiniosis. Serotype is an important characteristic of Y. enterocolitica strains, allowing differentiation for epidemiology, diagnosis and phylogeny studies. Conventional serotyping, performed by slide agglutination, is a tedious and laborious procedure whose interpretation tends to be subjective, leading to poor reproducibility. Here we present a PCR-based typing scheme for molecular identification and patho-serotyping of Y. enterocolitica. Genome-wide comparison of Y. enterocolitica sequences allowed analysis of the O-antigen gene clusters of different serotypes, uncovering their formerly unknown genomic locations, and selection of targets for serotype-specific amplification. Two multiplex PCRs and one additional PCR were designed and tested on various reference strains and isolates from different origins. Our genotypic assay proved to be highly specific for identification of Y. enterocolitica species, discrimination between virulent and non-virulent strains, distinguishing the main human-related serotypes, and typing of conventionally untypeable strains. This genotyping scheme could be applied in microbiology laboratories as an alternative or complementary method to the traditional phenotypic assays, providing data for epidemiological studies.

  6. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes

    PubMed Central

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-01-01

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat. PMID:28300172

  7. 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.

  8. Genome-Wide Analysis, Classification, Evolution, and Expression Analysis of the Cytochrome P450 93 Family in Land Plants.

    PubMed

    Du, Hai; Ran, Feng; Dong, Hong-Li; Wen, Jing; Li, Jia-Na; Liang, Zhe

    2016-01-01

    Cytochrome P450 93 family (CYP93) belonging to the cytochrome P450 superfamily plays important roles in diverse plant processes. However, no previous studies have investigated the evolution and expression of the members of this family. In this study, we performed comprehensive genome-wide analysis to identify CYP93 genes in 60 green plants. In all, 214 CYP93 proteins were identified; they were specifically found in flowering plants and could be classified into ten subfamilies-CYP93A-K, with the last two being identified first. CYP93A is the ancestor that was derived in flowering plants, and the remaining showed lineage-specific distribution-CYP93B and CYP93C are present in dicots; CYP93F is distributed only in Poaceae; CYP93G and CYP93J are monocot-specific; CYP93E is unique to legumes; CYP93H and CYP93K are only found in Aquilegia coerulea, and CYP93D is Brassicaceae-specific. Each subfamily generally has conserved gene numbers, structures, and characteristics, indicating functional conservation during evolution. Synonymous nucleotide substitution (dN/dS) analysis showed that CYP93 genes are under strong negative selection. Comparative expression analyses of CYP93 genes in dicots and monocots revealed that they are preferentially expressed in the roots and tend to be induced by biotic and/or abiotic stresses, in accordance with their well-known functions in plant secondary biosynthesis.

  9. Genome-Wide Analysis, Classification, Evolution, and Expression Analysis of the Cytochrome P450 93 Family in Land Plants

    PubMed Central

    Du, Hai; Ran, Feng; Dong, Hong-Li; Wen, Jing; Li, Jia-Na; Liang, Zhe

    2016-01-01

    Cytochrome P450 93 family (CYP93) belonging to the cytochrome P450 superfamily plays important roles in diverse plant processes. However, no previous studies have investigated the evolution and expression of the members of this family. In this study, we performed comprehensive genome-wide analysis to identify CYP93 genes in 60 green plants. In all, 214 CYP93 proteins were identified; they were specifically found in flowering plants and could be classified into ten subfamilies—CYP93A–K, with the last two being identified first. CYP93A is the ancestor that was derived in flowering plants, and the remaining showed lineage-specific distribution—CYP93B and CYP93C are present in dicots; CYP93F is distributed only in Poaceae; CYP93G and CYP93J are monocot-specific; CYP93E is unique to legumes; CYP93H and CYP93K are only found in Aquilegia coerulea, and CYP93D is Brassicaceae-specific. Each subfamily generally has conserved gene numbers, structures, and characteristics, indicating functional conservation during evolution. Synonymous nucleotide substitution (dN/dS) analysis showed that CYP93 genes are under strong negative selection. Comparative expression analyses of CYP93 genes in dicots and monocots revealed that they are preferentially expressed in the roots and tend to be induced by biotic and/or abiotic stresses, in accordance with their well-known functions in plant secondary biosynthesis. PMID:27760179

  10. Analysis of copy number variations in Mexican Holstein cattle using axiom genome-wide Bos 1 array

    PubMed Central

    Salomon-Torres, Ricardo; Villa-Angulo, Rafael; Villa-Angulo, Carlos

    2015-01-01

    Recently, for copy number variation (CNV) analysis, bovine researchers have focused mainly on the use of genome-wide SNP genotyping arrays. One of the highest densities commercially available SNPchips for cattle is the Affymetrix axiom genome-wide Bos 1, which assays 648,315 informative SNPs across the whole bovine genome. Here, we describe the microarray data, quality controls and validation implemented in a study published in Genetics and Molecular Research Journal in 2015 [1]. The microarray raw data has been deposited into Gene Expression Omnibus under accession #GSE54813. PMID:26981375

  11. Genome-wide DNA methylation analysis using massively parallel sequencing technologies.

    PubMed

    Suzuki, Masako; Greally, John M

    2013-01-01

    "Epigenetics" refers to a heritable change in transcriptional status without alteration in the primary nucleotide sequence. Epigenetics provides an extra layer of transcriptional control and plays a crucial role in normal development, as well as in pathological conditions. DNA methylation is one of the best known and well-studied epigenetic modifications. Genome-wide DNA methylation profiling has become recognized as a biologically and clinically important epigenomic assay. In this review, we discuss the strengths and weaknesses of the protocols for genome-wide DNA methylation profiling using massively parallel sequencing (MPS) techniques. We will also describe recently discovered DNA modifications, and the protocols to detect these modifications.

  12. Genome-wide association study reveals the genetic architecture of flowering time in rapeseed (Brassica napus L.)

    PubMed Central

    Xu, Liping; Hu, Kaining; Zhang, Zhenqian; Guan, Chunyun; Chen, Song; Hua, Wei; Li, Jiana; Wen, Jing; Yi, Bin; Shen, Jinxiong; Ma, Chaozhi; Tu, Jinxing; Fu, Tingdong

    2016-01-01

    Flowering time adaptation is a major breeding goal in the allopolyploid species Brassica napus. To investigate the genetic architecture of flowering time, a genome-wide association study (GWAS) of flowering time was conducted with a diversity panel comprising 523 B. napus cultivars and inbred lines grown in eight different environments. Genotyping was performed with a Brassica 60K Illumina Infinium SNP array. A total of 41 single-nucleotide polymorphisms (SNPs) distributed on 14 chromosomes were found to be associated with flowering time, and 12 SNPs located in the confidence intervals of quantitative trait loci (QTL) identified in previous researches based on linkage analyses. Twenty-five candidate genes were orthologous to Arabidopsis thaliana flowering genes. To further our understanding of the genetic factors influencing flowering time in different environments, GWAS was performed on two derived traits, environment sensitivity and temperature sensitivity. The most significant SNPs were found near Bn-scaff_16362_1-p380982, just 13 kb away from BnaC09g41990D, which is orthologous to A. thaliana CONSTANS (CO), an important gene in the photoperiod flowering pathway. These results provide new insights into the genetic control of flowering time in B. napus and indicate that GWAS is an effective method by which to reveal natural variations of complex traits in B. napus. PMID:26659471

  13. Genome-wide association study reveals the genetic architecture of flowering time in rapeseed (Brassica napus L.).

    PubMed

    Xu, Liping; Hu, Kaining; Zhang, Zhenqian; Guan, Chunyun; Chen, Song; Hua, Wei; Li, Jiana; Wen, Jing; Yi, Bin; Shen, Jinxiong; Ma, Chaozhi; Tu, Jinxing; Fu, Tingdong

    2016-02-01

    Flowering time adaptation is a major breeding goal in the allopolyploid species Brassica napus. To investigate the genetic architecture of flowering time, a genome-wide association study (GWAS) of flowering time was conducted with a diversity panel comprising 523 B. napus cultivars and inbred lines grown in eight different environments. Genotyping was performed with a Brassica 60K Illumina Infinium SNP array. A total of 41 single-nucleotide polymorphisms (SNPs) distributed on 14 chromosomes were found to be associated with flowering time, and 12 SNPs located in the confidence intervals of quantitative trait loci (QTL) identified in previous researches based on linkage analyses. Twenty-five candidate genes were orthologous to Arabidopsis thaliana flowering genes. To further our understanding of the genetic factors influencing flowering time in different environments, GWAS was performed on two derived traits, environment sensitivity and temperature sensitivity. The most significant SNPs were found near Bn-scaff_16362_1-p380982, just 13 kb away from BnaC09g41990D, which is orthologous to A. thaliana CONSTANS (CO), an important gene in the photoperiod flowering pathway. These results provide new insights into the genetic control of flowering time in B. napus and indicate that GWAS is an effective method by which to reveal natural variations of complex traits in B. napus.

  14. Genome-wide patterns of genetic distances reveal candidate Loci contributing to human population-specific traits.

    PubMed

    de Magalhães, João Pedro; Matsuda, Alex

    2012-03-01

    Modern humans originated in Africa before migrating across the world with founder effects and adaptations to new environments contributing to their present phenotypic diversity. Determining the genetic basis of differences between populations may provide clues about our evolutionary history and may have clinical implications. Herein, we develop a method to detect genes and biological processes in which populations most differ by calculating the genetic distance between modern populations and a hypothetical ancestral population. We apply our method to large-scale single nucleotide polymorphism (SNP) data from human populations of African, European and Asian origin. As expected, ancestral alleles were more conserved in the African populations and we found evidence of high divergence in genes previously suggested as targets of selection related to skin pigmentation, immune response, senses and dietary adaptations. Our genome-wide scan also reveals novel candidates for contributing to population-specific traits. These include genes related to neuronal development and behavior that may have been influenced by cultural processes. Moreover, in the African populations, we found a high divergence in genes related to UV protection and to the male reproductive system. Taken together, these results confirm and expand previous findings, providing new clues about the evolution and genetics of human phenotypic diversity.

  15. Genome-Wide Association Mapping of Fertility Reduction upon Heat Stress Reveals Developmental Stage-Specific QTLs in Arabidopsis thaliana

    PubMed Central

    Bac-Molenaar, Johanna A.; Fradin, Emilie F.; Becker, Frank F.M.; Rienstra, Juriaan A.; van der Schoot, J.; Vreugdenhil, Dick; Keurentjes, Joost J.B.

    2015-01-01

    For crops that are grown for their fruits or seeds, elevated temperatures that occur during flowering and seed or fruit set have a stronger effect on yield than high temperatures during the vegetative stage. Even short-term exp