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Sample records for genome-wide transcriptional analysis

  1. Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways

    PubMed Central

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

    2013-01-01

    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. PMID:21971039

  2. Genome-wide analysis of alternative transcripts in human breast cancer

    PubMed Central

    Wen, Ji; Toomer, Kevin H.

    2016-01-01

    Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA-Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein-coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients’ tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve “hub” genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the “hub” genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome. PMID:25913416

  3. 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

  4. 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

  5. Comparative genome-wide transcriptional analysis of human left and right internal mammary arteries

    PubMed Central

    Ferrari, Giovanni; Quackenbush, John; Strobeck, John; Hu, Lan; Johnson, Christopher K.; Mak, Andrew; Shaw, Richard E.; Sayles, Kathleen; Brizzio, Mariano E.; Zapolanski, Alex; Grau, Juan B.

    2014-01-01

    In coronary artery bypass grafting (CABG), the combined use of left and right internal mammary arteries (LIMA and RIMA) — collectively known as bilateral IMAs (BIMAs) provides a survival advantage over the use of LIMA alone. However, gene expression in RIMA has never been compared to that in LIMA. Here we report a genome-wide transcriptional analysis of BIMA to investigate the expression profiles of these conduits in patients undergoing CABG. As expected, in comparing the BIMAs to the aorta, we found differences in pathways and processes associated with atherosclerosis, inflammation, and cell signaling — pathways which provide biological support for the observation that BIMA grafts deliver long-term benefits to the patients and protect against continued atherosclerosis. These data support the widespread use of BIMAs as the preferred conduits in CABG. PMID:24858532

  6. [Genome-wide analysis and functional prediction of the Trihelix transcription factor family in rice].

    PubMed

    Jianhui, Ji; Yingjun, Zhou; Hehe, Wu; Liming, Yang

    2015-12-01

    The Trihelix transcription factor family plays an essential role in plant growth, development and stress response. However, the studies about identification and analysis of this gene family in rice on the genome-wide level have not been reported. In this study, 31 members of the Trihelix family, which contain highly conserved and characteristic trihelix domain through sequence clustering and functional domains analysis, were identified in rice genome database using bioinformatic tools. These members could be classified into 5 subfamilies (I~V) based on the evolutionary relationship and domain characteristics. Clustering analyses of the Trihelix family in rice, Arabidopsis, Brachypodium distachyom and Sorghum bicolor showed that each species contained different members of subfamily although the classification of the Trihelix family were consistent in these four species, which indicated that the differentiation of the Trihelix gene family occur earlier than that of these species. The conserved motifs in the Trihelix family of rice analyzed using the MEME program were highly consistent with the results of clustering analyses. Intraspecific and interspecific chromosomal replication in partial Trihelix family members were found to exist in rice and between rice and other species through chromosome replication analysis. Microarray data analysis revealed diverse expression patterns of Trihelix family genes in different tissues of rice or in response to six different phytohormones. Moreover, 20 members of the Trihelix transcription factor family were found to interact with other proteins in rice using RiceFRIEND online database analysis. Therefore, our results preliminarily identified the evolution, chromosome distribution and replication, expression patterns, phytohormones response of the Trihelix transcription factor family and the interaction between trihelix family proteins and other proteins in rice, which will provide a basis to further reveal the molecular evolution

  7. Genome-wide transcription analysis of clinal genetic variation in Drosophila.

    PubMed

    Chen, Ying; Lee, Siu F; Blanc, Eric; Reuter, Caroline; Wertheim, Bregje; Martinez-Diaz, Pedro; Hoffmann, Ary A; Partridge, Linda

    2012-01-01

    Clinal variation in quantitative traits is widespread, but its genetic basis awaits identification. Drosophila melanogaster shows adaptive, clinal variation in traits such as body size along latitudinal gradients on multiple continents. To investigate genome wide transcription differentiation between North and South that might contribute to the clinal phenotypic variation, we compared RNA expression patterns during development of D. melanogaster from tropical northern and temperate southern populations using whole genome tiling arrays. We found that genes that were differentially expressed between the cline ends were generally associated with metabolism and growth, and experimental alteration of expression of a sample of them generally resulted in altered body size in the predicted direction, sometimes significantly so. We further identified the serpent (srp) transcription factor binding sites to be enriched near genes up-regulated in expression in the south. Analysis of clinal populations revealed a significant cline in the expression level of srp. Experimental over-expression of srp increased body size, as predicted from its clinal expression pattern, suggesting that it may be involved in regulating adaptive clinal variation in Drosophila. This study identified a handful of genes that contributed to clinal phenotypic variation through altered gene expression level, yet misexpression of individual gene led to modest body size change. PMID:22514645

  8. Genome-Wide Identification and Analysis of the MYB Transcription Factor Superfamily in Solanum lycopersicum.

    PubMed

    Li, Zhenjun; Peng, Rihe; Tian, Yongsheng; Han, Hongjuan; Xu, Jing; Yao, Quanhong

    2016-08-01

    MYB proteins constitute one of the largest transcription factor families in the plant kingdom, members of which perform a variety of functions in plant biological processes. However, there are only very limited reports on the characterization of MYB transcription factors in tomato (Solanum lycopersicum). In our study, a total of 127 MYB genes have been identified in the tomato genome. A complete overview of these MYB genes is presented, including the phylogeny, gene structures, protein motifs, chromosome locations and expression patterns. The 127 SlMYB proteins could be classified into 18 subgroups based on domain similarity and phylogenetic topology. Phylogenetic analysis of SlMYBs along with MYBs from Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) indicated 14 subfamilies. Conserved motifs outside the MYB domain may reflect their functional conservation. The identified tomato MYB genes were distributed on 12 chromosomes at various densities but mainly in chromosomes 6 and 10 (12.6% and 11.8%, respectively). Genome-wide segmental and tandem duplications were also found, which may contribute to the expansion of SlMYB genes. RNA-sequencing and microarray data revealed tissue-specific and stress-responsive expression patterns of SlMYB genes. The expression profiles of SlMYB genes in response to salicylic acid (SA) and jasmonic acid methyl ester (MeJA) were also investigated by real-time PCR. Moreover, ethylene-responsive element-binding factor-associated amphiphilic repression (EAR) motifs were found in 24 SlMYB proteins. Collectively, our comprehensive analysis of SlMYB genes will facilitate future functional studies of the tomato MYB gene family and probably other Solanaceae plants. PMID:27279646

  9. 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. PMID:15704171

  10. 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.

  11. Genome-Wide DNA Methylation Patterns and Transcription Analysis in Sheep Muscle

    PubMed Central

    Couldrey, Christine; Brauning, Rudiger; Bracegirdle, Jeremy; Maclean, Paul; Henderson, Harold V.; McEwan, John C.

    2014-01-01

    DNA methylation plays a central role in regulating many aspects of growth and development in mammals through regulating gene expression. The development of next generation sequencing technologies have paved the way for genome-wide, high resolution analysis of DNA methylation landscapes using methodology known as reduced representation bisulfite sequencing (RRBS). While RRBS has proven to be effective in understanding DNA methylation landscapes in humans, mice, and rats, to date, few studies have utilised this powerful method for investigating DNA methylation in agricultural animals. Here we describe the utilisation of RRBS to investigate DNA methylation in sheep Longissimus dorsi muscles. RRBS analysis of ∼1% of the genome from Longissimus dorsi muscles provided data of suitably high precision and accuracy for DNA methylation analysis, at all levels of resolution from genome-wide to individual nucleotides. Combining RRBS data with mRNAseq data allowed the sheep Longissimus dorsi muscle methylome to be compared with methylomes from other species. While some species differences were identified, many similarities were observed between DNA methylation patterns in sheep and other more commonly studied species. The RRBS data presented here highlights the complexity of epigenetic regulation of genes. However, the similarities observed across species are promising, in that knowledge gained from epigenetic studies in human and mice may be applied, with caution, to agricultural species. The ability to accurately measure DNA methylation in agricultural animals will contribute an additional layer of information to the genetic analyses currently being used to maximise production gains in these species. PMID:25010796

  12. Genome-wide chromatin occupancy analysis reveals a role for ASH2 in transcriptional pausing.

    PubMed

    Pérez-Lluch, Sílvia; Blanco, Enrique; Carbonell, Albert; Raha, Debasish; Snyder, Michael; Serras, Florenci; Corominas, Montserrat

    2011-06-01

    An important mechanism for gene regulation involves chromatin changes via histone modification. One such modification is histone H3 lysine 4 trimethylation (H3K4me3), which requires histone methyltranferase complexes (HMT) containing the trithorax-group (trxG) protein ASH2. Mutations in ash2 cause a variety of pattern formation defects in the Drosophila wing. We have identified genome-wide binding of ASH2 in wing imaginal discs using chromatin immunoprecipitation combined with sequencing (ChIP-Seq). Our results show that genes with functions in development and transcriptional regulation are activated by ASH2 via H3K4 trimethylation in nearby nucleosomes. We have characterized the occupancy of phosphorylated forms of RNA Polymerase II and histone marks associated with activation and repression of transcription. ASH2 occupancy correlates with phosphorylated forms of RNA Polymerase II and histone activating marks in expressed genes. Additionally, RNA Polymerase II phosphorylation on serine 5 and H3K4me3 are reduced in ash2 mutants in comparison to wild-type flies. Finally, we have identified specific motifs associated with ASH2 binding in genes that are differentially expressed in ash2 mutants. Our data suggest that recruitment of the ASH2-containing HMT complexes is context specific and points to a function of ASH2 and H3K4me3 in transcriptional pausing control.

  13. Genome Wide Binding Site Analysis Reveals Transcriptional Coactivation of Cytokinin-Responsive Genes by DELLA Proteins

    PubMed Central

    Marín-de la Rosa, Nora; Pfeiffer, Anne; Hill, Kristine; Locascio, Antonella; Bhalerao, Rishikesh P.; Miskolczi, Pal; Grønlund, Anne L.; Wanchoo-Kohli, Aakriti; Thomas, Stephen G.; Bennett, Malcolm J.; Lohmann, Jan U.; Blázquez, Miguel A.; Alabadí, David

    2015-01-01

    The ability of plants to provide a plastic response to environmental cues relies on the connectivity between signaling pathways. DELLA proteins act as hubs that relay environmental information to the multiple transcriptional circuits that control growth and development through physical interaction with transcription factors from different families. We have analyzed the presence of one DELLA protein at the Arabidopsis genome by chromatin immunoprecipitation coupled to large-scale sequencing and we find that it binds at the promoters of multiple genes. Enrichment analysis shows a strong preference for cis elements recognized by specific transcription factor families. In particular, we demonstrate that DELLA proteins are recruited by type-B ARABIDOPSIS RESPONSE REGULATORS (ARR) to the promoters of cytokinin-regulated genes, where they act as transcriptional co-activators. The biological relevance of this mechanism is underpinned by the necessity of simultaneous presence of DELLAs and ARRs to restrict root meristem growth and to promote photomorphogenesis. PMID:26134422

  14. Genome-Wide Analysis of Basic/Helix-Loop-Helix Transcription Factor Family in Rice and Arabidopsis1[W

    PubMed Central

    Li, Xiaoxing; Duan, Xuepeng; Jiang, Haixiong; Sun, Yujin; Tang, Yuanping; Yuan, Zheng; Guo, Jingkang; Liang, Wanqi; Chen, Liang; Yin, Jingyuan; Ma, Hong; Wang, Jian; Zhang, Dabing

    2006-01-01

    The basic/helix-loop-helix (bHLH) transcription factors and their homologs form a large family in plant and animal genomes. They are known to play important roles in the specification of tissue types in animals. On the other hand, few plant bHLH proteins have been studied functionally. Recent completion of whole genome sequences of model plants Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) allows genome-wide analysis and comparison of the bHLH family in flowering plants. We have identified 167 bHLH genes in the rice genome, and their phylogenetic analysis indicates that they form well-supported clades, which are defined as subfamilies. In addition, sequence analysis of potential DNA-binding activity, the sequence motifs outside the bHLH domain, and the conservation of intron/exon structural patterns further support the evolutionary relationships among these proteins. The genome distribution of rice bHLH genes strongly supports the hypothesis that genome-wide and tandem duplication contributed to the expansion of the bHLH gene family, consistent with the birth-and-death theory of gene family evolution. Bioinformatics analysis suggests that rice bHLH proteins can potentially participate in a variety of combinatorial interactions, endowing them with the capacity to regulate a multitude of transcriptional programs. In addition, similar expression patterns suggest functional conservation between some rice bHLH genes and their close Arabidopsis homologs. PMID:16896230

  15. Genome-Wide Identification and Expression Analysis of the NAC Transcription Factor Family in Cassava.

    PubMed

    Hu, Wei; Wei, Yunxie; Xia, Zhiqiang; Yan, Yan; Hou, Xiaowan; Zou, Meiling; Lu, Cheng; Wang, Wenquan; Peng, Ming

    2015-01-01

    NAC [no apical meristem (NAM), Arabidopsis transcription activation factor [ATAF1/2] and cup-shaped cotyledon (CUC2)] proteins is one of the largest groups of plant specific transcription factors and plays a crucial role in plant growth, development, and adaption to the environment. Currently, no information is known about the NAC family in cassava. In this study, 96 NAC genes (MeNACs) were identified from the cassava genome. Phylogenetic analysis of the NACs from cassava and Arabidopsis showed that MeNAC proteins can be clustered into 16 subgroups. Gene structure analysis found that the number of introns of MeNAC genes varied from 0 to 5, with the majority of MeNAC genes containing two introns, indicating a small gene structure diversity of cassava NAC genes. Conserved motif analysis revealed that all of the identified MeNACs had the conserved NAC domain and/or NAM domain. Global expression analysis suggested that MeNAC genes exhibited different expression profiles in different tissues between wild subspecies and cultivated varieties, indicating their involvement in the functional diversity of different accessions. Transcriptome analysis demonstrated that MeNACs had a widely transcriptional response to drought stress and that they had differential expression profiles in different accessions, implying their contribution to drought stress resistance in cassava. Finally, the expression of twelve MeNAC genes was analyzed under osmotic, salt, cold, ABA, and H2O2 treatments, indicating that cassava NACs may represent convergence points of different signaling pathways. Taken together, this work found some excellent tissue-specific and abiotic stress-responsive candidate MeNAC genes, which would provide a solid foundation for functional investigation of the NAC family, crop improvement and improved understanding of signal transduction in plants. These data bring new insight on the complexity of the transcriptional control of MeNAC genes and support the hypothesis that

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

    PubMed Central

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

    2015-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    2005-01-01

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

  18. Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos.

    PubMed

    Armant, Olivier; März, Martin; Schmidt, Rebecca; Ferg, Marco; Diotel, Nicolas; Ertzer, Raymond; Bryne, Jan Christian; Yang, Lixin; Baader, Isabelle; Reischl, Markus; Legradi, Jessica; Mikut, Ralf; Stemple, Derek; van IJcken, Wilfred; van der Sloot, Antoine; Lenhard, Boris; Strähle, Uwe; Rastegar, Sepand

    2013-08-15

    Transcription is the primary step in the retrieval of genetic information. A substantial proportion of the protein repertoire of each organism consists of transcriptional regulators (TRs). It is believed that the differential expression and combinatorial action of these TRs is essential for vertebrate development and body homeostasis. We mined the zebrafish genome exhaustively for genes encoding TRs and determined their expression in the zebrafish embryo by sequencing to saturation and in situ hybridisation. At the evolutionary conserved phylotypic stage, 75% of the 3302 TR genes encoded in the genome are already expressed. The number of expressed TR genes increases only marginally in subsequent stages and is maintained during adulthood suggesting important roles of the TR genes in body homeostasis. Fewer than half of the TR genes (45%, n=1711 genes) are expressed in a tissue-restricted manner in the embryo. Transcripts of 207 genes were detected in a single tissue in the 24h embryo, potentially acting as regulators of specific processes. Other TR genes were expressed in multiple tissues. However, with the exception of certain territories in the nervous system, we did not find significant synexpression suggesting that most tissue-restricted TRs act in a freely combinatorial fashion. Our data indicate that elaboration of body pattern and function from the phylotypic stage onward relies mostly on redeployment of TRs and post-transcriptional processes. PMID:23684812

  19. Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos

    PubMed Central

    Armant, Olivier; März, Martin; Schmidt, Rebecca; Ferg, Marco; Diotel, Nicolas; Ertzer, Raymond; Bryne, Jan Christian; Yang, Lixin; Baader, Isabelle; Reischl, Markus; Legradi, Jessica; Mikut, Ralf; Stemple, Derek; van IJcken, Wilfred; van der Sloot, Antoine; Lenhard, Boris; Strähle, Uwe; Rastegar, Sepand

    2015-01-01

    Transcription is the primary step in the retrieval of genetic information. A substantial proportion of the protein repertoire of each organism consists of transcriptional regulators (TRs). It is believed that the differential expression and combinatorial action of these TRs is essential for vertebrate development and body homeostasis. We mined the zebrafish genome exhaustively for genes encoding TRs and determined their expression in the zebrafish embryo by sequencing to saturation and in situ hybridisation. At the evolutionary conserved phylotypic stage, 75% of the 3302 TR genes encoded in the genome are already expressed. The number of expressed TR genes increases only marginally in subsequent stages and is maintained during adulthood suggesting important roles of the TR genes in body homeostasis. Fewer than half of the TR genes (45%, n=1711 genes) are expressed in a tissue-restricted manner in the embryo. Transcripts of 207 genes were detected in a single tissue in the 24 h embryo, potentially acting as regulators of specific processes. Other TR genes were expressed in multiple tissues. However, with the exception of certain territories in the nervous system, we did not find significant synexpression suggesting that most tissue-restricted TRs act in a freely combinatorial fashion. Our data indicate that elaboration of body pattern and function from the phylotypic stage onward relies mostly on redeployment of TRs and post-transcriptional processes. PMID:23684812

  20. Genome-Wide Phylogenetic Comparative Analysis of Plant Transcriptional Regulation: A Timeline of Loss, Gain, Expansion, and Correlation with Complexity

    PubMed Central

    Lang, Daniel; Weiche, Benjamin; Timmerhaus, Gerrit; Richardt, Sandra; Riaño-Pachón, Diego M.; Corrêa, Luiz G. G.; Reski, Ralf; Mueller-Roeber, Bernd; Rensing, Stefan A.

    2010-01-01

    Evolutionary retention of duplicated genes encoding transcription-associated proteins (TAPs, comprising transcription factors and other transcriptional regulators) has been hypothesized to be positively correlated with increasing morphological complexity and paleopolyploidizations, especially within the plant kingdom. Here, we present the most comprehensive set of classification rules for TAPs and its application for genome-wide analyses of plants and algae. Using a dated species tree and phylogenetic comparative (PC) analyses, we define the timeline of TAP loss, gain, and expansion among Viridiplantae and find that two major bursts of gain/expansion occurred, coinciding with the water-to-land transition and the radiation of flowering plants. For the first time, we provide PC proof for the long-standing hypothesis that TAPs are major driving forces behind the evolution of morphological complexity, the latter in Plantae being shaped significantly by polyploidization and subsequent biased paleolog retention. Principal component analysis incorporating the number of TAPs per genome provides an alternate and significant proxy for complexity, ideally suited for PC genomics. Our work lays the ground for further interrogation of the shaping of gene regulatory networks underlying the evolution of organism complexity. PMID:20644220

  1. Genome-wide phylogenetic comparative analysis of plant transcriptional regulation: a timeline of loss, gain, expansion, and correlation with complexity.

    PubMed

    Lang, Daniel; Weiche, Benjamin; Timmerhaus, Gerrit; Richardt, Sandra; Riaño-Pachón, Diego M; Corrêa, Luiz G G; Reski, Ralf; Mueller-Roeber, Bernd; Rensing, Stefan A

    2010-07-19

    Evolutionary retention of duplicated genes encoding transcription-associated proteins (TAPs, comprising transcription factors and other transcriptional regulators) has been hypothesized to be positively correlated with increasing morphological complexity and paleopolyploidizations, especially within the plant kingdom. Here, we present the most comprehensive set of classification rules for TAPs and its application for genome-wide analyses of plants and algae. Using a dated species tree and phylogenetic comparative (PC) analyses, we define the timeline of TAP loss, gain, and expansion among Viridiplantae and find that two major bursts of gain/expansion occurred, coinciding with the water-to-land transition and the radiation of flowering plants. For the first time, we provide PC proof for the long-standing hypothesis that TAPs are major driving forces behind the evolution of morphological complexity, the latter in Plantae being shaped significantly by polyploidization and subsequent biased paleolog retention. Principal component analysis incorporating the number of TAPs per genome provides an alternate and significant proxy for complexity, ideally suited for PC genomics. Our work lays the ground for further interrogation of the shaping of gene regulatory networks underlying the evolution of organism complexity.

  2. Genome-wide transcriptional analysis of super-embryogenic Medicago truncatula explant cultures

    PubMed Central

    Imin, Nijat; Goffard, Nicolas; Nizamidin, Mahira; Rolfe, Barry G

    2008-01-01

    Background The Medicago truncatula (M. truncatula) line 2HA has a 500-fold greater capacity to regenerate plants in culture by somatic embryogenesis than its wild type progenitor Jemalong. To understand the molecular basis for the regeneration capacity of this super-embryogenic line 2HA, using Affymetrix GeneChip®, we have compared transcriptomes of explant leaf cultures of these two lines that were grown on media containing the auxin NAA (1-naphthaleneacetic acid) and the cytokinin BAP (6-benzylaminopurine) for two weeks, an early time point for tissue culture proliferation. Results Using Affymetrix GeneChip®, GCRMA normalisation and statistical analysis, we have shown that more than 196 and 49 probe sets were significantly (p < 0.05) up- or down-regulated respectively more than 2 fold in expression. We have utilised GeneBins, a database for classifying gene expression data to distinguish differentially displayed pathways among these two cultures which showed changes in number of biochemical pathways including carbon and flavonoid biosynthesis, phytohormone biosynthesis and signalling. The up-regulated genes in the embryogenic 2HA culture included nodulins, transporters, regulatory genes, embryogenesis related arabinogalactans and genes involved in redox homeostasis, the transition from vegetative growth to reproductive growth and cytokinin signalling. Down-regulated genes included protease inhibitors, wound-induced proteins, and genes involved in biosynthesis and signalling of phytohormones auxin, gibberellin and ethylene. These changes indicate essential differences between the super-embryogenic line 2HA and Jemalong not only in many aspects of biochemical pathways but also in their response to auxin and cytokinin. To validate the GeneChip results, we used quantitative real-time RT-PCR to examine the expression of the genes up-regulated in 2HA such as transposase, RNA-directed DNA polymerase, glycoside hydrolase, RESPONSE REGULATOR 10, AGAMOUS-LIKE 20, flower

  3. Genome-wide transcriptional analysis of the human cell cycle identifies genes differentially regulated in normal and cancer cells

    PubMed Central

    Bar-Joseph, Ziv; Siegfried, Zahava; Brandeis, Michael; Brors, Benedikt; Lu, Yong; Eils, Roland; Dynlacht, Brian D.; Simon, Itamar

    2008-01-01

    Characterization of the transcriptional regulatory network of the normal cell cycle is essential for understanding the perturbations that lead to cancer. However, the complete set of cycling genes in primary cells has not yet been identified. Here, we report the results of genome-wide expression profiling experiments on synchronized primary human foreskin fibroblasts across the cell cycle. Using a combined experimental and computational approach to deconvolve measured expression values into “single-cell” expression profiles, we were able to overcome the limitations inherent in synchronizing nontransformed mammalian cells. This allowed us to identify 480 periodically expressed genes in primary human foreskin fibroblasts. Analysis of the reconstructed primary cell profiles and comparison with published expression datasets from synchronized transformed cells reveals a large number of genes that cycle exclusively in primary cells. This conclusion was supported by both bioinformatic analysis and experiments performed on other cell types. We suggest that this approach will help pinpoint genetic elements contributing to normal cell growth and cellular transformation. PMID:18195366

  4. Genome-Wide Identification and Expression Analysis of WRKY Transcription Factors under Multiple Stresses in Brassica napus.

    PubMed

    He, Yajun; Mao, Shaoshuai; Gao, Yulong; Zhu, Liying; Wu, Daoming; Cui, Yixin; Li, Jiana; Qian, Wei

    2016-01-01

    WRKY transcription factors play important roles in responses to environmental stress stimuli. Using a genome-wide domain analysis, we identified 287 WRKY genes with 343 WRKY domains in the sequenced genome of Brassica napus, 139 in the A sub-genome and 148 in the C sub-genome. These genes were classified into eight groups based on phylogenetic analysis. In the 343 WRKY domains, a total of 26 members showed divergence in the WRKY domain, and 21 belonged to group I. This finding suggested that WRKY genes in group I are more active and variable compared with genes in other groups. Using genome-wide identification and analysis of the WRKY gene family in Brassica napus, we observed genome duplication, chromosomal/segmental duplications and tandem duplication. All of these duplications contributed to the expansion of the WRKY gene family. The duplicate segments that were detected indicated that genome duplication events occurred in the two diploid progenitors B. rapa and B. olearecea before they combined to form B. napus. Analysis of the public microarray database and EST database for B. napus indicated that 74 WRKY genes were induced or preferentially expressed under stress conditions. According to the public QTL data, we identified 77 WRKY genes in 31 QTL regions related to various stress tolerance. We further evaluated the expression of 26 BnaWRKY genes under multiple stresses by qRT-PCR. Most of the genes were induced by low temperature, salinity and drought stress, indicating that the WRKYs play important roles in B. napus stress responses. Further, three BnaWRKY genes were strongly responsive to the three multiple stresses simultaneously, which suggests that these 3 WRKY may have multi-functional roles in stress tolerance and can potentially be used in breeding new rapeseed cultivars. We also found six tandem repeat pairs exhibiting similar expression profiles under the various stress conditions, and three pairs were mapped in the stress related QTL regions

  5. Genome-Wide Identification and Expression Analysis of WRKY Transcription Factors under Multiple Stresses in Brassica napus.

    PubMed

    He, Yajun; Mao, Shaoshuai; Gao, Yulong; Zhu, Liying; Wu, Daoming; Cui, Yixin; Li, Jiana; Qian, Wei

    2016-01-01

    WRKY transcription factors play important roles in responses to environmental stress stimuli. Using a genome-wide domain analysis, we identified 287 WRKY genes with 343 WRKY domains in the sequenced genome of Brassica napus, 139 in the A sub-genome and 148 in the C sub-genome. These genes were classified into eight groups based on phylogenetic analysis. In the 343 WRKY domains, a total of 26 members showed divergence in the WRKY domain, and 21 belonged to group I. This finding suggested that WRKY genes in group I are more active and variable compared with genes in other groups. Using genome-wide identification and analysis of the WRKY gene family in Brassica napus, we observed genome duplication, chromosomal/segmental duplications and tandem duplication. All of these duplications contributed to the expansion of the WRKY gene family. The duplicate segments that were detected indicated that genome duplication events occurred in the two diploid progenitors B. rapa and B. olearecea before they combined to form B. napus. Analysis of the public microarray database and EST database for B. napus indicated that 74 WRKY genes were induced or preferentially expressed under stress conditions. According to the public QTL data, we identified 77 WRKY genes in 31 QTL regions related to various stress tolerance. We further evaluated the expression of 26 BnaWRKY genes under multiple stresses by qRT-PCR. Most of the genes were induced by low temperature, salinity and drought stress, indicating that the WRKYs play important roles in B. napus stress responses. Further, three BnaWRKY genes were strongly responsive to the three multiple stresses simultaneously, which suggests that these 3 WRKY may have multi-functional roles in stress tolerance and can potentially be used in breeding new rapeseed cultivars. We also found six tandem repeat pairs exhibiting similar expression profiles under the various stress conditions, and three pairs were mapped in the stress related QTL regions

  6. Genome-Wide Identification and Expression Analysis of WRKY Transcription Factors under Multiple Stresses in Brassica napus

    PubMed Central

    He, Yajun; Mao, Shaoshuai; Gao, Yulong; Zhu, Liying; Wu, Daoming; Cui, Yixin; Li, Jiana; Qian, Wei

    2016-01-01

    WRKY transcription factors play important roles in responses to environmental stress stimuli. Using a genome-wide domain analysis, we identified 287 WRKY genes with 343 WRKY domains in the sequenced genome of Brassica napus, 139 in the A sub-genome and 148 in the C sub-genome. These genes were classified into eight groups based on phylogenetic analysis. In the 343 WRKY domains, a total of 26 members showed divergence in the WRKY domain, and 21 belonged to group I. This finding suggested that WRKY genes in group I are more active and variable compared with genes in other groups. Using genome-wide identification and analysis of the WRKY gene family in Brassica napus, we observed genome duplication, chromosomal/segmental duplications and tandem duplication. All of these duplications contributed to the expansion of the WRKY gene family. The duplicate segments that were detected indicated that genome duplication events occurred in the two diploid progenitors B. rapa and B. olearecea before they combined to form B. napus. Analysis of the public microarray database and EST database for B. napus indicated that 74 WRKY genes were induced or preferentially expressed under stress conditions. According to the public QTL data, we identified 77 WRKY genes in 31 QTL regions related to various stress tolerance. We further evaluated the expression of 26 BnaWRKY genes under multiple stresses by qRT-PCR. Most of the genes were induced by low temperature, salinity and drought stress, indicating that the WRKYs play important roles in B. napus stress responses. Further, three BnaWRKY genes were strongly responsive to the three multiple stresses simultaneously, which suggests that these 3 WRKY may have multi-functional roles in stress tolerance and can potentially be used in breeding new rapeseed cultivars. We also found six tandem repeat pairs exhibiting similar expression profiles under the various stress conditions, and three pairs were mapped in the stress related QTL regions

  7. Genome-wide identification and analysis of the B3 superfamily of transcription factors in Brassicaceae and major crop plants.

    PubMed

    Peng, Fred Y; Weselake, Randall J

    2013-05-01

    The plant-specific B3 superfamily of transcription factors has diverse functions in plant growth and development. Using a genome-wide domain analysis, we identified 92, 187, 58, 90, 81, 55, and 77 B3 transcription factor genes in the sequenced genome of Arabidopsis, Brassica rapa, castor bean (Ricinus communis), cocoa (Theobroma cacao), soybean (Glycine max), maize (Zea mays), and rice (Oryza sativa), respectively. The B3 superfamily has substantially expanded during the evolution in eudicots particularly in Brassicaceae, as compared to monocots in the analysis. We observed domain duplication in some of these B3 proteins, forming more complex domain architectures than currently understood. We found that the length of B3 domains exhibits a large variation, which may affect their exact number of α-helices and β-sheets in the core structure of B3 domains, and possibly have functional implications. Analysis of the public microarray data indicated that most of the B3 gene pairs encoding Arabidopsis-rice orthologs are preferentially expressed in different tissues, suggesting their different roles in these two species. Using ESTs in crops, we identified many B3 genes preferentially expressed in reproductive tissues. In a sequence-based quantitative trait loci analysis in rice and maize, we have found many B3 genes associated with traits such as grain yield, seed weight and number, and protein content. Our results provide a framework for future studies into the function of B3 genes in different phases of plant development, especially the ones related to traits in major crops.

  8. 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

  9. 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.

  10. Genome-wide analysis of the bHLH transcription factor family in Chinese cabbage (Brassica rapa ssp. pekinensis).

    PubMed

    Song, Xiao-Ming; Huang, Zhi-Nan; Duan, Wei-Ke; Ren, Jun; Liu, Tong-Kun; Li, Ying; Hou, Xi-Lin

    2014-02-01

    Basic helix-loop-helix (bHLH) transcription factors are widely distributed in eukaryotic organisms and are thought to be one of the largest families of regulatory proteins. This important family of transcriptional regulators plays crucial roles in plant development. However, a systematic analysis of the bHLH transcription factor family has not been reported in Chinese cabbage. In this study, 230 bHLH transcription factors were identified from the whole Chinese cabbage genome and compared with proteins from other representative plants, fungi and metazoans. The Chinese cabbage bHLH (BrabHLH) gene family could be classified into 24 subfamilies. Phylogenetic analysis of BrabHLHs along with bHLHs from Arabidopsis and rice indicated 26 subfamilies. The identification, classification, phylogenetic reconstruction, conserved motifs, chromosome distribution, functional annotation, expression patterns and interaction networks of BrabHLHs were analyzed. Distribution mapping showed that BrabHLHs were non-randomly located on the ten Chinese cabbage chromosomes. One hundred and twenty-four orthologous bHLH genes were identified between Chinese cabbage and Arabidopsis, and the interaction networks of the orthologous genes were constructed in Chinese cabbage. Quantitative RT-PCR analysis showed that expressions of BrabHLH genes varied widely under different abiotic stress treatments for different times. Thus, this comprehensive analysis of BrabHLHs represents a rich resource, aiding the elucidation of the roles of bHLH family members in plant growth and development. Furthermore, the comparative genomics analysis deepened our understanding of the evolution of this gene family after a polyploidy event.

  11. Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy

    PubMed Central

    Johnson, Keven R.; Nicodemus-Johnson, Jessie; Spindler, Mathew J.

    2015-01-01

    In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo. PMID:26192751

  12. Genome-Wide Analysis of Ethylene-Responsive Element Binding Factor-Associated Amphiphilic Repression Motif-Containing Transcriptional Regulators in Arabidopsis1[W][OA

    PubMed Central

    Kagale, Sateesh; Links, Matthew G.; Rozwadowski, Kevin

    2010-01-01

    The ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif is a transcriptional regulatory motif identified in members of the ethylene-responsive element binding factor, C2H2, and auxin/indole-3-acetic acid families of transcriptional regulators. Sequence comparison of the core EAR motif sites from these proteins revealed two distinct conservation patterns: LxLxL and DLNxxP. Proteins containing these motifs play key roles in diverse biological functions by negatively regulating genes involved in developmental, hormonal, and stress signaling pathways. Through a genome-wide bioinformatics analysis, we have identified the complete repertoire of the EAR repressome in Arabidopsis (Arabidopsis thaliana) comprising 219 proteins belonging to 21 different transcriptional regulator families. Approximately 72% of these proteins contain a LxLxL type of EAR motif, 22% contain a DLNxxP type of EAR motif, and the remaining 6% have a motif where LxLxL and DLNxxP are overlapping. Published in vitro and in planta investigations support approximately 40% of these proteins functioning as negative regulators of gene expression. Comparative sequence analysis of EAR motif sites and adjoining regions has identified additional preferred residues and potential posttranslational modification sites that may influence the functionality of the EAR motif. Homology searches against protein databases of poplar (Populus trichocarpa), grapevine (Vitis vinifera), rice (Oryza sativa), and sorghum (Sorghum bicolor) revealed that the EAR motif is conserved across these diverse plant species. This genome-wide analysis represents the most extensive survey of EAR motif-containing proteins in Arabidopsis to date and provides a resource enabling investigations into their biological roles and the mechanism of EAR motif-mediated transcriptional regulation. PMID:20097792

  13. Genome-wide analysis of the AP2/ERF transcription factor superfamily in Chinese cabbage (Brassica rapa ssp. pekinensis)

    PubMed Central

    2013-01-01

    Background Chinese cabbage (Brassica rapa ssp. pekinensis) is a member of one of the most important leaf vegetables grown worldwide, which has experienced thousands of years in cultivation and artificial selection. The entire Chinese cabbage genome sequence, and more than forty thousand proteins have been obtained to date. The genome has undergone triplication events since its divergence from Arabidopsis thaliana (13 to 17 Mya), however a high degree of sequence similarity and conserved genome structure remain between the two species. Arabidopsis is therefore a viable reference species for comparative genomics studies. Variation in the number of members in gene families due to genome triplication may contribute to the broad range of phenotypic plasticity, and increased tolerance to environmental extremes observed in Brassica species. Transcription factors are important regulators involved in plant developmental and physiological processes. The AP2/ERF proteins, one of the most important families of transcriptional regulators, play a crucial role in plant growth, and in response to biotic and abiotic stressors. Our analysis will provide resources for understanding the tolerance mechanisms in Brassica rapa ssp. pekinensis. Results In the present study, 291 putative AP2/ERF transcription factor proteins were identified from the Chinese cabbage genome database, and compared with proteins from 15 additional species. The Chinese cabbage AP2/ERF superfamily was classified into four families, including AP2, ERF, RAV, and Soloist. The ERF family was further divided into DREB and ERF subfamilies. The AP2/ERF superfamily was subsequently divided into 15 groups. The identification, classification, phylogenetic reconstruction, conserved motifs, chromosome distribution, functional annotation, expression patterns, and interaction networks of the AP2/ERF transcription factor superfamily were predicted and analyzed. Distribution mapping results showed AP2/ERF superfamily genes were

  14. Genome-wide characterization and analysis of bZIP transcription factor gene family related to abiotic stress in cassava.

    PubMed

    Hu, Wei; Yang, Hubiao; Yan, Yan; Wei, Yunxie; Tie, Weiwei; Ding, Zehong; Zuo, Jiao; Peng, Ming; Li, Kaimian

    2016-01-01

    The basic leucine zipper (bZIP) transcription factor family plays crucial roles in various aspects of biological processes. Currently, no information is available regarding the bZIP family in the important tropical crop cassava. Herein, 77 bZIP genes were identified from cassava. Evolutionary analysis indicated that MebZIPs could be divided into 10 subfamilies, which was further supported by conserved motif and gene structure analyses. Global expression analysis suggested that MebZIPs showed similar or distinct expression patterns in different tissues between cultivated variety and wild subspecies. Transcriptome analysis of three cassava genotypes revealed that many MebZIP genes were activated by drought in the root of W14 subspecies, indicating the involvement of these genes in the strong resistance of cassava to drought. Expression analysis of selected MebZIP genes in response to osmotic, salt, cold, ABA, and H2O2 suggested that they might participate in distinct signaling pathways. Our systematic analysis of MebZIPs reveals constitutive, tissue-specific and abiotic stress-responsive candidate MebZIP genes for further functional characterization in planta, yields new insights into transcriptional regulation of MebZIP genes, and lays a foundation for understanding of bZIP-mediated abiotic stress response. PMID:26947924

  15. Genome-wide characterization and analysis of bZIP transcription factor gene family related to abiotic stress in cassava.

    PubMed

    Hu, Wei; Yang, Hubiao; Yan, Yan; Wei, Yunxie; Tie, Weiwei; Ding, Zehong; Zuo, Jiao; Peng, Ming; Li, Kaimian

    2016-03-07

    The basic leucine zipper (bZIP) transcription factor family plays crucial roles in various aspects of biological processes. Currently, no information is available regarding the bZIP family in the important tropical crop cassava. Herein, 77 bZIP genes were identified from cassava. Evolutionary analysis indicated that MebZIPs could be divided into 10 subfamilies, which was further supported by conserved motif and gene structure analyses. Global expression analysis suggested that MebZIPs showed similar or distinct expression patterns in different tissues between cultivated variety and wild subspecies. Transcriptome analysis of three cassava genotypes revealed that many MebZIP genes were activated by drought in the root of W14 subspecies, indicating the involvement of these genes in the strong resistance of cassava to drought. Expression analysis of selected MebZIP genes in response to osmotic, salt, cold, ABA, and H2O2 suggested that they might participate in distinct signaling pathways. Our systematic analysis of MebZIPs reveals constitutive, tissue-specific and abiotic stress-responsive candidate MebZIP genes for further functional characterization in planta, yields new insights into transcriptional regulation of MebZIP genes, and lays a foundation for understanding of bZIP-mediated abiotic stress response.

  16. Genome-wide characterization and analysis of bZIP transcription factor gene family related to abiotic stress in cassava

    PubMed Central

    Hu, Wei; Yang, Hubiao; Yan, Yan; Wei, Yunxie; Tie, Weiwei; Ding, Zehong; Zuo, Jiao; Peng, Ming; Li, Kaimian

    2016-01-01

    The basic leucine zipper (bZIP) transcription factor family plays crucial roles in various aspects of biological processes. Currently, no information is available regarding the bZIP family in the important tropical crop cassava. Herein, 77 bZIP genes were identified from cassava. Evolutionary analysis indicated that MebZIPs could be divided into 10 subfamilies, which was further supported by conserved motif and gene structure analyses. Global expression analysis suggested that MebZIPs showed similar or distinct expression patterns in different tissues between cultivated variety and wild subspecies. Transcriptome analysis of three cassava genotypes revealed that many MebZIP genes were activated by drought in the root of W14 subspecies, indicating the involvement of these genes in the strong resistance of cassava to drought. Expression analysis of selected MebZIP genes in response to osmotic, salt, cold, ABA, and H2O2 suggested that they might participate in distinct signaling pathways. Our systematic analysis of MebZIPs reveals constitutive, tissue-specific and abiotic stress-responsive candidate MebZIP genes for further functional characterization in planta, yields new insights into transcriptional regulation of MebZIP genes, and lays a foundation for understanding of bZIP-mediated abiotic stress response. PMID:26947924

  17. Genome-wide analysis and expression profiling of the ERF transcription factor family in potato (Solanum tuberosum L.).

    PubMed

    Charfeddine, Mariam; Saïdi, Mohamed Najib; Charfeddine, Safa; Hammami, Asma; Gargouri Bouzid, Radhia

    2015-04-01

    The ERF transcription factors belong to the AP2/ERF superfamily, one of the largest transcription factor families in plants. They play important roles in plant development processes, as well as in the response to biotic, abiotic, and hormone signaling. In the present study, 155 putative ERF transcription factor genes were identified from the potato (Solanum tuberosum) genome database, and compared with those from Arabidopsis thaliana. The StERF proteins are divided into ten phylogenetic groups. Expression analyses of five StERFs were carried out by semi-quantitative RT-PCR and compared with published RNA-seq data. These latter analyses were used to distinguish tissue-specific, biotic, and abiotic stress genes as well as hormone-responsive StERF genes. The results are of interest to better understand the role of the AP2/ERF genes in response to diverse types of stress in potatoes. A comprehensive analysis of the physiological functions and biological roles of the ERF family genes in S. tuberosum is required to understand crop stress tolerance mechanisms.

  18. Genome-Wide Transcriptional Profile Analysis of Prunus persica in Response to Low Sink Demand after Fruit Removal.

    PubMed

    Duan, Wei; Xu, Hongguo; Liu, Guotian; Fan, Peige; Liang, Zhenchang; Li, Shaohua

    2016-01-01

    Prunus persica fruits were removed from 1-year-old shoots to analysis photosynthesis, chlorophyll fluorescence and genes changes in leaves to low sink demand caused by fruit removal (-fruit) during the final stage of rapid fruit growth. A decline in net photosynthesis rate was observed, accompanied with a decrease in stomatal conductance. The intercellular CO2 concentrations and leaf temperature increased as compared with a normal fruit load (+fruit). Moreover, low sink demand significantly inhibited the donor side and the reaction center of photosystem II. 382 genes in leaf with an absolute fold change ≥1 change in expression level, representing 116 up- and 266 down-regulated genes except for unknown transcripts. Among these, 25 genes for photosynthesis were down-regulated, 69 stress and 19 redox related genes up-regulated under the low sink demand. These studies revealed high leaf temperature may result in a decline of net photosynthesis rate through down-regulation in photosynthetic related genes and up-regulation in redox and stress related genes, especially heat shock proteins genes. The complex changes in genes at the transcriptional level under low sink demand provided useful starting points for in-depth analyses of source-sink relationship in P. persica. PMID:27446115

  19. Genome-Wide Transcriptional Profile Analysis of Prunus persica in Response to Low Sink Demand after Fruit Removal

    PubMed Central

    Duan, Wei; Xu, Hongguo; Liu, Guotian; Fan, Peige; Liang, Zhenchang; Li, Shaohua

    2016-01-01

    Prunus persica fruits were removed from 1-year-old shoots to analysis photosynthesis, chlorophyll fluorescence and genes changes in leaves to low sink demand caused by fruit removal (−fruit) during the final stage of rapid fruit growth. A decline in net photosynthesis rate was observed, accompanied with a decrease in stomatal conductance. The intercellular CO2 concentrations and leaf temperature increased as compared with a normal fruit load (+fruit). Moreover, low sink demand significantly inhibited the donor side and the reaction center of photosystem II. 382 genes in leaf with an absolute fold change ≥1 change in expression level, representing 116 up- and 266 down-regulated genes except for unknown transcripts. Among these, 25 genes for photosynthesis were down-regulated, 69 stress and 19 redox related genes up-regulated under the low sink demand. These studies revealed high leaf temperature may result in a decline of net photosynthesis rate through down-regulation in photosynthetic related genes and up-regulation in redox and stress related genes, especially heat shock proteins genes. The complex changes in genes at the transcriptional level under low sink demand provided useful starting points for in-depth analyses of source-sink relationship in P. persica. PMID:27446115

  20. Genome-Wide Transcriptional Profile Analysis of Prunus persica in Response to Low Sink Demand after Fruit Removal.

    PubMed

    Duan, Wei; Xu, Hongguo; Liu, Guotian; Fan, Peige; Liang, Zhenchang; Li, Shaohua

    2016-01-01

    Prunus persica fruits were removed from 1-year-old shoots to analysis photosynthesis, chlorophyll fluorescence and genes changes in leaves to low sink demand caused by fruit removal (-fruit) during the final stage of rapid fruit growth. A decline in net photosynthesis rate was observed, accompanied with a decrease in stomatal conductance. The intercellular CO2 concentrations and leaf temperature increased as compared with a normal fruit load (+fruit). Moreover, low sink demand significantly inhibited the donor side and the reaction center of photosystem II. 382 genes in leaf with an absolute fold change ≥1 change in expression level, representing 116 up- and 266 down-regulated genes except for unknown transcripts. Among these, 25 genes for photosynthesis were down-regulated, 69 stress and 19 redox related genes up-regulated under the low sink demand. These studies revealed high leaf temperature may result in a decline of net photosynthesis rate through down-regulation in photosynthetic related genes and up-regulation in redox and stress related genes, especially heat shock proteins genes. The complex changes in genes at the transcriptional level under low sink demand provided useful starting points for in-depth analyses of source-sink relationship in P. persica.

  1. Genome-Wide Survey of the Soybean GATA Transcription Factor Gene Family and Expression Analysis under Low Nitrogen Stress

    PubMed Central

    Zhang, Chanjuan; Hou, Yuqing; Hao, Qingnan; Chen, Haifeng; Chen, Limiao; Yuan, Songli; Shan, Zhihui; Zhang, Xiaojuan; Yang, Zhonglu; Qiu, Dezhen; Zhou, Xinan; Huang, Wenjun

    2015-01-01

    GATA transcription factors are transcriptional regulatory proteins that contain a characteristic type-IV zinc finger DNA-binding domain and recognize the conserved GATA motif in the promoter sequence of target genes. Previous studies demonstrated that plant GATA factors possess critical functions in developmental control and responses to the environment. To date, the GATA factors in soybean (Glycine max) have yet to be characterized. Thus, this study identified 64 putative GATA factors from the entire soybean genomic sequence. The chromosomal distributions, gene structures, duplication patterns, phylogenetic tree, tissue expression patterns, and response to low nitrogen stress of the 64 GATA factors in soybean were analyzed to further investigate the functions of these factors. Results indicated that segmental duplication predominantly contributed to the expansion of the GATA factor gene family in soybean. These GATA proteins were phylogenetically clustered into four distinct subfamilies, wherein their gene structure and motif compositions were considerably conserved. A comparative phylogenetic analysis of the GATA factor zinc finger domain sequences in soybean, Arabidopsis (Arabidopsis thaliana), and rice (Oryza sativa) revealed four major classes. The GATA factors in soybean exhibited expression diversity among different tissues; some of these factors showed tissue-specific expression patterns. Numerous GATA factors displayed upregulation or downregulation in soybean leaf in response to low nitrogen stress, and two GATA factors GATA44 and GATA58 were likely to be involved in the regulation of nitrogen metabolism in soybean. Overexpression of GmGATA44 complemented the reduced chlorophyll phenotype of the Arabidopsis ortholog AtGATA21 mutant, implying that GmGATA44 played an important role in modulating chlorophyll biosynthesis. Overall, our study provides useful information for the further analysis of the biological functions of GATA factors in soybean and other

  2. Genome-wide identification, classification and expression analysis of the heat shock transcription factor family in Chinese cabbage.

    PubMed

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

    2014-08-01

    The Hsf gene family, one of the most important transcription factor families, plays crucial roles in regulating heat resistance. However, a systematic and comprehensive analysis of this gene family has not been reported in Chinese cabbage. Therefore, systematic analysis of the Hsf gene family in Chinese cabbage has profound significance. In this study, 35 BrHsf genes were identified from Chinese cabbage, which could be classified into three groups according to their structural characteristics and phylogenetic comparisons with Arabidopsis and rice. Thirty-three BrHsf genes mapped on chromosomes were further assigned to three subgenomes and eight ancestral karyotypes. Distribution mapping showed that BrHsf genes were non-randomly localized on chromosomes. Chinese cabbage and Arabidopsis shared 22 orthologous gene pairs. The expansion of BrHsf genes mainly resulted from genome triplication. Comparative analysis showed that the most Hsf genes were in Chinese cabbage among the five species analyzed. Interestingly, the number of Hsf genes of heat-resistant plants (Theobroma cacao and Musa acuminata) was fewer than that in Chinese cabbage. The expression patterns of BrHsf genes were different in six tissues, based on RNA-seq. Quantitative real-time-PCR analysis showed that the expression level of BrHsf genes varied under various abiotic stresses. In conclusion, this comprehensive analysis of BrHsf genes will provide rich resources, aiding the determination of Hsfs functions in plant heat resistance. Furthermore, the comparative genomics analysis deepened our understanding of Hsf genes' evolution accompanied by the polyploidy event of Chinese cabbage. PMID:24609322

  3. Genome-wide analysis of the R2R3-MYB transcription factor gene family in sweet orange (Citrus sinensis).

    PubMed

    Liu, Chaoyang; Wang, Xia; Xu, Yuantao; Deng, Xiuxin; Xu, Qiang

    2014-10-01

    MYB transcription factor represents one of the largest gene families in plant genomes. Sweet orange (Citrus sinensis) is one of the most important fruit crops worldwide, and recently the genome has been sequenced. This provides an opportunity to investigate the organization and evolutionary characteristics of sweet orange MYB genes from whole genome view. In the present study, we identified 100 R2R3-MYB genes in the sweet orange genome. A comprehensive analysis of this gene family was performed, including the phylogeny, gene structure, chromosomal localization and expression pattern analyses. The 100 genes were divided into 29 subfamilies based on the sequence similarity and phylogeny, and the classification was also well supported by the highly conserved exon/intron structures and motif composition. The phylogenomic comparison of MYB gene family among sweet orange and related plant species, Arabidopsis, cacao and papaya suggested the existence of functional divergence during evolution. Expression profiling indicated that sweet orange R2R3-MYB genes exhibited distinct temporal and spatial expression patterns. Our analysis suggested that the sweet orange MYB genes may play important roles in different plant biological processes, some of which may be potentially involved in citrus fruit quality. These results will be useful for future functional analysis of the MYB gene family in sweet orange.

  4. 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. PMID:27499876

  5. Genome-wide identification and transcriptional expression analysis of mitogen-activated protein kinase and mitogen-activated protein kinase kinase genes in Capsicum annuum.

    PubMed

    Liu, Zhiqin; Shi, Lanping; Liu, Yanyan; Tang, Qian; Shen, Lei; Yang, Sheng; Cai, Jinsen; Yu, Huanxin; Wang, Rongzhang; Wen, Jiayu; Lin, Youquan; Hu, Jiong; Liu, Cailing; Zhang, Yangwen; Mou, Shaoliang; He, Shuilin

    2015-01-01

    The tripartite mitogen-activated protein kinase (MAPK) signaling cascades have been implicated in plant growth, development, and environment adaptation, but a comprehensive understanding of MAPK signaling at genome-wide level is limited in Capsicum annuum. Herein, genome-wide identification and transcriptional expression analysis of MAPK and MAPK kinase (MAPKK) were performed in pepper. A total of 19 pepper MAPK (CaMAPKs) genes and five MAPKK (CaMAPKKs) genes were identified. Phylogenetic analysis indicated that CaMAPKs and CaMAPKKs could be classified into four groups and each group contains similar exon-intron structures. However, significant divergences were also found. Notably, five members of the pepper MAPKK family were much less conserved than those found in Arabidopsis, and 9 Arabidopsis MAPKs did not have orthologs in pepper. Additionally, 7 MAPKs in Arabidopsis had either two or three orthologs in the pepper genome, and six pepper MAPKs and one MAPKK differing in sequence were found in three pepper varieties. Quantitative real-time RT-PCR analysis showed that the majority of MAPK and MAPKK genes were ubiquitously expressed and transcriptionally modified in pepper leaves after treatments with heat, salt, and Ralstonia solanacearum inoculation as well as exogenously applied salicylic acid, methyl jasmonate, ethephon, and abscisic acid. The MAPKK-MAPK interactome was tested by yeast two-hybrid assay, the results showed that one MAPKK might interact with multiple MAPKs, one MAPK might also interact with more than one MAPKKs, constituting MAPK signaling networks which may collaborate in transmitting upstream signals into appropriate downstream cellular responses and processes. These results will facilitate future functional characterization of MAPK cascades in pepper. PMID:26442088

  6. Genome-wide identification and transcriptional expression analysis of mitogen-activated protein kinase and mitogen-activated protein kinase kinase genes in Capsicum annuum

    PubMed Central

    Liu, Zhiqin; Shi, Lanping; Liu, Yanyan; Tang, Qian; Shen, Lei; Yang, Sheng; Cai, Jinsen; Yu, Huanxin; Wang, Rongzhang; Wen, Jiayu; Lin, Youquan; Hu, Jiong; Liu, Cailing; Zhang, Yangwen; Mou, Shaoliang; He, Shuilin

    2015-01-01

    The tripartite mitogen-activated protein kinase (MAPK) signaling cascades have been implicated in plant growth, development, and environment adaptation, but a comprehensive understanding of MAPK signaling at genome-wide level is limited in Capsicum annuum. Herein, genome-wide identification and transcriptional expression analysis of MAPK and MAPK kinase (MAPKK) were performed in pepper. A total of 19 pepper MAPK (CaMAPKs) genes and five MAPKK (CaMAPKKs) genes were identified. Phylogenetic analysis indicated that CaMAPKs and CaMAPKKs could be classified into four groups and each group contains similar exon-intron structures. However, significant divergences were also found. Notably, five members of the pepper MAPKK family were much less conserved than those found in Arabidopsis, and 9 Arabidopsis MAPKs did not have orthologs in pepper. Additionally, 7 MAPKs in Arabidopsis had either two or three orthologs in the pepper genome, and six pepper MAPKs and one MAPKK differing in sequence were found in three pepper varieties. Quantitative real-time RT-PCR analysis showed that the majority of MAPK and MAPKK genes were ubiquitously expressed and transcriptionally modified in pepper leaves after treatments with heat, salt, and Ralstonia solanacearum inoculation as well as exogenously applied salicylic acid, methyl jasmonate, ethephon, and abscisic acid. The MAPKK-MAPK interactome was tested by yeast two-hybrid assay, the results showed that one MAPKK might interact with multiple MAPKs, one MAPK might also interact with more than one MAPKKs, constituting MAPK signaling networks which may collaborate in transmitting upstream signals into appropriate downstream cellular responses and processes. These results will facilitate future functional characterization of MAPK cascades in pepper. PMID:26442088

  7. Genome-wide transcription factor binding: beyond direct target regulation.

    PubMed

    MacQuarrie, Kyle L; Fong, Abraham P; Morse, Randall H; Tapscott, Stephen J

    2011-04-01

    The binding of transcription factors to specific DNA target sequences is the fundamental basis of gene regulatory networks. Chromatin immunoprecipitation combined with DNA tiling arrays or high-throughput sequencing (ChIP-chip and ChIP-seq, respectively) has been used in many recent studies that detail the binding sites of various transcription factors. Surprisingly, data from a variety of model organisms and tissues have demonstrated that transcription factors vary greatly in their number of genomic binding sites, and that binding events can significantly exceed the number of known or possible direct gene targets. Thus, current understanding of transcription factor function must expand to encompass what role, if any, binding might have outside of direct transcriptional target regulation. In this review, we discuss the biological significance of genome-wide binding of transcription factors and present models that can account for this phenomenon.

  8. 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

  9. Genome-wide identification, classification, and analysis of heat shock transcription factor family in Chinese cabbage (Brassica rapa pekinensis).

    PubMed

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

    2015-03-27

    Chinese cabbage (Brassica rapa ssp. pekinensis) is one of the most important vegetable crops grown worldwide, and various methods exist for selection, propagation, and cultivation. The entire Chinese cabbage genome has been sequenced, and the heat shock transcription factor family (Hsfs) has been found to play a central role in plant growth and development and in the response to biotic and abiotic stress conditions, particularly in acquired thermotolerance. We analyzed heat tolerance mechanisms in Chinese cabbage. In this study, 30 Hsfs were identified from the Chinese cabbage genome database. The classification, phylogenetic reconstruction, chromosome distribution, conserved motifs, expression analysis, and interaction networks of the Hsfs were predicted and analyzed. Thirty BrHsfs were classified into 3 major classes (class A, B, and C) according to their structural characteristics and phylogenetic comparisons, and class A was further subdivided into 8 subclasses. Distribution mapping results showed that Hsf genes were located on 10 Chinese cabbage chromosomes. The expression profile indicated that Hsfs play differential roles in 5 organs in Chinese cabbage, and likely participate in the development of underground parts and regulation of reproductive growth. An orthologous gene interaction network was constructed, and included MBF1C, ROF1, TBP2, CDC2, and HSP70 5 genes, which are closely related to heat stress. Our results contribute to the understanding of the complexity of Hsfs in Chinese cabbage and provide a basis for further functional gene research.

  10. Genome-wide identification, classification, and analysis of heat shock transcription factor family in Chinese cabbage (Brassica rapa pekinensis).

    PubMed

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

    2015-01-01

    Chinese cabbage (Brassica rapa ssp. pekinensis) is one of the most important vegetable crops grown worldwide, and various methods exist for selection, propagation, and cultivation. The entire Chinese cabbage genome has been sequenced, and the heat shock transcription factor family (Hsfs) has been found to play a central role in plant growth and development and in the response to biotic and abiotic stress conditions, particularly in acquired thermotolerance. We analyzed heat tolerance mechanisms in Chinese cabbage. In this study, 30 Hsfs were identified from the Chinese cabbage genome database. The classification, phylogenetic reconstruction, chromosome distribution, conserved motifs, expression analysis, and interaction networks of the Hsfs were predicted and analyzed. Thirty BrHsfs were classified into 3 major classes (class A, B, and C) according to their structural characteristics and phylogenetic comparisons, and class A was further subdivided into 8 subclasses. Distribution mapping results showed that Hsf genes were located on 10 Chinese cabbage chromosomes. The expression profile indicated that Hsfs play differential roles in 5 organs in Chinese cabbage, and likely participate in the development of underground parts and regulation of reproductive growth. An orthologous gene interaction network was constructed, and included MBF1C, ROF1, TBP2, CDC2, and HSP70 5 genes, which are closely related to heat stress. Our results contribute to the understanding of the complexity of Hsfs in Chinese cabbage and provide a basis for further functional gene research. PMID:25867366

  11. RNA-Seq analysis of stuA mutants in Fusarium verticillioides indicates dramatic genomic wide transcriptional reprogramming

    Technology Transfer Automated Retrieval System (TEKTRAN)

    StuA, first discovered in Aspergillus nidulans and a member of the APSES class of transcription factors, regulates several essential developmental stages in fungi such as virulence, sporulation and toxin production in phytopathogenic fungi. Fusarium verticillioides (Fv), a maize phytopathogen, produ...

  12. ChIP on chip and ChIP-Seq assays: genome-wide analysis of transcription factor binding and histone modifications.

    PubMed

    Pillai, Smitha; Chellappan, Srikumar P

    2015-01-01

    Deregulation of transcriptional activity of many genes has been causatively linked to human diseases including cancer. Altered patterns of gene expression in normal and cancer cells are the result of inappropriate expression of transcription factors and chromatin modifying proteins. Chromatin immunoprecipitation assay is a well-established tool for investigating the interactions between regulatory proteins and DNA at distinct stages of gene activation. ChIP coupled with DNA microarrays, known as ChIP on chip, or sequencing of DNA associated with the factors (ChIP-Seq) allow us to determine the entire spectrum of in vivo DNA binding sites for a given protein. This has been of immense value because ChIP on chip assays and ChIP-Seq experiments can provide a snapshot of the transcriptional regulatory mechanisms on a genome-wide scale. This chapter outlines the general strategies used to carry out ChIP-chip assays to study the differential recruitment of regulatory molecules based on the studies conducted in our lab as well as other published protocols; these can be easily modified to a ChIP-Seq analysis.

  13. Identification of genes associated with nitrogen-use efficiency by genome-wide transcriptional analysis of two soybean genotypes

    PubMed Central

    2011-01-01

    Background Soybean is a valuable crop that provides protein and oil. Soybean requires a large amount of nitrogen (N) to accumulate high levels of N in the seed. The yield and protein content of soybean seeds are directly affected by the N-use efficiency (NUE) of the plant, and improvements in NUE will improve yields and quality of soybean products. Genetic engineering is one of the approaches to improve NUE, but at present, it is hampered by the lack of information on genes associated with NUE. Solexa sequencing is a new method for estimating gene expression in the transcription level. Here, the expression profiles were analyzed between two soybean varieties in N-limited conditions to identify genes related to NUE. Results Two soybean genotypes were grown under N-limited conditions; a low-N-tolerant variety (No.116) and a low-N-sensitive variety (No.84-70). The shoots and roots of soybeans were used for sequencing. Eight libraries were generated for analysis: 2 genotypes × 2 tissues (roots and shoots) × 2 time periods [short-term (0.5 to 12 h) and long-term (3 to 12 d) responses] and compared the transcriptomes by high-throughput tag-sequencing analysis. 5,739,999, 5,846,807, 5,731,901, 5,970,775, 5,476,878, 5,900,343, 5,930,716, and 5,862,642 clean tags were obtained for the eight libraries: L1, 116-shoot short-term; L2 84-70-shoot short-term; L3 116-shoot long-term; L4 84-70-shoot long-term; L5 116-root short-term; L6 84-70-root short-term; L7 116-root long-term;L8 84-70-root long-term; these corresponded to 224,154, 162,415, 191,994, 181,792, 204,639, 206,998, 233,839 and 257,077 distinct tags, respectively. The clean tags were mapped to the reference sequences for annotation of expressed genes. Many genes showed substantial differences in expression among the libraries. In total, 3,231genes involved in twenty-two metabolic and signal transduction pathways were up- or down-regulated. Twenty-four genes were randomly selected and confirmed their expression

  14. Genome-wide in silico identification and analysis of cis natural antisense transcripts (cis-NATs) in ten species

    PubMed Central

    Zhang, Yong; Liu, X. Shirley; Liu, Qing-Rong; Wei, Liping

    2006-01-01

    We developed a fast, integrative pipeline to identify cis natural antisense transcripts (cis-NATs) at genome scale. The pipeline mapped mRNAs and ESTs in UniGene to genome sequences in GoldenPath to find overlapping transcripts and combining information from coding sequence, poly(A) signal, poly(A) tail and splicing sites to deduce transcription orientation. We identified cis-NATs in 10 eukaryotic species, including 7830 candidate sense–antisense (SA) genes in 3915 SA pairs in human. The abundance of SA genes is remarkably low in worm and does not seem to be caused by the prevalence of operons. Hundreds of SA pairs are conserved across different species, even maintaining the same overlapping patterns. The convergent SA class is prevalent in fly, worm and sea squirt, but not in human or mouse as reported previously. The percentage of SA genes among imprinted genes in human and mouse is 24–47%, a range between the two previous reports. There is significant shortage of SA genes on Chromosome X in human and mouse but not in fly or worm, supporting X-inactivation in mammals as a possible cause. SA genes are over-represented in the catalytic activities and basic metabolism functions. All candidate cis-NATs can be downloaded from . PMID:16849434

  15. Genome-wide Expression Analysis and Metabolite Profiling Elucidate Transcriptional Regulation of Flavonoid Biosynthesis and Modulation under Abiotic Stresses in Banana

    PubMed Central

    Pandey, Ashutosh; Alok, Anshu; Lakhwani, Deepika; Singh, Jagdeep; Asif, Mehar H.; Trivedi, Prabodh K.

    2016-01-01

    Flavonoid biosynthesis is largely regulated at the transcriptional level due to the modulated expression of genes related to the phenylpropanoid pathway in plants. Although accumulation of different flavonoids has been reported in banana, a staple fruit crop, no detailed information is available on regulation of the biosynthesis in this important plant. We carried out genome-wide analysis of banana (Musa acuminata, AAA genome) and identified 28 genes belonging to 9 gene families associated with flavonoid biosynthesis. Expression analysis suggested spatial and temporal regulation of the identified genes in different tissues of banana. Analysis revealed enhanced expression of genes related to flavonol and proanthocyanidin (PA) biosynthesis in peel and pulp at the early developmental stages of fruit. Genes involved in anthocyanin biosynthesis were highly expressed during banana fruit ripening. In general, higher accumulation of metabolites was observed in the peel as compared to pulp tissue. A correlation between expression of genes and metabolite content was observed at the early stage of fruit development. Furthermore, this study also suggests regulation of flavonoid biosynthesis, at transcriptional level, under light and dark exposures as well as methyl jasmonate (MJ) treatment in banana. PMID:27539368

  16. Genome-wide Expression Analysis and Metabolite Profiling Elucidate Transcriptional Regulation of Flavonoid Biosynthesis and Modulation under Abiotic Stresses in Banana.

    PubMed

    Pandey, Ashutosh; Alok, Anshu; Lakhwani, Deepika; Singh, Jagdeep; Asif, Mehar H; Trivedi, Prabodh K

    2016-01-01

    Flavonoid biosynthesis is largely regulated at the transcriptional level due to the modulated expression of genes related to the phenylpropanoid pathway in plants. Although accumulation of different flavonoids has been reported in banana, a staple fruit crop, no detailed information is available on regulation of the biosynthesis in this important plant. We carried out genome-wide analysis of banana (Musa acuminata, AAA genome) and identified 28 genes belonging to 9 gene families associated with flavonoid biosynthesis. Expression analysis suggested spatial and temporal regulation of the identified genes in different tissues of banana. Analysis revealed enhanced expression of genes related to flavonol and proanthocyanidin (PA) biosynthesis in peel and pulp at the early developmental stages of fruit. Genes involved in anthocyanin biosynthesis were highly expressed during banana fruit ripening. In general, higher accumulation of metabolites was observed in the peel as compared to pulp tissue. A correlation between expression of genes and metabolite content was observed at the early stage of fruit development. Furthermore, this study also suggests regulation of flavonoid biosynthesis, at transcriptional level, under light and dark exposures as well as methyl jasmonate (MJ) treatment in banana. PMID:27539368

  17. Genome-wide characterization and expression analysis of common bean bHLH transcription factors in response to excess salt concentration.

    PubMed

    Kavas, Musa; Baloğlu, Mehmet Cengiz; Atabay, Elif Seda; Ziplar, Ummugulsum Tanman; Daşgan, Hayriye Yıldız; Ünver, Turgay

    2016-02-01

    Members of basic helix-loop-helix (bHLH) gene family found in all eukaryotes play crucial roles in response to stress. Though, most eukaryotes carry the proteins of this family, biological functions of the most bHLH family members are not deeply evaluated in plants. In this study, we conducted a comprehensive genome-wide analysis of bHLH transcription factors in salt tolerant common bean. We identified 155 bHLH protein-encoding genes (PvbHLH) by using in silico comparative genomics tools. Based on the phylogenetic tree, PvbHLH genes were classified into 8 main groups with 21 subfamilies. Exon-intron analysis indicated that proteins belonging to same main groups exhibited a closely related gene structure. While, the PvbHLH gene family has been mainly expanded through segmental duplications, a total of 11 tandem duplication were detected. Genome-wide expression analysis of bHLH genes showed that 63 PvbHLH genes were differentially expressed in at least one tissue. Three of them displayed higher expression values in both leaf and root tissues. The in silico micro-RNA target transcript analyses revealed that totally 100 PvHLH genes targeted by 86 plant miRNAs. The most abundant transcripts, which were targeted by all 18 plant miRNA, were belonging to PvHLH-22 and PvHLH-44 genes. The expression of 16 PvbHLH genes in the root and leaf tissues of salt-stressed common bean was evaluated using qRT-PCR. Among them, two of PvbHLHs, PvbHLH-54, PvbHLH-148, were found to be up-regulated in both tissues in correlation with RNA-seq measurements. The results of this study could help improve understanding of biological functions of common bean bHLH family under salt stress. Additionally, it may provide basic resources for analyzing bHLH protein function for improving economic, agronomic and ecological benefit in common bean and other species.

  18. Identification of differentially expressed genes associated with flower color in peach using genome-wide transcriptional analysis.

    PubMed

    Zhou, Y; Wu, X X; Zhang, Z; Gao, Z H

    2015-01-01

    Flower color is an important trait of the ornamental peach (Prunus persica L.). However, the mechanism responsible for the different colors that appear in the same genotype remains unclear. In this study, red samples showed higher anthocyanins content (0.122 ± 0.009 mg/g), which was significantly different from that in white samples (0.066 ± 0.010 mg/g). Similarly to carotenoids content, red extract (0.058 ± 0.004 mg/L) was significantly higher in white extract (0.015 ± 0.004 mg/L). We estimated gene expression using Illumina sequencing technology in libraries from white and red flower buds. A total of 3,599,960 and 3,464,141 tags were sequenced from the 2 libraries, respectively. Moreover, we identified 106 significantly differentially expressed genes between the 2 libraries. Among these, 78 and 28 represented transcripts with a higher or lower abundance of more than 2-fold than in the white flower library, respectively. GO annotation indicated that highly ranked genes were involved in the pigment biosynthetic process. Expression patterns of 11 genes were verified using quantitative reverse transcription-polymerase chain reaction assays. The results suggest that hydroxycinnamoyl-coenzyme A shikimate/quinate hydroxycinnamoyltransferase, 2-oxoglutarate-dependent dioxygenase, isoflavone reductase, riboflavin kinase, zeta-carotene desaturase, and ATP binding cassette transporter may be associated with the flower color formation. Our results may be useful for scientists focusing on Prunus persica floral development and biotechnology.

  19. Integrative analysis of SF-1 transcription factor dosage impact on genome-wide binding and gene expression regulation.

    PubMed

    Doghman, Mabrouka; Figueiredo, Bonald C; Volante, Marco; Papotti, Mauro; Lalli, Enzo

    2013-10-01

    Steroidogenic Factor-1 (SF-1) is a nuclear receptor that has a pivotal role in the development of adrenal glands and gonads and in the control of steroid hormone production, being also implicated in the pathogenesis of adrenocortical tumors. We have analyzed the mechanisms how SF-1 controls gene expression in adrenocortical cells and showed that it regulates different categories of genes according to its dosage. Significant correlations exist between the localization of SF-1-binding sites in chromatin under different dosage conditions and dosage-dependent regulation of gene expression. Our study revealed unexpected functional interactions between SF-1 and Neuron-Restrictive Silencer Factor/RE1-Silencing Transcription Factor (NRSF/REST), which was first characterized as a repressor of neuronal gene expression in non-neuronal tissues, in the regulation of gene expression in steroidogenic cells. When overexpressed, SF-1 reshapes the repertoire of NRSF/REST-regulated genes, relieving repression of key steroidogenic genes. These data show that NRSF/REST has a novel function in regulating gene expression in steroidogenic cells and suggest that it may have a broad role in regulating tissue-specific gene expression programs. PMID:23907384

  20. 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.

  1. Genome-wide transcriptional analysis of Drosophila larvae infected by entomopathogenic nematodes shows involvement of complement, recognition and extracellular matrix proteins.

    PubMed

    Arefin, Badrul; Kucerova, Lucie; Dobes, Pavel; Markus, Robert; Strnad, Hynek; Wang, Zhi; Hyrsl, Pavel; Zurovec, Michal; Theopold, Ulrich

    2014-01-01

    Heterorhabditis bacteriophora is an entomopathogenic nematode (EPN) which infects its host by accessing the hemolymph where it releases endosymbiotic bacteria of the species Photorhabdus luminescens. We performed a genome-wide transcriptional analysis of the Drosophila response to EPN infection at the time point at which the nematodes reached the hemolymph either via the cuticle or the gut and the bacteria had started to multiply. Many of the most strongly induced genes have been implicated in immune responses in other infection models. Mapping of the complete set of differentially regulated genes showed the hallmarks of a wound response, but also identified a large fraction of EPN-specific transcripts. Several genes identified by transcriptome profiling or their homologues play protective roles during nematode infections. Genes that positively contribute to controlling nematobacterial infections encode: a homolog of thioester-containing complement protein 3, a basement membrane component (glutactin), a recognition protein (GNBP-like 3) and possibly several small peptides. Of note is that several of these genes have not previously been implicated in immune responses.

  2. Genome-wide identification of MAPKK and MAPKKK gene families in tomato and transcriptional profiling analysis during development and stress response.

    PubMed

    Wu, Jian; Wang, Jie; Pan, Changtian; Guan, Xiaoyan; Wang, Yan; Liu, Songyu; He, Yanjun; Chen, Jingli; Chen, Lifei; Lu, Gang

    2014-01-01

    Mitogen-activated protein kinase (MAPK) cascades have important functions in plant growth, development, and response to various stresses. The MAPKK and MAPKKK gene families in tomato have never been systematically analyzed. In this study, we performed a genome-wide analysis of the MAPKK and MAPKKK gene families in tomato and identified 5 MAPKK genes and 89 MAPKKK genes. Phylogenetic analyses of the MAPKK and MAPKKK gene families showed that all the MAPKK genes formed four groups (groups A, B, C, and D), whereas all the MAPKKK genes were classified into three subfamilies, namely, MEKK, RAF, and ZIK. Evolutionary analysis showed that whole genome or chromosomal segment duplications were the main factors responsible for the expansion of the MAPKK and MAPKKK gene families in tomato. Quantitative real-time RT-PCR analysis showed that the majority of MAPKK and MAPKKK genes were expressed in all tested organs with considerable differences in transcript levels indicating that they might be constitutively expressed. However, the expression level of most of these genes changed significantly under heat, cold, drought, salt, and Pseudomonas syringae treatment. Furthermore, their expression levels exhibited significant changes in response to salicylic acid and indole-3-acetic acid treatment, implying that these genes might have important roles in the plant hormone network. Our comparative analysis of the MAPKK and MAPKKK families would improve our understanding of the evolution and functional characterization of MAPK cascades in tomato.

  3. Design and bioinformatics analysis of genome-wide CLIP experiments

    PubMed Central

    Wang, Tao; Xiao, Guanghua; Chu, Yongjun; Zhang, Michael Q.; Corey, David R.; Xie, Yang

    2015-01-01

    The past decades have witnessed a surge of discoveries revealing RNA regulation as a central player in cellular processes. RNAs are regulated by RNA-binding proteins (RBPs) at all post-transcriptional stages, including splicing, transportation, stabilization and translation. Defects in the functions of these RBPs underlie a broad spectrum of human pathologies. Systematic identification of RBP functional targets is among the key biomedical research questions and provides a new direction for drug discovery. The advent of cross-linking immunoprecipitation coupled with high-throughput sequencing (genome-wide CLIP) technology has recently enabled the investigation of genome-wide RBP–RNA binding at single base-pair resolution. This technology has evolved through the development of three distinct versions: HITS-CLIP, PAR-CLIP and iCLIP. Meanwhile, numerous bioinformatics pipelines for handling the genome-wide CLIP data have also been developed. In this review, we discuss the genome-wide CLIP technology and focus on bioinformatics analysis. Specifically, we compare the strengths and weaknesses, as well as the scopes, of various bioinformatics tools. To assist readers in choosing optimal procedures for their analysis, we also review experimental design and procedures that affect bioinformatics analyses. PMID:25958398

  4. Genome Wide Analysis of the Apple MYB Transcription Factor Family Allows the Identification of MdoMYB121 Gene Confering Abiotic Stress Tolerance in Plants

    PubMed Central

    Wang, Rong-Kai; Zhang, Rui-Fen; Hao, Yu-Jin

    2013-01-01

    The MYB proteins comprise one of the largest families of transcription factors (TFs) in plants. Although several MYB genes have been characterized to play roles in secondary metabolism, the MYB family has not yet been identified in apple. In this study, 229 apple MYB genes were identified through a genome-wide analysis and divided into 45 subgroups. A computational analysis was conducted using the apple genomic database to yield a complete overview of the MYB family, including the intron-exon organizations, the sequence features of the MYB DNA-binding domains, the carboxy-terminal motifs, and the chromosomal locations. Subsequently, the expression of 18 MYB genes, including 12 were chosen from stress-related subgroups, while another 6 ones from other subgroups, in response to various abiotic stresses was examined. It was found that several of these MYB genes, particularly MdoMYB121, were induced by multiple stresses. The MdoMYB121 was then further functionally characterized. Its predicted protein was found to be localized in the nucleus. A transgenic analysis indicated that the overexpression of the MdoMYB121 gene remarkably enhanced the tolerance to high salinity, drought, and cold stresses in transgenic tomato and apple plants. Our results indicate that the MYB genes are highly conserved in plant species and that MdoMYB121 can be used as a target gene in genetic engineering approaches to improve the tolerance of plants to multiple abiotic stresses. PMID:23950843

  5. 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

  6. Genome-wide analysis correlates Ayurveda Prakriti.

    PubMed

    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

    2015-10-29

    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 10(6) 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.

  7. Heterosis in early maize ear inflorescence development: a genome-wide transcription analysis for two maize inbred lines and their hybrid.

    PubMed

    Ding, Haiping; Qin, Cheng; Luo, Xirong; Li, Lujiang; Chen, Zhe; Liu, Hongjun; Gao, Jian; Lin, Haijian; Shen, Yaou; Zhao, Maojun; Lübberstedt, Thomas; Zhang, Zhiming; Pan, Guangtang

    2014-08-11

    Heterosis, or hybrid vigor, contributes to superior agronomic performance of hybrids compared to their inbred parents. Despite its importance, little is known about the genetic and molecular basis of heterosis. Early maize ear inflorescences formation affects grain yield, and are thus an excellent model for molecular mechanisms involved in heterosis. To determine the parental contributions and their regulation during maize ear-development-genesis, we analyzed genome-wide digital gene expression profiles in two maize elite inbred lines (B73 and Mo17) and their F1 hybrid using deep sequencing technology. Our analysis revealed 17,128 genes expressed in these three genotypes and 22,789 genes expressed collectively in the present study. Approximately 38% of the genes were differentially expressed in early maize ear inflorescences from heterotic cross, including many transcription factor genes and some presence/absence variations (PAVs) genes, and exhibited multiple modes of gene action. These different genes showing differential expression patterns were mainly enriched in five cellular component categories (organelle, cell, cell part, organelle part and macromolecular complex), five molecular function categories (structural molecule activity, binding, transporter activity, nucleic acid binding transcription factor activity and catalytic activity), and eight biological process categories (cellular process, metabolic process, biological regulation, regulation of biological process, establishment of localization, cellular component organization or biogenesis, response to stimulus and localization). Additionally, a significant number of genes were expressed in only one inbred line or absent in both inbred lines. Comparison of the differences of modes of gene action between previous studies and the present study revealed only a small number of different genes had the same modes of gene action in both maize seedlings and ear inflorescences. This might be an indication that in

  8. Heterosis in Early Maize Ear Inflorescence Development: A Genome-Wide Transcription Analysis for Two Maize Inbred Lines and Their Hybrid

    PubMed Central

    Ding, Haiping; Qin, Cheng; Luo, Xirong; Li, Lujiang; Chen, Zhe; Liu, Hongjun; Gao, Jian; Lin, Haijian; Shen, Yaou; Zhao, Maojun; Lübberstedt, Thomas; Zhang, Zhiming; Pan, Guangtang

    2014-01-01

    Heterosis, or hybrid vigor, contributes to superior agronomic performance of hybrids compared to their inbred parents. Despite its importance, little is known about the genetic and molecular basis of heterosis. Early maize ear inflorescences formation affects grain yield, and are thus an excellent model for molecular mechanisms involved in heterosis. To determine the parental contributions and their regulation during maize ear-development-genesis, we analyzed genome-wide digital gene expression profiles in two maize elite inbred lines (B73 and Mo17) and their F1 hybrid using deep sequencing technology. Our analysis revealed 17,128 genes expressed in these three genotypes and 22,789 genes expressed collectively in the present study. Approximately 38% of the genes were differentially expressed in early maize ear inflorescences from heterotic cross, including many transcription factor genes and some presence/absence variations (PAVs) genes, and exhibited multiple modes of gene action. These different genes showing differential expression patterns were mainly enriched in five cellular component categories (organelle, cell, cell part, organelle part and macromolecular complex), five molecular function categories (structural molecule activity, binding, transporter activity, nucleic acid binding transcription factor activity and catalytic activity), and eight biological process categories (cellular process, metabolic process, biological regulation, regulation of biological process, establishment of localization, cellular component organization or biogenesis, response to stimulus and localization). Additionally, a significant number of genes were expressed in only one inbred line or absent in both inbred lines. Comparison of the differences of modes of gene action between previous studies and the present study revealed only a small number of different genes had the same modes of gene action in both maize seedlings and ear inflorescences. This might be an indication that in

  9. Genome-wide analysis and identification of stress-responsive genes of the NAM-ATAF1,2-CUC2 transcription factor family in apple.

    PubMed

    Su, Hongyan; Zhang, Shizhong; Yuan, Xiaowei; Chen, Changtian; Wang, Xiao-Fei; Hao, Yu-Jin

    2013-10-01

    NAC (NAM, ATAF1,2, and CUC2) proteins constitute one of the largest families of plant-specific transcription factors. To date, little is known about the NAC genes in the apple (Malus domestica). In this study, a total of 180 NAC genes were identified in the apple genome and were phylogenetically clustered into six groups (I-VI) with the NAC genes from Arabidopsis and rice. The predicted apple NAC genes were distributed across all of 17 chromosomes at various densities. Additionally, the gene structure and motif compositions of the apple NAC genes were analyzed. Moreover, the expression of 29 selected apple NAC genes was analyzed in different tissues and under different abiotic stress conditions. All of the selected genes, with the exception of four genes, were expressed in at least one of the tissues tested, which indicates that the NAC genes are involved in various aspects of the physiological and developmental processes of the apple. Encouragingly, 17 of the selected genes were found to respond to one or more of the abiotic stress treatments, and these 17 genes included not only the expected 7 genes that were clustered with the well-known stress-related marker genes in group IV but also 10 genes located in other subgroups, none of which contains members that have been reported to be stress-related. To the best of our knowledge, this report describes the first genome-wide analysis of the apple NAC gene family, and the results should provide valuable information for understanding the classification and putative functions of this family.

  10. Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution.

    PubMed

    Hu, Jinchuan; Adar, Sheera; Selby, Christopher P; Lieb, Jason D; Sancar, Aziz

    2015-05-01

    We developed a method for genome-wide mapping of DNA excision repair named XR-seq (excision repair sequencing). Human nucleotide excision repair generates two incisions surrounding the site of damage, creating an ∼30-mer. In XR-seq, this fragment is isolated and subjected to high-throughput sequencing. We used XR-seq to produce stranded, nucleotide-resolution maps of repair of two UV-induced DNA damages in human cells: cyclobutane pyrimidine dimers (CPDs) and (6-4) pyrimidine-pyrimidone photoproducts [(6-4)PPs]. In wild-type cells, CPD repair was highly associated with transcription, specifically with the template strand. Experiments in cells defective in either transcription-coupled excision repair or general excision repair isolated the contribution of each pathway to the overall repair pattern and showed that transcription-coupled repair of both photoproducts occurs exclusively on the template strand. XR-seq maps capture transcription-coupled repair at sites of divergent gene promoters and bidirectional enhancer RNA (eRNA) production at enhancers. XR-seq data also uncovered the repair characteristics and novel sequence preferences of CPDs and (6-4)PPs. XR-seq and the resulting repair maps will facilitate studies of the effects of genomic location, chromatin context, transcription, and replication on DNA repair in human cells.

  11. Genome-wide analysis of DNA methylation in hepatoblastoma tissues

    PubMed Central

    Cui, Ximao; Liu, Baihui; Zheng, Shan; Dong, Kuiran; Dong, Rui

    2016-01-01

    DNA methylation has a crucial role in cancer biology. In the present study, a genome-wide analysis of DNA methylation in hepatoblastoma (HB) tissues was performed to verify differential methylation levels between HB and normal tissues. As alpha-fetoprotein (AFP) has a critical role in HB, AFP methylation levels were also detected using pyrosequencing. Normal and HB liver tissue samples (frozen tissue) were obtained from patients with HB. Genome-wide analysis of DNA methylation in these tissues was performed using an Infinium HumanMethylation450 BeadChip, and the results were confirmed with reverse transcription-quantitative polymerase chain reaction. The Infinium HumanMethylation450 BeadChip demonstrated distinctively less methylation in HB tissues than in non-tumor tissues. In addition, methylation enrichment was observed in positions near the transcription start site of AFP, which exhibited lower methylation levels in HB tissues than in non-tumor liver tissues. Lastly, a significant negative correlation was observed between AFP messenger RNA expression and DNA methylation percentage, using linear Pearson's R correlation coefficients. The present results demonstrate differential methylation levels between HB and normal tissues, and imply that aberrant methylation of AFP in HB could reflect HB development. Expansion of these findings could provide useful insight into HB biology. PMID:27446465

  12. Genome-wide characterization and comparative analysis of R2R3-MYB transcription factors shows the complexity of MYB-associated regulatory networks in Salvia miltiorrhiza

    PubMed Central

    2014-01-01

    Background MYB is the largest plant transcription factor gene family playing vital roles in plant growth and development. However, it has not been systematically studied in Salvia miltiorrhiza, an economically important medicinal plant. Results Here we report the genome-wide identification and characterization of 110 R2R3-MYBs, the largest subfamily of MYBs in S. miltiorrhiza. The MYB domain and other motifs of SmMYBs are largely conserved with Arabidopsis AtMYBs, whereas the divergence of SmMYBs and AtMYBs also exists, suggesting the conservation and diversity of plant MYBs. SmMYBs and AtMYBs may be classified into 37 subgroups, of which 31 include proteins from S. miltiorrhiza and Arabidopsis, whereas 6 are specific to a species, indicating that the majority of MYBs play conserved roles, while others may exhibit species-specialized functions. SmMYBs are differentially expressed in various tissues of S. miltiorrhiza. The expression profiles are largely consistent with known functions of their Arabidopsis counterparts. The expression of a subset of SmMYBs is regulated by microRNAs, such as miR159, miR319, miR828 and miR858. Based on functional conservation of MYBs in a subgroup, SmMYBs potentially involved in the biosynthesis of bioactive compounds were identified. Conclusions A total of 110 R2R3-MYBs were identified and analyzed. The results suggest the complexity of MYB-mediated regulatory networks in S. miltiorrhiza and provide a foundation for understanding the regulatory mechanism of SmMYBs. PMID:24725266

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. Genome-Wide Epigenetic Regulation of Gene Transcription in Maize Seeds

    PubMed Central

    Chai, Zhenguang; Guo, Wenzhu; Chen, Rumei; Wang, Lei; Zhao, Jun; Lang, Zhihong; Fan, Yunliu; Zhao, Jiuran; Zhang, Chunyi

    2015-01-01

    Background Epigenetic regulation is well recognized for its importance in gene expression in organisms. DNA methylation, an important epigenetic mark, has received enormous attention in recent years as it’s a key player in many biological processes. It remains unclear how DNA methylation contributes to gene transcription regulation in maize seeds. Here, we take advantage of recent technologies to examine the genome-wide association of DNA methylation with transcription of four types of DNA sequences, including protein-coding genes, pseudogenes, transposable elements, and repeats in maize embryo and endosperm, respectively. Results The methylation in CG, CHG and CHH contexts plays different roles in the control of gene expression. Methylation around the transcription start sites and transcription stop regions of protein-coding genes is negatively correlated, but in gene bodies positively correlated, to gene expression level. The upstream regions of protein-coding genes are enriched with 24-nt siRNAs and contain high levels of CHH methylation, which is correlated to gene expression level. The analysis of sequence content within CG, CHG, or CHH contexts reveals that only CHH methylation is affected by its local sequences, which is different from Arabidopsis. Conclusions In summary, we conclude that methylation-regulated transcription varies with the types of DNA sequences, sequence contexts or parts of a specific gene in maize seeds and differs from that in other plant species. Our study helps people better understand from a genome-wide viewpoint that how transcriptional expression is controlled by DNA methylation, one of the important factors influencing transcription, and how the methylation is associated with small RNAs. PMID:26469520

  18. Genome-wide transcriptome analysis of 150 cell samples.

    PubMed

    Irimia, Daniel; Mindrinos, Michael; Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G; Davis, Ronald W; Toner, Mehmet

    2009-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples.

  19. Genome-wide transcriptome analysis of 150 cell samples†

    PubMed Central

    Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G.; Davis, Ronald W.; Toner, Mehmet

    2013-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples. PMID:20023796

  20. 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.

  1. Massively expedited genome-wide heritability analysis (MEGHA).

    PubMed

    Ge, Tian; Nichols, Thomas E; Lee, Phil H; Holmes, Avram J; Roffman, Joshua L; Buckner, Randy L; Sabuncu, Mert R; Smoller, Jordan W

    2015-02-24

    The discovery and prioritization of heritable phenotypes is a computational challenge in a variety of settings, including neuroimaging genetics and analyses of the vast phenotypic repositories in electronic health record systems and population-based biobanks. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Genome-wide complex trait analysis is an alternative tool to compute heritability estimates from unrelated individuals, using genome-wide data that are increasingly ubiquitous, but is computationally demanding and becomes difficult to apply in evaluating very large numbers of phenotypes. Here we present a fast and accurate statistical method for high-dimensional heritability analysis using genome-wide SNP data from unrelated individuals, termed massively expedited genome-wide heritability analysis (MEGHA) and accompanying nonparametric sampling techniques that enable flexible inferences for arbitrary statistics of interest. MEGHA produces estimates and significance measures of heritability with several orders of magnitude less computational time than existing methods, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. As a demonstration of application, we conducted heritability analyses on global and local morphometric measurements derived from brain structural MRI scans, using genome-wide SNP data from 1,320 unrelated young healthy adults of non-Hispanic European ancestry. We also computed surface maps of heritability for cortical thickness measures and empirically localized cortical regions where thickness measures were significantly heritable. Our analyses demonstrate the unique capability of MEGHA for large-scale heritability-based screening and high-dimensional heritability profile construction.

  2. Genome-Wide Transcriptional Profiling and Metabolic Analysis Uncover Multiple Molecular Responses of the Grass Species Lolium perenne Under Low-Intensity Xenobiotic Stress

    PubMed Central

    Serra, Anne-Antonella; Couée, Ivan; Heijnen, David; Michon-Coudouel, Sophie; Sulmon, Cécile; Gouesbet, Gwenola

    2015-01-01

    Lolium perenne, which is a major component of pastures, lawns, and grass strips, can be exposed to xenobiotic stresses due to diffuse and residual contaminations of soil. L. perenne was recently shown to undergo metabolic adjustments in response to sub-toxic levels of xenobiotics. To gain insight in such chemical stress responses, a de novo transcriptome analysis was carried out on leaves from plants subjected at the root level to low levels of xenobiotics, glyphosate, tebuconazole, and a combination of the two, leading to no adverse physiological effect. Chemical treatments influenced significantly the relative proportions of functional categories and of transcripts related to carbohydrate processes, to signaling, to protein-kinase cascades, such as Serine/Threonine-protein kinases, to transcriptional regulations, to responses to abiotic or biotic stimuli and to responses to phytohormones. Transcriptomics-based expressions of genes encoding different types of SNF1 (sucrose non-fermenting 1)-related kinases involved in sugar and stress signaling or encoding key metabolic enzymes were in line with specific qRT-PCR analysis or with the important metabolic and regulatory changes revealed by metabolomic analysis. The effects of pesticide treatments on metabolites and gene expression strongly suggest that pesticides at low levels, as single molecule or as mixture, affect cell signaling and functioning even in the absence of major physiological impact. This global analysis of L. perenne therefore highlighted the interactions between molecular regulation of responses to xenobiotics, and also carbohydrate dynamics, energy dysfunction, phytohormones and calcium signaling. PMID:26734031

  3. NAC transcription factor genes: genome-wide identification, phylogenetic, motif and cis-regulatory element analysis in pigeonpea (Cajanus cajan (L.) Millsp.).

    PubMed

    Satheesh, Viswanathan; Jagannadham, P Tej Kumar; Chidambaranathan, Parameswaran; Jain, P K; Srinivasan, R

    2014-12-01

    The NAC (NAM, ATAF and CUC) proteins are plant-specific transcription factors implicated in development and stress responses. In the present study 88 pigeonpea NAC genes were identified from the recently published draft genome of pigeonpea by using homology based and de novo prediction programmes. These sequences were further subjected to phylogenetic, motif and promoter analyses. In motif analysis, highly conserved motifs were identified in the NAC domain and also in the C-terminal region of the NAC proteins. A phylogenetic reconstruction using pigeonpea, Arabidopsis and soybean NAC genes revealed 33 putative stress-responsive pigeonpea NAC genes. Several stress-responsive cis-elements were identified through in silico analysis of the promoters of these putative stress-responsive genes. This analysis is the first report of NAC gene family in pigeonpea and will be useful for the identification and selection of candidate genes associated with stress tolerance. PMID:25108674

  4. 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.

  5. 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. PMID:25971861

  6. Genome-Wide Classification and Evolutionary Analysis of the bHLH Family of Transcription Factors in Arabidopsis, Poplar, Rice, Moss, and Algae1[W

    PubMed Central

    Carretero-Paulet, Lorenzo; Galstyan, Anahit; Roig-Villanova, Irma; Martínez-García, Jaime F.; Bilbao-Castro, Jose R.; Robertson, David L.

    2010-01-01

    Basic helix-loop-helix proteins (bHLHs) are found throughout the three eukaryotic kingdoms and constitute one of the largest families of transcription factors. A growing number of bHLH proteins have been functionally characterized in plants. However, some of these have not been previously classified. We present here an updated and comprehensive classification of the bHLHs encoded by the whole sequenced genomes of Arabidopsis (Arabidopsis thaliana), Populus trichocarpa, Oryza sativa, Physcomitrella patens, and five algae species. We define a plant bHLH consensus motif, which allowed the identification of novel highly diverged atypical bHLHs. Using yeast two-hybrid assays, we confirm that (1) a highly diverged bHLH has retained protein interaction activity and (2) the two most conserved positions in the consensus play an essential role in dimerization. Phylogenetic analysis permitted classification of the 638 bHLH genes identified into 32 subfamilies. Evolutionary and functional relationships within subfamilies are supported by intron patterns, predicted DNA-binding motifs, and the architecture of conserved protein motifs. Our analyses reveal the origin and evolutionary diversification of plant bHLHs through differential expansions, domain shuffling, and extensive sequence divergence. At the functional level, this would translate into different subfamilies evolving specific DNA-binding and protein interaction activities as well as differential transcriptional regulatory roles. Our results suggest a role for bHLH proteins in generating plant phenotypic diversity and provide a solid framework for further investigations into the role carried out in the transcriptional regulation of key growth and developmental processes. PMID:20472752

  7. Genome-wide transcription responses to synchrotron microbeam radiotherapy.

    PubMed

    Sprung, Carl N; Yang, Yuqing; Forrester, Helen B; Li, Jason; Zaitseva, Marina; Cann, Leonie; Restall, Tina; Anderson, Robin L; Crosbie, Jeffrey C; Rogers, Peter A W

    2012-10-01

    The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4-48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam.

  8. Genome-wide transcription responses to synchrotron microbeam radiotherapy.

    PubMed

    Sprung, Carl N; Yang, Yuqing; Forrester, Helen B; Li, Jason; Zaitseva, Marina; Cann, Leonie; Restall, Tina; Anderson, Robin L; Crosbie, Jeffrey C; Rogers, Peter A W

    2012-10-01

    The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4-48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam. PMID:22974124

  9. Genome-wide identification and characterization of WRKY transcriptional factor family in apple and analysis of their responses to waterlogging and drought stress.

    PubMed

    Meng, Dong; Li, Yuanyuan; Bai, Yang; Li, Mingjun; Cheng, Lailiang

    2016-06-01

    As one of the largest transcriptional factor families in plants, WRKY genes play significant roles in various biotic and abiotic stress responses. Although the WRKY gene family has been characterized in a few plant species, the details remain largely unknown in the apple (Malus domestica Borkh.). In this study, we identified a total of 127 MdWRKYs from the apple genome, which were divided into four subgroups according to the WRKY domains and zinc finger motif. Most of them were mapped onto the apple's 17 chromosomes and were expressed in more than one tissue, including shoot tips, mature leaves, fruit and apple calli. We then contrasted WRKY expression patterns between calli grown in solid medium (control) and liquid medium (representing waterlogging stress) and found that 34 WRKY genes were differentially expressed between the two growing conditions. Finally, we determined the expression patterns of 10 selected WRKY genes in an apple rootstock, G41, in response to waterlogging and drought stress, which identified candidate genes involved in responses to water stress for functional analysis. Our data provide interesting candidate MdWRKYs for future functional analysis and demonstrate that apple callus is a useful system for characterizing gene expression and function in apple. PMID:26970718

  10. Genome wide copy number analysis of single cells

    PubMed Central

    Baslan, Timour; Kendall, Jude; Rodgers, Linda; Cox, Hilary; Riggs, Mike; Stepansky, Asya; Troge, Jennifer; Ravi, Kandasamy; Esposito, Diane; Lakshmi, B.; Wigler, Michael; Navin, Nicholas; Hicks, James

    2016-01-01

    Summary Copy number variation (CNV) is increasingly recognized as an important contributor to phenotypic variation in health and disease. Most methods for determining CNV rely on admixtures of cells, where information regarding genetic heterogeneity is lost. Here, we present a protocol that allows for the genome wide copy number analysis of single nuclei isolated from mixed populations of cells. Single nucleus sequencing (SNS), combines flow sorting of single nuclei based on DNA content, whole genome amplification (WGA), followed by next generation sequencing to quantize genomic intervals in a genome wide manner. Multiplexing of single cells is discussed. Additionally, we outline informatic approaches that correct for biases inherent in the WGA procedure and allow for accurate determination of copy number profiles. All together, the protocol takes ~3 days from flow cytometry to sequence-ready DNA libraries. PMID:22555242

  11. Genome-Wide Analysis of the AP2/ERF Transcription Factors Family and the Expression Patterns of DREB Genes in Moso Bamboo (Phyllostachys edulis).

    PubMed

    Wu, Huili; Lv, Hao; Li, Long; Liu, Jun; Mu, Shaohua; Li, Xueping; Gao, Jian

    2015-01-01

    The AP2/ERF transcription factor family, one of the largest families unique to plants, performs a significant role in terms of regulation of growth and development, and responses to biotic and abiotic stresses. Moso bamboo (Phyllostachys edulis) is a fast-growing non-timber forest species with the highest ecological, economic and social values of all bamboos in Asia. The draft genome of moso bamboo and the available genomes of other plants provide great opportunities to research global information on the AP2/ERF family in moso bamboo. In total, 116 AP2/ERF transcription factors were identified in moso bamboo. The phylogeny analyses indicated that the 116 AP2/ERF genes could be divided into three subfamilies: AP2, RAV and ERF; and the ERF subfamily genes were divided into 11 groups. The gene structures, exons/introns and conserved motifs of the PeAP2/ERF genes were analyzed. Analysis of the evolutionary patterns and divergence showed the PeAP2/ERF genes underwent a large-scale event around 15 million years ago (MYA) and the division time of AP2/ERF family genes between rice and moso bamboo was 15-23 MYA. We surveyed the putative promoter regions of the PeDREBs and showed that largely stress-related cis-elements existed in these genes. Further analysis of expression patterns of PeDREBs revealed that the most were strongly induced by drought, low-temperature and/or high salinity stresses in roots and, in contrast, most PeDREB genes had negative functions in leaves under the same respective stresses. In this study there were two main interesting points: there were fewer members of the PeDREB subfamily in moso bamboo than in other plants and there were differences in DREB gene expression profiles between leaves and roots triggered in response to abiotic stress. The information produced from this study may be valuable in overcoming challenges in cultivating moso bamboo. PMID:25985202

  12. Genome-Wide Analysis of the AP2/ERF Transcription Factors Family and the Expression Patterns of DREB Genes in Moso Bamboo (Phyllostachys edulis)

    PubMed Central

    Li, Long; Liu, Jun; Mu, Shaohua; Li, Xueping; Gao, Jian

    2015-01-01

    The AP2/ERF transcription factor family, one of the largest families unique to plants, performs a significant role in terms of regulation of growth and development, and responses to biotic and abiotic stresses. Moso bamboo (Phyllostachys edulis) is a fast-growing non-timber forest species with the highest ecological, economic and social values of all bamboos in Asia. The draft genome of moso bamboo and the available genomes of other plants provide great opportunities to research global information on the AP2/ERF family in moso bamboo. In total, 116 AP2/ERF transcription factors were identified in moso bamboo. The phylogeny analyses indicated that the 116 AP2/ERF genes could be divided into three subfamilies: AP2, RAV and ERF; and the ERF subfamily genes were divided into 11 groups. The gene structures, exons/introns and conserved motifs of the PeAP2/ERF genes were analyzed. Analysis of the evolutionary patterns and divergence showed the PeAP2/ERF genes underwent a large-scale event around 15 million years ago (MYA) and the division time of AP2/ERF family genes between rice and moso bamboo was 15–23 MYA. We surveyed the putative promoter regions of the PeDREBs and showed that largely stress-related cis-elements existed in these genes. Further analysis of expression patterns of PeDREBs revealed that the most were strongly induced by drought, low-temperature and/or high salinity stresses in roots and, in contrast, most PeDREB genes had negative functions in leaves under the same respective stresses. In this study there were two main interesting points: there were fewer members of the PeDREB subfamily in moso bamboo than in other plants and there were differences in DREB gene expression profiles between leaves and roots triggered in response to abiotic stress. The information produced from this study may be valuable in overcoming challenges in cultivating moso bamboo. PMID:25985202

  13. Genome-wide analysis of the H-NS and Sfh regulatory networks in Salmonella Typhimurium identifies a plasmid-encoded transcription silencing mechanism.

    PubMed

    Dillon, Shane C; Cameron, Andrew D S; Hokamp, Karsten; Lucchini, Sacha; Hinton, Jay C D; Dorman, Charles J

    2010-06-01

    The conjugative IncHI1 plasmid pSfR27 from Shigella flexneri 2a strain 2457T encodes the Sfh protein, a paralogue of the global transcriptional repressor H-NS. Sfh allows pSfR27 to be transmitted to new bacterial hosts with minimal impact on host fitness, providing a 'stealth' function whose molecular mechanism has yet to be determined. The impact of the Sfh protein on the Salmonella enterica serovar Typhimurium transcriptome was assessed and binding sites for Sfh in the Salmonella Typhimurium genome were identified by chromatin immunoprecipitation. Sfh did not bind uniquely to any sites. Instead, it bound to a subset of the larger H-NS regulatory network. Analysis of Sfh binding in the absence of H-NS revealed a greatly expanded population of Sfh binding sites that included the majority of H-NS target genes. Furthermore, the presence of plasmid pSfR27 caused a decrease in H-NS interactions with the S. Typhimurium chromosome, suggesting that the A + T-rich DNA of this large plasmid acts to titrate H-NS, removing it from chromosomal locations. It is proposed that Sfh acts as a molecular backup for H-NS and that it provides its 'stealth' function by replacing H-NS on the chromosome, thus minimizing disturbances to the H-NS-DNA binding pattern in cells that acquire pSfR27.

  14. Genome-wide analysis of gene expression reveals function of the bZIP transcription factor HY5 in the UV-B response of Arabidopsis.

    PubMed

    Ulm, Roman; Baumann, Alexander; Oravecz, Attila; Máté, Zoltán; Adám, Eva; Oakeley, Edward J; Schäfer, Eberhard; Nagy, Ferenc

    2004-02-01

    The light environment is a key factor that governs a multitude of developmental processes during the entire life cycle of plants. An important and increasing part of the incident sunlight encompasses a segment of the UV-B region (280-320 nm) that is not entirely absorbed by the ozone layer in the stratosphere of the earth. This portion of the solar radiation, which inevitably reaches the sessile plants, can act both as an environmental stress factor and an informational signal. To identify Arabidopsis genes involved in the UV response, we monitored the gene expression profile of UV-B-irradiated seedlings by using high-density oligonucleotide microarrays comprising almost the full Arabidopsis genome (>24,000 genes). A robust set of early low-level UV-B-responsive genes, 100 activated and 7 repressed, was identified. In all cases analyzed, UV-B induction was found to be independent of known photoreceptors. This group of genes is suggested to represent the molecular readout of the signaling cascade triggered by the elusive UV-B photoreceptor(s). Moreover, our analysis identified interactions between cellular responses to different UV-B ranges that led us to postulate the presence of partially distinct but interacting UV-B perception and signaling mechanisms. Finally, we demonstrate that the bZIP transcription factor HY5 is required for UV-B-mediated regulation of a subset of genes.

  15. Where to begin? Mapping transcription start sites genome-wide in Escherichia coli.

    PubMed

    Wade, Joseph T

    2015-01-01

    Recent genome-wide studies of bacterial transcription have revealed large numbers of promoters located inside genes. In this issue of the Journal of Bacteriology, Thomason and colleagues (J. Bacteriol. 197:18-28, 2015, doi:10.1128/JB.02096-14) map transcription start sites in Escherichia coli on an unprecedented scale. This work provides important insights into the regulation of transcripts that initiate inside genes and sources of variability between studies aimed at identifying these RNAs.

  16. The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: genome-wide transcriptional analysis

    PubMed Central

    2014-01-01

    Background The nootropic neuroprotective peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) has proved efficient in the therapy of brain stroke; however, the molecular mechanisms underlying its action remain obscure. Our genome-wide study was designed to investigate the response of the transcriptome of ischemized rat brain cortex tissues to the action of Semax in vivo. Results The gene-expression alteration caused by the action of the peptide Semax was compared with the gene expression of the “ischemia” group animals at 3 and 24 h after permanent middle cerebral artery occlusion (pMCAO). The peptide predominantly enhanced the expression of genes related to the immune system. Three hours after pMCAO, Semax influenced the expression of some genes that affect the activity of immune cells, and, 24 h after pMCAO, the action of Semax on the immune response increased considerably. The genes implicated in this response represented over 50% of the total number of genes that exhibited Semax-induced altered expression. Among the immune-response genes, the expression of which was modulated by Semax, genes that encode immunoglobulins and chemokines formed the most notable groups. In response to Semax administration, 24 genes related to the vascular system exhibited altered expression 3 h after pMCAO, whereas 12 genes were changed 24 h after pMCAO. These genes are associated with such processes as the development and migration of endothelial tissue, the migration of smooth muscle cells, hematopoiesis, and vasculogenesis. Conclusions Semax affects several biological processes involved in the function of various systems. The immune response is the process most markedly affected by the drug. Semax altered the expression of genes that modulate the amount and mobility of immune cells and enhanced the expression of genes that encode chemokines and immunoglobulins. In conditions of rat brain focal ischemia, Semax influenced the expression of genes that promote the formation and

  17. Genome-Wide Transcriptional Changes in Streptococcus gordonii in Response to Competence Signaling Peptide▿ †

    PubMed Central

    Vickerman, M. M.; Iobst, S.; Jesionowski, A. M.; Gill, S. R.

    2007-01-01

    Streptococcus gordonii is a primary colonizer of the multispecies biofilm on tooth surfaces forming dental plaque and a potential agent of endocarditis. The recent completion of the genome sequence of the naturally competent strain Challis allowed the design of a spotted oligonucleotide microarray to examine a genome-wide response of this organism to environmental stimuli such as signal peptides. Based on temporal responses to synthetic competence signaling peptide (CSP) as indicated by transformation frequencies, the S. gordonii transcriptome was analyzed at various time points after CSP exposure. Microarray analysis identified 35 candidate early genes and 127 candidate late genes that were up-regulated at 5 and 15 min, respectively; these genes were often grouped in clusters. Results supported published findings on S. gordonii competence, showing up-regulation of 12 of 16 genes that have been reported to affect transformation frequencies in this species. Comparison of CSP-induced S. gordonii transcriptomes to results published for Streptococcus pneumoniae strains identified both conserved and species-specific genes. Putative intergenic regulatory sites, such as the conserved combox sequence thought to be a binding site for competence sigma factor, were found preceding S. gordonii late responsive genes. In contrast, S. gordonii early CSP-responsive genes were not preceded by the direct repeats found in S. pneumoniae. These studies provide the first insights into a genome-wide transcriptional response of an oral commensal organism. They offer an extensive analysis of transcriptional changes that accompany competence in S. gordonii and form a basis for future intra- and interspecies comparative analyses of this ecologically important phenotype. PMID:17720781

  18. Genome-Wide Mapping of the Binding Sites and Structural Analysis of Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 2 Reveal that It Is a DNA-Binding Transcription Factor

    PubMed Central

    Hu, Haidai; Dong, Jiazhen; Liang, Deguang; Gao, Zengqiang; Bai, Lei; Sun, Rui; Hu, Hao; Zhang, Heng

    2015-01-01

    DNA-binding properties remain poorly understood. In this study, we performed the first genome-wide vIRF2-binding site mapping in the human genome and found vIRF2 can bind to the promoter regions of 100 target cellular genes. X-ray structure analysis and functional studies provided unique insights into its DNA-binding potency and regulation of target gene expression. Our study suggested that vIRF2 could act as a transcription factor of its target genes and contribute to KSHV infection and pathogenesis through versatile functions. PMID:26537687

  19. Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii

    PubMed Central

    2010-01-01

    Background Genome-wide computational analysis of alternative splicing (AS) in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs. Results Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy. Conclusions The extent of AS in Chlamydomonas that we observed is much smaller than observed in

  20. 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

  1. Identification of a Salmonella ancillary copper detoxification mechanism by a comparative analysis of the genome-wide transcriptional response to copper and zinc excess.

    PubMed

    Pontel, Lucas B; Scampoli, Nadia L; Porwollik, Steffen; Checa, Susana K; McClelland, Michael; Soncini, Fernando C

    2014-08-01

    Copper and zinc are essential metal ions, but toxic in excess. Bacteria have evolved different strategies to control their intracellular concentrations, ensuring proper supply while avoiding toxicity, including the induction of metal-specific as well as non-specific mechanisms. We compared the transcriptional profiles of Salmonella Typhimurium after exposure to either copper or zinc ions in both rich and minimal media. Besides metal-specific regulatory networks many global stress-response pathways react to an excess of either of these metal ions. Copper excess affects both zinc and iron homeostasis by inducing transcription of these metal-specific regulons. In addition to the control of zinc-specific regulons, zinc excess affects the Cpx regulon and the σ(E) envelope-stress responses. Finally, novel metal-specific upregulated genes were detected including a new copper-detoxification pathway that involves the siderophore enterobactin and the outer-membrane protein TolC. This work sheds light onto the transcriptional landscape of Salmonella after copper or zinc overload, and discloses a new mechanism of copper detoxification.

  2. Methodological challenges of genome-wide association analysis in Africa

    PubMed Central

    Teo, Yik-Ying; Small, Kerrin S.; Kwiatkowski, Dominic P.

    2013-01-01

    Medical research in Africa has yet to benefit from the advent of genome-wide association (GWA) analysis, partly because the genotyping tools and statistical methods that have been developed for European and Asian populations struggle to deal with the high levels of genome diversity and population structure in Africa. However, the haplotypic diversity of African populations might help to overcome one of the major roadblocks in GWA research, the fine mapping of causal variants. We review the methodological challenges and consider how GWA studies in Africa will be transformed by new approaches in statistical imputation and large-scale genome sequencing. PMID:20084087

  3. Genome-Wide Transcriptional Analysis of the Cold Shock Response in Wild-Type and Cold-Sensitive, Quadruple-csp-Deletion Strains of Escherichia coli

    PubMed Central

    Phadtare, Sangita; Inouye, Masayori

    2004-01-01

    A DNA microarray-based global transcript profiling of Escherichia coli in response to cold shock showed that in addition to the known cold shock-inducible genes, new genes such as the flagellar operon, those encoding proteins involved in sugar transport and metabolism, and remarkably, genes encoding certain heat shock proteins are induced by cold shock. In the light of strong reduction in metabolic activity of the cell after temperature downshift, the induction of sugar metabolism machinery is unexpected. The deletion of four csps (cspA, cspB, cspG, and cspE) affected cold shock induction of mostly those genes that are transiently induced in the acclimation phase, emphasizing that CspA homologues are essential in the acclimation phase. Relevance of these findings with respect to the known RNA chaperone function of CspA homologues is discussed. PMID:15466053

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

    PubMed

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

    2014-11-01

    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.

  5. A genome-wide analysis reveals that the Drosophila transcription factor Lola promotes axon growth in part by suppressing expression of the actin nucleation factor Spire

    PubMed Central

    2011-01-01

    Background The phylogenetically conserved transcription factor Lola is essential for many aspects of axon growth and guidance, synapse formation and neural circuit development in Drosophila. To date it has been difficult, however, to obtain an overall view of Lola functions and mechanisms. Results We use expression microarrays to identify the lola-dependent transcriptome in the Drosophila embryo. We find that lola regulates the expression of a large selection of genes that are known to affect each of several lola-dependent developmental processes. Among other loci, we find lola to be a negative regulator of spire, an actin nucleation factor that has been studied for its essential role in oogenesis. We show that spire is expressed in the nervous system and is required for a known lola-dependent axon guidance decision, growth of ISNb motor axons. We further show that reducing spire gene dosage suppresses this aspect of the lola phenotype, verifying that derepression of spire is an important contributor to the axon stalling phenotype of embryonic motor axons in lola mutants. Conclusions These data shed new light on the molecular mechanisms of many lola-dependent processes, and also identify several developmental processes not previously linked to lola that are apt to be regulated by this transcription factor. These data further demonstrate that excessive expression of the actin nucleation factor Spire is as deleterious for axon growth in vivo as is the loss of Spire, thus highlighting the need for a balance in the elementary steps of actin dynamics to achieve effective neuronal morphogenesis. PMID:22129300

  6. Genome-wide analysis of transcriptional changes in the thoracic muscle of the migratory locust, Locusta migratoria, exposed to hypobaric hypoxia.

    PubMed

    Zhao, De Jian; Zhang, Zhen Yu; Harrison, Jon; Kang, Le

    2012-11-01

    Hypobaric hypoxia has both beneficial and detrimental effects on living organisms in high altitude regions. The impact of hypobaric hypoxia has been investigated in numerous vertebrates. However, it is still not well characterized how invertebrates respond to hypobaric hypoxia. In this study, we examined the transcriptional profiles of locust thoracic muscles using microarrays to disclose their strategies to cope with hypobaric hypoxia. We found that hypoxia-inducible factor (HIF) and its target genes did not respond significantly to hypobaric hypoxia. As with severe, normobaric hypoxia, mitochondrial activities were systemically suppressed, mainly involving in energy production and mitochondrial biogenesis. The surveillance processes, involving in clearance of dysfunctional proteins in endoplasmic reticulum, were activated, e.g. endoplasmic reticulum-associated degradation, protein glycosylation, and protein folding. In contrast to severe, normobaric hypoxia, glycolysis was suppressed and the pentose phosphate pathway strengthened. Our data suggested that hypobaric hypoxia induced an oxidative stress rather than an energy crisis in locust thoracic muscles. Our research provides a different perspective of biological responses to hypoxia, complementing the well-studied biological responses to extreme, normobaric hypoxia. PMID:22985864

  7. Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes.

    PubMed

    Raab, Jesse R; Resnick, Samuel; Magnuson, Terry

    2015-12-01

    Multiple positions within the SWI/SNF chromatin remodeling complex can be filled by mutually exclusive subunits. Inclusion or exclusion of these proteins defines many unique forms of SWI/SNF and has profound functional consequences. Often this complex is studied as a single entity within a particular cell type and we understand little about the functional relationship between these biochemically distinct forms of the remodeling complex. Here we examine the functional relationships among three complex-specific ARID (AT-Rich Interacting Domain) subunits using genome-wide chromatin immunoprecipitation, transcriptome analysis, and transcription factor binding maps. We find widespread overlap in transcriptional regulation and the genomic binding of distinct SWI/SNF complexes. ARID1B and ARID2 participate in wide-spread cooperation to repress hundreds of genes. Additionally, we find numerous examples of competition between ARID1A and another ARID, and validate that gene expression changes following loss of one ARID are dependent on the function of an alternative ARID. These distinct regulatory modalities are correlated with differential occupancy by transcription factors. Together, these data suggest that distinct SWI/SNF complexes dictate gene-specific transcription through functional interactions between the different forms of the SWI/SNF complex and associated co-factors. Most genes regulated by SWI/SNF are controlled by multiple biochemically distinct forms of the complex, and the overall expression of a gene is the product of the interaction between these different SWI/SNF complexes. The three mutually exclusive ARID family members are among the most frequently mutated chromatin regulators in cancer, and understanding the functional interactions and their role in transcriptional regulation provides an important foundation to understand their role in cancer.

  8. Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes

    PubMed Central

    Raab, Jesse R.; Resnick, Samuel; Magnuson, Terry

    2015-01-01

    Multiple positions within the SWI/SNF chromatin remodeling complex can be filled by mutually exclusive subunits. Inclusion or exclusion of these proteins defines many unique forms of SWI/SNF and has profound functional consequences. Often this complex is studied as a single entity within a particular cell type and we understand little about the functional relationship between these biochemically distinct forms of the remodeling complex. Here we examine the functional relationships among three complex-specific ARID (AT-Rich Interacting Domain) subunits using genome-wide chromatin immunoprecipitation, transcriptome analysis, and transcription factor binding maps. We find widespread overlap in transcriptional regulation and the genomic binding of distinct SWI/SNF complexes. ARID1B and ARID2 participate in wide-spread cooperation to repress hundreds of genes. Additionally, we find numerous examples of competition between ARID1A and another ARID, and validate that gene expression changes following loss of one ARID are dependent on the function of an alternative ARID. These distinct regulatory modalities are correlated with differential occupancy by transcription factors. Together, these data suggest that distinct SWI/SNF complexes dictate gene-specific transcription through functional interactions between the different forms of the SWI/SNF complex and associated co-factors. Most genes regulated by SWI/SNF are controlled by multiple biochemically distinct forms of the complex, and the overall expression of a gene is the product of the interaction between these different SWI/SNF complexes. The three mutually exclusive ARID family members are among the most frequently mutated chromatin regulators in cancer, and understanding the functional interactions and their role in transcriptional regulation provides an important foundation to understand their role in cancer. PMID:26716708

  9. Genome-wide analysis and expression patterns of ZF-HD transcription factors under different developmental tissues and abiotic stresses in Chinese cabbage.

    PubMed

    Wang, Wenli; Wu, Peng; Li, Ying; Hou, XiLin

    2016-06-01

    The ZF-HD gene family plays an important role in plant developmental processes and stress responses. However, the function of the ZF-HD genes in Chinese cabbage remains largely unknown. Chinese cabbage (Brassica rapa ssp. pekinensis) is a member of one of the most important leaf vegetables grown worldwide. The entire Chinese cabbage genome sequence has been determined, and more than forty thousand proteins have been identified to date. In this study, 31 ZF-HD genes were identified in Chinese cabbage. We show here that the BraZF-HD genes could be categorized into ZHD and MIF subfamilies. Among them, ZHD genes are plant-specific, nearly all intronless, and related to MINI ZINC FINGER genes that possess only the zinc finger. Phylogenetic analysis suggested that ZHDs have expanded considerably during angiosperm evolution. In addition, the ZHD group has 24 members, which is twice as much as the Arabidopsis ZHD group, indicating that the Chinese cabbage ZHD genes have been retained more frequently than other group genes. Real-time PCR analysis showed that most of BraZF-HD genes are preferentially expressed in flower. Furthermore, most of these genes are significantly induced under photoperiod or vernalization conditions, as well as abiotic stresses. Thereby implying that they may play important roles in these processes. This study provides insight into the evolution of ZF-HD genes in Chinese cabbage genome and may aid efforts to further characterize the function of these predicted ZF-HD genes in flowering and resistance.

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

    PubMed

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

    2016-04-26

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

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

    PubMed Central

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

    2016-01-01

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

  12. Genome-wide analysis and expression patterns of ZF-HD transcription factors under different developmental tissues and abiotic stresses in Chinese cabbage.

    PubMed

    Wang, Wenli; Wu, Peng; Li, Ying; Hou, XiLin

    2016-06-01

    The ZF-HD gene family plays an important role in plant developmental processes and stress responses. However, the function of the ZF-HD genes in Chinese cabbage remains largely unknown. Chinese cabbage (Brassica rapa ssp. pekinensis) is a member of one of the most important leaf vegetables grown worldwide. The entire Chinese cabbage genome sequence has been determined, and more than forty thousand proteins have been identified to date. In this study, 31 ZF-HD genes were identified in Chinese cabbage. We show here that the BraZF-HD genes could be categorized into ZHD and MIF subfamilies. Among them, ZHD genes are plant-specific, nearly all intronless, and related to MINI ZINC FINGER genes that possess only the zinc finger. Phylogenetic analysis suggested that ZHDs have expanded considerably during angiosperm evolution. In addition, the ZHD group has 24 members, which is twice as much as the Arabidopsis ZHD group, indicating that the Chinese cabbage ZHD genes have been retained more frequently than other group genes. Real-time PCR analysis showed that most of BraZF-HD genes are preferentially expressed in flower. Furthermore, most of these genes are significantly induced under photoperiod or vernalization conditions, as well as abiotic stresses. Thereby implying that they may play important roles in these processes. This study provides insight into the evolution of ZF-HD genes in Chinese cabbage genome and may aid efforts to further characterize the function of these predicted ZF-HD genes in flowering and resistance. PMID:26546019

  13. The CHR site: definition and genome-wide identification of a cell cycle transcriptional element

    PubMed Central

    Müller, Gerd A.; Wintsche, Axel; Stangner, Konstanze; Prohaska, Sonja J.; Stadler, Peter F.; Engeland, Kurt

    2014-01-01

    The cell cycle genes homology region (CHR) has been identified as a DNA element with an important role in transcriptional regulation of late cell cycle genes. It has been shown that such genes are controlled by DREAM, MMB and FOXM1-MuvB and that these protein complexes can contact DNA via CHR sites. However, it has not been elucidated which sequence variations of the canonical CHR are functional and how frequent CHR-based regulation is utilized in mammalian genomes. Here, we define the spectrum of functional CHR elements. As the basis for a computational meta-analysis, we identify new CHR sequences and compile phylogenetic motif conservation as well as genome-wide protein-DNA binding and gene expression data. We identify CHR elements in most late cell cycle genes binding DREAM, MMB, or FOXM1-MuvB. In contrast, Myb- and forkhead-binding sites are underrepresented in both early and late cell cycle genes. Our findings support a general mechanism: sequential binding of DREAM, MMB and FOXM1-MuvB complexes to late cell cycle genes requires CHR elements. Taken together, we define the group of CHR-regulated genes in mammalian genomes and provide evidence that the CHR is the central promoter element in transcriptional regulation of late cell cycle genes by DREAM, MMB and FOXM1-MuvB. PMID:25106871

  14. 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. PMID:25798919

  15. Genome-Wide Transcriptional Response of Saccharomyces cerevisiae to Stress-Induced Perturbations

    PubMed Central

    Taymaz-Nikerel, Hilal; Cankorur-Cetinkaya, Ayca; Kirdar, Betul

    2016-01-01

    Cells respond to environmental and/or genetic perturbations in order to survive and proliferate. Characterization of the changes after various stimuli at different -omics levels is crucial to comprehend the adaptation of cells to the changing conditions. Genome-wide quantification and analysis of transcript levels, the genes affected by perturbations, extends our understanding of cellular metabolism by pointing out the mechanisms that play role in sensing the stress caused by those perturbations and related signaling pathways, and in this way guides us to achieve endeavors, such as rational engineering of cells or interpretation of disease mechanisms. Saccharomyces cerevisiae as a model system has been studied in response to different perturbations and corresponding transcriptional profiles were followed either statically or/and dynamically, short and long term. This review focuses on response of yeast cells to diverse stress inducing perturbations, including nutritional changes, ionic stress, salt stress, oxidative stress, osmotic shock, and to genetic interventions such as deletion and overexpression of genes. It is aimed to conclude on common regulatory phenomena that allow yeast to organize its transcriptomic response after any perturbation under different external conditions. PMID:26925399

  16. A Robust Analytical Pipeline for Genome-Wide Identification of the Genes Regulated by a Transcription Factor: Combinatorial Analysis Performed Using gSELEX-Seq and RNA-Seq.

    PubMed

    Kojima, Takaaki; Kunitake, Emi; Ihara, Kunio; Kobayashi, Tetsuo; Nakano, Hideo

    2016-01-01

    For identifying the genes that are regulated by a transcription factor (TF), we have established an analytical pipeline that combines genomic systematic evolution of ligands by exponential enrichment (gSELEX)-Seq and RNA-Seq. Here, SELEX was used to select DNA fragments from an Aspergillus nidulans genomic library that bound specifically to AmyR, a TF from A. nidulans. High-throughput sequencing data were obtained for the DNAs enriched through the selection, following which various in silico analyses were performed. Mapping reads to the genome revealed the binding motifs including the canonical AmyR-binding motif, CGGN8CGG, as well as the candidate promoters controlled by AmyR. In parallel, differentially expressed genes related to AmyR were identified by using RNA-Seq analysis with samples from A. nidulans WT and amyR deletant. By obtaining the intersecting set of genes detected using both gSELEX-Seq and RNA-Seq, the genes directly regulated by AmyR in A. nidulans can be identified with high reliability. This analytical pipeline is a robust platform for comprehensive genome-wide identification of the genes that are regulated by a target TF.

  17. A Robust Analytical Pipeline for Genome-Wide Identification of the Genes Regulated by a Transcription Factor: Combinatorial Analysis Performed Using gSELEX-Seq and RNA-Seq

    PubMed Central

    Kojima, Takaaki; Kunitake, Emi; Ihara, Kunio; Kobayashi, Tetsuo; Nakano, Hideo

    2016-01-01

    For identifying the genes that are regulated by a transcription factor (TF), we have established an analytical pipeline that combines genomic systematic evolution of ligands by exponential enrichment (gSELEX)-Seq and RNA-Seq. Here, SELEX was used to select DNA fragments from an Aspergillus nidulans genomic library that bound specifically to AmyR, a TF from A. nidulans. High-throughput sequencing data were obtained for the DNAs enriched through the selection, following which various in silico analyses were performed. Mapping reads to the genome revealed the binding motifs including the canonical AmyR-binding motif, CGGN8CGG, as well as the candidate promoters controlled by AmyR. In parallel, differentially expressed genes related to AmyR were identified by using RNA-Seq analysis with samples from A. nidulans WT and amyR deletant. By obtaining the intersecting set of genes detected using both gSELEX-Seq and RNA-Seq, the genes directly regulated by AmyR in A. nidulans can be identified with high reliability. This analytical pipeline is a robust platform for comprehensive genome-wide identification of the genes that are regulated by a target TF. PMID:27411092

  18. 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. PMID:25296770

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. Improved Statistics for Genome-Wide Interaction Analysis

    PubMed Central

    Ueki, Masao; Cordell, Heather J.

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new “joint effects” statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  4. Improved statistics for genome-wide interaction analysis.

    PubMed

    Ueki, Masao; Cordell, Heather J

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new "joint effects" statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  5. Genome-wide transcriptional profiling of human glioblastoma cells in response to ITE treatment.

    PubMed

    Kang, Bo; Zhou, Yanwen; Zheng, Min; Wang, Ying-Jie

    2015-09-01

    A ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is recently revealed to play a key role in embryogenesis and tumorigenesis (Feng et al. [1], Safe et al. [2]) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) (Song et al. [3]) is an endogenous AhR ligand that possesses anti-tumor activity. In order to gain insights into how ITE acts via the AhR in embryogenesis and tumorigenesis, we analyzed the genome-wide transcriptional profiles of the following three groups of cells: the human glioblastoma U87 parental cells, U87 tumor sphere cells treated with vehicle (DMSO) and U87 tumor sphere cells treated with ITE. Here, we provide the details of the sample gathering strategy and show the quality controls and the analyses associated with our gene array data deposited into the Gene Expression Omnibus (GEO) under the accession code of GSE67986.

  6. Decoding genome-wide GadEWX-transcriptional regulatory networks reveals multifaceted cellular responses to acid stress in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2015-01-01

    The regulators GadE, GadW and GadX (which we refer to as GadEWX) play a critical role in the transcriptional regulation of the glutamate-dependent acid resistance (GDAR) system in Escherichia coli K-12 MG1655. However, the genome-wide regulatory role of GadEWX is still unknown. Here we comprehensively reconstruct the genome-wide GadEWX transcriptional regulatory network and RpoS involvement in E. coli K-12 MG1655 under acidic stress. Integrative data analysis reveals that GadEWX regulons consist of 45 genes in 31 transcription units and 28 of these genes were associated with RpoS-binding sites. We demonstrate that GadEWX directly and coherently regulate several proton-generating/consuming enzymes with pairs of negative-feedback loops for pH homeostasis. In addition, GadEWX regulate genes with assorted functions, including molecular chaperones, acid resistance, stress response and other regulatory activities. These results show how GadEWX simultaneously coordinate many cellular processes to produce the overall response of E. coli to acid stress. PMID:26258987

  7. Decoding genome-wide GadEWX-transcriptional regulatory networks reveals multifaceted cellular responses to acid stress in Escherichia coli

    PubMed Central

    Seo, Sang Woo; Kim, Donghyuk; O'Brien, Edward J.; Szubin, Richard; Palsson, Bernhard O.

    2015-01-01

    The regulators GadE, GadW and GadX (which we refer to as GadEWX) play a critical role in the transcriptional regulation of the glutamate-dependent acid resistance (GDAR) system in Escherichia coli K-12 MG1655. However, the genome-wide regulatory role of GadEWX is still unknown. Here we comprehensively reconstruct the genome-wide GadEWX transcriptional regulatory network and RpoS involvement in E. coli K-12 MG1655 under acidic stress. Integrative data analysis reveals that GadEWX regulons consist of 45 genes in 31 transcription units and 28 of these genes were associated with RpoS-binding sites. We demonstrate that GadEWX directly and coherently regulate several proton-generating/consuming enzymes with pairs of negative-feedback loops for pH homeostasis. In addition, GadEWX regulate genes with assorted functions, including molecular chaperones, acid resistance, stress response and other regulatory activities. These results show how GadEWX simultaneously coordinate many cellular processes to produce the overall response of E. coli to acid stress. PMID:26258987

  8. Genome-Wide Transcriptional Response of the Archaeon Thermococcus gammatolerans to Cadmium

    PubMed Central

    Lagorce, Arnaud; Fourçans, Aude; Dutertre, Murielle; Bouyssiere, Brice; Zivanovic, Yvan; Confalonieri, Fabrice

    2012-01-01

    Thermococcus gammatolerans, the most radioresistant archaeon known to date, is an anaerobic and hyperthermophilic sulfur-reducing organism living in deep-sea hydrothermal vents. Knowledge of mechanisms underlying archaeal metal tolerance in such metal-rich ecosystem is still poorly documented. We showed that T. gammatolerans exhibits high resistance to cadmium (Cd), cobalt (Co) and zinc (Zn), a weaker tolerance to nickel (Ni), copper (Cu) and arsenate (AsO4) and that cells exposed to 1 mM Cd exhibit a cellular Cd concentration of 67 µM. A time-dependent transcriptomic analysis using microarrays was performed at a non-toxic (100 µM) and a toxic (1 mM) Cd dose. The reliability of microarray data was strengthened by real time RT-PCR validations. Altogether, 114 Cd responsive genes were revealed and a substantial subset of genes is related to metal homeostasis, drug detoxification, re-oxidization of cofactors and ATP production. This first genome-wide expression profiling study of archaeal cells challenged with Cd showed that T. gammatolerans withstands induced stress through pathways observed in both prokaryotes and eukaryotes but also through new and original strategies. T. gammatolerans cells challenged with 1 mM Cd basically promote: 1) the induction of several transporter/permease encoding genes, probably to detoxify the cell; 2) the upregulation of Fe transporters encoding genes to likely compensate Cd damages in iron-containing proteins; 3) the induction of membrane-bound hydrogenase (Mbh) and membrane-bound hydrogenlyase (Mhy2) subunits encoding genes involved in recycling reduced cofactors and/or in proton translocation for energy production. By contrast to other organisms, redox homeostasis genes appear constitutively expressed and only a few genes encoding DNA repair proteins are regulated. We compared the expression of 27 Cd responsive genes in other stress conditions (Zn, Ni, heat shock, γ-rays), and showed that the Cd transcriptional pattern is

  9. Genome-wide transcriptional response of the archaeon Thermococcus gammatolerans to cadmium.

    PubMed

    Lagorce, Arnaud; Fourçans, Aude; Dutertre, Murielle; Bouyssiere, Brice; Zivanovic, Yvan; Confalonieri, Fabrice

    2012-01-01

    Thermococcus gammatolerans, the most radioresistant archaeon known to date, is an anaerobic and hyperthermophilic sulfur-reducing organism living in deep-sea hydrothermal vents. Knowledge of mechanisms underlying archaeal metal tolerance in such metal-rich ecosystem is still poorly documented. We showed that T. gammatolerans exhibits high resistance to cadmium (Cd), cobalt (Co) and zinc (Zn), a weaker tolerance to nickel (Ni), copper (Cu) and arsenate (AsO(4)) and that cells exposed to 1 mM Cd exhibit a cellular Cd concentration of 67 µM. A time-dependent transcriptomic analysis using microarrays was performed at a non-toxic (100 µM) and a toxic (1 mM) Cd dose. The reliability of microarray data was strengthened by real time RT-PCR validations. Altogether, 114 Cd responsive genes were revealed and a substantial subset of genes is related to metal homeostasis, drug detoxification, re-oxidization of cofactors and ATP production. This first genome-wide expression profiling study of archaeal cells challenged with Cd showed that T. gammatolerans withstands induced stress through pathways observed in both prokaryotes and eukaryotes but also through new and original strategies. T. gammatolerans cells challenged with 1 mM Cd basically promote: 1) the induction of several transporter/permease encoding genes, probably to detoxify the cell; 2) the upregulation of Fe transporters encoding genes to likely compensate Cd damages in iron-containing proteins; 3) the induction of membrane-bound hydrogenase (Mbh) and membrane-bound hydrogenlyase (Mhy2) subunits encoding genes involved in recycling reduced cofactors and/or in proton translocation for energy production. By contrast to other organisms, redox homeostasis genes appear constitutively expressed and only a few genes encoding DNA repair proteins are regulated. We compared the expression of 27 Cd responsive genes in other stress conditions (Zn, Ni, heat shock, γ-rays), and showed that the Cd transcriptional pattern is

  10. Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

    PubMed

    Vizcaíno, Carolina; Núñez, Luz-Elena; Morís, Francisco; Portugal, José

    2014-01-01

    Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

  11. Computational modelling of genome-wide [corrected] transcription assembly networks using a fluidics analogy.

    PubMed

    Azmy, Yousry Y; Gupta, Anshuman; Pugh, B Franklin

    2008-08-28

    Understanding how a myriad of transcription regulators work to modulate mRNA output at thousands of genes remains a fundamental challenge in molecular biology. Here we develop a computational tool to aid in assessing the plausibility of gene regulatory models derived from genome-wide expression profiling of cells mutant for transcription regulators. mRNA output is modelled as fluid flow in a pipe lattice, with assembly of the transcription machinery represented by the effect of valves. Transcriptional regulators are represented as external pressure heads that determine flow rate. Modelling mutations in regulatory proteins is achieved by adjusting valves' on/off settings. The topology of the lattice is designed by the experimentalist to resemble the expected interconnection between the modelled agents and their influence on mRNA expression. Users can compare multiple lattice configurations so as to find the one that minimizes the error with experimental data. This computational model provides a means to test the plausibility of transcription regulation models derived from large genomic data sets.

  12. Genome-wide transcriptional responses of Alteromonas naphthalenivorans SN2 to contaminated seawater and marine tidal flat sediment

    PubMed Central

    Jin, Hyun Mi; Jeong, Hye Im; Kim, Kyung Hyun; Hahn, Yoonsoo; Madsen, Eugene L.; Jeon, Che Ok

    2016-01-01

    A genome-wide transcriptional analysis of Alteromonas naphthalenivorans SN2 was performed to investigate its ecophysiological behavior in contaminated tidal flats and seawater. The experimental design mimicked these habitats that either added naphthalene or pyruvate; tidal flat-naphthalene (TF-N), tidal flat-pyruvate (TF-P), seawater-naphthalene (SW-N), and seawater-pyruvate (SW-P). The transcriptional profiles clustered by habitat (TF-N/TF-P and SW-N/SW-P), rather than carbon source, suggesting that the former may exert a greater influence on genome-wide expression in strain SN2 than the latter. Metabolic mapping of cDNA reads from strain SN2 based on KEGG pathway showed that metabolic and regulatory genes associated with energy metabolism, translation, and cell motility were highly expressed in all four test conditions, probably highlighting the copiotrophic properties of strain SN2 as an opportunistic marine r-strategist. Differential gene expression analysis revealed that strain SN2 displayed specific cellular responses to environmental variables (tidal flat, seawater, naphthalene, and pyruvate) and exhibited certain ecological fitness traits –– its notable PAH degradation capability in seasonally cold tidal flat might be reflected in elevated expression of stress response and chaperone proteins, while fast growth in nitrogen-deficient and aerobic seawater probably correlated with high expression of glutamine synthetase, enzymes utilizing nitrite/nitrate, and those involved in the removal of reactive oxygen species. PMID:26887987

  13. Genome-wide transcriptional responses of Alteromonas naphthalenivorans SN2 to contaminated seawater and marine tidal flat sediment.

    PubMed

    Jin, Hyun Mi; Jeong, Hye Im; Kim, Kyung Hyun; Hahn, Yoonsoo; Madsen, Eugene L; Jeon, Che Ok

    2016-01-01

    A genome-wide transcriptional analysis of Alteromonas naphthalenivorans SN2 was performed to investigate its ecophysiological behavior in contaminated tidal flats and seawater. The experimental design mimicked these habitats that either added naphthalene or pyruvate; tidal flat-naphthalene (TF-N), tidal flat-pyruvate (TF-P), seawater-naphthalene (SW-N), and seawater-pyruvate (SW-P). The transcriptional profiles clustered by habitat (TF-N/TF-P and SW-N/SW-P), rather than carbon source, suggesting that the former may exert a greater influence on genome-wide expression in strain SN2 than the latter. Metabolic mapping of cDNA reads from strain SN2 based on KEGG pathway showed that metabolic and regulatory genes associated with energy metabolism, translation, and cell motility were highly expressed in all four test conditions, probably highlighting the copiotrophic properties of strain SN2 as an opportunistic marine r-strategist. Differential gene expression analysis revealed that strain SN2 displayed specific cellular responses to environmental variables (tidal flat, seawater, naphthalene, and pyruvate) and exhibited certain ecological fitness traits -- its notable PAH degradation capability in seasonally cold tidal flat might be reflected in elevated expression of stress response and chaperone proteins, while fast growth in nitrogen-deficient and aerobic seawater probably correlated with high expression of glutamine synthetase, enzymes utilizing nitrite/nitrate, and those involved in the removal of reactive oxygen species. PMID:26887987

  14. Drosophila Genome-Wide RNAi Screen Identifies Multiple Regulators of HIF–Dependent Transcription in Hypoxia

    PubMed Central

    Dekanty, Andrés; Romero, Nuria M.; Bertolin, Agustina P.; Thomas, María G.; Leishman, Claudia C.; Perez-Perri, Joel I.; Boccaccio, Graciela L.; Wappner, Pablo

    2010-01-01

    Hypoxia-inducible factors (HIFs) are a family of evolutionary conserved alpha-beta heterodimeric transcription factors that induce a wide range of genes in response to low oxygen tension. Molecular mechanisms that mediate oxygen-dependent HIF regulation operate at the level of the alpha subunit, controlling protein stability, subcellular localization, and transcriptional coactivator recruitment. We have conducted an unbiased genome-wide RNA interference (RNAi) screen in Drosophila cells aimed to the identification of genes required for HIF activity. After 3 rounds of selection, 30 genes emerged as critical HIF regulators in hypoxia, most of which had not been previously associated with HIF biology. The list of genes includes components of chromatin remodeling complexes, transcription elongation factors, and translational regulators. One remarkable hit was the argonaute 1 (ago1) gene, a central element of the microRNA (miRNA) translational silencing machinery. Further studies confirmed the physiological role of the miRNA machinery in HIF–dependent transcription. This study reveals the occurrence of novel mechanisms of HIF regulation, which might contribute to developing novel strategies for therapeutic intervention of HIF–related pathologies, including heart attack, cancer, and stroke. PMID:20585616

  15. 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. PMID:26438844

  16. 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.

  17. A high definition look at the NF-Y regulome reveals genome-wide associations with selected transcription factors.

    PubMed

    Dolfini, Diletta; Zambelli, Federico; Pedrazzoli, Maurizio; Mantovani, Roberto; Pavesi, Giulio

    2016-06-01

    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

  18. 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

  19. Phenome-wide analysis of genome-wide polygenic scores

    PubMed Central

    Krapohl, E; Euesden, J; Zabaneh, D; Pingault, J-B; Rimfeld, K; von Stumm, S; Dale, P S; Breen, G; O'Reilly, P F; Plomin, R

    2016-01-01

    Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents' behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development. PMID:26303664

  20. Genome-Wide Identification of the Target Genes of AP2-O, a Plasmodium AP2-Family Transcription Factor

    PubMed Central

    Kaneko, Izumi; Iwanaga, Shiroh; Kato, Tomomi; Kobayashi, Issei; Yuda, Masao

    2015-01-01

    Stage-specific transcription is a fundamental biological process in the life cycle of the Plasmodium parasite. Proteins containing the AP2 DNA-binding domain are responsible for stage-specific transcriptional regulation and belong to the only known family of transcription factors in Plasmodium parasites. Comprehensive identification of their target genes will advance our understanding of the molecular basis of stage-specific transcriptional regulation and stage-specific parasite development. AP2-O is an AP2 family transcription factor that is expressed in the mosquito midgut-invading stage, called the ookinete, and is essential for normal morphogenesis of this stage. In this study, we identified the genome-wide target genes of AP2-O by chromatin immunoprecipitation-sequencing and elucidate how this AP2 family transcription factor contributes to the formation of this motile stage. The analysis revealed that AP2-O binds specifically to the upstream genomic regions of more than 500 genes, suggesting that approximately 10% of the parasite genome is directly regulated by AP2-O. These genes are involved in distinct biological processes such as morphogenesis, locomotion, midgut penetration, protection against mosquito immunity and preparation for subsequent oocyst development. This direct and global regulation by AP2-O provides a model for gene regulation in Plasmodium parasites and may explain how these parasites manage to control their complex life cycle using a small number of sequence-specific AP2 transcription factors. PMID:26018192

  1. 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…

  2. Genome-Wide Analysis of Acute Endurance Exercise-Induced Translational Regulation in Mouse Skeletal Muscle

    PubMed Central

    Sako, Hiroaki; Yada, Koichi; Suzuki, Katsuhiko

    2016-01-01

    Exercise dynamically changes skeletal muscle protein synthesis to respond and adapt to the external and internal stimuli. Many studies have focused on overall protein synthesis to understand how exercise regulates the muscular adaptation. However, despite the probability that each gene transcript may have its own unique translational characteristics and would be differentially regulated at translational level, little attention has been paid to how exercise affects translational regulation of individual genes at a genome-wide scale. Here, we conducted a genome-wide translational analysis using ribosome profiling to investigate the effect of a single bout of treadmill running (20 m/min for 60 min) on mouse gastrocnemius. Global translational profiles largely differed from those in transcription even at a basal resting condition as well as immediately after exercise. As for individual gene, Slc25a25 (Solute carrier family 25, member 25), localized in mitochondrial inner membrane and maintaining ATP homeostasis and endurance performance, showed significant up-regulation at translational level. However, multiple regression analysis suggests that Slc25a25 protein degradation may also have a role in mediating Slc25a25 protein abundance in the basal and early stages after acute endurance exercise. PMID:26845575

  3. 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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27752099

  5. Genome-wide view of natural antisense transcripts in Arabidopsis thaliana.

    PubMed

    Yuan, Chunhui; Wang, Jingjing; Harrison, Andrew P; Meng, Xianwen; Chen, Dijun; Chen, Ming

    2015-06-01

    Natural antisense transcripts (NATs) are endogenous transcripts that can form double-stranded RNA structures. Many protein-coding genes (PCs) and non-protein-coding genes (NPCs) tend to form cis-NATs and trans-NATs, respectively. In this work, we identified 4,080 cis-NATs and 2,491 trans-NATs genome-widely in Arabidopsis. Of these, 5,385 NAT-siRNAs were detected from the small RNA sequencing data. NAT-siRNAs are typically 21nt, and are processed by Dicer-like 1 (DCL1)/DCL2 and RDR6 and function in epigenetically activated situations, or 24nt, suggesting these are processed by DCL3 and RDR2 and function in environment stress. NAT-siRNAs are significantly derived from PC/PC pairs of trans-NATs and NPC/NPC pairs of cis-NATs. Furthermore, NAT pair genes typically have similar pattern of epigenetic status. Cis-NATs tend to be marked by euchromatic modifications, whereas trans-NATs tend to be marked by heterochromatic modifications. PMID:25922535

  6. Genome-wide view of natural antisense transcripts in Arabidopsis thaliana.

    PubMed

    Yuan, Chunhui; Wang, Jingjing; Harrison, Andrew P; Meng, Xianwen; Chen, Dijun; Chen, Ming

    2015-06-01

    Natural antisense transcripts (NATs) are endogenous transcripts that can form double-stranded RNA structures. Many protein-coding genes (PCs) and non-protein-coding genes (NPCs) tend to form cis-NATs and trans-NATs, respectively. In this work, we identified 4,080 cis-NATs and 2,491 trans-NATs genome-widely in Arabidopsis. Of these, 5,385 NAT-siRNAs were detected from the small RNA sequencing data. NAT-siRNAs are typically 21nt, and are processed by Dicer-like 1 (DCL1)/DCL2 and RDR6 and function in epigenetically activated situations, or 24nt, suggesting these are processed by DCL3 and RDR2 and function in environment stress. NAT-siRNAs are significantly derived from PC/PC pairs of trans-NATs and NPC/NPC pairs of cis-NATs. Furthermore, NAT pair genes typically have similar pattern of epigenetic status. Cis-NATs tend to be marked by euchromatic modifications, whereas trans-NATs tend to be marked by heterochromatic modifications.

  7. Genome-wide computational prediction and analysis of core promoter elements across plant monocots and dicots

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transcription initiation, essential to gene expression regulation, involves recruitment of basal transcription factors to the core promoter elements (CPEs). The distribution of currently known CPEs across plant genomes is largely unknown. This is the first large scale genome-wide report on the compu...

  8. Genome-wide proximal promoter analysis and interpretation.

    PubMed

    Guruceaga, Elizabeth; Segura, Victor; Corrales, Fernando J; Rubio, Angel

    2010-01-01

    High-throughput gene expression technologies based on DNA microarrays allow the examination of biological systems. However, the interpretation of the complex molecular descriptions generated by these approaches is still challenging. The development of new methodologies to identify common regulatory mechanisms involved in the control of the expression of a set of co-expressed genes might enhance our capacity to extract functional information from genomic data sets. In this chapter, we describe a method that integrates different sources of information: gene expression data, genome sequence information, described transcription factor binding sites (TFBSs), functional information, and bibliographic data. The starting point of the analysis is the extraction of promoter sequences from a whole genome and the detection of TFBSs in each gene promoter. This information allows the identification of enriched TFBSs in the proximal promoter of differentially expressed genes. The functional and bibliographic interpretation of the results improves our biological insight into the regulatory mechanisms involved in a microarray experiment. PMID:19957149

  9. Genome-wide identification and characterization of transcription start sites and promoters in the tunicate Ciona intestinalis.

    PubMed

    Yokomori, Rui; Shimai, Kotaro; Nishitsuji, Koki; Suzuki, Yutaka; Kusakabe, Takehiro G; Nakai, Kenta

    2016-01-01

    The tunicate Ciona intestinalis, an invertebrate chordate, has recently emerged as a powerful model organism for gene regulation analysis. However, few studies have been conducted to identify and characterize its transcription start sites (TSSs) and promoters at the genome-wide level. Here, using TSS-seq, we identified TSSs at the genome-wide scale and characterized promoters in C. intestinalis. Specifically, we identified TSS clusters (TSCs), high-density regions of TSS-seq tags, each of which appears to originate from an identical promoter. TSCs were found not only at known TSSs but also in other regions, suggesting the existence of many unknown transcription units in the genome. We also identified candidate promoters of 79 ribosomal protein (RP) genes, each of which had the major TSS in a polypyrimidine tract and showed a sharp TSS distribution like human RP gene promoters. Ciona RP gene promoters, however, did not appear to have typical TATA boxes, unlike human RP gene promoters. In Ciona non-RP promoters, two pyrimidine-purine dinucleotides, CA and TA, were frequently used as TSSs. Despite the absence of CpG islands, Ciona TATA-less promoters showed low expression specificity like CpG-associated human TATA-less promoters. By using TSS-seq, we also predicted trans-spliced gene TSSs and found that their downstream regions had higher G+T content than those of non-trans-spliced gene TSSs. Furthermore, we identified many putative alternative promoters, some of which were regulated in a tissue-specific manner. Our results provide valuable information about TSSs and promoter characteristics in C. intestinalis and will be helpful in future analysis of transcriptional regulation in chordates. PMID:26668163

  10. Genome-Wide Chromatin Immunoprecipitation Sequencing Analysis Shows that WhiB Is a Transcription Factor That Cocontrols Its Regulon with WhiA To Initiate Developmental Cell Division in Streptomyces

    PubMed Central

    Chandra, Govind; Bibb, Maureen J.; Findlay, Kim C.; Buttner, Mark J.

    2016-01-01

    ABSTRACT WhiB is the founding member of a family of proteins (the WhiB-like [Wbl] family) that carry a [4Fe-4S] iron-sulfur cluster and play key roles in diverse aspects of the biology of actinomycetes, including pathogenesis, antibiotic resistance, and the control of development. In Streptomyces, WhiB is essential for the process of developmentally controlled cell division that leads to sporulation. The biochemical function of Wbl proteins has been controversial; here, we set out to determine unambiguously if WhiB functions as a transcription factor using chromatin immunoprecipitation sequencing (ChIP-seq) in Streptomyces venezuelae. In the first demonstration of in vivo genome-wide Wbl binding, we showed that WhiB regulates the expression of key genes required for sporulation by binding upstream of ~240 transcription units. Strikingly, the WhiB regulon is identical to the previously characterized WhiA regulon, providing an explanation for the identical phenotypes of whiA and whiB mutants. Using ChIP-seq, we demonstrated that in vivo DNA binding by WhiA depends on WhiB and vice versa, showing that WhiA and WhiB function cooperatively to control expression of a common set of WhiAB target genes. Finally, we show that mutation of the cysteine residues that coordinate the [4Fe-4S] cluster in WhiB prevents DNA binding by both WhiB and WhiA in vivo. PMID:27094333

  11. Genome-wide prediction and annotation of Burkholderia pseudomallei AraC/XylS family transcription regulator.

    PubMed

    Lim, Boon-San; Chong, Chan-Eng; Zamrod, Zulkeflie; Nathan, Sheila; Mohamed, Rahmah

    2007-01-01

    Many members of the AraC/XylS family transcription regulator have been proven to play a critical role in regulating bacterial virulence factors in response to environmental stress. By using the Hidden Markov Model (HMM) profile built from the alignment of a 99 amino acid conserved domain sequence of 273 AraC/XylS family transcription regulators, we detected a total of 45 AraC/XylS family transcription regulators in the genome of the Gram-negative pathogen, Burkholderia pseudomallei. Further in silico analysis of each detected AraC/XylS family transcription regulatory protein and its neighboring genes allowed us to make a first-order guess on the role of some of these transcription regulators in regulating important virulence factors such as those involved in three type III secretion systems and biosynthesis of pyochelin, exopolysaccharide (EPS) and phospholipase C. This paper has demonstrated an efficient and systematic genome-wide scale prediction of the AraC/XylS family that can be applied to other protein families. PMID:18391231

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  15. From Human Monocytes to Genome-Wide Binding Sites - A Protocol for Small Amounts of Blood: Monocyte Isolation/ChIP-Protocol/Library Amplification/Genome Wide Computational Data Analysis

    PubMed Central

    Weiterer, Sebastian; Uhle, Florian; Bhuju, Sabin; Jarek, Michael; Weigand, Markus A.; Bartkuhn, Marek

    2014-01-01

    Chromatin immunoprecipitation in combination with a genome-wide analysis via high-throughput sequencing is the state of the art method to gain genome-wide representation of histone modification or transcription factor binding profiles. However, chromatin immunoprecipitation analysis in the context of human experimental samples is limited, especially in the case of blood cells. The typically extremely low yields of precipitated DNA are usually not compatible with library amplification for next generation sequencing. We developed a highly reproducible protocol to present a guideline from the first step of isolating monocytes from a blood sample to analyse the distribution of histone modifications in a genome-wide manner. Conclusion: The protocol describes the whole work flow from isolating monocytes from human blood samples followed by a high-sensitivity and small-scale chromatin immunoprecipitation assay with guidance for generating libraries compatible with next generation sequencing from small amounts of immunoprecipitated DNA. PMID:24732314

  16. Genome-wide analysis of the maternal-to-zygotic transition in Drosophila primordial germ cells

    PubMed Central

    2012-01-01

    Background During the maternal-to-zygotic transition (MZT) vast changes in the embryonic transcriptome are produced by a combination of two processes: elimination of maternally provided mRNAs and synthesis of new transcripts from the zygotic genome. Previous genome-wide analyses of the MZT have been restricted to whole embryos. Here we report the first such analysis for primordial germ cells (PGCs), the progenitors of the germ-line stem cells. Results We purified PGCs from Drosophila embryos, defined their proteome and transcriptome, and assessed the content, scale and dynamics of their MZT. Transcripts encoding proteins that implement particular types of biological functions group into nine distinct expression profiles, reflecting coordinate control at the transcriptional and posttranscriptional levels. mRNAs encoding germ-plasm components and cell-cell signaling molecules are rapidly degraded while new transcription produces mRNAs encoding the core transcriptional and protein synthetic machineries. The RNA-binding protein Smaug is essential for the PGC MZT, clearing transcripts encoding proteins that regulate stem cell behavior, transcriptional and posttranscriptional processes. Computational analyses suggest that Smaug and AU-rich element binding proteins function independently to control transcript elimination. Conclusions The scale of the MZT is similar in the soma and PGCs. However, the timing and content of their MZTs differ, reflecting the distinct developmental imperatives of these cell types. The PGC MZT is delayed relative to that in the soma, likely because relief of PGC-specific transcriptional silencing is required for zygotic genome activation as well as for efficient maternal transcript clearance. PMID:22348290

  17. 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

  18. 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

    2016-01-01

    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. PMID:27323069

  19. Vector algebra in the analysis of genome-wide expression data

    PubMed Central

    Kuruvilla, Finny G; Park, Peter J; Schreiber, Stuart L

    2002-01-01

    Background Data from thousands of transcription-profiling experiments in organisms ranging from yeast to humans are now publicly available. How best to analyze these data remains an important challenge. A variety of tools have been used for this purpose, including hierarchical clustering, self-organizing maps and principal components analysis. In particular, concepts from vector algebra have proven useful in the study of genome-wide expression data. Results Here we present a framework based on vector algebra for the analysis of transcription profiles that is geometrically intuitive and computationally efficient. Concepts in vector algebra such as angles, magnitudes, subspaces, singular value decomposition, bases and projections have natural and powerful interpretations in the analysis of microarray data. Angles in particular offer a rigorous method of defining 'similarity' and are useful in evaluating the claims of a microarray-based study. We present a sample analysis of cells treated with rapamycin, an immunosuppressant whose effects have been extensively studied with microarrays. In addition, the algebraic concept of a basis for a space affords the opportunity to simplify data analysis and uncover a limited number of expression vectors to span the transcriptional range of cell behavior. Conclusions This framework represents a compact, powerful and scalable construction for analysis and computation. As the amount of microarray data in the public domain grows, these vector-based methods are relevant in determining statistical significance. These approaches are also well suited to extract biologically meaningful information in the analysis of signaling networks. PMID:11897023

  20. Genome-Wide Transcriptional Analysis of Differentially Expressed Genes in Diabetic, Healing Corneal Epithelial Cells: Hyperglycemia-Suppressed TGFβ3 Expression Contributes to the Delay of Epithelial Wound Healing in Diabetic Corneas

    PubMed Central

    Bettahi, Ilham; Sun, Haijing; Gao, Nan; Wang, Feng; Mi, Xiaofan; Chen, Weiping; Liu, Zuguo; Yu, Fu-Shin X.

    2014-01-01

    Patients with diabetes mellitus (DM) may develop corneal complications and delayed wound healing. The aims of this study are to characterize the molecular signatures and biological pathways leading to delayed epithelial wound healing and to delineate the involvement of TGFβ3 therein. Genome-wide cDNA microarray analysis revealed 1,888 differentially expressed genes in the healing epithelia of normal (NL) versus type 1 DM rat corneas. Gene ontology and enrichment analyses indicated TGFβ signaling as a major altered pathway. Among three TGFβ isoforms, TGF-β1 and β3 were upregulated in response to wounding in NL corneal epithelial cells (CECs), whereas the latter was greatly suppressed by hyperglycemia in rat type 1 and 2 and mouse type 1 DM models. Functional analysis indicated that TGF-β3 contributed to wound healing in NL corneas. Moreover, exogenously added TGF-β3 accelerated epithelial wound closure in type 2 rat and type 1 mouse DM corneas via Smad and PI3K-AKT signaling pathways, autoregulation, and/or upregulation of Serpine1, a well-known TGFβ target gene. Taken together, our study for the first time provides a comprehensive list of genes differentially expressed in the healing CECs of NL versus diabetic corneas and suggests the therapeutic potential of TGF-β3 for treating corneal and skin wounds in diabetic patients. PMID:24306208

  1. Genome-wide Scanning and Characterization of Sorghum bicolor L. Heat Shock Transcription Factors.

    PubMed

    Nagaraju, M; Reddy, Palakolanu Sudhakar; Kumar, S Anil; Srivastava, Rakesh K; Kishor, P B Kavi; Rao, D Manohar

    2015-08-01

    A genome-wide scanning of Sorghum bicolor resulted in the identification of 25 SbHsf genes. Phylogenetic analysis shows the ortholog genes that are clustered with only rice, representing a common ancestor. Promoter analysis revealed the identification of different cis-acting elements that are responsible for abiotic as well as biotic stresses. Hsf domains like DBD, NLS, NES, and AHA have been analyzed for their sequence similarity and functional characterization. Tissue specific expression patterns of Hsfs in different tissues like mature embryo, seedling, root, and panicle were studied using real-time PCR. While Hsfs4 and 22 are highly expressed in panicle, 4 and 9 are expressed in seedlings. Sorghum plants were exposed to different abiotic stress treatments but no expression of any Hsf was observed when seedlings were treated with ABA. High level expression of Hsf1 was noticed during high temperature as well as cold stresses, 4 and 6 during salt and 5, 6, 10, 13, 19, 23 and 25 during drought stress. This comprehensive analysis of SbHsf genes will provide an insight on how these genes are regulated in different tissues and also under different abiotic stresses and help to determine the functions of Hsfs during drought and temperature stress tolerance. PMID:27006630

  2. Genome-wide Scanning and Characterization of Sorghum bicolor L. Heat Shock Transcription Factors

    PubMed Central

    Nagaraju, M.; Reddy, Palakolanu Sudhakar; Kumar, S. Anil; Srivastava, Rakesh K.; Kishor, P. B. Kavi; Rao, D. Manohar

    2015-01-01

    A genome-wide scanning of Sorghum bicolor resulted in the identification of 25 SbHsf genes. Phylogenetic analysis shows the ortholog genes that are clustered with only rice, representing a common ancestor. Promoter analysis revealed the identification of different cis-acting elements that are responsible for abiotic as well as biotic stresses. Hsf domains like DBD, NLS, NES, and AHA have been analyzed for their sequence similarity and functional characterization. Tissue specific expression patterns of Hsfs in different tissues like mature embryo, seedling, root, and panicle were studied using real-time PCR. While Hsfs4 and 22 are highly expressed in panicle, 4 and 9 are expressed in seedlings. Sorghum plants were exposed to different abiotic stress treatments but no expression of any Hsf was observed when seedlings were treated with ABA. High level expression of Hsf1 was noticed during high temperature as well as cold stresses, 4 and 6 during salt and 5, 6, 10, 13, 19, 23 and 25 during drought stress. This comprehensive analysis of SbHsf genes will provide an insight on how these genes are regulated in different tissues and also under different abiotic stresses and help to determine the functions of Hsfs during drought and temperature stress tolerance. PMID:27006630

  3. Genome-wide analysis of Polycomb targets in Drosophila

    SciTech Connect

    Schwartz, Yuri B.; Kahn, Tatyana G.; Nix, David A.; Li,Xiao-Yong; Bourgon, Richard; Biggin, Mark; Pirrotta, Vincenzo

    2006-04-01

    Polycomb Group (PcG) complexes are multiprotein assemblages that bind to chromatin and establish chromatin states leading to epigenetic silencing. PcG proteins regulate homeotic genes in flies and vertebrates but little is known about other PcG targets and the role of the PcG in development, differentiation and disease. We have determined the distribution of the PcG proteins PC, E(Z) and PSC and of histone H3K27 trimethylation in the Drosophila genome. At more than 200 PcG target genes, binding sites for the three PcG proteins colocalize to presumptive Polycomb Response Elements (PREs). In contrast, H3 me3K27 forms broad domains including the entire transcription unit and regulatory regions. PcG targets are highly enriched in genes encoding transcription factors but receptors, signaling proteins, morphogens and regulators representing all major developmental pathways are also included.

  4. Mammalian NET-seq analysis defines nascent RNA profiles and associated RNA processing genome-wide.

    PubMed

    Nojima, Takayuki; Gomes, Tomás; Carmo-Fonseca, Maria; Proudfoot, Nicholas J

    2016-03-01

    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

  5. Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

    PubMed

    Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

    2015-03-01

    The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes.

  6. Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

    PubMed Central

    Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

    2015-01-01

    The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPRER) to restore ER homeostasis. The AAA+ ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPRER genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA+ ATPase, as a novel repressor of a subset of UPRER genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPRER genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. PMID:25652260

  7. Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

    PubMed

    Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

    2015-03-01

    The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. PMID:25652260

  8. Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency

    PubMed Central

    2012-01-01

    Background Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. Results A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. Conclusions The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency. PMID:22433273

  9. 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.

  10. 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

  11. Genomic-Wide Analysis with Microarrays in Human Oncology

    PubMed Central

    Inaoka, Kenichi; Inokawa, Yoshikuni; Nomoto, Shuji

    2015-01-01

    DNA microarray technologies have advanced rapidly and had a profound impact on examining gene expression on a genomic scale in research. This review discusses the history and development of microarray and DNA chip devices, and specific microarrays are described along with their methods and applications. In particular, microarrays have detected many novel cancer-related genes by comparing cancer tissues and non-cancerous tissues in oncological research. Recently, new methods have been in development, such as the double-combination array and triple-combination array, which allow more effective analysis of gene expression and epigenetic changes. Analysis of gene expression alterations in precancerous regions compared with normal regions and array analysis in drug-resistance cancer tissues are also successfully performed. Compared with next-generation sequencing, a similar method of genome analysis, several important differences distinguish these techniques and their applications. Development of novel microarray technologies is expected to contribute to further cancer research.

  12. Genome-wide identification and characterization of reference genes with different transcript abundances for Streptomyces coelicolor

    PubMed Central

    Li, Shanshan; Wang, Weishan; Li, Xiao; Fan, Keqiang; Yang, Keqian

    2015-01-01

    The lack of reliable reference genes (RGs) in the genus Streptomyces hampers effort to obtain the precise data of transcript levels. To address this issue, we aimed to identify reliable RGs in the model organism Streptomyces coelicolor. A pool of potential RGs containing 1,471 genes was first identified by determining the intersection of genes with stable transcript levels from four time-series transcriptome microarray datasets of S. coelicolor M145 cultivated in different conditions. Then, following a strict rational selection scheme including homology analysis, disturbance analysis, function analysis and transcript abundance analysis, 13 candidates were selected from the 1,471 genes. Based on real-time quantitative reverse transcription PCR assays, SCO0710, SCO6185, SCO1544, SCO3183 and SCO4758 were identified as the top five genes with the most stable transcript levels among the 13 candidates. Further analyses showed these five genes also maintained stable transcript levels in different S. coelicolor strains, as well as in Streptomyces avermitilis MA-4680 and Streptomyces clavuligerus NRRL 3585, suggesting they could fulfill the requirements of accurate data normalization in streptomycetes. Moreover, the systematic strategy employed in this work could be used for reference in other microorganism to select reliable RGs. PMID:26527303

  13. Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease

    PubMed Central

    Forabosco, Paola; Neuhausen, Susan L.; Greco, Luigi; Naluai, Åsa Torinsson; Wijmenga, Cisca; Saavalainen, Päivi; Houlston, Richard S.; Ciclitira, Paul J.; Babron, Marie-Claude; Lewis, Cathryn M.

    2009-01-01

    Objective A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. Methods Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. Results Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. Conclusion This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants. PMID:19622889

  14. Genome-wide transcriptional response of silkworm (Bombyx mori) to infection by the microsporidian Nosema bombycis.

    PubMed

    Ma, Zhengang; Li, Chunfeng; Pan, Guoqing; Li, Zhihong; Han, Bing; Xu, Jinshan; Lan, Xiqian; Chen, Jie; Yang, Donglin; Chen, Quanmei; Sang, Qi; Ji, Xiaocun; Li, Tian; Long, Mengxian; Zhou, Zeyang

    2013-01-01

    Microsporidia have attracted much attention because they infect a variety of species ranging from protists to mammals, including immunocompromised patients with AIDS or cancer. Aside from the study on Nosema ceranae, few works have focused on elucidating the mechanism in host response to microsporidia infection. Nosema bombycis is a pathogen of silkworm pébrine that causes great economic losses to the silkworm industry. Detailed understanding of the host (Bombyx mori) response to infection by N. bombycis is helpful for prevention of this disease. A genome-wide survey of the gene expression profile at 2, 4, 6 and 8 days post-infection by N. bombycis was performed and results showed that 64, 244, 1,328, 1,887 genes were induced, respectively. Up to 124 genes, which are involved in basal metabolism pathways, were modulated. Notably, B. mori genes that play a role in juvenile hormone synthesis and metabolism pathways were induced, suggesting that the host may accumulate JH as a response to infection. Interestingly, N. bombycis can inhibit the silkworm serine protease cascade melanization pathway in hemolymph, which may be due to the secretion of serpins in the microsporidia. N. bombycis also induced up-regulation of several cellular immune factors, in which CTL11 has been suggested to be involved in both spore recognition and immune signal transduction. Microarray and real-time PCR analysis indicated the activation of silkworm Toll and JAK/STAT pathways. The notable up-regulation of antimicrobial peptides, including gloverins, lebocins and moricins, strongly indicated that antimicrobial peptide defense mechanisms were triggered to resist the invasive microsporidia. An analysis of N. bombycis-specific response factors suggested their important roles in anti-microsporidia defense. Overall, this study primarily provides insight into the potential molecular mechanisms for the host-parasite interaction between B. mori and N. bombycis and may provide a foundation for

  15. Genome-Wide Transcriptional Response of Silkworm (Bombyx mori) to Infection by the Microsporidian Nosema bombycis

    PubMed Central

    Pan, Guoqing; Li, Zhihong; Han, Bing; Xu, Jinshan; Lan, Xiqian; Chen, Jie; Yang, Donglin; Chen, Quanmei; Sang, Qi; Ji, Xiaocun; Li, Tian; Long, Mengxian; Zhou, Zeyang

    2013-01-01

    Microsporidia have attracted much attention because they infect a variety of species ranging from protists to mammals, including immunocompromised patients with AIDS or cancer. Aside from the study on Nosema ceranae, few works have focused on elucidating the mechanism in host response to microsporidia infection. Nosema bombycis is a pathogen of silkworm pébrine that causes great economic losses to the silkworm industry. Detailed understanding of the host (Bombyx mori) response to infection by N. bombycis is helpful for prevention of this disease. A genome-wide survey of the gene expression profile at 2, 4, 6 and 8 days post-infection by N. bombycis was performed and results showed that 64, 244, 1,328, 1,887 genes were induced, respectively. Up to 124 genes, which are involved in basal metabolism pathways, were modulated. Notably, B. mori genes that play a role in juvenile hormone synthesis and metabolism pathways were induced, suggesting that the host may accumulate JH as a response to infection. Interestingly, N. bombycis can inhibit the silkworm serine protease cascade melanization pathway in hemolymph, which may be due to the secretion of serpins in the microsporidia. N. bombycis also induced up-regulation of several cellular immune factors, in which CTL11 has been suggested to be involved in both spore recognition and immune signal transduction. Microarray and real-time PCR analysis indicated the activation of silkworm Toll and JAK/STAT pathways. The notable up-regulation of antimicrobial peptides, including gloverins, lebocins and moricins, strongly indicated that antimicrobial peptide defense mechanisms were triggered to resist the invasive microsporidia. An analysis of N. bombycis-specific response factors suggested their important roles in anti-microsporidia defense. Overall, this study primarily provides insight into the potential molecular mechanisms for the host-parasite interaction between B. mori and N. bombycis and may provide a foundation for

  16. 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

  17. Genome-wide Comparative Analysis of Annexin Superfamily in Plants

    PubMed Central

    Jami, Sravan Kumar; Clark, Greg B.; Ayele, Belay T.; Ashe, Paula; Kirti, Pulugurtha Bharadwaja

    2012-01-01

    Most annexins are calcium-dependent, phospholipid-binding proteins with suggested functions in response to environmental stresses and signaling during plant growth and development. They have previously been identified and characterized in Arabidopsis and rice, and constitute a multigene family in plants. In this study, we performed a comparative analysis of annexin gene families in the sequenced genomes of Viridiplantae ranging from unicellular green algae to multicellular plants, and identified 149 genes. Phylogenetic studies of these deduced annexins classified them into nine different arbitrary groups. The occurrence and distribution of bona fide type II calcium binding sites within the four annexin domains were found to be different in each of these groups. Analysis of chromosomal distribution of annexin genes in rice, Arabidopsis and poplar revealed their localization on various chromosomes with some members also found on duplicated chromosomal segments leading to gene family expansion. Analysis of gene structure suggests sequential or differential loss of introns during the evolution of land plant annexin genes. Intron positions and phases are well conserved in annexin genes from representative genomes ranging from Physcomitrella to higher plants. The occurrence of alternative motifs such as K/R/HGD was found to be overlapping or at the mutated regions of the type II calcium binding sites indicating potential functional divergence in certain plant annexins. This study provides a basis for further functional analysis and characterization of annexin multigene families in the plant lineage. PMID:23133603

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

    PubMed Central

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

    2015-01-01

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

  19. Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy.

    PubMed

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

    2015-03-01

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

  20. TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile.

    PubMed

    Huang, Yen-Tsung; Hsu, Thomas; Christiani, David C

    2014-01-01

    The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X (2) distributions that can be obtained using permutation with scaled X (2) approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small-cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 × 10(-5)), including the PTEN pathway (7.8 × 10(-7)), the gene set up-regulated under heat shock (3.6 × 10(-6)), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 × 10(-6)) and for transcriptional control of leukocytes (2.2 × 10(-5)), and the ganglioside biosynthesis pathway (2.7 × 10(-5)). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study.

  1. Genome-wide analysis of mobile genetic element insertion sites

    PubMed Central

    Rawal, Kamal; Ramaswamy, Ram

    2011-01-01

    Mobile genetic elements (MGEs) account for a significant fraction of eukaryotic genomes and are implicated in altered gene expression and disease. We present an efficient computational protocol for MGE insertion site analysis. ELAN, the suite of tools described here uses standard techniques to identify different MGEs and their distribution on the genome. One component, DNASCANNER analyses known insertion sites of MGEs for the presence of signals that are based on a combination of local physical and chemical properties. ISF (insertion site finder) is a machine-learning tool that incorporates information derived from DNASCANNER. ISF permits classification of a given DNA sequence as a potential insertion site or not, using a support vector machine. We have studied the genomes of Homo sapiens, Mus musculus, Drosophila melanogaster and Entamoeba histolytica via a protocol whereby DNASCANNER is used to identify a common set of statistically important signals flanking the insertion sites in the various genomes. These are used in ISF for insertion site prediction, and the current accuracy of the tool is over 65%. We find similar signals at gene boundaries and splice sites. Together, these data are suggestive of a common insertion mechanism that operates in a variety of eukaryotes. PMID:21609951

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

    PubMed Central

    Kann, Martin; Ettou, Sandrine; Jung, Youngsook L.; Lenz, Maximilian O.; Taglienti, Mary E.; Park, Peter J.; Schermer, Bernhard

    2015-01-01

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

  3. Defining the RNA polymerase III transcriptome: Genome-wide localization of the RNA polymerase III transcription machinery in human cells

    PubMed Central

    Canella, Donatella; Praz, Viviane; Reina, Jaime H.; Cousin, Pascal; Hernandez, Nouria

    2010-01-01

    Our view of the RNA polymerase III (Pol III) transcription machinery in mammalian cells arises mostly from studies of the RN5S (5S) gene, the Ad2 VAI gene, and the RNU6 (U6) gene, as paradigms for genes with type 1, 2, and 3 promoters. Recruitment of Pol III onto these genes requires prior binding of well-characterized transcription factors. Technical limitations in dealing with repeated genomic units, typically found at mammalian Pol III genes, have so far hampered genome-wide studies of the Pol III transcription machinery and transcriptome. We have localized, genome-wide, Pol III and some of its transcription factors. Our results reveal broad usage of the known Pol III transcription machinery and define a minimal Pol III transcriptome in dividing IMR90hTert fibroblasts. This transcriptome consists of some 500 actively transcribed genes including a few dozen candidate novel genes, of which we confirmed nine as Pol III transcription units by additional methods. It does not contain any of the microRNA genes previously described as transcribed by Pol III, but reveals two other microRNA genes, MIR886 (hsa-mir-886) and MIR1975 (RNY5, hY5, hsa-mir-1975), which are genuine Pol III transcription units. PMID:20413673

  4. Genome-wide organization and expression profiling of the NAC transcription factor family in potato (Solanum tuberosum L.).

    PubMed

    Singh, Anil Kumar; Sharma, Vishal; Pal, Awadhesh Kumar; Acharya, Vishal; Ahuja, Paramvir Singh

    2013-08-01

    NAC [no apical meristem (NAM), Arabidopsis thaliana transcription activation factor [ATAF1/2] and cup-shaped cotyledon (CUC2)] proteins belong to one of the largest plant-specific transcription factor (TF) families and play important roles in plant development processes, response to biotic and abiotic cues and hormone signalling. Our genome-wide analysis identified 110 StNAC genes in potato encoding for 136 proteins, including 14 membrane-bound TFs. The physical map positions of StNAC genes on 12 potato chromosomes were non-random, and 40 genes were found to be distributed in 16 clusters. The StNAC proteins were phylogenetically clustered into 12 subgroups. Phylogenetic analysis of StNACs along with their Arabidopsis and rice counterparts divided these proteins into 18 subgroups. Our comparative analysis has also identified 36 putative TNAC proteins, which appear to be restricted to Solanaceae family. In silico expression analysis, using Illumina RNA-seq transcriptome data, revealed tissue-specific, biotic, abiotic stress and hormone-responsive expression profile of StNAC genes. Several StNAC genes, including StNAC072 and StNAC101that are orthologs of known stress-responsive Arabidopsis RESPONSIVE TO DEHYDRATION 26 (RD26) were identified as highly abiotic stress responsive. Quantitative real-time polymerase chain reaction analysis largely corroborated the expression profile of StNAC genes as revealed by the RNA-seq data. Taken together, this analysis indicates towards putative functions of several StNAC TFs, which will provide blue-print for their functional characterization and utilization in potato improvement.

  5. 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

  6. Genome-wide phylogenetic analysis of differences in thermotolerance among closely related Acetobacter pasteurianus strains.

    PubMed

    Matsutani, Minenosuke; Hirakawa, Hideki; Saichana, Natsaran; Soemphol, Wichai; Yakushi, Toshiharu; Matsushita, Kazunobu

    2012-01-01

    Acetobacter pasteurianus is a Gram-negative strictly aerobic bacterium that is widely used for the industrial production of vinegar. Three Acetobacter pasteurianus strains, SKU1108, NBRC 3283 and IFO 3191, have the same 16S rRNA sequence (100 % sequence identity) but show differences in thermotolerance. To clarify the relationships between phylogeny and thermotolerance of these strains, genome-wide analysis of these three strains was performed. Concatenated phylogenetic analysis of a dataset of 1864 orthologues has shown that the more thermotolerant strains, SKU1108 and NBRC 3283, are more closely related to each other than to the more thermosensitive strain, IFO 3191. In addition, we defined a dataset of 2010 unique orthologues among these three strains, and compared the frequency of amino acid mutations among them. Genes involved in translation, transcription and signal transduction are highly conserved among each unique orthologous dataset. The results also showed that there are several genes with increased mutation rates in IFO 3191 compared with the thermotolerant strains, SKU1108 and NBRC 3283. Analysis of the mutational directions of these genes suggested that some of them might be correlated with the thermosensitivity of IFO 3191. Concatenated phylogenetic analysis of these closely related strains revealed that there is a phylogenetic relationship associated with this phenotype among the thermotolerant and thermosensitive strains.

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

    PubMed

    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.

  8. 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

  9. 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

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

    PubMed

    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

  11. RAX2: a genome-wide detection method of condition-associated transcription variation

    PubMed Central

    Tan, Yuan-De; Deng, Jixin; Neilson, Joel R

    2015-01-01

    Most mammalian genes have mRNA variants due to alternative promoter usage, alternative splicing, and alternative cleavage and polyadenylation. Expression of alternative RNA isoforms has been found to be associated with tumorigenesis, proliferation and differentiation. Detection of condition-associated transcription variation requires association methods. Traditional association methods such as Pearson chi-square test and Fisher Exact test are single test methods and do not work on count data with replicates. Although the Cochran Mantel Haenszel (CMH) approach can handle replicated count data, our simulations showed that multiple CMH tests still had very low power. To identify condition-associated variation of transcription, we here proposed a ranking analysis of chi-squares (RAX2) for large-scale association analysis. RAX2 is a nonparametric method and has accurate and conservative estimation of FDR profile. Simulations demonstrated that RAX2 performs well in finding condition-associated transcription variants. We applied RAX2 to primary T-cell transcriptomic data and identified 1610 (16.3%) tags associated in transcription with immune stimulation at FDR < 0.05. Most of these tags also had differential expression. Analysis of two and three tags within genes revealed that under immune stimulation short RNA isoforms were preferably used. PMID:25953852

  12. 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

  13. 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.

  14. Genome-wide Identification of TCP Family Transcription Factors from Populus euphratica and Their Involvement in Leaf Shape Regulation.

    PubMed

    Ma, Xiaodong; Ma, Jianchao; Fan, Di; Li, Chaofeng; Jiang, Yuanzhong; Luo, Keming

    2016-01-01

    Higher plants have been shown to experience a juvenile vegetative phase, an adult vegetative phase, and a reproductive phase during its postembryonic development and distinct lateral organ morphologies have been observed at the different development stages. Populus euphratica, commonly known as a desert poplar, has developed heteromorphic leaves during its development. The TCP family genes encode a group of plant-specific transcription factors involved in several aspects of plant development. In particular, TCPs have been shown to influence leaf size and shape in many herbaceous plants. However, whether these functions are conserved in woody plants remains unknown. In the present study, we carried out genome-wide identification of TCP genes in P. euphratica and P. trichocarpa, and 33 and 36 genes encoding putative TCP proteins were found, respectively. Phylogenetic analysis of the poplar TCPs together with Arabidopsis TCPs indicated a biased expansion of the TCP gene family via segmental duplications. In addition, our results have also shown a correlation between different expression patterns of several P. euphratica TCP genes and leaf shape variations, indicating their involvement in the regulation of leaf shape development. PMID:27605130

  15. Genome-wide Identification of TCP Family Transcription Factors from Populus euphratica and Their Involvement in Leaf Shape Regulation

    PubMed Central

    Ma, Xiaodong; Ma, Jianchao; Fan, Di; Li, Chaofeng; Jiang, Yuanzhong; Luo, Keming

    2016-01-01

    Higher plants have been shown to experience a juvenile vegetative phase, an adult vegetative phase, and a reproductive phase during its postembryonic development and distinct lateral organ morphologies have been observed at the different development stages. Populus euphratica, commonly known as a desert poplar, has developed heteromorphic leaves during its development. The TCP family genes encode a group of plant-specific transcription factors involved in several aspects of plant development. In particular, TCPs have been shown to influence leaf size and shape in many herbaceous plants. However, whether these functions are conserved in woody plants remains unknown. In the present study, we carried out genome-wide identification of TCP genes in P. euphratica and P. trichocarpa, and 33 and 36 genes encoding putative TCP proteins were found, respectively. Phylogenetic analysis of the poplar TCPs together with Arabidopsis TCPs indicated a biased expansion of the TCP gene family via segmental duplications. In addition, our results have also shown a correlation between different expression patterns of several P. euphratica TCP genes and leaf shape variations, indicating their involvement in the regulation of leaf shape development. PMID:27605130

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

    PubMed

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

    2011-05-01

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

  17. 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

  18. 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...

  19. Genome-Wide Transcriptome and Expression Profile Analysis of Phalaenopsis during Explant Browning

    PubMed Central

    Xu, Chuanjun; Zeng, Biyu; Huang, Junmei; Huang, Wen; Liu, Yumei

    2015-01-01

    Background Explant browning presents a major problem for in vitro culture, and can lead to the death of the explant and failure of regeneration. Considerable work has examined the physiological mechanisms underlying Phalaenopsis leaf explant browning, but the molecular mechanisms of browning remain elusive. In this study, we used whole genome RNA sequencing to examine Phalaenopsis leaf explant browning at genome-wide level. Methodology/Principal Findings We first used Illumina high-throughput technology to sequence the transcriptome of Phalaenopsis and then performed de novo transcriptome assembly. We assembled 79,434,350 clean reads into 31,708 isogenes and generated 26,565 annotated unigenes. We assigned Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, and potential Pfam domains to each transcript. Using the transcriptome data as a reference, we next analyzed the differential gene expression of explants cultured for 0, 3, and 6 d, respectively. We then identified differentially expressed genes (DEGs) before and after Phalaenopsis explant browning. We also performed GO, KEGG functional enrichment and Pfam analysis of all DEGs. Finally, we selected 11 genes for quantitative real-time PCR (qPCR) analysis to confirm the expression profile analysis. Conclusions/Significance Here, we report the first comprehensive analysis of transcriptome and expression profiles during Phalaenopsis explant browning. Our results suggest that Phalaenopsis explant browning may be due in part to gene expression changes that affect the secondary metabolism, such as: phenylpropanoid pathway and flavonoid biosynthesis. Genes involved in photosynthesis and ATPase activity have been found to be changed at transcription level; these changes may perturb energy metabolism and thus lead to the decay of plant cells and tissues. This study provides comprehensive gene expression data for Phalaenopsis browning. Our data constitute an important resource for further

  20. Physiological, biochemical, and genome-wide transcriptional analysis reveals that elevated CO2 mitigates the impact of combined heat wave and drought stress in Arabidopsis thaliana at multiple organizational levels.

    PubMed

    Zinta, Gaurav; AbdElgawad, Hamada; Domagalska, Malgorzata A; Vergauwen, Lucia; Knapen, Dries; Nijs, Ivan; Janssens, Ivan A; Beemster, Gerrit T S; Asard, Han

    2014-12-01

    Climate changes increasingly threaten plant growth and productivity. Such changes are complex and involve multiple environmental factors, including rising CO2 levels and climate extreme events. As the molecular and physiological mechanisms underlying plant responses to realistic future climate extreme conditions are still poorly understood, a multiple organizational level analysis (i.e. eco-physiological, biochemical, and transcriptional) was performed, using Arabidopsis exposed to incremental heat wave and water deficit under ambient and elevated CO2 . The climate extreme resulted in biomass reduction, photosynthesis inhibition, and considerable increases in stress parameters. Photosynthesis was a major target as demonstrated at the physiological and transcriptional levels. In contrast, the climate extreme treatment induced a protective effect on oxidative membrane damage, most likely as a result of strongly increased lipophilic antioxidants and membrane-protecting enzymes. Elevated CO2 significantly mitigated the negative impact of a combined heat and drought, as apparent in biomass reduction, photosynthesis inhibition, chlorophyll fluorescence decline, H2 O2 production, and protein oxidation. Analysis of enzymatic and molecular antioxidants revealed that the stress-mitigating CO2 effect operates through up-regulation of antioxidant defense metabolism, as well as by reduced photorespiration resulting in lowered oxidative pressure. Therefore, exposure to future climate extreme episodes will negatively impact plant growth and production, but elevated CO2 is likely to mitigate this effect.

  1. On the Analysis of a Repeated Measure Design in Genome-Wide Association Analysis

    PubMed Central

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

    2014-01-01

    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. PMID:25464127

  2. MYB Transcription Factors in Chinese Pear (Pyrus bretschneideri Rehd.): Genome-Wide Identification, Classification, and Expression Profiling during Fruit Development.

    PubMed

    Cao, Yunpeng; Han, Yahui; Li, Dahui; Lin, Yi; Cai, Yongping

    2016-01-01

    The MYB family is one of the largest families of transcription factors in plants. Although, some MYBs were reported to play roles in secondary metabolism, no comprehensive study of the MYB family in Chinese pear (Pyrus bretschneideri Rehd.) has been reported. In the present study, we performed genome-wide analysis of MYB genes in Chinese pear, designated as PbMYBs, including analyses of their phylogenic relationships, structures, chromosomal locations, promoter regions, GO annotations, and collinearity. A total of 129 PbMYB genes were identified in the pear genome and were divided into 31 subgroups based on phylogenetic analysis. These PbMYBs were unevenly distributed among 16 chromosomes (total of 17 chromosomes). The occurrence of gene duplication events indicated that whole-genome duplication and segmental duplication likely played key roles in expansion of the PbMYB gene family. Ka/Ks analysis suggested that the duplicated PbMYBs mainly experienced purifying selection with restrictive functional divergence after the duplication events. Interspecies microsynteny analysis revealed maximum orthology between pear and peach, followed by plum and strawberry. Subsequently, the expression patterns of 20 PbMYB genes that may be involved in lignin biosynthesis according to their phylogenetic relationships were examined throughout fruit development. Among the 20 genes examined, PbMYB25 and PbMYB52 exhibited expression patterns consistent with the typical variations in the lignin content previously reported. Moreover, sub-cellular localization analysis revealed that two proteins PbMYB25 and PbMYB52 were localized to the nucleus. All together, PbMYB25 and PbMYB52 were inferred to be candidate genes involved in the regulation of lignin biosynthesis during the development of pear fruit. This study provides useful information for further functional analysis of the MYB gene family in pear. PMID:27200050

  3. MYB Transcription Factors in Chinese Pear (Pyrus bretschneideri Rehd.): Genome-Wide Identification, Classification, and Expression Profiling during Fruit Development.

    PubMed

    Cao, Yunpeng; Han, Yahui; Li, Dahui; Lin, Yi; Cai, Yongping

    2016-01-01

    The MYB family is one of the largest families of transcription factors in plants. Although, some MYBs were reported to play roles in secondary metabolism, no comprehensive study of the MYB family in Chinese pear (Pyrus bretschneideri Rehd.) has been reported. In the present study, we performed genome-wide analysis of MYB genes in Chinese pear, designated as PbMYBs, including analyses of their phylogenic relationships, structures, chromosomal locations, promoter regions, GO annotations, and collinearity. A total of 129 PbMYB genes were identified in the pear genome and were divided into 31 subgroups based on phylogenetic analysis. These PbMYBs were unevenly distributed among 16 chromosomes (total of 17 chromosomes). The occurrence of gene duplication events indicated that whole-genome duplication and segmental duplication likely played key roles in expansion of the PbMYB gene family. Ka/Ks analysis suggested that the duplicated PbMYBs mainly experienced purifying selection with restrictive functional divergence after the duplication events. Interspecies microsynteny analysis revealed maximum orthology between pear and peach, followed by plum and strawberry. Subsequently, the expression patterns of 20 PbMYB genes that may be involved in lignin biosynthesis according to their phylogenetic relationships were examined throughout fruit development. Among the 20 genes examined, PbMYB25 and PbMYB52 exhibited expression patterns consistent with the typical variations in the lignin content previously reported. Moreover, sub-cellular localization analysis revealed that two proteins PbMYB25 and PbMYB52 were localized to the nucleus. All together, PbMYB25 and PbMYB52 were inferred to be candidate genes involved in the regulation of lignin biosynthesis during the development of pear fruit. This study provides useful information for further functional analysis of the MYB gene family in pear.

  4. MYB Transcription Factors in Chinese Pear (Pyrus bretschneideri Rehd.): Genome-Wide Identification, Classification, and Expression Profiling during Fruit Development

    PubMed Central

    Cao, Yunpeng; Han, Yahui; Li, Dahui; Lin, Yi; Cai, Yongping

    2016-01-01

    The MYB family is one of the largest families of transcription factors in plants. Although, some MYBs were reported to play roles in secondary metabolism, no comprehensive study of the MYB family in Chinese pear (Pyrus bretschneideri Rehd.) has been reported. In the present study, we performed genome-wide analysis of MYB genes in Chinese pear, designated as PbMYBs, including analyses of their phylogenic relationships, structures, chromosomal locations, promoter regions, GO annotations, and collinearity. A total of 129 PbMYB genes were identified in the pear genome and were divided into 31 subgroups based on phylogenetic analysis. These PbMYBs were unevenly distributed among 16 chromosomes (total of 17 chromosomes). The occurrence of gene duplication events indicated that whole-genome duplication and segmental duplication likely played key roles in expansion of the PbMYB gene family. Ka/Ks analysis suggested that the duplicated PbMYBs mainly experienced purifying selection with restrictive functional divergence after the duplication events. Interspecies microsynteny analysis revealed maximum orthology between pear and peach, followed by plum and strawberry. Subsequently, the expression patterns of 20 PbMYB genes that may be involved in lignin biosynthesis according to their phylogenetic relationships were examined throughout fruit development. Among the 20 genes examined, PbMYB25 and PbMYB52 exhibited expression patterns consistent with the typical variations in the lignin content previously reported. Moreover, sub-cellular localization analysis revealed that two proteins PbMYB25 and PbMYB52 were localized to the nucleus. All together, PbMYB25 and PbMYB52 were inferred to be candidate genes involved in the regulation of lignin biosynthesis during the development of pear fruit. This study provides useful information for further functional analysis of the MYB gene family in pear. PMID:27200050

  5. Genome-wide mapping of conserved microRNAs and their host transcripts in Tribolium castaneum.

    PubMed

    Luo, Qibin; Zhou, Qing; Yu, Xiaomin; Lin, Hongbin; Hu, Songnian; Yu, Jun

    2008-06-01

    MicroRNAs (miRNAs) are endogenous 22-nt RNAs, which play important regulatory roles by post-transcriptional gene silencing. A computational strategy has been developed for the identification of conserved miRNAs based on features of known metazoan miRNAs in red flour beetle (Tribolium castaneum), which is regarded as one of the major laboratory models of arthropods. Among 118 putative miRNAs, 47% and 53% of the predicted miRNAs from the red flour beetle are harbored by known protein-coding genes (intronic) and genes located outside (intergenic miRNA), respectively. There are 31 intronic miRNAs in the same transcriptional orientation as the host genes, which may share RNA polymerase II and spliceosomal machinery with their host genes for their biogenesis. A hypothetical feedback model has been proposed based on the analysis of the relationship between intronic miRNAs and their host genes in the development of red flour beetle.

  6. 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

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

    PubMed

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

    2016-09-01

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

  8. Genome-wide review of transcriptional complexity in mouse protein kinases and phosphatases

    PubMed Central

    Forrest, Alistair RR; Taylor, Darrin F; Crowe, Mark L; Chalk, Alistair M; Waddell, Nic J; Kolle, Gabriel; Faulkner, Geoffrey J; Kodzius, Rimantas; Katayama, Shintaro; Wells, Christine; Kai, Chikatoshi; Kawai, Jun; Carninci, Piero; Hayashizaki, Yoshihide; Grimmond, Sean M

    2006-01-01

    Background Alternative transcripts of protein kinases and protein phosphatases are known to encode peptides with altered substrate affinities, subcellular localizations, and activities. We undertook a systematic study to catalog the variant transcripts of every protein kinase-like and phosphatase-like locus of mouse . Results By reviewing all available transcript evidence, we found that at least 75% of kinase and phosphatase loci in mouse generate alternative splice forms, and that 44% of these loci have well supported alternative 5' exons. In a further analysis of full-length cDNAs, we identified 69% of loci as generating more than one peptide isoform. The 1,469 peptide isoforms generated from these loci correspond to 1,080 unique Interpro domain combinations, many of which lack catalytic or interaction domains. We also report on the existence of likely dominant negative forms for many of the receptor kinases and phosphatases, including some 26 secreted decoys (seven known and 19 novel: Alk, Csf1r, Egfr, Epha1, 3, 5,7 and 10, Ephb1, Flt1, Flt3, Insr, Insrr, Kdr, Met, Ptk7, Ptprc, Ptprd, Ptprg, Ptprl, Ptprn, Ptprn2, Ptpro, Ptprr, Ptprs, and Ptprz1) and 13 transmembrane forms (four known and nine novel: Axl, Bmpr1a, Csf1r, Epha4, 5, 6 and 7, Ntrk2, Ntrk3, Pdgfra, Ptprk, Ptprm, Ptpru). Finally, by mining public gene expression data (MPSS and microarrays), we confirmed tissue-specific expression of ten of the novel isoforms. Conclusion These findings suggest that alternative transcripts of protein kinases and phosphatases are produced that encode different domain structures, and that these variants are likely to play important roles in phosphorylation-dependent signaling pathways. PMID:16507138

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

    PubMed Central

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

    2014-01-01

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

  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. COPS: Detecting Co-Occurrence and Spatial Arrangement of Transcription Factor Binding Motifs in Genome-Wide Datasets

    PubMed Central

    Lohmann, Ingrid

    2012-01-01

    In multi-cellular organisms, spatiotemporal activity of cis-regulatory DNA elements depends on their occupancy by different transcription factors (TFs). In recent years, genome-wide ChIP-on-Chip, ChIP-Seq and DamID assays have been extensively used to unravel the combinatorial interaction of TFs with cis-regulatory modules (CRMs) in the genome. Even though genome-wide binding profiles are increasingly becoming available for different TFs, single TF binding profiles are in most cases not sufficient for dissecting complex regulatory networks. Thus, potent computational tools detecting statistically significant and biologically relevant TF-motif co-occurrences in genome-wide datasets are essential for analyzing context-dependent transcriptional regulation. We have developed COPS (Co-Occurrence Pattern Search), a new bioinformatics tool based on a combination of association rules and Markov chain models, which detects co-occurring TF binding sites (BSs) on genomic regions of interest. COPS scans DNA sequences for frequent motif patterns using a Frequent-Pattern tree based data mining approach, which allows efficient performance of the software with respect to both data structure and implementation speed, in particular when mining large datasets. Since transcriptional gene regulation very often relies on the formation of regulatory protein complexes mediated by closely adjoining TF binding sites on CRMs, COPS additionally detects preferred short distance between co-occurring TF motifs. The performance of our software with respect to biological significance was evaluated using three published datasets containing genomic regions that are independently bound by several TFs involved in a defined biological process. In sum, COPS is a fast, efficient and user-friendly tool mining statistically and biologically significant TFBS co-occurrences and therefore allows the identification of TFs that combinatorially regulate gene expression. PMID:23272209

  12. Tomato Genome-Wide Transcriptional Responses to Fusarium Wilt and Tomato Mosaic Virus

    PubMed Central

    Andolfo, Giuseppe; Ferriello, Francesca; Tardella, Luca; Ferrarini, Alberto; Sigillo, Loredana; Frusciante, Luigi; Ercolano, Maria Raffaella

    2014-01-01

    Since gene expression approaches constitute a starting point for investigating plant–pathogen systems, we performed a transcriptional analysis to identify a set of genes of interest in tomato plants infected with F. oxysporum f. sp. lycopersici (Fol) and Tomato Mosaic Virus (ToMV). Differentially expressed tomato genes upon inoculation with Fol and ToMV were identified at two days post-inoculation. A large overlap was found in differentially expressed genes throughout the two incompatible interactions. However, Gene Ontology enrichment analysis evidenced specific categories in both interactions. Response to ToMV seems more multifaceted, since more than 70 specific categories were enriched versus the 30 detected in Fol interaction. In particular, the virus stimulated the production of an invertase enzyme that is able to redirect the flux of carbohydrates, whereas Fol induced a homeostatic response to prevent the fungus from killing cells. Genomic mapping of transcripts suggested that specific genomic regions are involved in resistance response to pathogen. Coordinated machinery could play an important role in prompting the response, since 60% of pathogen receptor genes (NB-ARC-LRR, RLP, RLK) were differentially regulated during both interactions. Assessment of genomic gene expression patterns could help in building up models of mediated resistance responses. PMID:24804963

  13. Blood Genome-Wide Transcriptional Profiles of HER2 Negative Breast Cancers Patients

    PubMed Central

    Balacescu, Ovidiu; Balacescu, Loredana; Gherman, Claudia; Drigla, Flaviu; Pop, Laura; Bolba-Morar, Gabriela; Tudoran, Oana; Berindan-Neagoe, Ioana

    2016-01-01

    Tumors act systemically to sustain cancer progression, affecting the physiological processes in the host and triggering responses in the blood circulating cells. In this study, we explored blood transcriptional patterns of patients with two subtypes of HER2 negative breast cancers, with different prognosis and therapeutic outcome. Peripheral blood samples from seven healthy female donors and 29 women with breast cancer including 14 triple-negative breast cancers and 15 hormone-dependent breast cancers were evaluated by microarray. We also evaluated the stroma in primary tumors. Transcriptional analysis revealed distinct molecular signatures in the blood of HER2− breast cancer patients according to ER/PR status. Our data showed the implication of immune signaling in both breast cancer subtypes with an enrichment of these processes in the blood of TNBC patients. We observed a significant alteration of “chemokine signaling,” “IL-8 signaling,” and “communication between innate and adaptive immune cells” pathways in the blood of TNBC patients correlated with an increased inflammation and necrosis in their primary tumors. Overall, our data indicate that the presence of triple-negative breast cancer is associated with an enrichment of altered systemic immune-related pathways, suggesting that immunotherapy could possibly be synergistic to the chemotherapy, to improve the clinical outcome of these patients. PMID:26884644

  14. Genome-wide mapping of conserved microRNAs and their host transcripts in Tribolium castaneum.

    PubMed

    Luo, Qibin; Zhou, Qing; Yu, Xiaomin; Lin, Hongbin; Hu, Songnian; Yu, Jun

    2008-06-01

    MicroRNAs (miRNAs) are endogenous 22-nt RNAs, which play important regulatory roles by post-transcriptional gene silencing. A computational strategy has been developed for the identification of conserved miRNAs based on features of known metazoan miRNAs in red flour beetle (Tribolium castaneum), which is regarded as one of the major laboratory models of arthropods. Among 118 putative miRNAs, 47% and 53% of the predicted miRNAs from the red flour beetle are harbored by known protein-coding genes (intronic) and genes located outside (intergenic miRNA), respectively. There are 31 intronic miRNAs in the same transcriptional orientation as the host genes, which may share RNA polymerase II and spliceosomal machinery with their host genes for their biogenesis. A hypothetical feedback model has been proposed based on the analysis of the relationship between intronic miRNAs and their host genes in the development of red flour beetle. PMID:18571123

  15. Genome-wide identification of soybean WRKY transcription factors in response to salt stress.

    PubMed

    Yu, Yanchong; Wang, Nan; Hu, Ruibo; Xiang, Fengning

    2016-01-01

    Members of the large family of WRKY transcription factors are involved in a wide range of developmental and physiological processes, most particularly in the plant response to biotic and abiotic stress. Here, an analysis of the soybean genome sequence allowed the identification of the full complement of 188 soybean WRKY genes. Phylogenetic analysis revealed that soybean WRKY genes were classified into three major groups (I, II, III), with the second group further categorized into five subgroups (IIa-IIe). The soybean WRKYs from each group shared similar gene structures and motif compositions. The location of the GmWRKYs was dispersed over all 20 soybean chromosomes. The whole genome duplication appeared to have contributed significantly to the expansion of the family. Expression analysis by RNA-seq indicated that in soybean root, 66 of the genes responded rapidly and transiently to the imposition of salt stress, all but one being up-regulated. While in aerial part, 49 GmWRKYs responded, all but two being down-regulated. RT-qPCR analysis showed that in the whole soybean plant, 66 GmWRKYs exhibited distinct expression patterns in response to salt stress, of which 12 showed no significant change, 35 were decreased, while 19 were induced. The data present here provide critical clues for further functional studies of WRKY gene in soybean salt tolerance. PMID:27386364

  16. Genome-wide analysis of SAUR gene family in Solanaceae species.

    PubMed

    Wu, Jian; Liu, Songyu; He, Yanjun; Guan, Xiaoyan; Zhu, Xiangfei; Cheng, Lin; Wang, Jie; Lu, Gang

    2012-11-01

    The plant hormone auxin plays a vital role in regulating many aspects of plant growth and development. Small auxin up-regulated RNAs (SAURs) are primary auxin response genes hypothesized to be involved in auxin signaling pathway, but their functions remain unclear. Here, a genome-wide search for SAUR gene homologues in Solanaceae species identified 99 and 134 members of SAUR gene family from tomato and potato, respectively. Phylogenetic analysis indicated that the SAUR proteins from Arabidopsis, rice, sorghum, tomato and potato were divided into four major groups with 16 subgroups. Among them, 25 histidine-rich SAURs genes with metal-binding characteristics were found in Arabidopsis, sorghum and Solanaceae species, but not in rice. Using tomato as a model, a comprehensive overview of SAUR gene family is presented, including the gene structures, phylogeny and chromosome locations. Quantitative real-time PCR analysis indicated that 11 randomly selected SlSAUR genes in tomato could be expressed at least in one of the tomato organs/tissues tested. However, different SlSAUR genes displayed distinctive expression levels. SlSAUR16 and SlSAUR71 exhibited highly tissue-specific expression patterns. Almost all of the detected SlSAURs showed an accumulating pattern of mRNA along tomato flower and fruit development. Some of them displayed differential response to exogenous IAA treatment. The abiotic (cold, salt and drought) stresses significantly modified transcript levels of SlSAURs genes. Most of them were down-regulated in response to abiotic stresses (drought, heat and salinity), but SlSAUR58, as a histidine-rich SAUR gene, was up-regulated after salt treatment, indicating that it may play a specific role in the salt signaling transduction pathway. Our comparative analysis provides some basic genomic information for the SAUR genes in the Solanaceae species and will pave the way for deciphering their function during plant development.

  17. Genome-wide identification and characterization of GRAS transcription factors in sacred lotus (Nelumbo nucifera)

    PubMed Central

    Zhou, Ying; Zhou, Yu; Yang, Jie

    2016-01-01

    The GRAS gene family is one of the most important plant-specific gene families, which encodes transcriptional regulators and plays an essential role in plant development and physiological processes. The GRAS gene family has been well characterized in many higher plants such as Arabidopsis, rice, Chinese cabbage, tomato and tobacco. In this study, we identified 38 GRAS genes in sacred lotus (Nelumbo nucifera), analyzed their physical and chemical characteristics and performed phylogenetic analysis using the GRAS genes from eight representative plant species to show the evolution of GRAS genes in Planta. In addition, the gene structures and motifs of the sacred lotus GRAS proteins were characterized in detail. Comparative analysis identified 42 orthologous and 9 co-orthologous gene pairs between sacred lotus and Arabidopsis, and 35 orthologous and 22 co-orthologous gene pairs between sacred lotus and rice. Based on publically available RNA-seq data generated from leaf, petiole, rhizome and root, we found that most of the sacred lotus GRAS genes exhibited a tissue-specific expression pattern. Eight of the ten PAT1-clade GRAS genes, particularly NnuGRAS-05, NnuGRAS-10 and NnuGRAS-25, were preferentially expressed in rhizome and root. In summary, this is the first in silico analysis of the GRAS gene family in sacred lotus, which will provide valuable information for further molecular and biological analyses of this important gene family. PMID:27635351

  18. Genome-wide identification and characterization of GRAS transcription factors in sacred lotus (Nelumbo nucifera)

    PubMed Central

    Zhou, Ying; Zhou, Yu; Yang, Jie

    2016-01-01

    The GRAS gene family is one of the most important plant-specific gene families, which encodes transcriptional regulators and plays an essential role in plant development and physiological processes. The GRAS gene family has been well characterized in many higher plants such as Arabidopsis, rice, Chinese cabbage, tomato and tobacco. In this study, we identified 38 GRAS genes in sacred lotus (Nelumbo nucifera), analyzed their physical and chemical characteristics and performed phylogenetic analysis using the GRAS genes from eight representative plant species to show the evolution of GRAS genes in Planta. In addition, the gene structures and motifs of the sacred lotus GRAS proteins were characterized in detail. Comparative analysis identified 42 orthologous and 9 co-orthologous gene pairs between sacred lotus and Arabidopsis, and 35 orthologous and 22 co-orthologous gene pairs between sacred lotus and rice. Based on publically available RNA-seq data generated from leaf, petiole, rhizome and root, we found that most of the sacred lotus GRAS genes exhibited a tissue-specific expression pattern. Eight of the ten PAT1-clade GRAS genes, particularly NnuGRAS-05, NnuGRAS-10 and NnuGRAS-25, were preferentially expressed in rhizome and root. In summary, this is the first in silico analysis of the GRAS gene family in sacred lotus, which will provide valuable information for further molecular and biological analyses of this important gene family.

  19. Genome-wide identification and characterization of GRAS transcription factors in sacred lotus (Nelumbo nucifera).

    PubMed

    Wang, Yu; Shi, Shenglu; Zhou, Ying; Zhou, Yu; Yang, Jie; Tang, Xiaoqing

    2016-01-01

    The GRAS gene family is one of the most important plant-specific gene families, which encodes transcriptional regulators and plays an essential role in plant development and physiological processes. The GRAS gene family has been well characterized in many higher plants such as Arabidopsis, rice, Chinese cabbage, tomato and tobacco. In this study, we identified 38 GRAS genes in sacred lotus (Nelumbo nucifera), analyzed their physical and chemical characteristics and performed phylogenetic analysis using the GRAS genes from eight representative plant species to show the evolution of GRAS genes in Planta. In addition, the gene structures and motifs of the sacred lotus GRAS proteins were characterized in detail. Comparative analysis identified 42 orthologous and 9 co-orthologous gene pairs between sacred lotus and Arabidopsis, and 35 orthologous and 22 co-orthologous gene pairs between sacred lotus and rice. Based on publically available RNA-seq data generated from leaf, petiole, rhizome and root, we found that most of the sacred lotus GRAS genes exhibited a tissue-specific expression pattern. Eight of the ten PAT1-clade GRAS genes, particularly NnuGRAS-05, NnuGRAS-10 and NnuGRAS-25, were preferentially expressed in rhizome and root. In summary, this is the first in silico analysis of the GRAS gene family in sacred lotus, which will provide valuable information for further molecular and biological analyses of this important gene family. PMID:27635351

  20. Meta-analysis of 32 genome-wide linkage studies of schizophrenia

    PubMed Central

    Ng, MYM; Levinson, DF; Faraone, SV; Suarez, BK; DeLisi, LE; Arinami, T; Riley, B; Paunio, T; Pulver, AE; Irmansyah; Holmans, PA; Escamilla, M; Wildenauer, DB; Williams, NM; Laurent, C; Mowry, BJ; Brzustowicz, LM; Maziade, M; Sklar, P; Garver, DL; Abecasis, GR; Lerer, B; Fallin, MD; Gurling, HMD; Gejman, PV; Lindholm, E; Moises, HW; Byerley, W; Wijsman, EM; Forabosco, P; Tsuang, MT; Hwu, H-G; Okazaki, Y; Kendler, KS; Wormley, B; Fanous, A; Walsh, D; O’Neill, FA; Peltonen, L; Nestadt, G; Lasseter, VK; Liang, KY; Papadimitriou, GM; Dikeos, DG; Schwab, SG; Owen, MJ; O’Donovan, MC; Norton, N; Hare, E; Raventos, H; Nicolini, H; Albus, M; Maier, W; Nimgaonkar, VL; Terenius, L; Mallet, J; Jay, M; Godard, S; Nertney, D; Alexander, M; Crowe, RR; Silverman, JM; Bassett, AS; Roy, M-A; Mérette, C; Pato, CN; Pato, MT; Roos, J Louw; Kohn, Y; Amann-Zalcenstein, D; Kalsi, G; McQuillin, A; Curtis, D; Brynjolfson, J; Sigmundsson, T; Petursson, H; Sanders, AR; Duan, J; Jazin, E; Myles-Worsley, M; Karayiorgou, M; Lewis, CM

    2009-01-01

    A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. PMID:19349958

  1. 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

  2. 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. PMID:26237428

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

    PubMed

    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

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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. PMID:27630648

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

    PubMed Central

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

    2014-01-01

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

  10. A Genome-wide Screen for Neurospora crassa Transcription Factors Regulating Glycogen Metabolism*

    PubMed Central

    Gonçalves, Rodrigo Duarte; Cupertino, Fernanda Barbosa; Freitas, Fernanda Zanolli; Luchessi, Augusto Ducati; Bertolini, Maria Célia

    2011-01-01

    Transcription factors play a key role in transcription regulation as they recognize and directly bind to defined sites in promoter regions of target genes, and thus modulate differential expression. The overall process is extremely dynamic, as they have to move through the nucleus and transiently bind to chromatin in order to regulate gene transcription. To identify transcription factors that affect glycogen accumulation in Neurospora crassa, we performed a systematic screen of a deletion strains set generated by the Neurospora Knockout Project and available at the Fungal Genetics Stock Center. In a wild-type strain of N. crassa, glycogen content reaches a maximal level at the end of the exponential growth phase, but upon heat stress the glycogen content rapidly drops. The gene encoding glycogen synthase (gsn) is transcriptionally down-regulated when the mycelium is exposed to the same stress condition. We identified 17 deleted strains having glycogen accumulation profiles different from that of the wild-type strain under both normal growth and heat stress conditions. Most of the transcription factors identified were annotated as hypothetical protein, however some of them, such as the PacC, XlnR, and NIT2 proteins, were biochemically well-characterized either in N. crassa or in other fungi. The identification of some of the transcription factors was coincident with the presence of DNA-binding motifs specific for the transcription factors in the gsn 5′-flanking region, and some of these DNA-binding motifs were demonstrated to be functional by Electrophoretic Mobility Shift Assay (EMSA) experiments. Strains knocked-out in these transcription factors presented impairment in the regulation of gsn expression, suggesting that the transcription factors regulate glycogen accumulation by directly regulating gsn gene expression. Five selected mutant strains showed defects in cell cycle progression, and two transcription factors were light-regulated. The results indicate

  11. Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder

    PubMed Central

    Neale, Benjamin M; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schäfer, 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 scans (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children’s Hospital of Philadelphia (CHOP), b) phase I of the International Multicenter ADHD Genetics project (IMAGE), c) phase II of IMAGE (IMAGE II), and d) the Pfizer funded study from the University of California, Los Angeles, Washington University and the Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases and 2,455 controls. For each study, we imputed HapMap SNPs, computed association test statistics and transformed them to Z-scores, and then combined weighted Z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g. rare ones, account for much of the disorder’s heritability. PMID:20732625

  12. Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Drosophila Development

    PubMed Central

    Kaplan, Tommy; Li, Xiao-Yong; Sabo, Peter J.; Thomas, Sean; Stamatoyannopoulos, John A.; Biggin, Mark D.; Eisen, Michael B.

    2011-01-01

    Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be

  13. 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.

  14. Genome-wide assessment of post-transcriptional control in the fly brain.

    PubMed

    Mezan, Shaul; Ashwal-Fluss, Reut; Shenhav, Rom; Garber, Manuel; Kadener, Sebastian

    2013-01-01

    Post-transcriptional control of gene expression has central importance during development and adulthood and in physiology in general. However, little is known about the extent of post-transcriptional control of gene expression in the brain. Most post-transcriptional regulatory effectors (e.g., miRNAs) destabilize target mRNAs by shortening their polyA tails. Hence, the fraction of a given mRNA that it is fully polyadenylated should correlate with its stability and serves as a good measure of post-transcriptional control. Here, we compared RNA-seq datasets from fly brains that were generated either from total (rRNA-depleted) or polyA-selected RNA. By doing this comparison we were able to compute a coefficient that measures the extent of post-transcriptional control for each brain-expressed mRNA. In agreement with current knowledge, we found that mRNAs encoding ribosomal proteins, metabolic enzymes, and housekeeping genes are among the transcripts with least post-transcriptional control, whereas mRNAs that are known to be highly unstable, like circadian mRNAs and mRNAs expressing synaptic proteins and proteins with neuronal functions, are under strong post-transcriptional control. Surprisingly, the latter group included many specific groups of genes relevant to brain function and behavior. In order to determine the importance of miRNAs in this regulation, we profiled miRNAs from fly brains using oligonucleotide microarrays. Surprisingly, we did not find a strong correlation between the expression levels of miRNAs in the brain and the stability of their target mRNAs; however, genes identified as highly regulated post-transcriptionally were strongly enriched for miRNA targets. This demonstrates a central role of miRNAs for modulating the levels and turnover of brain-specific mRNAs in the fly. PMID:24367289

  15. 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. PMID:27135401

  16. Genome-wide meta-analysis of longitudinal alcohol consumption across youth and early adulthood

    PubMed Central

    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.

    2016-01-01

    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 6 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. 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. PMID:26081443

  17. 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

    2016-01-01

    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

  18. 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

  19. Genome-wide analysis and molecular dissection of the SPL gene family in Salvia miltiorrhiza.

    PubMed

    Zhang, Linsu; Wu, Bin; Zhao, Degang; Li, Caili; Shao, Fenjuan; Lu, Shanfa

    2014-01-01

    SQUAMOSA promoter binding protein-likes (SPLs) are plant-specific transcription factors playing vital regulatory roles in plant growth and development. There is no information about SPLs in Salvia miltiorrhiza (Danshen), a significant medicinal plant widely used in Traditional Chinese medicine (TCM) for >1,700 years and an emerging model plant for TCM studies. Through genome-wide identification and subsequent molecular cloning, we identified a total 15 SmSPLs with divergent sequence features, gene structures, and motifs. Comparative analysis showed sequence conservation between SmSPLs and their Arabidopsis counterparts. A phylogenetic tree clusters SmSPLs into six groups. Many of the motifs identified commonly exist in a group/subgroup, implying their functional redundancy. Eight SmSPLs were predicted and experimentally validated to be targets of miR156/157. SmSPLs were differentially expressed in various tissues of S. milltiorrhiza. The expression of miR156/157-targeted SmSPLs was increased with the maturation of S. miltiorrhiza, whereas the expression of miR156/157 was decreased, confirming the regulatory roles of miR156/157 in SmSPLs and suggesting the functions of SmSPLs in S. miltiorrhiza development. The expression of miR156/157 was negatively correlated with miR172 during the maturation of S. miltiorrhiza. The results indicate the significance and complexity of SmSPL-, miR156-, and miR172-mediated regulation of developmental timing in S. miltiorrhiza. PMID:24112769

  20. Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Szubin, Richard; Palsson, Bernhard O

    2015-08-25

    Three transcription factors (TFs), OxyR, SoxR, and SoxS, play a critical role in transcriptional regulation of the defense system for oxidative stress in bacteria. However, their full genome-wide regulatory potential is unknown. Here, we perform a genome-scale reconstruction of the OxyR, SoxR, and SoxS regulons in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 68 genes in 51 transcription units (TUs) belong to these regulons. Among them, 48 genes showed more than 2-fold changes in expression level under single-TF-knockout conditions. This reconstruction expands the genome-wide roles of these factors to include direct activation of genes related to amino acid biosynthesis (methionine and aromatic amino acids), cell wall synthesis (lipid A biosynthesis and peptidoglycan growth), and divalent metal ion transport (Mn(2+), Zn(2+), and Mg(2+)). Investigating the co-regulation of these genes with other stress-response TFs reveals that they are independently regulated by stress-specific TFs.

  1. Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; Szubin, Richard; Palsson, Bernhard O

    2015-08-25

    Three transcription factors (TFs), OxyR, SoxR, and SoxS, play a critical role in transcriptional regulation of the defense system for oxidative stress in bacteria. However, their full genome-wide regulatory potential is unknown. Here, we perform a genome-scale reconstruction of the OxyR, SoxR, and SoxS regulons in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 68 genes in 51 transcription units (TUs) belong to these regulons. Among them, 48 genes showed more than 2-fold changes in expression level under single-TF-knockout conditions. This reconstruction expands the genome-wide roles of these factors to include direct activation of genes related to amino acid biosynthesis (methionine and aromatic amino acids), cell wall synthesis (lipid A biosynthesis and peptidoglycan growth), and divalent metal ion transport (Mn(2+), Zn(2+), and Mg(2+)). Investigating the co-regulation of these genes with other stress-response TFs reveals that they are independently regulated by stress-specific TFs. PMID:26279566

  2. 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

  3. BloodChIP: a database of comparative genome-wide transcription factor binding profiles in human blood cells.

    PubMed

    Chacon, Diego; Beck, Dominik; Perera, Dilmi; Wong, Jason W H; Pimanda, John E

    2014-01-01

    The BloodChIP database (http://www.med.unsw.edu.au/CRCWeb.nsf/page/BloodChIP) supports exploration and visualization of combinatorial transcription factor (TF) binding at a particular locus in human CD34-positive and other normal and leukaemic cells or retrieval of target gene sets for user-defined combinations of TFs across one or more cell types. Increasing numbers of genome-wide TF binding profiles are being added to public repositories, and this trend is likely to continue. For the power of these data sets to be fully harnessed by experimental scientists, there is a need for these data to be placed in context and easily accessible for downstream applications. To this end, we have built a user-friendly database that has at its core the genome-wide binding profiles of seven key haematopoietic TFs in human stem/progenitor cells. These binding profiles are compared with binding profiles in normal differentiated and leukaemic cells. We have integrated these TF binding profiles with chromatin marks and expression data in normal and leukaemic cell fractions. All queries can be exported into external sites to construct TF-gene and protein-protein networks and to evaluate the association of genes with cellular processes and tissue expression.

  4. BloodChIP: a database of comparative genome-wide transcription factor binding profiles in human blood cells

    PubMed Central

    Chacon, Diego; Beck, Dominik; Perera, Dilmi; Wong, Jason W. H.; Pimanda, John E.

    2014-01-01

    The BloodChIP database (http://www.med.unsw.edu.au/CRCWeb.nsf/page/BloodChIP) supports exploration and visualization of combinatorial transcription factor (TF) binding at a particular locus in human CD34-positive and other normal and leukaemic cells or retrieval of target gene sets for user-defined combinations of TFs across one or more cell types. Increasing numbers of genome-wide TF binding profiles are being added to public repositories, and this trend is likely to continue. For the power of these data sets to be fully harnessed by experimental scientists, there is a need for these data to be placed in context and easily accessible for downstream applications. To this end, we have built a user-friendly database that has at its core the genome-wide binding profiles of seven key haematopoietic TFs in human stem/progenitor cells. These binding profiles are compared with binding profiles in normal differentiated and leukaemic cells. We have integrated these TF binding profiles with chromatin marks and expression data in normal and leukaemic cell fractions. All queries can be exported into external sites to construct TF–gene and protein–protein networks and to evaluate the association of genes with cellular processes and tissue expression. PMID:24185696

  5. Genome-Wide Identification and Function Analyses of Heat Shock Transcription Factors in Potato

    PubMed Central

    Tang, Ruimin; Zhu, Wenjiao; Song, Xiaoyan; Lin, Xingzhong; Cai, Jinghui; Wang, Man; Yang, Qing

    2016-01-01

    Heat shock transcription factors (Hsfs) play vital roles in the regulation of tolerance to various stresses in living organisms. To dissect the mechanisms of the Hsfs in potato adaptation to abiotic stresses, genome and transcriptome analyses of Hsf gene family were investigated in Solanum tuberosum L. Twenty-seven StHsf members were identified by bioinformatics and phylogenetic analyses and were classified into A, B, and C groups according to their structural and phylogenetic features. StHsfs in the same class shared similar gene structures and conserved motifs. The chromosomal location analysis showed that 27 Hsfs were located in 10 of 12 chromosomes (except chromosome 1 and chromosome 5) and that 18 of these genes formed 9 paralogous pairs. Expression profiles of StHsfs in 12 different organs and tissues uncovered distinct spatial expression patterns of these genes and their potential roles in the process of growth and development. Promoter and quantitative real-time polymerase chain reaction (qRT-PCR) detections of StHsfs were conducted and demonstrated that these genes were all responsive to various stresses. StHsf004, StHsf007, StHsf009, StHsf014, and StHsf019 were constitutively expressed under non-stress conditions, and some specific Hsfs became the predominant Hsfs in response to different abiotic stresses, indicating their important and diverse regulatory roles in adverse conditions. A co-expression network between StHsfs and StHsf -co-expressed genes was generated based on the publicly-available potato transcriptomic databases and identified key candidate StHsfs for further functional studies. PMID:27148315

  6. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

    PubMed Central

    Chouraki, V; De Bruijn, RFAG; Chapuis, J; Bis, JC; Reitz, C; Schraen, S; Ibrahim-Verbaas, CA; Grenier-Boley, B; Delay, C; Rogers, R; Demiautte, F; Mounier, A; Fitzpatrick, AL; Berr, C; Dartigues, J-F; Uitterlinden, AG; Hofman, A; Breteler, M; Becker, JT; Lathrop, M; Schupf, N; Alpérovitch, A; Mayeux, R; van Duijn, CM; Buée, L; Amouyel, P; Lopez, OL; Ikram, MA; Tzourio, C; Lambert, J-C

    2014-01-01

    Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides’ functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1–40 and Aβ1–42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10−5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1–42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1–42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites. PMID:24535457

  7. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.

    PubMed

    Chouraki, V; De Bruijn, R F A G; Chapuis, J; Bis, J C; Reitz, C; Schraen, S; Ibrahim-Verbaas, C A; Grenier-Boley, B; Delay, C; Rogers, R; Demiautte, F; Mounier, A; Fitzpatrick, A L; Berr, C; Dartigues, J-F; Uitterlinden, A G; Hofman, A; Breteler, M; Becker, J T; Lathrop, M; Schupf, N; Alpérovitch, A; Mayeux, R; van Duijn, C M; Buée, L; Amouyel, P; Lopez, O L; Ikram, M A; Tzourio, C; Lambert, J-C

    2014-12-01

    Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

  8. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

    PubMed Central

    Smolonska, Joanna; Koppelman, Gerard H.; Wijmenga, Cisca; Vonk, Judith M.; Zanen, Pieter; Bruinenberg, Marcel; Curjuric, Ivan; Imboden, Medea; Thun, Gian-Andri; Franke, Lude; Probst-Hensch, Nicole M.; Nürnberg, Peter; Riemersma, Roland A.; van Schayck, Onno; Loth, Daan W.; Bruselle, Guy G.; Stricker, Bruno H; Hofman, Albert; Uitterlinden, André G.; Lahousse, Lies; London, Stephanie J.; Loehr, Laura R.; Manichaikul, Ani; Barr, R. Graham; Donohue, Kathleen M.; Rich, Stephen S.; Pare, Peter; Bossé, Yohan; Hao, Ke; van den Berge, Maarten; Groen, Harry J.M.; Lammers, Jan-Willem J.; Mali, Willem; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution. PMID:24993907

  9. Genome-wide investigation and expression profiling of AP2/ERF transcription factor superfamily in foxtail millet (Setaria italica L.).

    PubMed

    Lata, Charu; Mishra, Awdhesh Kumar; Muthamilarasan, Mehanathan; Bonthala, Venkata Suresh; Khan, Yusuf; Prasad, Manoj

    2014-01-01

    The APETALA2/ethylene-responsive element binding factor (AP2/ERF) family is one of the largest transcription factor (TF) families in plants that includes four major sub-families, namely AP2, DREB (dehydration responsive element binding), ERF (ethylene responsive factors) and RAV (Related to ABI3/VP). AP2/ERFs are known to play significant roles in various plant processes including growth and development and biotic and abiotic stress responses. Considering this, a comprehensive genome-wide study was conducted in foxtail millet (Setaria italica L.). A total of 171 AP2/ERF genes were identified by systematic sequence analysis and were physically mapped onto nine chromosomes. Phylogenetic analysis grouped AP2/ERF genes into six classes (I to VI). Duplication analysis revealed that 12 (∼7%) SiAP2/ERF genes were tandem repeated and 22 (∼13%) were segmentally duplicated. Comparative physical mapping between foxtail millet AP2/ERF genes and its orthologs of sorghum (18 genes), maize (14 genes), rice (9 genes) and Brachypodium (6 genes) showed the evolutionary insights of AP2/ERF gene family and also the decrease in orthology with increase in phylogenetic distance. The evolutionary significance in terms of gene-duplication and divergence was analyzed by estimating synonymous and non-synonymous substitution rates. Expression profiling of candidate AP2/ERF genes against drought, salt and phytohormones revealed insights into their precise and/or overlapping expression patterns which could be responsible for their functional divergence in foxtail millet. The study showed that the genes SiAP2/ERF-069, SiAP2/ERF-103 and SiAP2/ERF-120 may be considered as potential candidate genes for further functional validation as well for utilization in crop improvement programs for stress resistance since these genes were up-regulated under drought and salinity stresses in ABA dependent manner. Altogether the present study provides new insights into evolution, divergence and systematic

  10. Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell

    PubMed Central

    Peng, Zhaofeng; Wang, Linlin; Du, Linqing; Niu, Wenbin; Sun, Yingpu

    2016-01-01

    Polycystic ovary syndrome (PCOS) affects approximately 7% of the reproductive-age women. A growing body of evidence indicated that epigenetic mechanisms contributed to the development of PCOS. The role of DNA modification in human PCOS ovary granulosa cell is still unknown in PCOS progression. Global DNA methylation and hydroxymethylation were detected between PCOS’ and controls’ granulosa cell. Genome-wide DNA methylation was profiled to investigate the putative function of DNA methylaiton. Selected genes expressions were analyzed between PCOS’ and controls’ granulosa cell. Our results showed that the granulosa cell global DNA methylation of PCOS patients was significant higher than the controls’. The global DNA hydroxymethylation showed low level and no statistical difference between PCOS and control. 6936 differentially methylated CpG sites were identified between control and PCOS-obesity. 12245 differential methylated CpG sites were detected between control and PCOS-nonobesity group. 5202 methylated CpG sites were significantly differential between PCOS-obesity and PCOS-nonobesity group. Our results showed that DNA methylation not hydroxymethylation altered genome-wide in PCOS granulosa cell. The different methylation genes were enriched in development protein, transcription factor activity, alternative splicing, sequence-specific DNA binding and embryonic morphogenesis. YWHAQ, NCF2, DHRS9 and SCNA were up-regulation in PCOS-obesity patients with no significance different between control and PCOS-nonobesity patients, which may be activated by lower DNA methylaiton. Global and genome-wide DNA methylation alteration may contribute to different genes expression and PCOS clinical pathology. PMID:27056885

  11. Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED

    PubMed Central

    Hadžić, Tarik; Park, Dongkook; Abruzzi, Katharine C.; Yang, Lin; Trigg, Jennifer S.; Rohs, Remo; Rosbash, Michael; Taghert, Paul H.

    2015-01-01

    Neuroendocrine (NE) cells use large dense core vesicles (LDCVs) to traffic, process, store and secrete neuropeptide hormones through the regulated secretory pathway. The dimmed (DIMM) basic helix-loop-helix transcription factor of Drosophila controls the level of regulated secretory activity in NE cells. To pursue its mechanisms, we have performed two independent genome-wide analyses of DIMM's activities: (i) in vivo chromatin immunoprecipitation (ChIP) to define genomic sites of DIMM occupancy and (ii) deep sequencing of purified DIMM neurons to characterize their transcriptional profile. By this combined approach, we showed that DIMM binds to conserved E-boxes in enhancers of 212 genes whose expression is enriched in DIMM-expressing NE cells. DIMM binds preferentially to certain E-boxes within first introns of specific gene isoforms. Statistical machine learning revealed that flanking regions of putative DIMM binding sites contribute to its DNA binding specificity. DIMM's transcriptional repertoire features at least 20 LDCV constituents. In addition, DIMM notably targets the pro-secretory transcription factor, creb-A, but significantly, DIMM does not target any neuropeptide genes. DIMM therefore prescribes the scale of secretory activity in NE neurons, by a systematic control of both proximal and distal points in the regulated secretory pathway. PMID:25634895

  12. Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions.

    PubMed

    Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile J W; de Moor, Marleen H M; Madden, Pamela A F; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M

    2013-08-01

    Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. PMID:23211697

  13. Genome-Wide Transcriptional Responses to Carbon Starvation in Nongrowing Lactococcus lactis

    PubMed Central

    Ercan, Onur; Wels, Michiel; Smid, Eddy J.

    2015-01-01

    This paper describes the transcriptional adaptations of nongrowing, retentostat cultures of Lactococcus lactis to starvation. Near-zero-growth cultures (μ = 0.0001 h−1) obtained by extended retentostat cultivation were exposed to starvation by termination of the medium supply for 24 h, followed by a recovery period of another 24 h by reinitiating the medium supply to the retentostat culture. During starvation, the viability of the culture was largely retained, and the expression of genes involved in transcription and translational machineries, cell division, and cell membrane energy metabolism was strongly repressed. Expression of these genes was largely recovered following the reinitiation of the medium supply. Starvation triggered the elevated expression of genes associated with synthesis of branched-chain amino acids, histidine, purine, and riboflavin. The expression of these biosynthesis genes was found to remain at an elevated level after reinitiation of the medium supply. In addition, starvation induced the complete gene set predicted to be involved in natural competence in L. lactis KF147, and the elevated expression of these genes was sustained during the subsequent recovery period, but our attempts to experimentally demonstrate natural transformation in these cells failed. Mining the starvation response gene set identified a conserved cis-acting element that resembles the lactococcal CodY motif in the upstream regions of genes associated with transcription and translational machineries, purine biosynthesis, and natural transformation in L. lactis, suggesting a role for CodY in the observed transcriptome adaptations to starvation in nongrowing cells. PMID:25636846

  14. Impact of DNA damaging agents on genome-wide transcriptional profiles in two marine Synechococcus species

    PubMed Central

    Tetu, Sasha G.; Johnson, Daniel A.; Varkey, Deepa; Phillippy, Katherine; Stuart, Rhona K.; Dupont, Chris L.; Hassan, Karl A.; Palenik, Brian; Paulsen, Ian T.

    2013-01-01

    Marine microorganisms, particularly those residing in coastal areas, may come in contact with any number of chemicals of environmental or xenobiotic origin. The sensitivity and response of marine cyanobacteria to such chemicals is, at present, poorly understood. We have looked at the transcriptional response of well characterized Synechococcus open ocean (WH8102) and coastal (CC9311) isolates to two DNA damaging agents, mitomycin C and ethidium bromide, using whole-genome expression microarrays. The coastal strain showed differential regulation of a larger proportion of its genome following “shock” treatment with each agent. Many of the orthologous genes in these strains, including those encoding sensor kinases, showed different transcriptional responses, with the CC9311 genes more likely to show significant changes in both treatments. While the overall response of each strain was considerably different, there were distinct transcriptional responses common to both strains observed for each DNA damaging agent, linked to the mode of action of each chemical. In both CC9311 and WH8102 there was evidence of SOS response induction under mitomycin C treatment, with genes recA, lexA and umuC significantly upregulated in this experiment but not under ethidium bromide treatment. Conversely, ethidium bromide treatment tended to result in upregulation of the DNA-directed RNA polymerase genes, not observed following mitomycin C treatment. Interestingly, a large number of genes residing on putative genomic island regions of each genome also showed significant upregulation under one or both chemical treatments. PMID:23966990

  15. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells

    PubMed Central

    Pirola, Luciano; Balcerczyk, Aneta; Tothill, Richard W.; Haviv, Izhak; Kaspi, Antony; Lunke, Sebastian; Ziemann, Mark; Karagiannis, Tom; Tonna, Stephen; Kowalczyk, Adam; Beresford-Smith, Bryan; Macintyre, Geoff; Kelong, Ma; Hongyu, Zhang; Zhu, Jingde; El-Osta, Assam

    2011-01-01

    Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the diverse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content. PMID:21890681

  16. FVGWAS: Fast Voxelwise Genome Wide Association Analysis of Large-scale Imaging Genetic Data 1

    PubMed Central

    Huang, Meiyan; Nichols, Thomas; Huang, Chao; Yang, Yu; Lu, Zhaohua; Feng, Qianjing; Knickmeyer, Rebecca C; Zhu, Hongtu

    2015-01-01

    More and more large-scale imaging genetic studies are being widely conducted to collect a rich set of imaging, genetic, and clinical data to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. Several major big-data challenges arise from testing genome-wide (NC > 12 million known variants) associations with signals at millions of locations (NV ~ 106) in the brain from thousands of subjects (n ~ 103). The aim of this paper is to develop a Fast Voxelwise Genome Wide Association analysiS (FVGWAS) framework to e ciently carry out whole-genome analyses of whole-brain data. FVGWAS consists of three components including a heteroscedastic linear model, a global sure independence screening (G-SIS) procedure, and a detection procedure based on wild bootstrap methods. Specifically, for standard linear association, the computational complexity is O(nNV NC) for voxelwise genome wide association analysis (VGWAS) method compared with O((NC + NV)n2) for FVGWAS. Simulation studies show that FVGWAS is an effcient method of searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. Finally, we have successfully applied FVGWAS to a large-scale imaging genetic data analysis of ADNI data with 708 subjects, 193,275 voxels in RAVENS maps, and 501,584 SNPs, and the total processing time was 203,645 seconds for a single CPU. Our FVG-WAS may be a valuable statistical toolbox for large-scale imaging genetic analysis as the field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing. PMID:26025292

  17. 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 ...

  18. 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

  19. 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.

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

    PubMed

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

    2016-01-01

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

  1. 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

  2. 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.

  3. 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

  4. 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

    Li, Kang; 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

  5. Genomic-wide transcriptional profiling in primary myoblasts reveals Runx1-regulated genes in muscle regeneration

    PubMed Central

    Umansky, Kfir Baruch; Feldmesser, Ester; Groner, Yoram

    2015-01-01

    In response to muscle damage the muscle adult stem cells are activated and differentiate into myoblasts that regenerate the damaged tissue. We have recently showed that following myopathic damage the level of the Runx1 transcription factor (TF) is elevated and that during muscle regeneration this TF regulates the balance between myoblast proliferation and differentiation (Umansky et al.). We employed Runx1-dependent gene expression, Chromatin Immunoprecipitation sequencing (ChIP-seq), Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) and histone H3K4me1/H3K27ac modification analyses to identify a subset of Runx1-regulated genes that are co-occupied by the TFs MyoD and c-Jun and are involved in muscle regeneration (Umansky et al.). The data is available at the GEO database under the superseries accession number GSE56131. PMID:26697350

  6. Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb.

    PubMed

    Zhao, Liang; Glazov, Evgeny A; Pattabiraman, Diwakar R; Al-Owaidi, Faisal; Zhang, Ping; Brown, Matthew A; Leo, Paul J; Gonda, Thomas J

    2011-06-01

    To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation.

  7. Genome-Wide Analysis of the Binding of the Hox Protein Ultrabithorax and the Hox Cofactor Homothorax in Drosophila

    PubMed Central

    Choo, Siew Woh; White, Robert; Russell, Steven

    2011-01-01

    Hox genes encode a family of transcription factors that are key developmental regulators with a highly conserved role in specifying segmental diversity along the metazoan body axis. Although they have been shown to regulate a wide variety of downstream processes, direct transcriptional targets have been difficult to identify and this has been a major obstacle to our understanding of Hox gene function. We report the identification of genome-wide binding sites for the Hox protein Ultrabithorax (Ubx) using a YFP-tagged Drosophila protein-trap line together with chromatin immunoprecipitation and microarray analysis. We identify 1,147 genes bound by Ubx at high confidence in chromatin from the haltere imaginal disc, a prominent site of Ubx function where it specifies haltere versus wing development. The functional relevance of these genes is supported by their overlap with genes differentially expressed between wing and haltere imaginal discs. The Ubx-bound gene set is highly enriched in genes involved in developmental processes and contains both high-level regulators as well as genes involved in more basic cellular functions. Several signalling pathways are highly enriched in the Ubx target gene set and our analysis supports the view that Hox genes regulate many levels of developmental pathways and have targets distributed throughout the gene network. We also performed genome-wide analysis of the binding sites for the Hox cofactor Homothorax (Hth), revealing a striking similarity with the Ubx binding profile. We suggest that these binding profiles may be strongly influenced by chromatin accessibility and provide evidence of a link between Ubx/Hth binding and chromatin state at genes regulated by Polycomb silencing. Overall, we define a set of direct Ubx targets in the haltere imaginal disc and suggest that chromatin accessibility has important implications for Hox target selection and for transcription factor binding in general. PMID:21483667

  8. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

    PubMed Central

    Melum, Espen; Franke, Andre; Schramm, Christoph; Weismüller, Tobias J; Gotthardt, Daniel Nils; Offner, Felix A; Juran, Brian D; Laerdahl, Jon K; Labi, Verena; Björnsson, Einar; Weersma, Rinse K; Henckaerts, Liesbet; Teufel, Andreas; Rust, Christian; Ellinghaus, Eva; Balschun, Tobias; Boberg, Kirsten Muri; Ellinghaus, David; Bergquist, Annika; Sauer, Peter; Ryu, Euijung; Hov, Johannes Roksund; Wedemeyer, Jochen; Lindkvist, Björn; Wittig, Michael; Porte, Robert J; Holm, Kristian; Gieger, Christian; Wichmann, H-Erich; Stokkers, Pieter; Ponsioen, Cyriel Y; Runz, Heiko; Stiehl, Adolf; Wijmenga, Cisca; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Villunger, Andreas; Schrumpf, Erik; Lazaridis, Konstantinos N; Manns, Michael P; Schreiber, Stefan; Karlsen, Tom H

    2015-01-01

    Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). PMID:21151127

  9. 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.

  10. 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. PMID:26632684

  11. 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.

  12. Estimating binding properties of transcription factors from genome-wide binding profiles

    PubMed Central

    Zabet, Nicolae Radu; Adryan, Boris

    2015-01-01

    The binding of transcription factors (TFs) is essential for gene expression. One important characteristic is the actual occupancy of a putative binding site in the genome. In this study, we propose an analytical model to predict genomic occupancy that incorporates the preferred target sequence of a TF in the form of a position weight matrix (PWM), DNA accessibility data (in the case of eukaryotes), the number of TF molecules expected to be bound specifically to the DNA and a parameter that modulates the specificity of the TF. Given actual occupancy data in the form of ChIP-seq profiles, we backwards inferred copy number and specificity for five Drosophila TFs during early embryonic development: Bicoid, Caudal, Giant, Hunchback and Kruppel. Our results suggest that these TFs display thousands of molecules that are specifically bound to the DNA and that whilst Bicoid and Caudal display a higher specificity, the other three TFs (Giant, Hunchback and Kruppel) display lower specificity in their binding (despite having PWMs with higher information content). This study gives further weight to earlier investigations into TF copy numbers that suggest a significant proportion of molecules are not bound specifically to the DNA. PMID:25432957

  13. Genome-Wide Targets Regulated by the OsMADS1 Transcription Factor Reveals Its DNA Recognition Properties1[OPEN

    PubMed Central

    Khanday, Imtiyaz; Das, Sanjukta; Chongloi, Grace L; Vijayraghavan, Usha

    2016-01-01

    OsMADS1 controls rice (Oryza sativa) floral fate and organ development. Yet, its genome-wide targets and the mechanisms underlying its role as a transcription regulator controlling developmental gene expression are unknown. We identify 3112 gene-associated OsMADS1-bound sites in the floret genome. These occur in the vicinity of transcription start sites, within gene bodies, and in intergenic regions. Majority of the bound DNA contained CArG motif variants or, in several cases, only A-tracts. Sequences flanking the binding peak had a higher AT nucleotide content, implying that broader DNA structural features may define in planta binding. Sequences for binding by other transcription factor families like MYC, AP2/ERF, bZIP, etc. are enriched in OsMADS1-bound DNAs. Target genes implicated in transcription, chromatin remodeling, cellular processes, and hormone metabolism were enriched. Combining expression data from OsMADS1 knockdown florets with these DNA binding data, a snapshot of a gene regulatory network was deduced where targets, such as AP2/ERF and bHLH transcription factors and chromatin remodelers form nodes. We show that the expression status of these nodal factors can be altered by inducing the OsMADS1-GR fusion protein and present a model for a regulatory cascade where the direct targets of OsMADS1, OsbHLH108/SPT, OsERF034, and OsHSF24, in turn control genes such as OsMADS32 and OsYABBY5. This cascade, with other similar relationships, cumulatively contributes to floral organ development. Overall, OsMADS1 binds to several regulatory genes and, probably in combination with other factors, controls a gene regulatory network that ensures rice floret development. PMID:27457124

  14. Genome-Wide Targets Regulated by the OsMADS1 Transcription Factor Reveals Its DNA Recognition Properties.

    PubMed

    Khanday, Imtiyaz; Das, Sanjukta; Chongloi, Grace L; Bansal, Manju; Grossniklaus, Ueli; Vijayraghavan, Usha

    2016-09-01

    OsMADS1 controls rice (Oryza sativa) floral fate and organ development. Yet, its genome-wide targets and the mechanisms underlying its role as a transcription regulator controlling developmental gene expression are unknown. We identify 3112 gene-associated OsMADS1-bound sites in the floret genome. These occur in the vicinity of transcription start sites, within gene bodies, and in intergenic regions. Majority of the bound DNA contained CArG motif variants or, in several cases, only A-tracts. Sequences flanking the binding peak had a higher AT nucleotide content, implying that broader DNA structural features may define in planta binding. Sequences for binding by other transcription factor families like MYC, AP2/ERF, bZIP, etc. are enriched in OsMADS1-bound DNAs. Target genes implicated in transcription, chromatin remodeling, cellular processes, and hormone metabolism were enriched. Combining expression data from OsMADS1 knockdown florets with these DNA binding data, a snapshot of a gene regulatory network was deduced where targets, such as AP2/ERF and bHLH transcription factors and chromatin remodelers form nodes. We show that the expression status of these nodal factors can be altered by inducing the OsMADS1-GR fusion protein and present a model for a regulatory cascade where the direct targets of OsMADS1, OsbHLH108/SPT, OsERF034, and OsHSF24, in turn control genes such as OsMADS32 and OsYABBY5 This cascade, with other similar relationships, cumulatively contributes to floral organ development. Overall, OsMADS1 binds to several regulatory genes and, probably in combination with other factors, controls a gene regulatory network that ensures rice floret development. PMID:27457124

  15. Genome-Wide Analysis of DNA Methylation and Cigarette Smoking in a Chinese Population

    PubMed Central

    Zhu, Xiaoyan; Li, Jun; Deng, Siyun; Yu, Kuai; Liu, Xuezhen; Deng, Qifei; Sun, Huizhen; Zhang, Xiaomin; He, Meian; Guo, Huan; Chen, Weihong; Yuan, Jing; Zhang, Bing; Kuang, Dan; He, Xiaosheng; Bai, Yansen; Han, Xu; Liu, Bing; Li, Xiaoliang; Yang, Liangle; Jiang, Haijing; Zhang, Yizhi; Hu, Jie; Cheng, Longxian; Luo, Xiaoting; Mei, Wenhua; Zhou, Zhiming; Sun, Shunchang; Zhang, Liyun; Liu, Chuanyao; Guo, Yanjun; Zhang, Zhihong; Hu, Frank B.; Liang, Liming; Wu, Tangchun

    2016-01-01

    Background: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. Objectives: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. Methods: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. Results: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. Conclusion: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. Citation: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ

  16. Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.

    PubMed

    Chen, Zhao; Tang, Hua; Qayyum, Rehan; Schick, Ursula M; Nalls, Michael A; Handsaker, Robert; Li, Jin; Lu, Yingchang; Yanek, Lisa R; Keating, Brendan; Meng, Yan; van Rooij, Frank J A; Okada, Yukinori; Kubo, Michiaki; Rasmussen-Torvik, Laura; Keller, Margaux F; Lange, Leslie; Evans, Michele; Bottinger, Erwin P; Linderman, Michael D; Ruderfer, Douglas M; Hakonarson, Hakon; Papanicolaou, George; Zonderman, Alan B; Gottesman, Omri; Thomson, Cynthia; Ziv, Elad; Singleton, Andrew B; Loos, Ruth J F; Sleiman, Patrick M A; Ganesh, Santhi; McCarroll, Steven; Becker, Diane M; Wilson, James G; Lettre, Guillaume; Reiner, Alexander P

    2013-06-15

    Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

  17. 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

  18. Genome-Wide Analysis of Protein and mRNA Copy Numbers in Single Escherichia coli Cells with Single-Molecule Sensitivity.

    PubMed

    Taniguchi, Yuichi

    2015-01-01

    Single-cell proteomic and transcriptomic analysis is an emerging approach for providing quantitative and comprehensive characterization of gene functions in individual cells. This analysis, however, is often hampered by insufficient sensitivity for detecting low copy gene expression products such as transcription factors and regulators. Here I describe a method for the quantitative genome-wide analysis of single-cell protein and mRNA copy numbers with single molecule sensitivity for the model organism Escherichia coli.

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

    PubMed

    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

    2016-08-01

    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.

  20. [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.

  1. 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

  2. Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.

    PubMed

    Hancock, D B; Reginsson, G W; Gaddis, N C; Chen, X; Saccone, N L; Lutz, S M; Qaiser, B; Sherva, R; Steinberg, S; Zink, F; Stacey, S N; Glasheen, C; Chen, J; Gu, F; Frederiksen, B N; Loukola, A; Gudbjartsson, D F; Brüske, I; Landi, M T; Bickeböller, H; Madden, P; Farrer, L; Kaprio, J; Kranzler, H R; Gelernter, J; Baker, T B; Kraft, P; Amos, C I; Caporaso, N E; Hokanson, J E; Bierut, L J; Thorgeirsson, T E; Johnson, E O; Stefansson, K

    2015-01-01

    We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences. PMID:26440539

  3. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

    PubMed

    Stahl, Eli A; Raychaudhuri, Soumya; Remmers, Elaine F; Xie, Gang; Eyre, Stephen; Thomson, Brian P; Li, Yonghong; Kurreeman, Fina A S; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I; Ardlie, Kristin G; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P; Catanese, Joseph J; Coblyn, Jonathan; Coenen, Marieke J H; Costenbader, Karen H; Criswell, Lindsey A; Crusius, J Bart A; Cui, Jing; de Bakker, Paul I W; De Jager, Philip L; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J; Huizinga, Tom W J; Kastner, Daniel L; Ke, Xiayi; Lee, Annette T; Liu, Xiangdong; Martin, Paul; Morgan, Ann W; Padyukov, Leonid; Posthumus, Marcel D; Radstake, Timothy R D J; Reid, David M; Seielstad, Mark; Seldin, Michael F; Shadick, Nancy A; Steer, Sophia; Tak, Paul P; Thomson, Wendy; van der Helm-van Mil, Annette H M; van der Horst-Bruinsma, Irene E; van der Schoot, C Ellen; van Riel, Piet L C M; Weinblatt, Michael E; Wilson, Anthony G; Wolbink, Gert Jan; Wordsworth, B Paul; Wijmenga, Cisca; Karlson, Elizabeth W; Toes, Rene E M; de Vries, Niek; Begovich, Ann B; Worthington, Jane; Siminovitch, Katherine A; Gregersen, Peter K; Klareskog, Lars; Plenge, Robert M

    2010-06-01

    To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles. PMID:20453842

  4. Differential network analysis reveals the genome-wide landscape of estrogen receptor modulation in hormonal cancers

    PubMed Central

    Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Hsu, Pei-Yin; Lu, Tzu-Pin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Huang, Tim H.-M.; Chuang, Eric Y.; Chen, Yidong

    2016-01-01

    Several mutual information (MI)-based algorithms have been developed to identify dynamic gene-gene and function-function interactions governed by key modulators (genes, proteins, etc.). Due to intensive computation, however, these methods rely heavily on prior knowledge and are limited in genome-wide analysis. We present the modulated gene/gene set interaction (MAGIC) analysis to systematically identify genome-wide modulation of interaction networks. Based on a novel statistical test employing conjugate Fisher transformations of correlation coefficients, MAGIC features fast computation and adaption to variations of clinical cohorts. In simulated datasets MAGIC achieved greatly improved computation efficiency and overall superior performance than the MI-based method. We applied MAGIC to construct the estrogen receptor (ER) modulated gene and gene set (representing biological function) interaction networks in breast cancer. Several novel interaction hubs and functional interactions were discovered. ER+ dependent interaction between TGFβ and NFκB was further shown to be associated with patient survival. The findings were verified in independent datasets. Using MAGIC, we also assessed the essential roles of ER modulation in another hormonal cancer, ovarian cancer. Overall, MAGIC is a systematic framework for comprehensively identifying and constructing the modulated interaction networks in a whole-genome landscape. MATLAB implementation of MAGIC is available for academic uses at https://github.com/chiuyc/MAGIC. PMID:26972162

  5. 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

  6. Genome-wide association study and meta-analysis of intraocular pressure.

    PubMed

    Ozel, A Bilge; Moroi, Sayoko E; Reed, David M; Nika, Melisa; Schmidt, Caroline M; Akbari, Sara; Scott, Kathleen; Rozsa, Frank; Pawar, Hemant; Musch, David C; Lichter, Paul R; Gaasterland, Doug; Branham, Kari; Gilbert, Jesse; Garnai, Sarah J; Chen, Wei; Othman, Mohammad; Heckenlively, John; Swaroop, Anand; Abecasis, Gonçalo; Friedman, David S; Zack, Don; Ashley-Koch, Allison; Ulmer, Megan; Kang, Jae H; Liu, Yutao; Yaspan, Brian L; Haines, Jonathan; Allingham, R Rand; Hauser, Michael A; Pasquale, Louis; Wiggs, Janey; Richards, Julia E; Li, Jun Z

    2014-01-01

    Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10(-8)). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

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

    PubMed Central

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

    2012-01-01

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

  8. 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

  9. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    PubMed Central

    Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke JH; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I.W.; De Jager, Phillip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy RDJ; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet LCM; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.

    2014-01-01

    To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles. PMID:20453842

  10. Genome-Wide Analysis of Host Responses to Four Different Types of Microorganisms in Bombyx Mori (Lepidoptera: Bombycidae)

    PubMed Central

    Lin, Ping; Huang, Lulin; Wu, Yuqian; Jin, Shengkai; Liu, Chun; Xia, Qingyou

    2016-01-01

    Several pathogenic microorganisms have been used to investigate the genome-wide transcriptional responses of Bombyx mori to infection. However, studies have so far each focused on one microorganism, and systematic genome-wide comparison of transcriptional responses to different pathogenic microorganisms has not been undertaken. Here, we surveyed transcriptional responses of B. mori to its natural bacterial, viral, and fungal pathogens, Bacillus bombyseptieus, B. mori nucleopolyhedrovirus (BmNPV), and Beauveria bassiana, respectively, and to nonpathogenic Escherichia coli, by microarray analysis. In total, the expression of 2,436, 1,804, 1,743, and 912 B. mori genes was modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Notably, the expression of 620, 400, 177, or 165 of these genes was only modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, or E. coli, respectively. In contrast to the expression of genes related to juvenile hormone synthesis and metabolism, that of genes encoding juvenile hormone binding proteins was microorganism-specific. Three basal metabolic pathways were modulated by infection with any of the four microorganisms, and 3, 14, 5, and 2 metabolic pathways were specifically modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Interestingly, BmNPV infection modulated the JAK/STAT signaling pathway, whereas both the Imd and Toll signaling pathways were modulated by infection with B. bombyseptieus, B. bassiana, or E. coli. These results elucidate potential molecular mechanisms of the host response to different microorganisms, and provide a foundation for further work on host–pathogen interaction. PMID:27382132

  11. Genome-Wide Analysis of Host Responses to Four Different Types of Microorganisms in Bombyx Mori (Lepidoptera: Bombycidae).

    PubMed

    Cheng, Tingcai; Lin, Ping; Huang, Lulin; Wu, Yuqian; Jin, Shengkai; Liu, Chun; Xia, Qingyou

    2016-01-01

    Several pathogenic microorganisms have been used to investigate the genome-wide transcriptional responses of Bombyx mori to infection. However, studies have so far each focused on one microorganism, and systematic genome-wide comparison of transcriptional responses to different pathogenic microorganisms has not been undertaken. Here, we surveyed transcriptional responses of B. mori to its natural bacterial, viral, and fungal pathogens, Bacillus bombyseptieus, B. mori nucleopolyhedrovirus (BmNPV), and Beauveria bassiana, respectively, and to nonpathogenic Escherichia coli, by microarray analysis. In total, the expression of 2,436, 1,804, 1,743, and 912 B. mori genes was modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Notably, the expression of 620, 400, 177, or 165 of these genes was only modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, or E. coli, respectively. In contrast to the expression of genes related to juvenile hormone synthesis and metabolism, that of genes encoding juvenile hormone binding proteins was microorganism-specific. Three basal metabolic pathways were modulated by infection with any of the four microorganisms, and 3, 14, 5, and 2 metabolic pathways were specifically modulated by infection with B. bombyseptieus, BmNPV, B. bassiana, and E. coli, respectively. Interestingly, BmNPV infection modulated the JAK/STAT signaling pathway, whereas both the Imd and Toll signaling pathways were modulated by infection with B. bombyseptieus, B. bassiana, or E. coli These results elucidate potential molecular mechanisms of the host response to different microorganisms, and provide a foundation for further work on host-pathogen interaction. PMID:27382132

  12. Genome-wide analysis of host factors in nodavirus RNA replication.

    PubMed

    Hao, Linhui; Lindenbach, Brett; Wang, Xiaofeng; Dye, Billy; Kushner, David; He, Qiuling; Newton, Michael; Ahlquist, Paul

    2014-01-01

    Flock House virus (FHV), the best studied of the animal nodaviruses, has been used as a model for positive-strand RNA virus research. As one approach to identify host genes that affect FHV RNA replication, we performed a genome-wide analysis using a yeast single gene deletion library and a modified, reporter gene-expressing FHV derivative. A total of 4,491 yeast deletion mutants were tested for their ability to support FHV replication. Candidates for host genes modulating FHV replication were selected based on the initial genome-wide reporter gene assay and validated in repeated Northern blot assays for their ability to support wild type FHV RNA1 replication. Overall, 65 deletion strains were confirmed to show significant changes in the replication of both FHV genomic RNA1 and sub-genomic RNA3 with a false discovery rate of 5%. Among them, eight genes support FHV replication, since their deletion significantly reduced viral RNA accumulation, while 57 genes limit FHV replication, since their deletion increased FHV RNA accumulation. Of the gene products implicated in affecting FHV replication, three are localized to mitochondria, where FHV RNA replication occurs, 16 normally reside in the nucleus and may have indirect roles in FHV replication, and the remaining 46 are in the cytoplasm, with functions enriched in translation, RNA processing and trafficking. PMID:24752411

  13. Genome-wide interaction analysis reveals replicated epistatic effects on brain structure

    PubMed Central

    Hibar, Derrek P.; Stein, Jason L.; Jahanshad, Neda; Kohannim, Omid; Hua, Xue; Toga, Arthur W.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Weiner, Michael W.; Thompson, Paul M.

    2015-01-01

    The discovery of several genes that affect risk for Alzheimer's disease ignited a worldwide search for Single Nucleotide Polymorphisms (SNPs), common genetic variants that affect the brain. Genome-wide search of all possible SNP-SNP interactions is challenging and rarely attempted, due to the complexity of conducting ∼1011 pairwise statistical tests. However, recent advances in machine learning, e.g., iterative sure independence screening (SIS), make it possible to analyze datasets with vastly more predictors than observations. Using an implementation of the SIS algorithm (called EPISIS), we performed a genome-wide interaction analysis testing all possible SNP-SNP interactions affecting regional brain volumes measured on MRI and mapped using tensor-based morphometry. We identified a significant SNP-SNP interaction between rs1345203 and rs1213205 that explains 1.9% of the variance in temporal lobe volume. We mapped the whole-brain, voxelwise effects of the interaction in the ADNI dataset and separately in an independent replication dataset of healthy twins (QTIM). Each additional loading in the interaction effect was associated with ∼5% greater brain regional brain volume (a protective effect) in both ADNI and QTIM samples. PMID:25264344

  14. 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

  15. 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

  16. 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

  17. 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

  18. Pathway-based analysis using reduced gene subsets in genome-wide association studies

    PubMed Central

    2011-01-01

    Background Single Nucleotide Polymorphism (SNP) analysis only captures a small proportion of associated genetic variants in Genome-Wide Association Studies (GWAS) partly due to small marginal effects. Pathway level analysis incorporating prior biological information offers another way to analyze GWAS's of complex diseases, and promises to reveal the mechanisms leading to complex diseases. Biologically defined pathways are typically comprised of numerous genes. If only a subset of genes in the pathways is associated with disease then a joint analysis including all individual genes would result in a loss of power. To address this issue, we propose a pathway-based method that allows us to test for joint effects by using a pre-selected gene subset. In the proposed approach, each gene is considered as the basic unit, which reduces the number of genetic variants considered and hence reduces the degrees of freedom in the joint analysis. The proposed approach also can be used to investigate the joint effect of several genes in a candidate gene study. Results We applied this new method to a published GWAS of psoriasis and identified 6 biologically plausible pathways, after adjustment for multiple testing. The pathways identified in our analysis overlap with those reported in previous studies. Further, using simulations across a range of gene numbers and effect sizes, we demonstrate that the proposed approach enjoys higher power than several other approaches to detect associated pathways. Conclusions The proposed method could increase the power to discover susceptibility pathways and to identify associated genes using GWAS. In our analysis of genome-wide psoriasis data, we have identified a number of relevant pathways for psoriasis. PMID:21226955

  19. Genome-Wide Transcript Profiling Reveals the Coevolution of Plastid Gene Sequences and Transcript Processing Pathways in the Fucoxanthin Dinoflagellate Karlodinium veneficum

    PubMed Central

    Richardson, Elisabeth; Dorrell, Richard G.; Howe, Christopher J.

    2014-01-01

    Plastids utilize a complex gene expression machinery, which has coevolved with the underlying genome sequence. Relatively, little is known about the genome-wide evolution of transcript processing in algal plastids that have undergone complex endosymbiotic events. We present the first genome-wide study of transcript processing in a plastid acquired through serial endosymbiosis, in the fucoxanthin-containing dinoflagellate Karlodinium veneficum. The fucoxanthin dinoflagellate plastid has an extremely divergent genome and utilizes two unusual transcript processing pathways, 3′-poly(U) tail addition and sequence editing, which were acquired following the serial endosymbiosis event. We demonstrate that poly(U) addition and sequence editing are widespread features across the Karl. veneficum plastid transcriptome, whereas other dinoflagellate plastid lineages that have arisen through independent serial endosymbiosis events do not utilize either RNA processing pathway. These pathways constrain the effects of divergent sequence evolution in fucoxanthin plastids, for example by correcting mutations in the genomic sequence that would otherwise be deleterious, and are specifically associated with transcripts that encode functional plastid proteins over transcripts of recently generated pseudogenes. These pathways may have additionally facilitated divergent evolution within the Karl. veneficum plastid. Transcript editing, for example, has contributed to the evolution of a novel C-terminal sequence extension on the Karl. veneficum AtpA protein. We furthermore provide the first complete sequence of an episomal minicircle in a fucoxanthin dinoflagellate plastid, which contains the dnaK gene, and gives rise to polyuridylylated and edited transcripts. Our results indicate that RNA processing in fucoxanthin dinoflagellate plastids is evolutionarily dynamic, coevolving with the underlying genome sequence. PMID:24925926

  20. Genome-wide analysis of H4K5 acetylation associated with fear memory in mice

    PubMed Central

    2013-01-01

    Background Histone acetylation has been implicated in learning and memory in the brain, however, its function at the level of the genome and at individual genetic loci remains poorly investigated. This study examines a key acetylation mark, histone H4 lysine 5 acetylation (H4K5ac), genome-wide and its role in activity-dependent gene transcription in the adult mouse hippocampus following contextual fear conditioning. Results Using ChIP-Seq, we identified 23,235 genes in which H4K5ac correlates with absolute gene expression in the hippocampus. However, in the absence of transcription factor binding sites 150 bp upstream of the transcription start site, genes were associated with higher H4K5ac and expression levels. We further establish H4K5ac as a ubiquitous modification across the genome. Approximately one-third of all genes have above average H4K5ac, of which ~15% are specific to memory formation and ~65% are co-acetylated for H4K12. Although H4K5ac is prevalent across the genome, enrichment of H4K5ac at specific regions in the promoter and coding region are associated with different levels of gene expression. Additionally, unbiased peak calling for genes differentially acetylated for H4K5ac identified 114 unique genes specific to fear memory, over half of which have not previously been associated with memory processes. Conclusions Our data provide novel insights into potential mechanisms of gene priming and bookmarking by histone acetylation following hippocampal memory activation. Specifically, we propose that hyperacetylation of H4K5 may prime genes for rapid expression following activity. More broadly, this study strengthens the importance of histone posttranslational modifications for the differential regulation of transcriptional programs in cognitive processes. PMID:23927422

  1. Heritability and genome-wide linkage analysis of migraine in the genetic isolate of Norfolk Island.

    PubMed

    Cox, Hannah C; Lea, Rod A; Bellis, Claire; Nyholt, Dale R; Dyer, Thomas D; Haupt, Larisa M; Charlesworth, Jac; Matovinovic, Elizabeth; Blangero, John; Griffiths, Lyn R

    2012-02-15

    Migraine is a common neurovascular disorder with a complex envirogenomic aetiology. In an effort to identify migraine susceptibility genes, we conducted a study of the isolated population of Norfolk Island, Australia. A large portion of the permanent inhabitants of Norfolk Island are descended from 18th Century English sailors involved in the infamous mutiny on the Bounty and their Polynesian consorts. In total, 600 subjects were recruited including a large pedigree of 377 individuals with lineage to the founders. All individuals were phenotyped for migraine using International Classification of Headache Disorders-II criterion. All subjects were genotyped for a genome-wide panel of microsatellite markers. Genotype and phenotype data for the pedigree were analysed using heritability and linkage methods implemented in the programme SOLAR. Follow-up association analysis was performed using the CLUMP programme. A total of 154 migraine cases (25%) were identified indicating the Norfolk Island population is high-risk for migraine. Heritability estimation of the 377-member pedigree indicated a significant genetic component for migraine (h(2)=0.53, P=0.016). Linkage analysis showed peaks on chromosome 13q33.1 (P=0.003) and chromosome 9q22.32 (P=0.008). Association analysis of the key microsatellites in the remaining 223 unrelated Norfolk Island individuals showed evidence of association, which strengthen support for the linkage findings (P≤0.05). In conclusion, a genome-wide linkage analysis and follow-up association analysis of migraine in the genetic isolate of Norfolk Island provided evidence for migraine susceptibility loci on chromosomes 9q22.22 and 13q33.1. PMID:22197687

  2. 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.

  3. Exploring genome wide bisulfite sequencing for DNA methylation analysis in livestock: a technical assessment.

    PubMed

    Doherty, Rachael; Couldrey, Christine

    2014-01-01

    Recent advances made in "omics" technologies are contributing to a revolution in livestock selection and breeding practices. Epigenetic mechanisms, including DNA methylation are important determinants for the control of gene expression in mammals. DNA methylation research will help our understanding of how environmental factors contribute to phenotypic variation of complex production and health traits. High-throughput sequencing is a vital tool for the comprehensive analysis of DNA methylation, and bisulfite-based strategies coupled with DNA sequencing allows for quantitative, site-specific methylation analysis at the genome level or genome wide. Reduced representation bisulfite sequencing (RRBS) and more recently whole genome bisulfite sequencing (WGBS) have proven to be effective techniques for studying DNA methylation in both humans and mice. Here we report the development of RRBS and WGBS for use in sheep, the first application of this technology in livestock species. Important technical issues associated with these methodologies including fragment size selection and sequence depth are examined and discussed. PMID:24860595

  4. Identification of novel candidate genes involved in mineralization of dental enamel by genome-wide transcript profiling.

    PubMed

    Lacruz, Rodrigo S; Smith, Charles E; Bringas, Pablo; Chen, Yi-Bu; Smith, Susan M; Snead, Malcolm L; Kurtz, Ira; Hacia, Joseph G; Hubbard, Michael J; Paine, Michael L

    2012-05-01

    The gene repertoire regulating vertebrate biomineralization is poorly understood. Dental enamel, the most highly mineralized tissue in mammals, differs from other calcifying systems in that the formative cells (ameloblasts) lack remodeling activity and largely degrade and resorb the initial extracellular matrix. Enamel mineralization requires that ameloblasts undergo a profound functional switch from matrix-secreting to maturational (calcium transport, protein resorption) roles as mineralization progresses. During the maturation stage, extracellular pH decreases markedly, placing high demands on ameloblasts to regulate acidic environments present around the growing hydroxyapatite crystals. To identify the genetic events driving enamel mineralization, we conducted genome-wide transcript profiling of the developing enamel organ from rat incisors and highlight over 300 genes differentially expressed during maturation. Using multiple bioinformatics analyses, we identified groups of maturation-associated genes whose functions are linked to key mineralization processes including pH regulation, calcium handling, and matrix turnover. Subsequent qPCR and Western blot analyses revealed that a number of solute carrier (SLC) gene family members were up-regulated during maturation, including the novel protein Slc24a4 involved in calcium handling as well as other proteins of similar function (Stim1). By providing the first global overview of the cellular machinery required for enamel maturation, this study provide a strong foundation for improving basic understanding of biomineralization and its practical applications in healthcare.

  5. A Network Pharmacology Approach to Evaluating the Efficacy of Chinese Medicine Using Genome-Wide Transcriptional Expression Data

    PubMed Central

    Wu, Leihong; Wang, Yi; Nie, Jing; Cheng, Yiyu

    2013-01-01

    The research of multicomponent drugs, such as in Chinese Medicine, on both mechanism dissection and drug discovery is challenging, especially the approaches to systematically evaluating the efficacy at a molecular level. Here, we presented a network pharmacology-based approach to evaluating the efficacy of multicomponent drugs by genome-wide transcriptional expression data and applied it to Shenmai injection (SHENMAI), a widely used Chinese Medicine composed of red ginseng (RG) and Radix Ophiopogonis (RO) in clinically treating myocardial ischemia (MI) diseases. The disease network, MI network in this case, was constructed by combining the protein-protein interactions (PPI) involved in the MI enriched pathways. The therapeutic efficacy of SHENMAI, RG, and RO was therefore evaluated by a network parameter, namely, network recovery index (NRI), which quantitatively evaluates the overall recovery rate in MI network. The NRI of SHENMAI, RG, and RO were 0.876, 0.494, and 0.269 respectively, which indicated SHENMAI exerts protective effects and the synergistic effect of RG and RO on treating myocardial ischemia disease. The successful application of SHENMAI implied that the proposed network pharmacology-based approach could help researchers to better evaluate a multicomponent drug on a systematic and molecular level. PMID:23737854

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

    PubMed Central

    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

    2015-01-01

    Abstract 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 × 10−5). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10−6; and rs2732614 in KIAA1267–LRRC37A, P = 6.65 × 10−6) 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 × 10−15). 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. PMID:26632684

  7. 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

    2014-01-01

    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

  8. 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

  9. 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

  10. 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.

  11. Meta-analysis of genome-wide association studies for personality.

    PubMed

    de Moor, M H M; Costa, P T; Terracciano, A; Krueger, R F; de Geus, E J C; Toshiko, T; Penninx, B W J H; Esko, T; Madden, P A F; Derringer, J; Amin, N; Willemsen, G; Hottenga, J-J; Distel, M A; Uda, M; Sanna, S; Spinhoven, P; Hartman, C A; Sullivan, P; Realo, A; Allik, J; Heath, A C; Pergadia, M L; Agrawal, A; Lin, P; Grucza, R; Nutile, T; Ciullo, M; Rujescu, D; Giegling, I; Konte, B; Widen, E; Cousminer, D L; Eriksson, J G; Palotie, A; Peltonen, L; Luciano, M; Tenesa, A; Davies, G; Lopez, L M; Hansell, N K; Medland, S E; Ferrucci, L; Schlessinger, D; Montgomery, G W; Wright, M J; Aulchenko, Y S; Janssens, A C J W; Oostra, B A; Metspalu, A; Abecasis, G R; Deary, I J; Räikkönen, K; Bierut, L J; Martin, N G; van Duijn, C M; Boomsma, D I

    2012-03-01

    Personality can be thought of as a set of characteristics that influence people's thoughts, feelings and behavior across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in 10 discovery samples (17,375 adults) and five in silico replication samples (3294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data of ≈ 2.4M single-nucleotide polymorphisms (SNPs; directly typed and imputed using HapMap data) were available. In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P=2.8 × 10(-8) and 3.1 × 10(-8)) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P=4.9 × 10(-8)). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.

  12. Genome-wide Linkage Analysis of Carotid Artery Lumen Diameter: The Strong Heart Family Study

    PubMed Central

    Bella, Jonathan N.; Cole, Shelley A.; Laston, Sandy; Almasy, Laura; Comuzzie, Anthony; Lee, Elisa T.; Best, Lyle G.; Fabsitz, Richard R.; Howard, Barbara V.; MacCluer, Jean W.; Roman, Mary J.; Devereux, Richard B.; Göring, Harald H.H.

    2014-01-01

    Background A significant proportion of the variability in carotid artery lumen diameter is attributable to genetic factors. Methods Carotid ultrasonography and genotyping were performed in the 3,300 American Indian participants in the Strong Heart Family Study (SHFS) to identify chromosomal regions harboring novel genes associated with inter-individual variation in carotid artery lumen diameter. Genome-wide linkage analysis was conducted using standard variance component linkage methods, implemented in SOLAR, based on multipoint identity-by-descent matrices. Results Genome-wide linkage analysis revealed a significant evidence for linkage for a locus for left carotid artery diastolic and systolic lumen diameter in Arizona SHFS participants on chromosome 7 at 120 cM (lod=4.85 and 3.77, respectively, after sex and age adjustment, and lod=3.12 and 2.72, respectively, after adjustment for sex, age, height, weight, systolic and diastolic blood pressure, diabetes mellitus and current smoking). Other regions with suggestive evidence of linkage for left carotid artery diastolic and systolic lumen diameter was found on chromosome 12 at 153 cM (lod=2.20 and 2.60, respectively, after sex and age adjustment, and lod=2.44 and 2.16, respectively, after full covariate adjustment) in Oklahoma SHFS participants; suggestive linkage for right carotid artery diastolic and systolic lumen diameter was found on chromosome 9 at 154 cM (lod=2.72 and 3.19, respectively after sex and age adjustment, and lod=2.36 and 2.21, respectively, after full covariate adjustment) in Oklahoma SHFS participants. Conclusion We found significant evidence for loci influencing carotid artery lumen diameter on chromosome 7q and suggestive linkage on chromosomes 12q and 9q. PMID:23871337

  13. 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

  14. 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.

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

    PubMed

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

    2015-01-01

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

  16. What Cure Models Can Teach us About Genome-Wide Survival Analysis.

    PubMed

    Stringer, Sven; Denys, Damiaan; Kahn, René S; Derks, Eske M

    2016-03-01

    The aim of logistic regression is to estimate genetic effects on disease risk, while survival analysis aims to determine effects on age of onset. In practice, genetic variants may affect both types of outcomes. A cure survival model analyzes logistic and survival effects simultaneously. The aim of this simulation study is to assess the performance of logistic regression and traditional survival analysis under a cure model and to investigate the benefits of cure survival analysis. We simulated data under a cure model and varied the percentage of subjects at risk for disease (cure fraction), the logistic and survival effect sizes, and the contribution of genetic background risk factors. We then computed the error rates and estimation bias of logistic, Cox proportional hazards (PH), and cure PH analysis, respectively. The power of logistic and Cox PH analysis is sensitive to the cure fraction and background heritability. Our results show that traditional Cox PH analysis may erroneously detect age of onset effects if no such effects are present in the data. In the presence of genetic background risk even the cure model results in biased estimates of both the odds ratio and the hazard ratio. Cure survival analysis takes cure fractions into account and can be used to simultaneously estimate the effect of genetic variants on disease risk and age of onset. Since genome-wide cure survival analysis is not computationally feasible, we recommend this analysis for genetic variants that are significant in a traditional survival analysis. PMID:26552795

  17. Genome-wide investigation and expression analysis of AP2-ERF gene family in salt tolerant common bean

    PubMed Central

    Kavas, Musa; Kizildogan, Aslihan; Gökdemir, Gökhan; Baloglu, Mehmet Cengiz

    2015-01-01

    Apetala2-ethylene-responsive element binding factor (AP2-ERF) superfamily with common AP2-DNA binding domain have developmentally and physiologically important roles in plants. Since common bean genome project has been completed recently, it is possible to identify all of the AP2-ERF genes in the common bean genome. In this study, a comprehensive genome-wide in silico analysis identified 180 AP2-ERF superfamily genes in common bean (Phaseolus vulgaris). Based on the amino acid alignment and phylogenetic analyses, superfamily members were classified into four subfamilies: DREB (54), ERF (95), AP2 (27) and RAV (3), as well as one soloist. The physical and chemical characteristics of amino acids, interaction between AP2-ERF proteins, cis elements of promoter region of AP2-ERF genes and phylogenetic trees were predicted and analyzed. Additionally, expression levels of AP2-ERF genes were evaluated by in silico and qRT-PCR analyses. In silico micro-RNA target transcript analyses identified nearly all PvAP2-ERF genes as targets of by 44 different plant species' miRNAs were identified in this study. The most abundant target genes were PvAP2/ERF-20-25-62-78-113-173. miR156, miR172 and miR838 were the most important miRNAs found in targeting and BLAST analyses. Interactome analysis revealed that the transcription factor PvAP2-ERF78, an ortholog of Arabidopsis At2G28550, was potentially interacted with at least 15 proteins, indicating that it was very important in transcriptional regulation. Here we present the first study to identify and characterize the AP2-ERF transcription factors in common bean using whole-genome analysis, and the findings may serve as a references for future functional research on the transcription factors in common bean. PMID:27152109

  18. 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

  19. A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

    PubMed Central

    Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A. G.; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

  20. A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

    PubMed

    Mechelli, Rosella; Umeton, Renato; Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A G; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.

  1. Esophageal Cancer Epigenomics and Integrome Analysis of Genome-Wide Methylation and Expression in High Risk Northeast Indian Population.

    PubMed

    Singh, Virendra; Singh, Laishram Chandreshwor; Vasudevan, Madavan; Chattopadhyay, Indranil; Borthakar, Bibhuti Bhusan; Rai, Avdhesh Kumar; Phukan, Rup Kumar; Sharma, Jagannath; Mahanta, Jagadish; Kataki, Amal Chandra; Kapur, Sujala; Saxena, Sunita

    2015-11-01

    Esophageal cancer is a major global health burden with a strong host-environment interaction component and epigenomics underpinnings that remain to be elucidated further. Certain populations such as the Northeast Indians suffer at a disproportionately higher rate from this devastating disease. Promoter methylation is correlated with transcriptional silencing of various genes in esophageal cancer. Very few studies on genome-wide methylation for esophageal cancer exist and yet, no one has carried out an integromics analysis of methylation and gene expression. In the present study, genome-wide methylation was measured in samples collected from the Northeast Indian population by Infinium 450k array, and integration of the methylation data was performed. To prepare a network of genes displaying enriched pathways, together with the list of genes exhibiting promoter hypermethylation or hypomethylation with inversely correlated expression, we performed an integrome analysis. We identified 23 Integrome network enriched genes with relevance to tumor progression and associated with the processes involved in metastasis such as cell adhesion, integrin signaling, cytoskeleton, and extracellular matrix organizations. These included four genes (PTK2, RND1, RND3, and UBL3) with promoter hypermethylation and downregulation, and 19 genes (SEMG2, CD97, CTNND2, CADM3, OMD, NEFM, FBN2, CTNNB1, DLX6, UGT2B4, CCDC80, PZP, SERPINA4, TNFSF13B, NPC1, COL1A1, TAC3, BMP8A, and IL22RA2) with promoter hypomethylation and upregulation. A Methylation Efficiency Index was further calculated for these genes; the top five gene with the highest index were COL1A1, TAC3, SERPINA4, TNFSF13B, and IL22RA2. In conclusion, we recommend that the circulatory proteins IL22RA2, TNFSF13B, SERPINA4, and TAC3 in serum of patients and disease-free healthy controls can be examined in the future as putative noninvasive biomarkers.

  2. Heat shock factors in tomatoes: genome-wide identification, phylogenetic analysis and expression profiling under development and heat stress

    PubMed Central

    Yang, Xuedong; Zhang, Hui; Liu, Na; Tian, Shoubo

    2016-01-01

    The HSF (heat shock factor) gene family contains highly conserved plant-specific transcription factors that play an important role in plant high-temperature stress responses. The present study aimed to characterize the HSF transcription factor genes in tomato (Solanum lycopersicum), which is an important vegetable crop worldwide and the model plant for fruit development studies. Twenty-six SlyHSF genes were identified in tomato, and the phylogenetic analysis showed the possible evolution profile of subgroups among in the plant kingdom. A new group O was identified that involved HSF genes in primitive plant species, like in the green algae, mosses and lycophytes. The gene structure and motifs of each SlyHSF were comprehensively analyzed. We identified orthologous, co-orthologous and paralogous HSF gene pairs in tomato, Arabidopsis and rice, and constructed a complex interaction network among these genes. The SlyHSF genes were expressed differentially in different species and at a higher level in mature fruits. The qPCR analysis was performed and showed SlyHSF genes greatly participate in plant heat tolerant pathways. Our comprehensive genome-wide analysis provided insights into the HSF gene family of tomatoes. PMID:27190703

  3. Heat shock factors in tomatoes: genome-wide identification, phylogenetic analysis and expression profiling under development and heat stress.

    PubMed

    Yang, Xuedong; Zhu, Weimin; Zhang, Hui; Liu, Na; Tian, Shoubo

    2016-01-01

    The HSF (heat shock factor) gene family contains highly conserved plant-specific transcription factors that play an important role in plant high-temperature stress responses. The present study aimed to characterize the HSF transcription factor genes in tomato (Solanum lycopersicum), which is an important vegetable crop worldwide and the model plant for fruit development studies. Twenty-six SlyHSF genes were identified in tomato, and the phylogenetic analysis showed the possible evolution profile of subgroups among in the plant kingdom. A new group O was identified that involved HSF genes in primitive plant species, like in the green algae, mosses and lycophytes. The gene structure and motifs of each SlyHSF were comprehensively analyzed. We identified orthologous, co-orthologous and paralogous HSF gene pairs in tomato, Arabidopsis and rice, and constructed a complex interaction network among these genes. The SlyHSF genes were expressed differentially in different species and at a higher level in mature fruits. The qPCR analysis was performed and showed SlyHSF genes greatly participate in plant heat tolerant pathways. Our comprehensive genome-wide analysis provided insights into the HSF gene family of tomatoes. PMID:27190703

  4. Genome-wide analysis of tandem repeats in plants and green algae.

    PubMed

    Zhao, Zhixin; Guo, Cheng; Sutharzan, Sreeskandarajan; Li, Pei; Echt, Craig S; Zhang, Jie; Liang, Chun

    2014-01-01

    Tandem repeats (TRs) extensively exist in the genomes of prokaryotes and eukaryotes. Based on the sequenced genomes and gene annotations of 31 plant and algal species in Phytozome version 8.0 (http://www.phytozome.net/), we examined TRs in a genome-wide scale, characterized their distributions and motif features, and explored their putative biological functions. Among the 31 species, no significant correlation was detected between the TR density and genome size. Interestingly, green alga Chlamydomonas reinhardtii (42,059 bp/Mbp) and castor bean Ricinus communis (55,454 bp/Mbp) showed much higher TR densities than all other species (13,209 bp/Mbp on average). In the 29 land plants, including 22 dicots, 5 monocots, and 2 bryophytes, 5'-UTR and upstream intergenic 200-nt (UI200) regions had the first and second highest TR densities, whereas in the two green algae (C. reinhardtii and Volvox carteri) the first and second highest densities were found in intron and coding sequence (CDS) regions, respectively. In CDS regions, trinucleotide and hexanucleotide motifs were those most frequently represented in all species. In intron regions, especially in the two green algae, significantly more TRs were detected near the intron-exon junctions. Within intergenic regions in dicots and monocots, more TRs were found near both the 5' and 3' ends of genes. GO annotation in two green algae revealed that the genes with TRs in introns are significantly involved in transcriptional and translational processing. As the first systematic examination of TRs in plant and green algal genomes, our study showed that TRs displayed nonrandom distribution for both intragenic and intergenic regions, suggesting that they have potential roles in transcriptional or translational regulation in plants and green algae. PMID:24192840

  5. Genome-wide microarray analysis of gene expression profiling in major depression and antidepressant therapy.

    PubMed

    Lin, Eugene; Tsai, Shih-Jen

    2016-01-01

    Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy.

  6. Genome-wide identification of target genes of a mating-type α-domain transcription factor reveals functions beyond sexual development.

    PubMed

    Becker, Kordula; Beer, Christina; Freitag, Michael; Kück, Ulrich

    2015-06-01

    Penicillium chrysogenum is the main industrial producer of the β-lactam antibiotic penicillin, the most commonly used drug in the treatment of bacterial infections. Recently, a functional MAT1-1 locus encoding the α-box transcription factor MAT1-1-1 was discovered to control sexual development in P. chrysogenum. As only little was known from any organism about the regulatory functions mediated by MAT1-1-1, we applied chromatin immunoprecipitation combined with next-generation sequencing (ChIP-seq) to gain new insights into the factors that influence MAT1-1-1 functions on a molecular level and its role in genome-wide transcriptional regulatory networks. Most importantly, our data provide evidence for mating-type transcription factor functions that reach far beyond their previously understood role in sexual development. These new roles include regulation of hyphal morphology, asexual development, as well as amino acid, iron, and secondary metabolism. Furthermore, in vitro DNA-protein binding studies and downstream analysis in yeast and P. chrysogenum enabled the identification of a MAT1-1-1 DNA-binding motif, which is highly conserved among euascomycetes. Our studies pave the way to a more general understanding of these master switches for development and metabolism in all fungi, and open up new options for optimization of fungal high production strains. PMID:25728030

  7. Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

    PubMed Central

    Hancock, D B; Reginsson, G W; Gaddis, N C; Chen, X; Saccone, N L; Lutz, S M; Qaiser, B; Sherva, R; Steinberg, S; Zink, F; Stacey, S N; Glasheen, C; Chen, J; Gu, F; Frederiksen, B N; Loukola, A; Gudbjartsson, D F; Brüske, I; Landi, M T; Bickeböller, H; Madden, P; Farrer, L; Kaprio, J; Kranzler, H R; Gelernter, J; Baker, T B; Kraft, P; Amos, C I; Caporaso, N E; Hokanson, J E; Bierut, L J; Thorgeirsson, T E; Johnson, E O; Stefansson, K

    2015-01-01

    We conducted a 1000 Genomes–imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10−9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08–1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10−4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00–1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single ‘cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences. PMID:26440539

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2015-11-01

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

  10. 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.

  11. Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.

    PubMed

    Mägi, Reedik; Asimit, Jennifer L; Day-Williams, Aaron G; Zeggini, Eleftheria; Morris, Andrew P

    2012-12-01

    Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits. The majority of reproducible associations within these loci are with common variants, each of modest effect, which together explain only a small proportion of heritability. It has been suggested that much of the unexplained genetic component of complex traits can thus be attributed to rare variation. However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants. Nevertheless, we demonstrate here, by simulation, that imputation from an existing scaffold of genome-wide genotype data up to high-density reference panels has the potential to identify rare variant associations with complex traits, without the need for costly re-sequencing experiments. By application of this approach to genome-wide association studies of seven common complex diseases, imputed up to publicly available reference panels, we identify genome-wide significant evidence of rare variant association in PRDM10 with coronary artery disease and multiple genes in the major histocompatibility complex (MHC) with type 1 diabetes. The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.

  12. Genome-wide association for grain morphology in synthetic hexaploid wheats using digital imaging analysis

    PubMed Central

    2014-01-01

    Background Grain size and shape greatly influence grain weight which ultimately enhances grain yield in wheat. Digital imaging (DI) based phenomic characterization can capture the three dimensional variation in grain size and shape than has hitherto been possible. In this study, we report the results from using digital imaging of grain size and shape to understand the relationship among different components of this trait, their contribution to enhance grain weight, and to identify genomic regions (QTLs) controlling grain morphology using genome wide association mapping with high density diversity array technology (DArT) and allele-specific markers. Results Significant positive correlations were observed between grain weight and grain size measurements such as grain length (r = 0.43), width, thickness (r = 0.64) and factor from density (FFD) (r = 0.69). A total of 231 synthetic hexaploid wheats (SHWs) were grouped into five different sub-clusters by Bayesian structure analysis using unlinked DArT markers. Linkage disequilibrium (LD) decay was observed among DArT loci > 10 cM distance and approximately 28% marker pairs were in significant LD. In total, 197 loci over 60 chromosomal regions and 79 loci over 31 chromosomal regions were associated with grain morphology by genome wide analysis using general linear model (GLM) and mixed linear model (MLM) approaches, respectively. They were mainly distributed on homoeologous group 2, 3, 6 and 7 chromosomes. Twenty eight marker-trait associations (MTAs) on the D genome chromosomes 2D, 3D and 6D may carry novel alleles with potential to enhance grain weight due to the use of untapped wild accessions of Aegilops tauschii. Statistical simulations showed that favorable alleles for thousand kernel weight (TKW), grain length, width and thickness have additive genetic effects. Allelic variations for known genes controlling grain size and weight, viz. TaCwi-2A, TaSus-2B, TaCKX6-3D and TaGw2-6A, were also associated

  13. Genome-wide identification and expression analysis of calcium-dependent protein kinase in maize

    PubMed Central

    2013-01-01

    Background Calcium-dependent protein kinases (CDPKs) have been shown to play important roles in various physiological processes, including plant growth and development, abiotic and biotic stress responses and plant hormone signaling in plants. Results In this study, we performed a bioinformatics analysis of the entire maize genome and identified 40 CDPK genes. Phylogenetic analysis indicated that 40 ZmCPKs can be divided into four groups. Most maize CDPK genes exhibited different expression levels in different tissues and developmental stages. Twelve CDPK genes were selected to respond to various stimuli, including salt, drought and cold, as well as ABA and H2O2. Expression analyses suggested that maize CDPK genes are important components of maize development and multiple transduction pathways. Conclusion Here, we present a genome-wide analysis of the CDPK gene family in maize for the first time, and this genomic analysis of maize CDPK genes provides the first step towards a functional study of this gene family in maize. PMID:23815483

  14. 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. PMID:25809424

  15. 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.

  16. Genome-Wide Mapping of Binding Sites Reveals Multiple Biological Functions of the Transcription Factor Cst6p in Saccharomyces cerevisiae

    PubMed Central

    Bergenholm, David

    2016-01-01

    ABSTRACT In the model eukaryote Saccharomyces cerevisiae, the transcription factor Cst6p has been reported to play important roles in several biological processes. However, the genome-wide targets of Cst6p and its physiological functions remain unknown. Here, we mapped the genome-wide binding sites of Cst6p at high resolution. Cst6p binds to the promoter regions of 59 genes with various biological functions when cells are grown on ethanol but hardly binds to the promoter at any gene when cells are grown on glucose. The retarded growth of the CST6 deletion mutant on ethanol is attributed to the markedly decreased expression of NCE103, encoding a carbonic anhydrase, which is a direct target of Cst6p. The target genes of Cst6p have a large overlap with those of stress-responsive transcription factors, such as Sko1p and Skn7p. In addition, a CST6 deletion mutant growing on ethanol shows hypersensitivity to oxidative stress and ethanol stress, assigning Cst6p as a new member of the stress-responsive transcriptional regulatory network. These results show that mapping of genome-wide binding sites can provide new insights into the function of transcription factors and highlight the highly connected and condition-dependent nature of the transcriptional regulatory network in S. cerevisiae. PMID:27143390

  17. 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

  18. Joint Analysis for Genome-Wide Association Studies in Family-Based Designs

    PubMed Central

    Sha, Qiuying; Zhang, Zhaogong; Zhang, Shuanglin

    2011-01-01

    In family-based data, association information can be partitioned into the between-family information and the within-family information. Based on this observation, Steen et al. (Nature Genetics. 2005, 683–691) proposed an interesting two-stage test for genome-wide association (GWA) studies under family-based designs which performs genomic screening and replication using the same data set. In the first stage, a screening test based on the between-family information is used to select markers. In the second stage, an association test based on the within-family information is used to test association at the selected markers. However, we learn from the results of case-control studies (Skol et al. Nature Genetics. 2006, 209–213) that this two-stage approach may be not optimal. In this article, we propose a novel two-stage joint analysis for GWA studies under family-based designs. For this joint analysis, we first propose a new screening test that is based on the between-family information and is robust to population stratification. This new screening test is used in the first stage to select markers. Then, a joint test that combines the between-family information and within-family information is used in the second stage to test association at the selected markers. By extensive simulation studies, we demonstrate that the joint analysis always results in increased power to detect genetic association and is robust to population stratification. PMID:21799758

  19. 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

  20. Fast genome-wide pedigree quantitative trait loci analysis using MENDEL.

    PubMed

    Zhou, Hua; Zhou, Jin; Sobel, Eric M; Lange, Kenneth

    2014-01-01

    The linkage era left a rich legacy of pedigree samples that can be used for modern genome-wide association sequencing (GWAS) or next-generation sequencing (NGS) studies. Family designs are naturally equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Unfortunately, pedigree likelihoods are notoriously hard to compute, and current software for association mapping in pedigrees is prohibitively slow in processing dense marker maps. In a recent release of the comprehensive genetic analysis software MENDEL, we implemented an ultra-fast score test for association mapping with pedigree-based GWAS or NGS study data. Our implementation (a) works for random sample data, pedigree data, or a mix of both;(b) allows for covariate adjustment, including correction for population stratification;(c) accommodates both univariate and multivariate quantitative traits; and (d) allows missing values in multivariate traits. In this paper, we assess the capabilities of MENDEL on the Genetic Analysis Workshop 18 sequencing data. For instance, when jointly testing the 4 longitudinally measured diastolic blood pressure traits, it takes MENDEL less than 51 minutes on a standard laptop computer to read, quality check, and analyze a data set with 959 individuals and 8.3 million single-nucleotide polymorphisms (SNPs). Our analysis reveals association of one SNP in the q32.2 region of chromosome 1. MENDEL is freely available on http://www.genetics.ucla.edu/software.

  1. Genome-wide linkage analysis is a powerful prenatal diagnostic tool in families with unknown genetic defects.

    PubMed

    Arélin, Maria; Schulze, Bernt; Müller-Myhsok, Bertram; Horn, Denise; Diers, Alexander; Uhlenberg, Birgit; Nürnberg, Peter; Nürnberg, Gudrun; Becker, Christian; Mundlos, Stefan; Lindner, Tom H; Sperling, Karl; Hoffmann, Katrin

    2013-04-01

    Genome-wide linkage analysis is an established tool to map inherited diseases. To our knowledge it has not been used in prenatal diagnostics of any genetic disorder. We present a family with a severe recessive mental retardation syndrome, where the mother wished pregnancy termination to avoid delivering another affected child. By genome-wide scanning using the Affymetrix (Santa Clara, CA, USA) 10k chip we were able to establish the disease haplotype. Without knowing the exact genetic defect, we excluded the condition in the fetus. The woman finally gave birth to a healthy baby. We suggest that genome-wide linkage analysis--based on either SNP mapping or full-genome sequencing--is a very useful tool in prenatal diagnostics of diseases.

  2. 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

  3. 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

  4. Genome-wide transcriptome analysis in the ovaries of two goats identifies differentially expressed genes related to fecundity.

    PubMed

    Miao, Xiangyang; Luo, Qingmiao; Qin, Xiaoyu

    2016-05-10

    The goats are widely kept as livestock throughout the world. Two excellent domestic breeds in China, the Laiwu Black and Jining Grey goats, have different fecundities and prolificacies. Although the goat genome sequences have been resolved recently, little is known about the gene regulations at the transcriptional level in goat. To understand the molecular and genetic mechanisms related to the fecundities and prolificacies, we performed genome-wide sequencing of the mRNAs from two breeds of goat using the next-generation RNA-Seq technology and used functional annotation to identify pathways of interest. Digital gene expression analysis showed 338 genes were up-regulated in the Jining Grey goats and 404 were up-regulated in the Laiwu Black goats. Quantitative real-time PCR verified the reliability of the RNA-Seq data. This study suggests that multiple genes responsible for various biological functions and signaling pathways are differentially expressed in the two different goat breeds, and these genes might be involved in the regulation of goat fecundity and prolificacy. Taken together, our study provides insight into the transcriptional regulation in the ovaries of 2 species of goats that might serve as a key resource for understanding goat fecundity, prolificacy and genetic diversity between species.

  5. Genome-wide transcriptome analysis in the ovaries of two goats identifies differentially expressed genes related to fecundity.

    PubMed

    Miao, Xiangyang; Luo, Qingmiao; Qin, Xiaoyu

    2016-05-10

    The goats are widely kept as livestock throughout the world. Two excellent domestic breeds in China, the Laiwu Black and Jining Grey goats, have different fecundities and prolificacies. Although the goat genome sequences have been resolved recently, little is known about the gene regulations at the transcriptional level in goat. To understand the molecular and genetic mechanisms related to the fecundities and prolificacies, we performed genome-wide sequencing of the mRNAs from two breeds of goat using the next-generation RNA-Seq technology and used functional annotation to identify pathways of interest. Digital gene expression analysis showed 338 genes were up-regulated in the Jining Grey goats and 404 were up-regulated in the Laiwu Black goats. Quantitative real-time PCR verified the reliability of the RNA-Seq data. This study suggests that multiple genes responsible for various biological functions and signaling pathways are differentially expressed in the two different goat breeds, and these genes might be involved in the regulation of goat fecundity and prolificacy. Taken together, our study provides insight into the transcriptional regulation in the ovaries of 2 species of goats that might serve as a key resource for understanding goat fecundity, prolificacy and genetic diversity between species. PMID:26851539

  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

    2016-01-01

    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

  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. Multiple SNP Set Analysis for Genome-Wide Association Studies Through Bayesian Latent Variable Selection.

    PubMed

    Lu, Zhao-Hua; Zhu, Hongtu; Knickmeyer, Rebecca C; Sullivan, Patrick F; Williams, Stephanie N; Zou, Fei

    2015-12-01

    The power of genome-wide association studies (GWAS) for mapping complex traits with single-SNP analysis (where SNP is single-nucleotide polymorphism) may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint association mapping between a large number of SNP sets and complex traits. Compared with single SNP set analysis, such joint association mapping not only accounts for the correlation among SNP sets but also is capable of detecting causal SNP sets that are marginally uncorrelated with traits. The spike-and-slab prior assigned to the effects of SNP sets can greatly reduce the dimension of effective SNP sets, while speeding up computation. An efficient Markov chain Monte Carlo algorithm is developed. Simulations demonstrate that BLVS outperforms several competing variable selection methods in some important scenarios. PMID:26515609

  9. Meta-analysis of genome-wide association from genomic prediction models.

    PubMed

    Bernal Rubio, Y L; Gualdrón Duarte, J L; Bates, R O; Ernst, C W; Nonneman, D; Rohrer, G A; King, A; Shackelford, S D; Wheeler, T L; Cantet, R J C; Steibel, J P

    2016-02-01

    Genome-wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta-analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal-centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population-level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits.

  10. Integrative Network-based Analysis of Magnetic Resonance Spectroscopy and Genome Wide Expression in Glioblastoma multiforme

    PubMed Central

    Heiland, Dieter Henrik; Mader, Irina; Schlosser, Pascal; Pfeifer, Dietmar; Carro, Maria Stella; Lange, Thomas; Schwarzwald, Ralf; Vasilikos, Ioannis; Urbach, Horst; Weyerbrock, Astrid

    2016-01-01

    The goal of this study was to identify correlations between metabolites from proton MR spectroscopy and genetic pathway activity in glioblastoma multiforme (GBM). Twenty patients with primary GBM were analysed by short echo-time chemical shift imaging and genome-wide expression analyses. Weighed Gene Co-Expression Analysis was used for an integrative analysis of imaging and genetic data. N-acetylaspartate, normalised to the contralateral healthy side (nNAA), was significantly correlated to oligodendrocytic and neural development. For normalised creatine (nCr), a group with low nCr was linked to the mesenchymal subtype, while high nCr could be assigned to the proneural subtype. Moreover, clustering of normalised glutamine and glutamate (nGlx) revealed two groups, one with high nGlx being attributed to the neural subtype, and one with low nGlx associated with the classical subtype. Hence, the metabolites nNAA, nCr, and nGlx correlate with a specific gene expression pattern reflecting the previously described subtypes of GBM. Moreover high nNAA was associated with better clinical prognosis, whereas patients with lower nNAA revealed a shorter progression-free survival (PFS). PMID:27350391

  11. Genome-wide linkage analysis of multiple metabolic factors: evidence of genetic heterogeneity.

    PubMed

    Cheng, Ching-Yu; Lee, Kristine E; Duggal, Priya; Moore, Emily L; Wilson, Alexander F; Klein, Ronald; Bailey-Wilson, Joan E; Klein, Barbara E K

    2010-01-01

    The metabolic syndrome is a highly complex disease and has become one of the major public-health challenges worldwide. We sought to identify genetic loci with potential influence on multiple metabolic factors in a white population in Beaver Dam, Wisconsin, and to explore the possibility of genetic heterogeneity by family history of diabetes (FHD). Three metabolic factors were generated using principal-component factor analysis, and they represented: (i) glycemia, (ii) blood pressure, and (iii) combined (BMI, high-density lipoprotein (HDL) cholesterol, and serum uric acid) factors. Multipoint model-free linkage analysis of these factors with 385 microsatellite markers was performed on 1,055 sib-pairs, using Haseman-Elston regression. Genome-wide suggestive evidence of linkage was found at 30 cM on chromosome 22q (empirical P (P(e)) = 0.0002) for the glycemia factor, at 188-191 cM on chromosome 1q (P(e) = 0.0007) for the blood pressure factor, and at 82 cM on chromosome 17q (P(e) = 0.0007) for the combined factor. Subset analyses of the families by FHD showed evidence of genetic heterogeneity, with divergent linkage signals in the subsets on at least four chromosomes. We found evidence of genetic heterogeneity by FHD for the three metabolic factors. The results also confirmed findings of previous studies that mapped components of the metabolic syndrome to a chromosome 1q region.

  12. Semiparametric methods for genome-wide linkage analysis of human gene expression data.

    PubMed

    Diao, Guoqing; Lin, D Y

    2007-01-01

    With the availability of high-throughput microarray technologies, investigators can simultaneously measure the expression levels of many thousands of genes in a short period. Although there are rich statistical methods for analyzing microarray data in the literature, limited work has been done in mapping expression quantitative trait loci (eQTL) that influence the variation in levels of gene expression. Most existing eQTL mapping methods assume that the expression phenotypes follow a normal distribution and violation of the normality assumption may lead to inflated type I error and reduced power. QTL analysis of expression data involves the mapping of many expression phenotypes at thousands or hundreds of thousands of marker loci across the whole genome. An appropriate procedure to adjust for multiple testing is essential for guarding against an abundance of false positive results. In this study, we applied a semiparametric quantitative trait loci (SQTL) mapping method to human gene expression data. The SQTL mapping method is rank-based and therefore robust to non-normality and outliers. Furthermore, we apply an efficient Monte Carlo procedure to account for multiple testing and assess the genome-wide significance level. Particularly, we apply the SQTL mapping method and the Monte-Carlo approach to the gene expression data provided by Genetic Analysis Workshop 15.

  13. Semiparametric methods for genome-wide linkage analysis of human gene expression data

    PubMed Central

    Diao, Guoqing; Lin, DY

    2007-01-01

    With the availability of high-throughput microarray technologies, investigators can simultaneously measure the expression levels of many thousands of genes in a short period. Although there are rich statistical methods for analyzing microarray data in the literature, limited work has been done in mapping expression quantitative trait loci (eQTL) that influence the variation in levels of gene expression. Most existing eQTL mapping methods assume that the expression phenotypes follow a normal distribution and violation of the normality assumption may lead to inflated type I error and reduced power. QTL analysis of expression data involves the mapping of many expression phenotypes at thousands or hundreds of thousands of marker loci across the whole genome. An appropriate procedure to adjust for multiple testing is essential for guarding against an abundance of false positive results. In this study, we applied a semiparametric quantitative trait loci (SQTL) mapping method to human gene expression data. The SQTL mapping method is rank-based and therefore robust to non-normality and outliers. Furthermore, we apply an efficient Monte Carlo procedure to account for multiple testing and assess the genome-wide significance level. Particularly, we apply the SQTL mapping method and the Monte-Carlo approach to the gene expression data provided by Genetic Analysis Workshop 15. PMID:18466586

  14. Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas.

    PubMed

    Korabecna, M; Geryk, J; Hora, M; Steiner, P; Seda, O; Tesar, V

    2016-01-01

    Tubulocystic renal cell carcinoma (TRCC) represents a rare tumor with incidence lower than 1 % of all renal carcinomas. This study was undertaken to contribute to characterization of molecular signatures associated with TRCC and to compare them with the features of papillary renal cell carcinoma (PRCC) at the level of genome wide methylation analysis.We performed methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis (Roche NimbleGen). Using the CHARM package, we compared the levels of gene methylation between paired samples of tumors and control renal tissues of each examined individual. We found significant global demethylation in all tumor samples in comparison with adjacent kidney tissues of normal histological appearance but no significant differences in gene methylation between the both compared tumor entities. Therefore we focused on characterization of differentially methylated regions between both tumors and control tissues. We found 42 differentially methylated genes.Hypermethylated genes for protocadherins (PCDHG) and genes coding for products associated with functions of plasma membrane were evaluated as significantly overrepresented among hypermethylated genes detected in both types of renal cell carcinomas.In our pilot study, we provide the first evidence that identical features in the process of carcinogenesis leading to TRCC and/or to PRCC may be found at the gene methylation level.

  15. 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

  16. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

    PubMed Central

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J.; Krueger, Gerald G.; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T. S.; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L.; Qureshi, Abrar A.; de Bakker, Paul I. W.; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-01-01

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations. PMID:25903422

  17. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

    PubMed

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J; Krueger, Gerald G; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T S; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L; Qureshi, Abrar A; de Bakker, Paul I W; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-04-23

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

  18. 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.

  19. 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

    2016-01-01

    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

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

    PubMed

    Tang, Kai; Dong, Chunjuan; Liu, Jinyuan

    2016-02-01

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

  1. 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

  2. Genome-wide profiling and analysis of Festuca arundinacea miRNAs and transcriptomes in response to foliar glyphosate application.

    PubMed

    Unver, Turgay; Bakar, Mine; Shearman, Robert C; Budak, Hikmet

    2010-04-01

    Glyphosate is a broad spectrum herbicide which has been widely used for non-selective weed control in turfgrass management. Festuca arundinacea cv. Falcon was shown to be one of the tolerant turfgrass species in response to varying levels of glyphosate [5% (1.58 mM), 20% (6.32 mM)] recommended for weed control. However, there is a lack of knowledge on the mRNA expression patterns and miRNA, critical regulators of gene expression, in response to varying levels of glyphosate treatments. Here, we investigate the transcriptome and miRNA-guided post-transcriptional networks using plant miRNA microarray and Affymetrix GeneChip Wheat Genome Array platforms. Transcriptome analysis revealed 93 up-regulated and 78 down-regulated genes, whereas a smaller number showed inverse differential expressions. miRNA chip analysis indicated a number of (34 out of the 853) plant miRNAs were differentially regulated in response to glyphosate treatments. Target transcripts of differentially regulated miRNAs were predicted and nine of them were quantified by quantitative real-time PCR (qRT-PCR). Target transcripts of miRNAs validate the expression level change of miRNAs detected by miRNA microarray analysis. Down-regulation of miRNAs upon 5 and 20% glyphosate applications led to the up-regulation of their target observed by qRT-PCR or vice versa. Quantification of F. arundinacea miRNA, homologous of osa-miR1436, revealed the agreement between the Affymetrix and miRNA microarray analyses. In addition to miRNA microarray experiment, 25 conserved F. arundinacea miRNAs were identified through homology-based approach and their secondary structures were predicted. The results presented serve as analyses of genome-wide expression profiling of miRNAs and target mRNAs in response to foliar glyphosate treatment in grass species.

  3. 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

  4. Design and analysis issues in genome-wide somatic mutation studies of cancer.

    PubMed

    Parmigiani, Giovanni; Boca, Simina; Lin, Jimmy; Kinzler, Kenneth W; Velculescu, Victor; Vogelstein, Bert

    2009-01-01

    The availability of the human genome sequence and progress in sequencing and bioinformatic technologies have enabled genome-wide investigation of somatic mutations in human cancers. This article briefly reviews challenges arising in the statistical analysis of mutational data of this kind. A first challenge is that of designing studies that efficiently allocate sequencing resources. We show that this can be addressed by two-stage designs and demonstrate via simulations that even relatively small studies can produce lists of candidate cancer genes that are highly informative for future research efforts. A second challenge is to distinguish mutated genes that are selected for by cancer (drivers) from mutated genes that have no role in the development of cancer and simply happened to mutate (passengers). We suggest that this question is best approached as a classification problem and discuss some of the difficulties of more traditional testing-based approaches. A third challenge is to identify biologic processes affected by the driver genes. This can be pursued by gene set analyses. These can reliably identify functional groups and pathways that are enriched for mutated genes even when the individual genes involved in those pathways or sets are not mutated at sufficient frequencies to provide conclusive evidence as drivers.

  5. Genome-wide analysis in Brazilian Xavante Indians reveals low degree of admixture.

    PubMed

    Kuhn, Patricia C; Horimoto, Andréa R V Russo; Sanches, José Maurício; Vieira Filho, João Paulo B; Franco, Luciana; Fabbro, Amaury Dal; Franco, Laercio Joel; Pereira, Alexandre C; Moises, Regina S

    2012-01-01

    Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st) statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders. PMID:22900041

  6. 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.

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

    PubMed Central

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

    2015-01-01

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

  8. A genome-wide linkage analysis of dementia in the Amish

    PubMed Central

    Hahs, Daniel W.; McCauley, Jacob L.; Crunk, Amy E.; McFarland, Lynne L.; Gaskell, Perry C.; Jiang, Lan; Slifer, Susan H.; Vance, Jeffery M.; Scott, William K.; Welsh-Bohmer, Kathleen A.; Johnson, Stephanie R.; Jackson, Charles E.; Pericak-Vance, Margaret A.; Haines, Jonathan L.

    2008-01-01

    Susceptibility genes for Alzheimer's disease are proving to be highly challenging to detect and verify. Population heterogeneity may be a significant confounding factor contributing to this difficulty. To increase the power for disease susceptibility gene detection we conducted a genome-wide genetic linkage screen using individuals from the relatively isolated, genetically homogeneous, Amish population. Our genome linkage analysis used a 407 microsatellite marker map (average density 7 cM) to search for autosomal genes linked to dementia in five Amish families from four Midwestern U.S. counties. Our highest two-point lod score (3.01) was observed at marker D4S1548 on chromosome 4q31. Five other regions (10q22, 3q28, 11p13, 4q28, 19p13) also demonstrated suggestive linkage with markers having two-point lod scores >2.0. While two of these regions are novel (4q31 and 11p13), the other regions lie close to regions identified in previous genome scans in other populations. Our results identify regions of the genome that may harbor genes involved in a subset of dementia patients, in particular the North American Amish community. PMID:16389594

  9. High-Performance Mixed Models Based Genome-Wide Association Analysis with omicABEL software.

    PubMed

    Fabregat-Traver, Diego; Sharapov, Sodbo Zh; Hayward, Caroline; Rudan, Igor; Campbell, Harry; Aulchenko, Yurii; Bientinesi, Paolo

    2014-01-01

    To raise the power of genome-wide association studies (GWAS) and avoid false-positive results in structured populations, one can rely on mixed model based tests. When large samples are used, and when multiple traits are to be studied in the 'omics' context, this approach becomes computationally challenging. Here we consider the problem of mixed-model based GWAS for arbitrary number of traits, and demonstrate that for the analysis of single-trait and multiple-trait scenarios different computational algorithms are optimal. We implement these optimal algorithms in a high-performance computing framework that uses state-of-the-art linear algebra kernels, incorporates optimizations, and avoids redundant computations, increasing throughput while reducing memory usage and energy consumption. We show that, compared to existing libraries, our algorithms and software achieve considerable speed-ups. The OmicABEL software described in this manuscript is available under the GNU GPL v. 3 license as part of the GenABEL project for statistical genomics at http: //www.genabel.org/packages/OmicABEL. PMID:25717363

  10. Genome-Wide Analysis in Brazilian Xavante Indians Reveals Low Degree of Admixture

    PubMed Central

    Kuhn, Patricia C.; Horimoto, Andréa R. V. Russo.; Sanches, José Maurício; Vieira Filho, João Paulo B.; Franco, Luciana; Fabbro, Amaury Dal; Franco, Laercio Joel; Pereira, Alexandre C.; Moises, Regina S

    2012-01-01

    Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise Fst statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders. PMID:22900041

  11. Genome-wide analysis in Brazilian Xavante Indians reveals low degree of admixture.

    PubMed

    Kuhn, Patricia C; Horimoto, Andréa R V Russo; Sanches, José Maurício; Vieira Filho, João Paulo B; Franco, Luciana; Fabbro, Amaury Dal; Franco, Laercio Joel; Pereira, Alexandre C; Moises, Regina S

    2012-01-01

    Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st) statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.

  12. 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

  13. High-Performance Mixed Models Based Genome-Wide Association Analysis with omicABEL software

    PubMed Central

    Fabregat-Traver, Diego; Sharapov, Sodbo Zh.; Hayward, Caroline; Rudan, Igor; Campbell, Harry; Aulchenko, Yurii; Bientinesi, Paolo

    2014-01-01

    To raise the power of genome-wide association studies (GWAS) and avoid false-positive results in structured populations, one can rely on mixed model based tests. When large samples are used, and when multiple traits are to be studied in the ’omics’ context, this approach becomes computationally challenging. Here we consider the problem of mixed-model based GWAS for arbitrary number of traits, and demonstrate that for the analysis of single-trait and multiple-trait scenarios different computational algorithms are optimal. We implement these optimal algorithms in a high-performance computing framework that uses state-of-the-art linear algebra kernels, incorporates optimizations, and avoids redundant computations, increasing throughput while reducing memory usage and energy consumption. We show that, compared to existing libraries, our algorithms and software achieve considerable speed-ups. The OmicABEL software described in this manuscript is available under the GNU GPL v. 3 license as part of the GenABEL project for statistical genomics at http: //www.genabel.org/packages/OmicABEL. PMID:25717363

  14. 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.

  15. Genome-Wide Association Analysis of Adaptation Using Environmentally Predicted Traits

    PubMed Central

    van Zanten, Martijn

    2015-01-01

    Current methods for studying the genetic basis of adaptation evaluate genetic associations with ecologically relevant traits or single environmental variables, under the implicit assumption that natural selection imposes correlations between phenotypes, environments and genotypes. In practice, observed trait and environmental data are manifestations of unknown selective forces and are only indirectly associated with adaptive genetic variation. In theory, improved estimation of these forces could enable more powerful detection of loci under selection. Here we present an approach in which we approximate adaptive variation by modeling phenotypes as a function of the environment and using the predicted trait in multivariate and univariate genome-wide association analysis (GWAS). Based on computer simulations and published flowering time data from the model plant Arabidopsis thaliana, we find that environmentally predicted traits lead to higher recovery of functional loci in multivariate GWAS and are more strongly correlated to allele frequencies at adaptive loci than individual environmental variables. Our results provide an example of the use of environmental data to obtain independent and meaningful information on adaptive genetic variation. PMID:26496492

  16. The Genome-Wide Analysis of Carcinoembryonic Antigen Signaling by Colorectal Cancer Cells Using RNA Sequencing.

    PubMed

    Bajenova, Olga; 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

  17. Genome-Wide Analysis of Polymorphisms Associated with Cytokine Responses in Smallpox Vaccine Recipients

    PubMed Central

    Kennedy, Richard B.; Ovsyannikova, Inna G.; Pankratz, V. Shane; Haralambieva, Iana H.; Vierkant, Robert A.; Poland, Gregory A.

    2014-01-01

    The role that genetics plays in response to infection or disease is becoming increasingly clear as we learn more about immunogenetics and host-pathogen interactions. Here we report a genome-wide analysis of the effects of host genetic variation on cytokine responses to vaccinia virus stimulation in smallpox vaccine recipients. Our data show that vaccinia stimulation of immune individuals results in secretion of inflammatory and Th1 cytokines. We identified multiple SNPs significantly associated with variations in cytokine secretion. These SNPs are found in genes with known immune function, as well as in genes encoding for proteins involved in signal transduction, cytoskeleton, membrane channels and ion transport, as well as others with no previously identified connection to immune responses. The large number of significant SNP associations implies that cytokine secretion in response to vaccinia virus is a complex process controlled by multiple genes and gene families. Follow-up studies to replicate these findings and then pursue mechanistic studies will provide a greater understanding of how genetic variation influences vaccine responses. PMID:22610502

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

    PubMed

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

    2016-08-01

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

  19. Genome-wide analysis reveals specificities of Cpf1 endonucleases in human cells.

    PubMed

    Kim, Daesik; Kim, Jungeun; Hur, Junho K; Been, Kyung Wook; Yoon, Sun-Heui; Kim, Jin-Soo

    2016-08-01

    Programmable clustered regularly interspaced short palindromic repeats (CRISPR) Cpf1 endonucleases are single-RNA-guided (crRNA) enzymes that recognize thymidine-rich protospacer-adjacent motif (PAM) sequences and produce cohesive double-stranded breaks (DSBs). Genome editing with CRISPR-Cpf1 endonucleases could provide an alternative to CRISPR-Cas9 endonucleases, but the determinants of targeting specificity are not well understood. Using mismatched crRNAs we found that Cpf1 could tolerate single or double mismatches in the 3' PAM-distal region, but not in the 5' PAM-proximal region. Genome-wide analysis of cleavage sites in vitro for eight Cpf1 nucleases using Digenome-seq revealed that there were 6 (LbCpf1) and 12 (AsCpf1) cleavage sites per crRNA in the human genome, fewer than are present for Cas9 nucleases (>90). Most Cpf1 off-target cleavage sites did not produce mutations in cells. We found mismatches in either the 3' PAM-distal region or in the PAM sequence of 12 off-target sites that were validated in vivo. Off-target effects were completely abrogated by using preassembled, recombinant Cpf1 ribonucleoproteins.

  20. Genome-Wide Association Analysis of Adaptation Using Environmentally Predicted Traits.

    PubMed

    van Heerwaarden, Joost; van Zanten, Martijn; Kruijer, Willem

    2015-10-01

    Current methods for studying the genetic basis of adaptation evaluate genetic associations with ecologically relevant traits or single environmental variables, under the implicit assumption that natural selection imposes correlations between phenotypes, environments and genotypes. In practice, observed trait and environmental data are manifestations of unknown selective forces and are only indirectly associated with adaptive genetic variation. In theory, improved estimation of these forces could enable more powerful detection of loci under selection. Here we present an approach in which we approximate adaptive variation by modeling phenotypes as a function of the environment and using the predicted trait in multivariate and univariate genome-wide association analysis (GWAS). Based on computer simulations and published flowering time data from the model plant Arabidopsis thaliana, we find that environmentally predicted traits lead to higher recovery of functional loci in multivariate GWAS and are more strongly correlated to allele frequencies at adaptive loci than individual environmental variables. Our results provide an example of the use of environmental data to obtain independent and meaningful information on adaptive genetic variation.

  1. 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

  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 Analysis of Sterol-Lipid Storage and Trafficking in Saccharomyces cerevisiae▿

    PubMed Central

    Fei, Weihua; Alfaro, Gabriel; Muthusamy, Baby-Periyanayaki; Klaassen, Zachary; Graham, Todd R.; Yang, Hongyuan; Beh, Christopher T.

    2008-01-01

    The pandemic of lipid-related disease necessitates a determination of how cholesterol and other lipids are transported and stored within cells. The first step in this determination is the identification of the genes involved in these transport and storage processes. Using genome-wide screens, we identified 56 yeast (Saccharomyces cerevisiae) genes involved in sterol-lipid biosynthesis, intracellular trafficking, and/or neutral-lipid storage. Direct biochemical and cytological examination of mutant cells revealed an unanticipated link between secretory protein glycosylation and triacylglycerol (TAG)/steryl ester (SE) synthesis for the storage of lipids. Together with the analysis of other deletion mutants, these results suggested at least two distinct events for the biogenesis of lipid storage particles: a step affecting neutral-lipid synthesis, generating the lipid core of storage particles, and another step for particle assembly. In addition to the lipid storage mutants, we identified mutations that affect the localization of unesterified sterols, which are normally concentrated in the plasma membrane. These findings implicated phospholipase C and the protein phosphatase Ptc1p in the regulation of sterol distribution within cells. This study identified novel sterol-related genes that define several distinct processes maintaining sterol homeostasis. PMID:18156287

  4. A genome-wide RNA interference screen identifies a differential role of the mediator CDK8 module subunits for GATA/ RUNX-activated transcription in Drosophila.

    PubMed

    Gobert, Vanessa; Osman, Dani; Bras, Stéphanie; Augé, Benoit; Boube, Muriel; Bourbon, Henri-Marc; Horn, Thomas; Boutros, Michael; Haenlin, Marc; Waltzer, Lucas

    2010-06-01

    Transcription factors of the RUNX and GATA families play key roles in the control of cell fate choice and differentiation, notably in the hematopoietic system. During Drosophila hematopoiesis, the RUNX factor Lozenge and the GATA factor Serpent cooperate to induce crystal cell differentiation. We used Serpent/Lozenge-activated transcription as a paradigm to identify modulators of GATA/RUNX activity by a genome-wide RNA interference screen in cultured Drosophila blood cells. Among the 129 factors identified, several belong to the Mediator complex. Mediator is organized in three modules plus a regulatory "CDK8 module," composed of Med12, Med13, CycC, and Cdk8, which has long been thought to behave as a single functional entity. Interestingly, our data demonstrate that Med12 and Med13 but not CycC or Cdk8 are essential for Serpent/Lozenge-induced transactivation in cell culture. Furthermore, our in vivo analysis of crystal cell development show that, while the four CDK8 module subunits control the emergence and the proliferation of this lineage, only Med12 and Med13 regulate its differentiation. We thus propose that Med12/Med13 acts as a coactivator for Serpent/Lozenge during crystal cell differentiation independently of CycC/Cdk8. More generally, we suggest that the set of conserved factors identified herein may regulate GATA/RUNX activity in mammals. PMID:20368357

  5. Genome-wide identification and functional analysis of long noncoding RNAs involved in the response to graphene oxide.

    PubMed

    Wu, Qiuli; Zhou, Xuefeng; Han, Xiaoxiao; Zhuo, Yizhou; Zhu, Siting; Zhao, Yunli; Wang, Dayong

    2016-09-01

    Long noncoding RNAs (lncRNAs), which are defined as noncoding RNAs having at least 200 nucleotides, can potentially regulate various biological processes. However, the roles of lncRNAs in regulating cellular response to engineered nanomaterials (ENMs) are still unclear. Using Hiseq 2000 sequencing technique, we performed a genome-wide screen to identify lncRNAs involved in the control of toxicity of graphene oxide (GO) using in vivo Caenorhabditis elegans assay system. HiSeq 2000 sequencing, followed by quantitative analysis, identified only 34 dysregulated lncRNAs in GO exposed nematodes. Bioinformatics analysis implies the biological processes and signaling pathways mediated by candidate lncRNAs involved in the control of GO toxicity. A lncRNAs-miRNAs network possibly involved in the control of GO toxicity was further raised. Moreover, we identified the shared lncRNAs based on the molecular regulation basis for chemical surface modifications and/or genetic mutations in reducing GO toxicity. We further provide direct evidence that these shared lncRNAs, linc-37 and linc-14, were involved in the control of chemical surface modifications and genetic mutations in reducing GO toxicity. linc-37 binding to transcriptional factor FOXO/DAF-16 might be important for the control of GO toxicity. Our whole-genome identification and functional analysis of lncRNAs highlights the important roles of lncRNAs based molecular mechanisms for cellular responses to ENMs in organisms. PMID:27348851

  6. Genome-wide identification and functional analysis of long noncoding RNAs involved in the response to graphene oxide.

    PubMed

    Wu, Qiuli; Zhou, Xuefeng; Han, Xiaoxiao; Zhuo, Yizhou; Zhu, Siting; Zhao, Yunli; Wang, Dayong

    2016-09-01

    Long noncoding RNAs (lncRNAs), which are defined as noncoding RNAs having at least 200 nucleotides, can potentially regulate various biological processes. However, the roles of lncRNAs in regulating cellular response to engineered nanomaterials (ENMs) are still unclear. Using Hiseq 2000 sequencing technique, we performed a genome-wide screen to identify lncRNAs involved in the control of toxicity of graphene oxide (GO) using in vivo Caenorhabditis elegans assay system. HiSeq 2000 sequencing, followed by quantitative analysis, identified only 34 dysregulated lncRNAs in GO exposed nematodes. Bioinformatics analysis implies the biological processes and signaling pathways mediated by candidate lncRNAs involved in the control of GO toxicity. A lncRNAs-miRNAs network possibly involved in the control of GO toxicity was further raised. Moreover, we identified the shared lncRNAs based on the molecular regulation basis for chemical surface modifications and/or genetic mutations in reducing GO toxicity. We further provide direct evidence that these shared lncRNAs, linc-37 and linc-14, were involved in the control of chemical surface modifications and genetic mutations in reducing GO toxicity. linc-37 binding to transcriptional factor FOXO/DAF-16 might be important for the control of GO toxicity. Our whole-genome identification and functional analysis of lncRNAs highlights the important roles of lncRNAs based molecular mechanisms for cellular responses to ENMs in organisms.

  7. Bivariate Genome-Wide Linkage Analysis of Femoral Bone Traits and Leg Lean Mass: Framingham Study

    PubMed Central

    Karasik, David; Zhou, Yanhua; Cupples, L Adrienne; Hannan, Marian T; Kiel, Douglas P; Demissie, Serkalem

    2009-01-01

    The risk of osteoporotic fracture is a function of both applied muscle mass and bone tissue distribution. Leg lean mass (LLM) and femoral bone geometry are both known to have substantial genetic components. Therefore, we estimated shared heritability (h2) and performed linkage analysis to identify chromosomal regions governing both LLM and bone geometry. A genome-wide scan (using 636 microsatellite markers) for linkage analyses was performed on 1346 adults from 327 extended families of the Framingham study. DXA measures were LLM, femoral neck length, neck-shaft angle (NSA), subperiosteal width, cross-sectional area (CSA), and section modulus (Z) at the femoral narrow neck and shaft (S) regions. Variance component linkage analysis was performed on normalized residuals (adjusted for age, height, BMI, and estrogen status in women). The results indicated substantial h2 for LLM (0.42 ± 0.07) that was comparable to bone geometry traits. Phenotypic correlations between LLM and bone geometry phenotypes ranged from 0.033 with NSA (p > 0.05) to 0.251 with S_Z (p < 0.001); genetic correlations ranged from 0.087 (NSA, p > 0.05) to 0.454 (S_Z, p < 0.001). Univariate linkage analysis of covariate-adjusted LLM identified no chromosomal regions with LOD scores ≥2.0; however, bivariate analysis identified two loci with LOD scores >3.0, shared by LLM with S_CSA on chromosome 12p12.3–12p13.2, and with NSA, on 14q21.3–22.1. In conclusion, we identified chromosomal regions potentially linked to both LLM and femoral bone geometry. Identification and subsequent characterization of these shared loci may further elucidate the genetic contributions to both osteoporosis and sarcopenia. PMID:19063671

  8. Genome Wide Association Analysis of Copy Number Variation in Recurrent Depressive Disorder

    PubMed Central

    Rucker, James J.H.; Breen, Gerome; Pinto, Dalila; Pedroso, Inti; Lewis, Cathryn M.; Cohen-Woods, Sarah; Uher, Rudolf; Schosser, Alexandra; Rivera, Margarita; Aitchison, Katherine J.; Craddock, Nick; Owen, Michael J.; Jones, Lisa; Jones, Ian; Korszun, Ania; Muglia, Pierandrea; Barnes, Michael R.; Preisig, Martin; Mors, Ole; Gill, Mike; Maier, Wolfgang; Rice, John; Rietschel, Marcella; Holsboer, Florian; Farmer, Anne E.; Craig, Ian W.; Scherer, Stephen W.; McGuffin, Peter

    2014-01-01

    Large, rare copy number variants (CNV) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3,106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5,619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression while duplications were not. The effect was significant when comparing cases to WTCCC2 controls (p=7.7×10−6, OR =1.25 (95% CI 1.13 - 1.37)) and to screened controls (p=5.6×10−4, OR=1.52 (95% CI 1.20 - 1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared to screened controls (p=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression. PMID:22042228

  9. Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data.

    PubMed

    Farber, Charles R

    2010-11-01

    Bone mineral density (BMD) is influenced by a complex network of gene interactions; therefore, elucidating the relationships between genes and how those genes, in turn, influence BMD is critical for developing a comprehensive understanding of osteoporosis. To investigate the role of transcriptional networks in the regulation of BMD, we performed a weighted gene coexpression network analysis (WGCNA) using microarray expression data on monocytes from young individuals with low or high BMD. WGCNA groups genes into modules based on patterns of gene coexpression. and our analysis identified 11 gene modules. We observed that the overall expression of one module (referred to as module 9) was significantly higher in the low-BMD group (p = .03). Module 9 was highly enriched for genes belonging to the immune system-related gene ontology (GO) category "response to virus" (p = 7.6 × 10(-11)). Using publically available genome-wide association study data, we independently validated the importance of module 9 by demonstrating that highly connected module 9 hubs were more likely, relative to less highly connected genes, to be genetically associated with BMD. This study highlights the advantages of systems-level analyses to uncover coexpression modules associated with bone mass and suggests that particular monocyte expression patterns may mediate differences in BMD.

  10. Genome-wide analysis of auxin response factor gene family members in medicinal model plant Salvia miltiorrhiza

    PubMed Central

    Xu, Zhichao; Ji, Aijia; Chen, Shilin

    2016-01-01

    ABSTRACT Auxin response factors (ARFs) can function as transcriptional activators or repressors to regulate the expression of auxin response genes by specifically binding to auxin response elements (AuxREs) during plant development. Based on a genome-wide strategy using the medicinal model plant Salvia miltiorrhiza, 25 S. miltiorrhiza ARF (SmARF) gene family members in four classes (class Ia, IIa, IIb and III) were comprehensively analyzed to identify characteristics including gene structures, conserved domains, phylogenetic relationships and expression patterns. In a hybrid analysis of the phylogenetic tree, microRNA targets, and expression patterns of SmARFs in different organs, root tissues, and methyl jasmonate or indole-3-acetic acid treatment conditions, we screened for candidate SmARFs involved in various developmental processes of S. miltiorrhiza. Based on this analysis, we predicted that SmARF25, SmARF7, SmARF16 and SmARF20 are involved in flower, leaf, stem and root development, respectively. With the further insight into the targets of miR160 and miR167, specific SmARF genes in S. miltiorrhiza might encode products that participate in biological processes as described for ARF genes in Arabidopsis. Our results provide a foundation for understanding the molecular basis and regulatory mechanisms of SmARFs in S. miltiorrhiza. PMID:27230647

  11. Genome-wide analysis of auxin response factor gene family members in medicinal model plant Salvia miltiorrhiza.

    PubMed

    Xu, Zhichao; Ji, Aijia; Song, Jingyuan; Chen, Shilin

    2016-01-01

    Auxin response factors (ARFs) can function as transcriptional activators or repressors to regulate the expression of auxin response genes by specifically binding to auxin response elements (AuxREs) during plant development. Based on a genome-wide strategy using the medicinal model plant Salvia miltiorrhiza, 25 S. miltiorrhiza ARF (SmARF) gene family members in four classes (class Ia, IIa, IIb and III) were comprehensively analyzed to identify characteristics including gene structures, conserved domains, phylogenetic relationships and expression patterns. In a hybrid analysis of the phylogenetic tree, microRNA targets, and expression patterns of SmARFs in different organs, root tissues, and methyl jasmonate or indole-3-acetic acid treatment conditions, we screened for candidate SmARFs involved in various developmental processes of S. miltiorrhiza Based on this analysis, we predicted that SmARF25, SmARF7, SmARF16 and SmARF20 are involved in flower, leaf, stem and root development, respectively. With the further insight into the targets of miR160 and miR167, specific SmARF genes in S. miltiorrhiza might encode products that participate in biological processes as described for ARF genes in Arabidopsis Our results provide a foundation for understanding the molecular basis and regulatory mechanisms of SmARFs in S. miltiorrhiza. PMID:27230647

  12. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

    PubMed

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. PMID:25288136

  13. Genome-wide variant analysis of simplex autism families with an integrative clinical-bioinformatics pipeline

    PubMed Central

    Jiménez-Barrón, Laura T.; O'Rawe, Jason A.; Wu, Yiyang; Yoon, Margaret; Fang, Han; Iossifov, Ivan; Lyon, Gholson J.

    2015-01-01

    Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations. PMID:27148569

  14. Oxidative Stress and Heat-Shock Responses in Desulfovibrio vulgaris by Genome-Wide Transcriptomic Analysis

    SciTech Connect

    Zhang, Weiwen; Culley, David E.; Hogan, Mike; Vitiritti, Luigi; Brockman, Fred J.

    2006-05-30

    Abstract Sulfate-reducing bacteria, like Desulfovibrio vulgaris have developed a set of reactions allowing them to survive in environments. To obtain further knowledge of the protecting mechanisms employed in D. vulgaris against the oxidative stress and heat shock, we performed a genome-wide transcriptomic analysis to determine the cellular responses to both stimuli. The results showed that 130 genes were responsive to oxidative stress, while 427 genes responsive to heat-shock, respectively. Functional analyses suggested that the genes regulated were involved in a variety of cellular functions. Metabolic analysis showed that amino acid biosynthetic pathways were induced by both oxidative stress and heat shock treatments, while fatty acid metabolism, purine and cofactor biosynthesis were induced by heat shock only. Rubrerythrin gene (rbR) were upregulated by the oxidative stress, suggesting its important role in the oxidative resistance, whereas the expression of rubredoxin oxidoreductase (rbO), superoxide ismutase (sodB) and catalase (katA) genes were not subjected to regulation by oxidative stress in D. vulgaris. In addition, the results showed that thioredoxin reductase (trxB) was responsive to oxidative stress, suggesting the thiol-specific redox system might be involved in oxidative protection in D. vulgaris. Comparison of cellular responses to oxidative stress and heat-shock allowed the identification of 66 genes that showed a similar drastic response to both environmental stimuli, implying that they might be part of the general stress response (GSR) network in D. vulgaris, which was further supported by the finding of a conserved motif upstream these common-responsive genes.

  15. 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

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

    PubMed

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

    2016-04-01

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

  17. A combined analysis of genome-wide expression profiling of bipolar disorder in human prefrontal cortex.

    PubMed

    Wang, Jinglu; Qu, Susu; Wang, Weixiao; Guo, Liyuan; Zhang, Kunlin; Chang, Suhua; Wang, Jing

    2016-11-01

    Numbers of gene expression profiling studies of bipolar disorder have been published. Besides different array chips and tissues, variety of the data processes in different cohorts aggravated the inconsistency of results of these genome-wide gene expression profiling studies. By searching the gene expression databases, we obtained six data sets for prefrontal cortex (PFC) of bipolar disorder with raw data and combinable platforms. We used standardized pre-processing and quality control procedures to analyze each data set separately and then combined them into a large gene expression matrix with 101 bipolar disorder subjects and 106 controls. A standard linear mixed-effects model was used to calculate the differentially expressed genes (DEGs). Multiple levels of sensitivity analyses and cross validation with genetic data were conducted. Functional and network analyses were carried out on basis of the DEGs. In the result, we identified 198 unique differentially expressed genes in the PFC of bipolar disorder and control. Among them, 115 DEGs were robust to at least three leave-one-out tests or different pre-processing methods; 51 DEGs were validated with genetic association signals. Pathway enrichment analysis showed these DEGs were related with regulation of neurological system, cell death and apoptosis, and several basic binding processes. Protein-protein interaction network further identified one key hub gene. We have contributed the most comprehensive integrated analysis of bipolar disorder expression profiling studies in PFC to date. The DEGs, especially those with multiple validations, may denote a common signature of bipolar disorder and contribute to the pathogenesis of disease.

  18. Genome-wide linkage analysis for human longevity: Genetics of Healthy Ageing Study

    PubMed Central

    Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Frederieke; Christiansen, Lene; De Craen, Anton J.M.; Kirkwood, Tom B.L.; Rea, I. Meave; Poulain, Michel; Robine, Jean-Marie; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S.; Valensin, Silvana; Paternoster, Lavinia; Sørensen, Thorkild I.A.; Tan, Qihua; Helmer, Quinta; Van den Akker, Erik B.; Deelen, Joris; Martella, Francesca; Cordell, Heather J.; Ayers, Kristin L.; Vaupel, James W.; Törnwall, Outi; Johnson, Thomas E.; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi G.J.; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J.; Slagboom, P. Eline; Franceschi, Claudio

    2013-01-01

    Summary Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project. In the joint linkage analyses we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD=3.47), chromosome 17q12-q22 (LOD=2.95), chromosome 19p13.3-p13.11 (LOD=3.76) and chromosome 19q13.11-q13.32 (LOD=3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1,228 unrelated nonagenarian and 1,907 geographically matched controls. Using a fixed effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (p-value=9.6 × 10−8). By combined modeling of linkage and association we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with p-value=0.02 and p-value=1.0 × 10−5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22 and 19p13.3-p13.11. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity. PMID:23286790

  19. 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.

  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 meta-analysis identifies six novel loci associated with habitual coffee consumption.

    PubMed

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

  2. Genome-wide linkage analysis for loci affecting pulse pressure: the Family Blood Pressure Program.

    PubMed

    Bielinski, Suzette J; Lynch, Amy I; Miller, Michael B; Weder, Alan; Cooper, Richard; Oberman, Albert; Chen, Yii-Der Ida; Turner, Stephen T; Fornage, Myriam; Province, Michael; Arnett, Donna K

    2005-12-01

    Pulse pressure, the difference between systolic and diastolic blood pressure, is an independent risk factor for cardiovascular disease. Increased pulse pressure reflects reduced compliance of arteries and is a marker of atherosclerosis. To locate genes that affect pulse pressure, a genome-wide linkage scan for quantitative trait loci influencing pulse pressure was performed using variance components methods as implemented in sequential oligogenic linkage analysis routines. The analysis sample included 10 798 participants in 3320 families who were recruited as part of the Family Blood Pressure Program and were phenotyped with an oscillometric blood pressure measurement device using a consistent protocol across centers. Pulse pressure was adjusted for the effects of sex, age, age2, age-by-sex interaction, age2-by-sex interaction, body mass index, and field center to remove sources of variation other than the genetic effects related to pulse pressure. Significant linkage was observed on chromosome 18 (logarithm of odds [LOD]=3.2) in a combined racial sample, chromosome 20 (LOD=4.4), and 17 (LOD=3.6) in Hispanics, chromosome 21 (LOD=4.3) in whites, chromosome 19 (LOD=3.1) in a combined sample of blacks and whites, and chromosome 7 (logarithm of odds [LOD]=3.1) in blacks from the GenNet Network. Our genome scan shows significant evidence for linkage for pulse pressure in multiple areas of the genome, supporting previous published linkage studies. The identification of these loci for pulse pressure and the apparent congruence with other blood pressure phenotypes provide increased support that these regions contain genes influencing blood pressure phenotypes.

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

    PubMed

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

    2016-04-01

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

  4. A population structure and genome-wide association analysis on the USDA soybean germplasm collection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genotype-phenotype associations within the soybean (Glycine max) germplasm collection could provide valuable information on the frequency and distribution of alleles affecting economically important traits. Here we performed a genome-wide association study (GWAS) for seed protein and oil content in ...

  5. Genome-wide association analysis of symbiotic nitrogen fixation in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide association study (GWAS) was conducted to explore the genetic basis of variation for symbiotic nitrogen fixation (SNF) and related traits in the Andean diversity panel (ADP) comprised of 259 common bean (Phaseolus vulgaris) genotypes. The ADP was evaluated for SNF and related traits in...

  6. Implementing meta-analysis from genome-wide association studies for pork quality traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pork quality plays an important role in the meat processing industry, thus different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. Howe...

  7. 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...

  8. Meta-analysis of genome-wide expression patterns associated with behavioral maturation in honey bees

    PubMed Central

    Adams, Heather A; Southey, Bruce R; Robinson, Gene E; Rodriguez-Zas, Sandra L

    2008-01-01

    reported genes and helped identify genes (e.g. Tomosyn, Chitinase 5, Adar, Innexin 2, Transferrin 1, Sick, Oatp26F) and Gene Ontology categories (e.g. purine nucleotide binding) not previously associated with maturation in honey bees. Conclusion This study demonstrated that a combination of meta-analytical approaches best addresses the highly dimensional nature of genome-wide microarray studies. As expected, the integration of gene expression information from microarray studies using meta-analysis enhanced the characterization of the transcriptome of complex biological processes. PMID:18950506

  9. Genome-Wide Association Analysis of Eating Disorder-Related Symptoms, Behaviors, and Personality Traits

    PubMed Central

    Boraska, Vesna; Davis, Oliver SP; Cherkas, Lynn F; Helder, Sietske G; Harris, Juliette; Krug, Isabel; Pei-Chi Liao, Thomas; Treasure, Janet; Ntalla, Ioanna; Karhunen, Leila; Keski-Rahkonen, Anna; Christakopoulou, Danai; Raevuori, Anu; Shin, So-Youn; Dedoussis, George V; Kaprio, Jaakko; Soranzo, Nicole; Spector, Tim D; Collier, David A; Zeggini, Eleftheria

    2012-01-01

    Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10−5. Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits. © 2012 Wiley Periodicals, Inc. PMID:22911880

  10. Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits.

    PubMed

    Boraska, Vesna; Davis, Oliver S P; Cherkas, Lynn F; Helder, Sietske G; Harris, Juliette; Krug, Isabel; Liao, Thomas Pei-Chi; Treasure, Janet; Ntalla, Ioanna; Karhunen, Leila; Keski-Rahkonen, Anna; Christakopoulou, Danai; Raevuori, Anu; Shin, So-Youn; Dedoussis, George V; Kaprio, Jaakko; Soranzo, Nicole; Spector, Tim D; Collier, David A; Zeggini, Eleftheria

    2012-10-01

    Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits.

  11. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

    PubMed

    Joubert, Bonnie R; Felix, Janine F; Yousefi, Paul; Bakulski, Kelly M; Just, Allan C; Breton, Carrie; Reese, Sarah E; Markunas, Christina A; Richmond, Rebecca C; Xu, Cheng-Jian; Küpers, Leanne K; Oh, Sam S; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A; Duijts, Liesbeth; Sharp, Gemma C; Jankipersadsing, Soesma A; Nilsen, Roy M; Vaez, Ahmad; Fallin, M Daniele; Hu, Donglei; Litonjua, Augusto A; Fuemmeler, Bernard F; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M; Ren, Jie; Tost, Jörg; Gonzalez, Juan R; Peters, Marjolein J; Håberg, Siri E; Xu, Zongli; van Meurs, Joyce B; Gaunt, Tom R; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P; Eng, Celeste; Baccarelli, Andrea A; Benjamin Neelon, Sara E; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H; Wu, Michael C; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W; Barcellos, Lisa F; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K; DeMeo, Dawn L; Burchard, Esteban G; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H; Relton, Caroline L; Jaddoe, Vincent W V; Wilcox, Allen; Melén, Erik; London, Stephanie J

    2016-04-01

    Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

  12. Implementing meta-analysis from genome-wide association studies for pork quality traits.

    PubMed

    Bernal Rubio, Y L; Gualdrón Duarte, J L; Bates, R O; Ernst, C W; Nonneman, D; Rohrer, G A; King, D A; Shackelford, S D; Wheeler, T L; Cantet, R J C; Steibel, J P

    2015-12-01

    Pork quality plays an important role in the meat processing industry. Thus, different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. However, a limitation of many GWA in animal breeding is the limited power due to small sample sizes in animal populations. One alternative is to implement a meta-analysis of GWA (MA-GWA) combining results from independent association studies. The objective of this study was to identify significant genomic regions associated with meat quality traits by performing MA-GWA for 8 different traits in 3 independent pig populations. Results from MA-GWA were used to search for genes possibly associated with the set of evaluated traits. Data from 3 pig data sets (U.S. Meat Animal Research Center, commercial, and Michigan State University Pig Resource Population) were used. A MA was implemented by combining -scores derived for each SNP in every population and then weighting them using the inverse of estimated variance of SNP effects. A search for annotated genes retrieved genes previously reported as candidates for shear force (calpain-1 catalytic subunit [] and calpastatin []), as well as for ultimate pH, purge loss, and cook loss (protein kinase, AMP-activated, γ 3 noncatalytic subunit []). In addition, novel candidate genes were identified for intramuscular fat and cook loss (acyl-CoA synthetase family member 3 mitochondrial []) and for the objective measure of muscle redness, CIE a* (glycogen synthase 1, muscle [] and ferritin, light polypeptide []). Thus, implementation of MA-GWA allowed integration of results for economically relevant traits and identified novel genes to be tested as candidates for meat quality traits in pig populations.

  13. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    PubMed

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility.

  14. Genome-wide linkage analysis and physical mapping of the rippling muscle disease gene

    SciTech Connect

    Stephan, D.A.; Buist, N.R.M.; Bhaskar, A.C.

    1994-09-01

    Rippling muscle disease (RMD) is an inherited disorder of skeletal muscle in which mechanical stimuli provoke electrically silent contractions. The patient`s symptoms are muscle cramps, pain, and stiffness, particularly during or following exercise. Clinical signs are balling of muscle following percussion, and a characteristic lateral rolling movement of muscle occurring after contraction followed by stretching. We report a new 44-member pedigree segregating RMD as an autosomal dominant trait. A genome-wide genetic linkage study in this family, using a novel approach of testing closely spaced highly polymorphic markers in affected individuals, localized the responsible gene to the distal end of the long arm of chromosome 1 with a maximum multi-point lod score of 3.56 ({theta}=0). In this family, RMD is localized to a 6 cM region near D1S235. Physical mapping of the linked region yielded several positive YAC clones, one of which spans the entire 6 cM distance. Several candidate genes not present in the YAC contig, but in the region of 1q4, have been excluded as causative by either linkage analysis of intragenic microsatellite repeats (alpha-actinin, angiotensinogen) or by SSCP of exons (skeletal muscle alpha-actinin). We studied two previously reported German families for linkage to the same locus and this same area did not co-segregate with the disease, a finding that shows that different genetic defects can cause a similar clinical phenotype (genetic heterogeneity). An understanding of the defect in contraction control within the muscle fibers in this disease may lead to a better understanding of muscle force transduction, intracellular calcium homeostasis, or both.

  15. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

    PubMed Central

    Joubert, Bonnie R.; Felix, Janine F.; Yousefi, Paul; Bakulski, Kelly M.; Just, Allan C.; Breton, Carrie; Reese, Sarah E.; Markunas, Christina A.; Richmond, Rebecca C.; Xu, Cheng-Jian; Küpers, Leanne K.; Oh, Sam S.; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A.; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A.; Duijts, Liesbeth; Sharp, Gemma C.; Jankipersadsing, Soesma A.; Nilsen, Roy M.; Vaez, Ahmad; Fallin, M. Daniele; Hu, Donglei; Litonjua, Augusto A.; Fuemmeler, Bernard F.; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M.; Ren, Jie; Tost, Jörg; Gonzalez, Juan R.; Peters, Marjolein J.; Håberg, Siri E.; Xu, Zongli; van Meurs, Joyce B.; Gaunt, Tom R.; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P.; Eng, Celeste; Baccarelli, Andrea A.; Benjamin Neelon, Sara E.; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H.; Wu, Michael C.; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W.; Barcellos, Lisa F.; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W.; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M.; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K.; DeMeo, Dawn L.; Burchard, Esteban G.; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H.; Relton, Caroline L.; Jaddoe, Vincent W.V.; Wilcox, Allen; Melén, Erik; London, Stephanie J.

    2016-01-01

    Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. PMID:27040690

  16. Genome-wide analysis of esophageal adenocarcinoma yields specific copy number aberrations that correlate with prognosis.

    PubMed

    Frankel, Adam; Armour, Nicola; Nancarrow, Derek; Krause, Lutz; Hayward, Nicholas; Lampe, Guy; Smithers, B Mark; Barbour, Andrew

    2014-04-01

    The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5-year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome-wide examination of CNAs in 54 samples of EAC using single-nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such as EGFR, MYC, KLF12, and ERBB2, while frequently deleted regions included tumor suppressor genes such as CDKN2A/B, PTPRD, FHIT, and SMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer-related networks. Finally, we discovered that copy-neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under-reporting of cases suitable for such treatment.

  17. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    PubMed

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. PMID:26743605

  18. Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk.

    PubMed

    Hellwege, Jacklyn N; Palmer, Nicholette D; Raffield, Laura M; Ng, Maggie C Y; Hawkins, Gregory A; Long, Jirong; Lorenzo, Carlos; Norris, Jill M; Ida Chen, Y-D; Speliotes, Elizabeth K; Rotter, Jerome I; Langefeld, Carl D; Wagenknecht, Lynne E; Bowden, Donald W

    2014-05-01

    Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10(-19)) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10(-12)), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.

  19. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

    PubMed

    Joubert, Bonnie R; Felix, Janine F; Yousefi, Paul; Bakulski, Kelly M; Just, Allan C; Breton, Carrie; Reese, Sarah E; Markunas, Christina A; Richmond, Rebecca C; Xu, Cheng-Jian; Küpers, Leanne K; Oh, Sam S; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A; Duijts, Liesbeth; Sharp, Gemma C; Jankipersadsing, Soesma A; Nilsen, Roy M; Vaez, Ahmad; Fallin, M Daniele; Hu, Donglei; Litonjua, Augusto A; Fuemmeler, Bernard F; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M; Ren, Jie; Tost, Jörg; Gonzalez, Juan R; Peters, Marjolein J; Håberg, Siri E; Xu, Zongli; van Meurs, Joyce B; Gaunt, Tom R; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P; Eng, Celeste; Baccarelli, Andrea A; Benjamin Neelon, Sara E; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H; Wu, Michael C; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W; Barcellos, Lisa F; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K; DeMeo, Dawn L; Burchard, Esteban G; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H; Relton, Caroline L; Jaddoe, Vincent W V; Wilcox, Allen; Melén, Erik; London, Stephanie J

    2016-04-01

    Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not p