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Sample records for genomes uncovering candidate

  1. Candidate metastasis suppressor genes uncovered by array comparative genomic hybridization in a mouse allograft model of prostate cancer

    PubMed Central

    Yi, Yajun; Nandana, Srinivas; Case, Thomas; Nelson, Colleen; Radmilovic, Tatjana; Matusik, Robert J; Tsuchiya, Karen D

    2009-01-01

    Background The purpose of this study was to identify candidate metastasis suppressor genes from a mouse allograft model of prostate cancer (NE-10). This allograft model originally developed metastases by twelve weeks after implantation in male athymic nude mice, but lost the ability to metastasize after a number of in vivo passages. We performed high resolution array comparative genomic hybridization on the metastasizing and non-metastasizing allografts to identify chromosome imbalances that differed between the two groups of tumors. Results This analysis uncovered a deletion on chromosome 2 that differed between the metastasizing and non-metastasizing tumors. Bioinformatics filters were employed to mine this region of the genome for candidate metastasis suppressor genes. Of the 146 known genes that reside within the region of interest on mouse chromosome 2, four candidate metastasis suppressor genes (Slc27a2, Mall, Snrpb, and Rassf2) were identified. Quantitative expression analysis confirmed decreased expression of these genes in the metastasizing compared to non-metastasizing tumors. Conclusion This study presents combined genomics and bioinformatics approaches for identifying potential metastasis suppressor genes. The genes identified here are candidates for further studies to determine their functional role in inhibiting metastases in the NE-10 allograft model and human prostate cancer. PMID:19781100

  2. Comparative analysis of the Photorhabdus luminescens and the Yersinia enterocolitica genomes: uncovering candidate genes involved in insect pathogenicity

    PubMed Central

    Heermann, Ralf; Fuchs, Thilo M

    2008-01-01

    Background Photorhabdus luminescens and Yersinia enterocolitica are both enteric bacteria which are associated with insects. P. luminescens lives in symbiosis with soil nematodes and is highly pathogenic towards insects but not to humans. In contrast, Y. enterocolitica is widely found in the environment and mainly known to cause gastroenteritis in men, but has only recently been shown to be also toxic for insects. It is expected that both pathogens share an overlap of genetic determinants that play a role within the insect host. Results A selective genome comparison was applied. Proteins belonging to the class of two-component regulatory systems, quorum sensing, universal stress proteins, and c-di-GMP signalling have been analysed. The interorganismic synopsis of selected regulatory systems uncovered common and distinct signalling mechanisms of both pathogens used for perception of signals within the insect host. Particularly, a new class of LuxR-like regulators was identified, which might be involved in detecting insect-specific molecules. In addition, the genetic overlap unravelled a two-component system that is unique for the genera Photorhabdus and Yersinia and is therefore suggested to play a major role in the pathogen-insect relationship. Our analysis also highlights factors of both pathogens that are expressed at low temperatures as encountered in insects in contrast to higher (body) temperature, providing evidence that temperature is a yet under-investigated environmental signal for bacterial adaptation to various hosts. Common degradative metabolic pathways are described that might be used to explore nutrients within the insect gut or hemolymph, thus enabling the proliferation of P. luminescens and Y. enterocolitica in their invertebrate hosts. A strikingly higher number of genes encoding insecticidal toxins and other virulence factors in P. luminescens compared to Y. enterocolitica correlates with the higher virulence of P. luminescens towards insects

  3. Uncovering the Nucleus Candidate for NGC 253

    NASA Astrophysics Data System (ADS)

    Günthardt, G. I.; Agüero, M. P.; Camperi, J. A.; Díaz, R. J.; Gomez, P. L.; Bosch, G.; Schirmer, M.

    2015-11-01

    NGC 253 is the nearest spiral galaxy with a nuclear starburst that becomes the best candidate for studying the relationship between starburst and active galactic nucleus activity. However, this central region is veiled by large amounts of dust, and it has been so far unclear which is the true dynamical nucleus to the point that there is no strong evidence that the galaxy harbors a supermassive black hole co-evolving with the starburst as was supposed earlier. Near-infrared (NIR) spectroscopy, especially NIR emission line analysis, could be advantageous in shedding light on the true nucleus identity. Using Flamingos-2 at Gemini South we have taken deep K-band spectra along the major axis of the central structure and through the brightest infrared source. In this work, we present evidence showing that the brightest NIR and mid-infrared source in the central region, already known as radio source TH7 and so far considered just a large stellar supercluster, in fact presents various symptoms of a genuine galactic nucleus. Therefore, it should be considered a valid nucleus candidate. Mentioning some distinctive aspects, it is the most massive compact infrared object in the central region, located at 2.″0 of the symmetry center of the galactic bar, as measured in the K-band emission. Moreover, our data indicate that this object is surrounded by a large circumnuclear stellar disk and it is also located at the rotation center of the large molecular gas disk of NGC 253. Furthermore, a kinematic residual appears in the H2 rotation curve with a sinusoidal shape consistent with an outflow centered in the candidate nucleus position. The maximum outflow velocity is located about 14 pc from TH7, which is consistent with the radius of a shell detected around the nucleus candidate, observed at 18.3 μm (Qa) and 12.8 μm ([Ne ii]) with T-ReCS. Also, the Brγ emission line profile shows a pronounced blueshift and this emission line also has the highest equivalent width at this

  4. Phytophthora Genome Sequences Uncover Evolutionary Origins and Mechanisms of Pathogenesis

    SciTech Connect

    Lamour, Kurt H; McDonald, W Hayes; Savidor, Alon

    2006-01-01

    Genome sequences of the soybean pathogen, Phytophthora sojae, and the sudden oak death pathogen, Phytophthora ramorum, suggest a photosynthetic past and reveal recent massive expansion and diversification of potential pathogenicity gene families. Abstract: Draft genome sequences of the soybean pathogen, Phytophthora sojae, and the sudden oak death pathogen, Phytophthora ramorum, have been determined. O mycetes such as these Phytophthora species share the kingdom Stramenopila with photosynthetic algae such as diatoms and the presence of many Phytophthora genes of probable phototroph origin support a photosynthetic ancestry for the stramenopiles. Comparison of the two species' genomes reveals a rapid expansion and diversification of many protein families associated with plant infection such as hydrolases, ABC transporters, protein toxins, proteinase inhibitors and, in particular, a superfamily of 700 proteins with similarity to known o mycete avirulence genes.

  5. Phytophthora Genome Sequences Uncover Evolutionary Origins and Mechanisms of Pathogenesis

    SciTech Connect

    Tyler, Brett M.; Tripathy, Sucheta; Zhang, Xuemin; Dehal, Paramvir; Jiang, Rays H. Y.; Aerts, Andrea; Arredondo, Felipe D.; Baxter, Laura; Bensasson, Douda; Beynon, JIm L.; Chapman, Jarrod; Damasceno, Cynthia M. B.; Dorrance, Anne E.; Dou, Daolong; Dickerman, Allan W.; Dubchak, Inna L.; Garbelotto, Matteo; Gijzen, Mark; Gordon, Stuart G.; Govers, Francine; Grunwald, NIklaus J.; Huang, Wayne; Ivors, Kelly L.; Jones, Richard W.; Kamoun, Sophien; Krampis, Konstantinos; Lamour, Kurt H.; Lee, Mi-Kyung; McDonald, W. Hayes; Medina, Monica; Meijer, Harold J. G.; Nordberg, Erik K.; Maclean, Donald J.; Ospina-Giraldo, Manuel D.; Morris, Paul F.; Phuntumart, Vipaporn; Putnam, Nicholas J.; Rash, Sam; Rose, Jocelyn K. C.; Sakihama, Yasuko; Salamov, Asaf A.; Savidor, Alon; Scheuring, Chantel F.; Smith, Brian M.; Sobral, Bruno W. S.; Terry, Astrid; Torto-Alalibo, Trudy A.; Win, Joe; Xu, Zhanyou; Zhang, Hongbin; Grigoriev, Igor V.; Rokhsar, Daniel S.; Boore, Jeffrey L.

    2006-04-17

    Draft genome sequences have been determined for the soybean pathogen Phytophthora sojae and the sudden oak death pathogen Phytophthora ramorum. Oömycetes such as these Phytophthora species share the kingdom Stramenopila with photosynthetic algae such as diatoms, and the presence of many Phytophthora genes of probable phototroph origin supports a photosynthetic ancestry for the stramenopiles. Comparison of the two species' genomes reveals a rapid expansion and diversification of many protein families associated with plant infection such as hydrolases, ABC transporters, protein toxins, proteinase inhibitors, and, in particular, a superfamily of 700 proteins with similarity to known oömycete avirulence genes.

  6. PHYTOPHTHORA GENOME SEQUENCES UNCOVER EVOLUTIONARY ORIGINS AND MECHANISMS OF PATHOGENESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Draft genome sequences of the soybean pathogen Phytophthora sojae and the sudden oak death pathogen Phytophthora ramorum have been determined to depths of 9x and 7.7x, respectively. Oomycetes such as these Phytophthora species share the kingdom Stramenopiles with photosynthetic algae such as diatoms...

  7. Uncovering the genomic heterogeneity of multifocal breast cancer

    PubMed Central

    Desmedt, Christine; Fumagalli, Debora; Pietri, Elisabetta; Zoppoli, Gabriele; Brown, David; Nik-Zainal, Serena; Gundem, Gunes; Rothé, Françoise; Majjaj, Samira; Garuti, Anna; Carminati, Enrico; Loi, Sherene; Van Brussel, Thomas; Boeckx, Bram; Maetens, Marion; Mudie, Laura; Vincent, Delphine; Kheddoumi, Naima; Serra, Luigi; Massa, Ilaria; Ballestrero, Alberto; Amadori, Dino; Salgado, Roberto; de Wind, Alexandre; Lambrechts, Diether; Piccart, Martine; Larsimont, Denis; Campbell, Peter J; Sotiriou, Christos

    2015-01-01

    Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER, and HER2 status. Mutations were classified as ‘oncogenic’ in the case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep resequencing using an orthogonal platform. Whole-genome rearrangement screen was further conducted in 8/36 patients. Twenty-four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three-quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter-lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3, and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than homogeneous lesions. Genome-wide analyses of a limited number of patients identified a common somatic background in all studied MFBCs, including those with no mutation in common between the lesions. To conclude, as the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings highlight the presence of genomic inter-lesion heterogeneity in one-third, despite similar pathological features

  8. Uncovering the role of genomic "dark matter" in human disease.

    PubMed

    Martin, Lance; Chang, Howard Y

    2012-05-01

    The human genome encodes thousands of long noncoding RNAs (lncRNAs). Although most remain functionally uncharacterized biological "dark matter," lncRNAs have garnered considerable attention for their diverse roles in human biology, including developmental programs and tumor suppressor gene networks. As the number of lncRNAs associated with human disease grows, ongoing research efforts are focusing on their regulatory mechanisms. New technologies that enable enumeration of lncRNA interaction partners and determination of lncRNA structure are well positioned to drive deeper understanding of their functions and involvement in pathogenesis. In turn, lncRNAs may become targets for therapeutic intervention or new tools for biotechnology. PMID:22546862

  9. Distilling a Visual Network of Retinitis Pigmentosa Gene-Protein Interactions to Uncover New Disease Candidates

    PubMed Central

    Boloc, Daniel; Castillo-Lara, Sergio; Marfany, Gemma; Gonzàlez-Duarte, Roser; Abril, Josep F.

    2015-01-01

    Background Retinitis pigmentosa (RP) is a highly heterogeneous genetic visual disorder with more than 70 known causative genes, some of them shared with other non-syndromic retinal dystrophies (e.g. Leber congenital amaurosis, LCA). The identification of RP genes has increased steadily during the last decade, and the 30% of the cases that still remain unassigned will soon decrease after the advent of exome/genome sequencing. A considerable amount of genetic and functional data on single RD genes and mutations has been gathered, but a comprehensive view of the RP genes and their interacting partners is still very fragmentary. This is the main gap that needs to be filled in order to understand how mutations relate to progressive blinding disorders and devise effective therapies. Methodology We have built an RP-specific network (RPGeNet) by merging data from different sources: high-throughput data from BioGRID and STRING databases, manually curated data for interactions retrieved from iHOP, as well as interactions filtered out by syntactical parsing from up-to-date abstracts and full-text papers related to the RP research field. The paths emerging when known RP genes were used as baits over the whole interactome have been analysed, and the minimal number of connections among the RP genes and their close neighbors were distilled in order to simplify the search space. Conclusions In contrast to the analysis of single isolated genes, finding the networks linking disease genes renders powerful etiopathological insights. We here provide an interactive interface, RPGeNet, for the molecular biologist to explore the network centered on the non-syndromic and syndromic RP and LCA causative genes. By integrating tissue-specific expression levels and phenotypic data on top of that network, a more comprehensive biological view will highlight key molecular players of retinal degeneration and unveil new RP disease candidates. PMID:26267445

  10. Analysis of retrotransposon structural diversity uncovers properties and propensities in angiosperm genome evolution

    PubMed Central

    Vitte, Clémentine; Bennetzen, Jeffrey L.

    2006-01-01

    Analysis of LTR retrotransposon structures in five diploid angiosperm genomes uncovered very different relative levels of different types of genomic diversity. All species exhibited recent LTR retrotransposon mobility and also high rates of DNA removal by unequal homologous recombination and illegitimate recombination. The larger plant genomes contained many LTR retrotransposon families with >10,000 copies per haploid genome, whereas the smaller genomes contained few or no LTR retrotransposon families with >1,000 copies, suggesting that this differential potential for retroelement amplification is a primary factor in angiosperm genome size variation. The average ratios of transition to transversion mutations (Ts/Tv) in diverging LTRs were >1.5 for each species studied, suggesting that these elements are mostly 5-methylated at cytosines in an epigenetically silenced state. However, the diploid wheat Triticum monococcum and barley have unusually low Ts/Tv values (respectively, 1.9 and 1.6) compared with maize (3.9), medicago (3.6), and lotus (2.5), suggesting that this silencing is less complete in the two Triticeae. Such characteristics as the ratios of point mutations to indels (insertions and deletions) and the relative efficiencies of DNA removal by unequal homologous recombination compared with illegitimate recombination were highly variable between species. These latter variations did not correlate with genome size or phylogenetic relatedness, indicating that they frequently change during the evolutionary descent of plant lineages. In sum, the results indicate that the different sizes, contents, and structures of angiosperm genomes are outcomes of the same suite of mechanistic processes, but acting with different relative efficiencies in different plant lineages. PMID:17101966

  11. The cavefish genome reveals candidate genes for eye loss.

    PubMed

    McGaugh, Suzanne E; Gross, Joshua B; Aken, Bronwen; Blin, Maryline; Borowsky, Richard; Chalopin, Domitille; Hinaux, Hélène; Jeffery, William R; Keene, Alex; Ma, Li; Minx, Patrick; Murphy, Daniel; O'Quin, Kelly E; Rétaux, Sylvie; Rohner, Nicolas; Searle, Steve M J; Stahl, Bethany A; Tabin, Cliff; Volff, Jean-Nicolas; Yoshizawa, Masato; Warren, Wesley C

    2014-01-01

    Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction. PMID:25329095

  12. The cavefish genome reveals candidate genes for eye loss

    PubMed Central

    McGaugh, Suzanne E.; Gross, Joshua B.; Aken, Bronwen; Blin, Maryline; Borowsky, Richard; Chalopin, Domitille; Hinaux, Hélène; Jeffery, William R.; Keene, Alex; Ma, Li; Minx, Patrick; Murphy, Daniel; O’Quin, Kelly E.; Rétaux, Sylvie; Rohner, Nicolas; Searle, Steve M. J.; Stahl, Bethany A.; Tabin, Cliff; Volff, Jean-Nicolas; Yoshizawa, Masato; Warren, Wesley C.

    2014-01-01

    Natural populations subjected to strong environmental selection pressures offer a window into the genetic underpinnings of evolutionary change. Cavefish populations, Astyanax mexicanus (Teleostei: Characiphysi), exhibit repeated, independent evolution for a variety of traits including eye degeneration, pigment loss, increased size and number of taste buds and mechanosensory organs, and shifts in many behavioural traits. Surface and cave forms are interfertile making this system amenable to genetic interrogation; however, lack of a reference genome has hampered efforts to identify genes responsible for changes in cave forms of A. mexicanus. Here we present the first de novo genome assembly for Astyanax mexicanus cavefish, contrast repeat elements to other teleost genomes, identify candidate genes underlying quantitative trait loci (QTL), and assay these candidate genes for potential functional and expression differences. We expect the cavefish genome to advance understanding of the evolutionary process, as well as, analogous human disease including retinal dysfunction. PMID:25329095

  13. The proteome and phosphoproteome of maize pollen uncovers fertility candidate proteins.

    PubMed

    Chao, Qing; Gao, Zhi-Fang; Wang, Yue-Feng; Li, Zhe; Huang, Xia-He; Wang, Ying-Chun; Mei, Ying-Chang; Zhao, Biligen-Gaowa; Li, Liang; Jiang, Yu-Bo; Wang, Bai-Chen

    2016-06-01

    Maize is unique since it is both monoecious and diclinous (separate male and female flowers on the same plant). We investigated the proteome and phosphoproteome of maize pollen containing modified proteins and here we provide a comprehensive pollen proteome and phosphoproteome which contain 100,990 peptides from 6750 proteins and 5292 phosphorylated sites corresponding to 2257 maize phosphoproteins, respectively. Interestingly, among the total 27 overrepresented phosphosite motifs we identified here, 11 were novel motifs, which suggested different modification mechanisms in plants compared to those of animals. Enrichment analysis of pollen phosphoproteins showed that pathways including DNA synthesis/chromatin structure, regulation of RNA transcription, protein modification, cell organization, signal transduction, cell cycle, vesicle transport, transport of ions and metabolisms, which were involved in pollen development, the following germination and pollen tube growth, were regulated by phosphorylation. In this study, we also found 430 kinases and 105 phosphatases in the maize pollen phosphoproteome, among which calcium dependent protein kinases (CDPKs), leucine rich repeat kinase, SNF1 related protein kinases and MAPK family proteins were heavily enriched and further analyzed. From our research, we also uncovered hundreds of male sterility-associated proteins and phosphoproteins that might influence maize productivity and serve as targets for hybrid maize seed production. At last, a putative complex signaling pathway involving CDPKs, MAPKs, ubiquitin ligases and multiple fertility proteins was constructed. Overall, our data provides new insight for further investigation of protein phosphorylation status in mature maize pollen and construction of maize male sterile mutants in the future. PMID:26969016

  14. 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

  15. Uncovering major genomic features of essential genes in Bacteria and a methanogenic Archaea.

    PubMed

    Grazziotin, Ana Laura; Vidal, Newton M; Venancio, Thiago M

    2015-09-01

    Identification of essential genes is critical to understanding the physiology of a species, proposing novel drug targets and uncovering minimal gene sets required for life. Although essential gene sets of several organisms have been determined using large-scale mutagenesis techniques, systematic studies addressing their conservation, genomic context and functions remain scant. Here we integrate 17 essential gene sets from genome-wide in vitro screenings and three gene collections required for growth in vivo, encompassing 15 Bacteria and one Archaea. We refine and generalize important theories proposed using Escherichia coli. Essential genes are typically monogenic and more conserved than nonessential genes. Genes required in vivo are less conserved than those essential in vitro, suggesting that more divergent strategies are deployed when the organism is stressed by the host immune system and unstable nutrient availability. We identified essential analogous pathways that would probably be missed by orthology-based essentiality prediction strategies. For example, Streptococcus sanguinis carries horizontally transferred isoprenoid biosynthesis genes that are widespread in Archaea. Genes specifically essential in Mycobacterium tuberculosis and Burkholderia pseudomallei are reported as potential drug targets. Moreover, essential genes are not only preferentially located in operons, but also occupy the first position therein, supporting the influence of their regulatory regions in driving transcription of whole operons. Finally, these important genomic features are shared between Bacteria and at least one Archaea, suggesting that high order properties of gene essentiality and genome architecture were probably present in the last universal common ancestor or evolved independently in the prokaryotic domains. PMID:26084810

  16. A genomic view on epilepsy and autism candidate genes.

    PubMed

    Jabbari, Kamel; Nürnberg, Peter

    2016-07-01

    Epilepsy is a common complex disorder most frequently associated with psychiatric and neurological diseases. Massive parallel sequencing of individual or cohort genomes and exomes led the identification of several disease associated genes. We review here the candidate genes in epilepsy genetics with focus on exome and gene panel data. Together with the examination of brain expressed genes and post synaptic proteome the results show that: (1) Non-metabolic epilepsies and autism candidate genes tend to be AT-rich and (2) large transcript size and local AT-richness are characteristic features of genes involved in developmental brain disorders and synaptic functions. These results point to the preferential location of core epilepsy and autism candidate genes in late replicating, GC-poor chromosomal regions (isochores). These results indicate that the genomic alterations leading to some brain disorders are confined to responsive chromatin areas harboring brain critical genes. PMID:26772991

  17. Uncovering Genomic Features and Maternal Origin of Korean Native Chicken by Whole Genome Sequencing

    PubMed Central

    Oh, Jae-Don; Heo, Kang-Nyeong; Lee, Jun-Heon; Lee, Woon Kyu; Yoon, Sook Hee; Kim, Heebal; Cho, Seoae; Lee, Hak-Kyo

    2014-01-01

    The Korean Native Chicken (KNC) is an important endemic biological resource in Korea. While numerous studies have been conducted exploring this breed, none have used next-generation sequencing to identify its specific genomic features. We sequenced five strains of KNC and identified 10.9 million SNVs and 1.3 million InDels. Through the analysis, we found that the highly variable region common to all 5 strains had genes like PCHD15, CISD1, PIK3C2A, and NUCB2 that might be related to the phenotypic traits of the chicken such as auditory sense, growth rate and egg traits. In addition, we assembled unaligned reads that could not be mapped to the reference genome. By assembling the unaligned reads, we were able to present genomic sequences characteristic to the KNC. Based on this, we also identified genes related to the olfactory receptors and antigen that are common to all 5 strains. Finally, through the reconstructed mitochondrial genome sequences, we performed phylogenomic analysis and elucidated the maternal origin of the artificially restored KNC. Our results revealed that the KNC has multiple maternal origins which are in agreement with Korea's history of chicken breed imports. The results presented here provide a valuable basis for future research on genomic features of KNC and further understanding of KNC's origin. PMID:25501044

  18. Candidate phylum TM6 genome recovered from a hospital sink biofilm provides genomic insights into this uncultivated phylum

    PubMed Central

    McLean, Jeffrey S.; Lombardo, Mary-Jane; Badger, Jonathan H.; Edlund, Anna; Novotny, Mark; Yee-Greenbaum, Joyclyn; Vyahhi, Nikolay; Hall, Adam P.; Yang, Youngik; Dupont, Christopher L.; Ziegler, Michael G.; Chitsaz, Hamidreza; Allen, Andrew E.; Yooseph, Shibu; Tesler, Glenn; Pevzner, Pavel A.; Friedman, Robert M.; Nealson, Kenneth H.; Venter, J. Craig; Lasken, Roger S.

    2013-01-01

    The “dark matter of life” describes microbes and even entire divisions of bacterial phyla that have evaded cultivation and have yet to be sequenced. We present a genome from the globally distributed but elusive candidate phylum TM6 and uncover its metabolic potential. TM6 was detected in a biofilm from a sink drain within a hospital restroom by analyzing cells using a highly automated single-cell genomics platform. We developed an approach for increasing throughput and effectively improving the likelihood of sampling rare events based on forming small random pools of single-flow–sorted cells, amplifying their DNA by multiple displacement amplification and sequencing all cells in the pool, creating a “mini-metagenome.” A recently developed single-cell assembler, SPAdes, in combination with contig binning methods, allowed the reconstruction of genomes from these mini-metagenomes. A total of 1.07 Mb was recovered in seven contigs for this member of TM6 (JCVI TM6SC1), estimated to represent 90% of its genome. High nucleotide identity between a total of three TM6 genome drafts generated from pools that were independently captured, amplified, and assembled provided strong confirmation of a correct genomic sequence. TM6 is likely a Gram-negative organism and possibly a symbiont of an unknown host (nonfree living) in part based on its small genome, low-GC content, and lack of biosynthesis pathways for most amino acids and vitamins. Phylogenomic analysis of conserved single-copy genes confirms that TM6SC1 is a deeply branching phylum. PMID:23754396

  19. Genome Reduction Uncovers a Large Dispensable Genome and Adaptive Role for Copy Number Variation in Asexually Propagated Solanum tuberosum.

    PubMed

    Hardigan, Michael A; Crisovan, Emily; Hamilton, John P; Kim, Jeongwoon; Laimbeer, Parker; Leisner, Courtney P; Manrique-Carpintero, Norma C; Newton, Linsey; Pham, Gina M; Vaillancourt, Brieanne; Yang, Xueming; Zeng, Zixian; Douches, David S; Jiang, Jiming; Veilleux, Richard E; Buell, C Robin

    2016-02-01

    Clonally reproducing plants have the potential to bear a significantly greater mutational load than sexually reproducing species. To investigate this possibility, we examined the breadth of genome-wide structural variation in a panel of monoploid/doubled monoploid clones generated from native populations of diploid potato (Solanum tuberosum), a highly heterozygous asexually propagated plant. As rare instances of purely homozygous clones, they provided an ideal set for determining the degree of structural variation tolerated by this species and deriving its minimal gene complement. Extensive copy number variation (CNV) was uncovered, impacting 219.8 Mb (30.2%) of the potato genome with nearly 30% of genes subject to at least partial duplication or deletion, revealing the highly heterogeneous nature of the potato genome. Dispensable genes (>7000) were associated with limited transcription and/or a recent evolutionary history, with lower deletion frequency observed in genes conserved across angiosperms. Association of CNV with plant adaptation was highlighted by enrichment in gene clusters encoding functions for environmental stress response, with gene duplication playing a part in species-specific expansions of stress-related gene families. This study revealed unique impacts of CNV in a species with asexual reproductive habits and how CNV may drive adaption through evolution of key stress pathways. PMID:26772996

  20. Using comparative genomics to uncover new kinds of protein-based metabolic organelles in bacteria

    PubMed Central

    Jorda, Julien; Lopez, David; Wheatley, Nicole M; Yeates, Todd O

    2013-01-01

    Bacterial microcompartment (MCP) organelles are cytosolic, polyhedral structures consisting of a thin protein shell and a series of encapsulated, sequentially acting enzymes. To date, different microcompartments carrying out three distinct types of metabolic processes have been characterized experimentally in various bacteria. In the present work, we use comparative genomics to explore the existence of yet uncharacterized microcompartments encapsulating a broader set of metabolic pathways. A clustering approach was used to group together enzymes that show a strong tendency to be encoded in chromosomal proximity to each other while also being near genes for microcompartment shell proteins. The results uncover new types of putative microcompartments, including one that appears to encapsulate B12-independent, glycyl radical-based degradation of 1,2-propanediol, and another potentially involved in amino alcohol metabolism in mycobacteria. Preliminary experiments show that an unusual shell protein encoded within the glycyl radical-based microcompartment binds an iron-sulfur cluster, hinting at complex mechanisms in this uncharacterized system. In addition, an examination of the computed microcompartment clusters suggests the existence of specific functional variations within certain types of MCPs, including the alpha carboxysome and the glycyl radical-based microcompartment. The findings lead to a deeper understanding of bacterial microcompartments and the pathways they sequester. PMID:23188745

  1. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

    PubMed

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  2. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    PubMed Central

    Kilpeläinen, Tuomas O.; Carli, Jayne F. Martin; Skowronski, Alicja A.; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K.; Drong, Alexander W.; Hayes, James E.; Zhao, Jinghua; Pers, Tune H.; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Greco M, Fabiola Del; Pasko, Dorota; Renström, Frida; Willems, Sara M.; Mahajan, Anubha; Rose, Lynda M.; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E.; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S.; Ju Sung, Yun; Ramos, Yolande F.; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M.; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J. N.; Crosslin, David R.; Dale, Caroline E.; Dastani, Zari; Day, Felix R.; Deelen, Joris; Delgado, Graciela E.; Demirkan, Ayse; Finucane, Francis M.; Ford, Ian; Garcia, Melissa E.; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E.; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A.; Hunter, David J.; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S.; Jørgensen, Marit E.; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A.; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P.; Myers, Richard H.; Männistö, Satu; Nalls, Mike A.; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rathmann, Wolfgang; Rice, Treva K.; Brent Richards, J; Ridker, Paul M.; Sattar, Naveed; Savage, David B.; Söderberg, Stefan; Timpson, Nicholas J.; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R.; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I. A.; Sarzynski, Mark A.; Rao, D. C.; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G.; Heliövaara, Markku; Knekt, Paul B.; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K.; Viikari, Jorma S.; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P.; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W.; van Duijn, Cornelia M.; Harris, Tamara B.; Bouchard, Claude; Allison, Matthew A.; Chasman, Daniel I.; Ohlsson, Claes; Lind, Lars; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; Ferrucci, Luigi; Frayling, Timothy M.; Pramstaller, Peter P.; Borecki, Ingrid B.; Waterworth, Dawn M.; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B.; Eline Slagboom, P; Grallert, Harald; Spector, Tim D.; Jukema, J.W.; Klein, Robert J.; Schadt, Erik E; Franks, Paul W.; Lindgren, Cecilia M.; Leibel, Rudolph L.; Loos, Ruth J. F.

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  3. Genomic loci and candidate genes underlying inflammatory nociception

    PubMed Central

    Nair, Harsha K.; Hain, Heather; Quock, Raymond M.; Philip, Vivek M.; Chesler, Elissa J.; Belknap, John K.; Lariviere, William R.

    2011-01-01

    Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal (IP) acetic acid test and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in three distinct groups of BXD RI mouse strains in two separate experiments. Combined mapping results detected two QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to IP acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high priority candidate genes to investigate further in rodents and human association studies. PMID:21195549

  4. Uncovering Adaptation from Sequence Data: Lessons from Genome Resequencing of Four Cattle Breeds.

    PubMed

    Boitard, Simon; Boussaha, Mekki; Capitan, Aurélien; Rocha, Dominique; Servin, Bertrand

    2016-05-01

    Detecting the molecular basis of adaptation is one of the major questions in population genetics. With the advance in sequencing technologies, nearly complete interrogation of genome-wide polymorphisms in multiple populations is becoming feasible in some species, with the expectation that it will extend quickly to new ones. Here, we investigate the advantages of sequencing for the detection of adaptive loci in multiple populations, exploiting a recently published data set in cattle (Bos taurus). We used two different approaches to detect statistically significant signals of positive selection: a within-population approach aimed at identifying hard selective sweeps and a population-differentiation approach that can capture other selection events such as soft or incomplete sweeps. We show that the two methods are complementary in that they indeed capture different kinds of selection signatures. Our study confirmed some of the well-known adaptive loci in cattle (e.g., MC1R, KIT, GHR, PLAG1, NCAPG/LCORL) and detected some new ones (e.g., ARL15, PRLR, CYP19A1, PPM1L). Compared to genome scans based on medium- or high-density SNP data, we found that sequencing offered an increased detection power and a higher resolution in the localization of selection signatures. In several cases, we could even pinpoint the underlying causal adaptive mutation or at least a very small number of possible candidates (e.g., MC1R, PLAG1). Our results on these candidates suggest that a vast majority of adaptive mutations are likely to be regulatory rather than protein-coding variants. PMID:27017625

  5. Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types

    PubMed Central

    Giacomini, Craig P.; Sun, Steven; Varma, Sushama; Shain, A. Hunter; Giacomini, Marilyn M.; Balagtas, Jay; Sweeney, Robert T.; Lai, Everett; Del Vecchio, Catherine A.; Forster, Andrew D.; Clarke, Nicole; Montgomery, Kelli D.; Zhu, Shirley; Wong, Albert J.; van de Rijn, Matt; West, Robert B.; Pollack, Jonathan R.

    2013-01-01

    Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a “breakpoint analysis” pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis. PMID:23637631

  6. Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

    PubMed Central

    Almeida, Alexandre; Villain, Adrien; Joubrel, Caroline; Touak, Gérald; Sauvage, Elisabeth; Rosinski-Chupin, Isabelle

    2015-01-01

    ABSTRACT Streptococcus agalactiae (group B Streptococcus or GBS), a commensal of the human gut and genitourinary tract, is a leading cause of neonatal infections, in which vertical transmission from mother to child remains the most frequent route of contamination. Here, we investigated whether the progression of GBS from carriage to disease is associated with genomic adaptation. Whole-genome comparison of 47 GBS samples from 19 mother-child pairs uncovered 21 single nucleotide polymorphisms (SNPs) and seven insertions/deletions. Of the SNPs detected, 16 appear to have been fixed in the population sampled whereas five mutations were found to be polymorphic. In the infant strains, 14 mutations were detected, including two independently fixed variants affecting the covRS locus, which is known to encode a major regulatory system of virulence. A one-nucleotide insertion was also identified in the promoter region of the highly immunogenic surface protein Rib gene. Gene expression analysis after incubation in human blood showed that these mutations influenced the expression of virulence-associated genes. Additional identification of three mutated strains in the mothers' milk raised the possibility of the newborns also being a source of contamination for their mothers. Overall, our work showed that GBS strains in carriage and disease scenarios might undergo adaptive changes following colonization. The types and locations of the mutations found, together with the experimental results showing their phenotypic impact, suggest that those in a context of infection were positively selected during the transition of GBS from commensal to pathogen, contributing to an increased capacity to cause disease. IMPORTANCE Group B Streptococcus (GBS) is a major pathogen responsible for neonatal infections. Considering that its colonization of healthy adults is mostly asymptomatic, the mechanisms behind its switch from a commensal to an invasive state are largely unknown. In this work, we

  7. Genome-wide association study uncovers four QTL predisposing to supernumerary teats in cattle.

    PubMed

    Pausch, Hubert; Jung, Simone; Edel, Christian; Emmerling, Reiner; Krogmeier, Dieter; Götz, Kay-Uwe; Fries, Ruedi

    2012-12-01

    Supernumerary teats (hyperthelia, SNTs) are a common abnormality of the bovine udder with a medium to high heritability and a postulated oligogenic or polygenic inheritance pattern. SNTs not only negatively affect machine milking ability but also act as a reservoir for bacteria. A genome-wide association study was carried out to identify genes involved in the development of SNTs in the dual-purpose Fleckvieh breed. A total of 2467 progeny-tested bulls were genotyped at 43 698 single nucleotide polymorphisms, and daughter yield deviations (DYDs) for 'udder clearness' (UC) were used as high-heritability phenotypes. Massive structuring of the study population was accounted for by principal components analysis-based and mixed model-based approaches. Four loci on BTA5, BTA6, BTA11 and BTA17 were significantly associated with the UC DYD. Three associated regions contain genes of the highly conserved Wnt signalling pathway. The four QTL together account for 10.7% of the variance of the UC DYD, whereas the major fraction of the DYD variance is attributable to chromosomes with no identified QTL. Our results support both an oligogenic and a polygenic inheritance pattern of SNTs in cattle. The identified candidate genes permit insights into the genetic architecture of teat malformations in cattle and provide clues to unravel the molecular mechanisms of mammary gland alterations in cattle and other species. PMID:22497297

  8. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    PubMed Central

    Hansen, NT; Brunak, S; Altman, RB

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge, but they are expensive to generate manually and may therefore have incomplete coverage. We have developed a method that ranks 12,460 genes in the human genome on the basis of their potential relevance to a specific query drug and its putative indications. Our method uses known gene–drug interactions, networks of gene–gene interactions, and available measures of drug–drug similarity. It ranks genes by building a local network of known interactions and assessing the similarity of the query drug (by both structure and indication) with drugs that interact with gene products in the local network. In a comprehensive benchmark, our method achieves an overall area under the curve of 0.82. To showcase our method, we found novel gene candidates for warfarin, gefitinib, carboplatin, and gemcitabine, and we provide the molecular hypotheses for these predictions. PMID:19369935

  9. Exploiting Genomics Resources to Identify Candidate Genes Underlying Antioxidants Content in Tomato Fruit.

    PubMed

    Calafiore, Roberta; Ruggieri, Valentino; Raiola, Assunta; Rigano, Maria M; Sacco, Adriana; Hassan, Mohamed I; Frusciante, Luigi; Barone, Amalia

    2016-01-01

    The tomato is a model species for fleshy fruit development and ripening, as well as for genomics studies of others Solanaceae. Many genetic and genomics resources, including databases for sequencing, transcriptomics and metabolomics data, have been developed and are today available. The purpose of the present work was to uncover new genes and/or alleles that determine ascorbic acid and carotenoids accumulation, by exploiting one Solanum pennellii introgression lines (IL7-3) harboring quantitative trait loci (QTL) that increase the content of these metabolites in the fruit. The higher ascorbic acid and carotenoids content in IL7-3 was confirmed at three fruit developmental stages. The tomato genome reference sequence and the recently released S. pennellii genome sequence were investigated to identify candidate genes (CGs) that might control ascorbic acid and carotenoids accumulation. First of all, a refinement of the wild region borders in the IL7-3 was achieved by analyzing CAPS markers designed in our laboratory. Afterward, six CGs associated to ascorbic acid and one with carotenoids metabolism were identified exploring the annotation and the Gene Ontology terms of genes included in the region. Variants between the sequence of the wild and the cultivated alleles of these genes were investigated for their functional relevance and their potential effects on the protein sequences were predicted. Transcriptional levels of CGs in the introgression region were extracted from RNA-Seq data available for the entire S. pennellii introgression lines collection and verified by Real-Time qPCR. Finally, seven IL7-3 sub-lines were genotyped using 28 species-specific markers and then were evaluated for metabolites content. These analyses evidenced a significant decrease in transcript abundance for one 9-cis-epoxycarotenoid dioxygenase and one L-ascorbate oxidase homolog, whose role in the accumulation of carotenoids and ascorbic acid is discussed. Comprehensively, the reported

  10. Exploiting Genomics Resources to Identify Candidate Genes Underlying Antioxidants Content in Tomato Fruit

    PubMed Central

    Calafiore, Roberta; Ruggieri, Valentino; Raiola, Assunta; Rigano, Maria M.; Sacco, Adriana; Hassan, Mohamed I.; Frusciante, Luigi; Barone, Amalia

    2016-01-01

    The tomato is a model species for fleshy fruit development and ripening, as well as for genomics studies of others Solanaceae. Many genetic and genomics resources, including databases for sequencing, transcriptomics and metabolomics data, have been developed and are today available. The purpose of the present work was to uncover new genes and/or alleles that determine ascorbic acid and carotenoids accumulation, by exploiting one Solanum pennellii introgression lines (IL7-3) harboring quantitative trait loci (QTL) that increase the content of these metabolites in the fruit. The higher ascorbic acid and carotenoids content in IL7-3 was confirmed at three fruit developmental stages. The tomato genome reference sequence and the recently released S. pennellii genome sequence were investigated to identify candidate genes (CGs) that might control ascorbic acid and carotenoids accumulation. First of all, a refinement of the wild region borders in the IL7-3 was achieved by analyzing CAPS markers designed in our laboratory. Afterward, six CGs associated to ascorbic acid and one with carotenoids metabolism were identified exploring the annotation and the Gene Ontology terms of genes included in the region. Variants between the sequence of the wild and the cultivated alleles of these genes were investigated for their functional relevance and their potential effects on the protein sequences were predicted. Transcriptional levels of CGs in the introgression region were extracted from RNA-Seq data available for the entire S. pennellii introgression lines collection and verified by Real-Time qPCR. Finally, seven IL7-3 sub-lines were genotyped using 28 species-specific markers and then were evaluated for metabolites content. These analyses evidenced a significant decrease in transcript abundance for one 9-cis-epoxycarotenoid dioxygenase and one L-ascorbate oxidase homolog, whose role in the accumulation of carotenoids and ascorbic acid is discussed. Comprehensively, the reported

  11. Genome reorganization in F1 hybrids uncovers the role of retrotransposons in reproductive isolation

    PubMed Central

    Senerchia, Natacha; Felber, François; Parisod, Christian

    2015-01-01

    Interspecific hybridization leads to new interactions among divergent genomes, revealing the nature of genetic incompatibilities having accumulated during and after the origin of species. Conflicts associated with misregulation of transposable elements (TEs) in hybrids expectedly result in their activation and genome-wide changes that may be key to species boundaries. Repetitive genomes of wild wheats have diverged under differential dynamics of specific long terminal repeat retrotransposons (LTR-RTs), offering unparalleled opportunities to address the underpinnings of plant genome reorganization by selfish sequences. Using reciprocal F1 hybrids between three Aegilops species, restructuring and epigenetic repatterning was assessed at random and LTR-RT sequences with amplified fragment length polymorphism and sequence-specific amplified polymorphisms as well as their methylation-sensitive counterparts, respectively. Asymmetrical reorganization of LTR-RT families predicted to cause conflicting interactions matched differential survival of F1 hybrids. Consistent with the genome shock model, increasing divergence of merged LTR-RTs yielded higher levels of changes in corresponding genome fractions and lead to repeated reorganization of LTR-RT sequences in F1 hybrids. Such non-random reorganization of hybrid genomes is coherent with the necessary repression of incompatible TE loci in support of hybrid viability and indicates that TE-driven genomic conflicts may represent an overlooked factor supporting reproductive isolation. PMID:25716787

  12. Genome reorganization in F1 hybrids uncovers the role of retrotransposons in reproductive isolation.

    PubMed

    Senerchia, Natacha; Felber, François; Parisod, Christian

    2015-04-01

    Interspecific hybridization leads to new interactions among divergent genomes, revealing the nature of genetic incompatibilities having accumulated during and after the origin of species. Conflicts associated with misregulation of transposable elements (TEs) in hybrids expectedly result in their activation and genome-wide changes that may be key to species boundaries. Repetitive genomes of wild wheats have diverged under differential dynamics of specific long terminal repeat retrotransposons (LTR-RTs), offering unparalleled opportunities to address the underpinnings of plant genome reorganization by selfish sequences. Using reciprocal F1 hybrids between three Aegilops species, restructuring and epigenetic repatterning was assessed at random and LTR-RT sequences with amplified fragment length polymorphism and sequence-specific amplified polymorphisms as well as their methylation-sensitive counterparts, respectively. Asymmetrical reorganization of LTR-RT families predicted to cause conflicting interactions matched differential survival of F1 hybrids. Consistent with the genome shock model, increasing divergence of merged LTR-RTs yielded higher levels of changes in corresponding genome fractions and lead to repeated reorganization of LTR-RT sequences in F1 hybrids. Such non-random reorganization of hybrid genomes is coherent with the necessary repression of incompatible TE loci in support of hybrid viability and indicates that TE-driven genomic conflicts may represent an overlooked factor supporting reproductive isolation. PMID:25716787

  13. Uncovering the Potential Pan Proteomes Encoded by Genomic Strand RNAs of Influenza A Viruses

    PubMed Central

    Yang, Chu-Wen; Chen, Mei-Fang

    2016-01-01

    Influenza A virus genomes are composed of eight negative sense RNAs. In total, 16 proteins encoded by eight positive sense RNAs were identified. One putative protein coding sequence (PCS) encoded by genomic strand RNA of segment 8 has been previously proposed. In this study, 95,608, 123,965 and 35,699 genomic strand RNA sequences from influenza A viruses from avian, human and mammalian hosts, respectively, were used to identify PCSs encoded by the genomic strand RNAs. In total, 326,069 PCSs with lengths equal to or longer than 80 amino acids were identified and clustered into 270 PCS groups. Twenty of the 270 PCS groups which have greater than 10% proportion in influenza A viruses from avian, human or mammalian hosts were selected for detailed study. Maps of the 20 PCSGs in the influenza A virus genomes were constructed. The proportions of the 20 PCSGs in influenza A viruses from different hosts and serotypes were analyzed. One secretory and five membrane proteins predicted from the PCS groups encoded by genomic strand RNAs of segments 1, 2, 4, 6, 7 and 8 were identified. These results suggest the possibility of the ambisense nature of the influenza A virus genomic RNAs and a potential coding sequence reservoir encoding potential pan proteomes of influenza A viruses. PMID:26761196

  14. Genome sequence of Valsa canker pathogens uncovers a potential adaptation of colonization of woody bark.

    PubMed

    Yin, Zhiyuan; Liu, Huiquan; Li, Zhengpeng; Ke, Xiwang; Dou, Daolong; Gao, Xiaoning; Song, Na; Dai, Qingqing; Wu, Yuxing; Xu, Jin-Rong; Kang, Zhensheng; Huang, Lili

    2015-12-01

    Canker caused by ascomycetous Valsa species are among the most destructive diseases of woody plants worldwide. These pathogens are distinct from other pathogens because they only effectively attack tree bark in the field. To unravel the potential adaptation mechanism of bark colonization, we examined the genomes of Valsa mali and Valsa pyri that preferentially infect apple and pear, respectively. We reported the 44.7 and 35.7 Mb genomes of V. mali and V. pyri, respectively. We also identified the potential genomic determinants of wood colonization by comparing them with related cereal pathogens. Both genomes encode a plethora of pathogenicity-related genes involved in plant cell wall degradation and secondary metabolite biosynthesis. In order to adapt to the nutrient limitation and low pH environment in bark, they seem to employ membrane transporters associated with nitrogen uptake and secrete proteases predominantly with acidic pH optima. Remarkably, both Valsa genomes are especially suited for pectin decomposition, but are limited in lignocellulose and cutin degradation. Besides many similarities, the two genomes show distinct variations in many secondary metabolism gene clusters. Our results show a potential adaptation of Valsa canker pathogens to colonize woody bark. Secondary metabolism gene clusters are probably responsible for this host specificity. PMID:26137988

  15. Genome-scale computational analysis of DNA curvature and repeats in Arabidopsis and rice uncovers plant-specific genomic properties

    PubMed Central

    2011-01-01

    Background Due to its overarching role in genome function, sequence-dependent DNA curvature continues to attract great attention. The DNA double helix is not a rigid cylinder, but presents both curvature and flexibility in different regions, depending on the sequence. More in depth knowledge of the various orders of complexity of genomic DNA structure has allowed the design of sophisticated bioinformatics tools for its analysis and manipulation, which, in turn, have yielded a better understanding of the genome itself. Curved DNA is involved in many biologically important processes, such as transcription initiation and termination, recombination, DNA replication, and nucleosome positioning. CpG islands and tandem repeats also play significant roles in the dynamics and evolution of genomes. Results In this study, we analyzed the relationship between these three structural features within rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) genomes. A genome-scale prediction of curvature distribution in rice and Arabidopsis indicated that most of the chromosomes of both genomes have maximal chromosomal DNA curvature adjacent to the centromeric region. By analyzing tandem repeats across the genome, we found that frequencies of repeats are higher in regions adjacent to those with high curvature value. Further analysis of CpG islands shows a clear interdependence between curvature value, repeat frequencies and CpG islands. Each CpG island appears in a local minimal curvature region, and CpG islands usually do not appear in the centromere or regions with high repeat frequency. A statistical evaluation demonstrates the significance and non-randomness of these features. Conclusions This study represents the first systematic genome-scale analysis of DNA curvature, CpG islands and tandem repeats at the DNA sequence level in plant genomes, and finds that not all of the chromosomes in plants follow the same rules common to other eukaryote organisms, suggesting that some

  16. A joint modeling approach for uncovering associations between gene expression, bioactivity and chemical structure in early drug discovery to guide lead selection and genomic biomarker development.

    PubMed

    Perualila-Tan, Nolen; Kasim, Adetayo; Talloen, Willem; Verbist, Bie; Göhlmann, Hinrich W H; Shkedy, Ziv

    2016-08-01

    The modern drug discovery process involves multiple sources of high-dimensional data. This imposes the challenge of data integration. A typical example is the integration of chemical structure (fingerprint features), phenotypic bioactivity (bioassay read-outs) data for targets of interest, and transcriptomic (gene expression) data in early drug discovery to better understand the chemical and biological mechanisms of candidate drugs, and to facilitate early detection of safety issues prior to later and expensive phases of drug development cycles. In this paper, we discuss a joint model for the transcriptomic and the phenotypic variables conditioned on the chemical structure. This modeling approach can be used to uncover, for a given set of compounds, the association between gene expression and biological activity taking into account the influence of the chemical structure of the compound on both variables. The model allows to detect genes that are associated with the bioactivity data facilitating the identification of potential genomic biomarkers for compounds efficacy. In addition, the effect of every structural feature on both genes and pIC50 and their associations can be simultaneously investigated. Two oncology projects are used to illustrate the applicability and usefulness of the joint model to integrate multi-source high-dimensional information to aid drug discovery. PMID:27269248

  17. Read clouds uncover variation in complex regions of the human genome

    PubMed Central

    Bishara, Alex; Liu, Yuling; Weng, Ziming; Kashef-Haghighi, Dorna; Newburger, Daniel E.; West, Robert; Sidow, Arend; Batzoglou, Serafim

    2015-01-01

    Although an increasing amount of human genetic variation is being identified and recorded, determining variants within repeated sequences of the human genome remains a challenge. Most population and genome-wide association studies have therefore been unable to consider variation in these regions. Core to the problem is the lack of a sequencing technology that produces reads with sufficient length and accuracy to enable unique mapping. Here, we present a novel methodology of using read clouds, obtained by accurate short-read sequencing of DNA derived from long fragment libraries, to confidently align short reads within repeat regions and enable accurate variant discovery. Our novel algorithm, Random Field Aligner (RFA), captures the relationships among the short reads governed by the long read process via a Markov Random Field. We utilized a modified version of the Illumina TruSeq synthetic long-read protocol, which yielded shallow-sequenced read clouds. We test RFA through extensive simulations and apply it to discover variants on the NA12878 human sample, for which shallow TruSeq read cloud sequencing data are available, and on an invasive breast carcinoma genome that we sequenced using the same method. We demonstrate that RFA facilitates accurate recovery of variation in 155 Mb of the human genome, including 94% of 67 Mb of segmental duplication sequence and 96% of 11 Mb of transcribed sequence, that are currently hidden from short-read technologies. PMID:26286554

  18. Whole-genome resequencing uncovers molecular signatures of natural and sexual selection in wild bighorn sheep.

    PubMed

    Kardos, Marty; Luikart, Gordon; Bunch, Rowan; Dewey, Sarah; Edwards, William; McWilliam, Sean; Stephenson, John; Allendorf, Fred W; Hogg, John T; Kijas, James

    2015-11-01

    The identification of genes influencing fitness is central to our understanding of the genetic basis of adaptation and how it shapes phenotypic variation in wild populations. Here, we used whole-genome resequencing of wild Rocky Mountain bighorn sheep (Ovis canadensis) to >50-fold coverage to identify 2.8 million single nucleotide polymorphisms (SNPs) and genomic regions bearing signatures of directional selection (i.e. selective sweeps). A comparison of SNP diversity between the X chromosome and the autosomes indicated that bighorn males had a dramatically reduced long-term effective population size compared to females. This probably reflects a long history of intense sexual selection mediated by male-male competition for mates. Selective sweep scans based on heterozygosity and nucleotide diversity revealed evidence for a selective sweep shared across multiple populations at RXFP2, a gene that strongly affects horn size in domestic ungulates. The massive horns carried by bighorn rams appear to have evolved in part via strong positive selection at RXFP2. We identified evidence for selection within individual populations at genes affecting early body growth and cellular response to hypoxia; however, these must be interpreted more cautiously as genetic drift is strong within local populations and may have caused false positives. These results represent a rare example of strong genomic signatures of selection identified at genes with known function in wild populations of a nonmodel species. Our results also showcase the value of reference genome assemblies from agricultural or model species for studies of the genomic basis of adaptation in closely related wild taxa. PMID:26454263

  19. An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours.

    PubMed

    Mestdagh, P; Fredlund, E; Pattyn, F; Rihani, A; Van Maerken, T; Vermeulen, J; Kumps, C; Menten, B; De Preter, K; Schramm, A; Schulte, J; Noguera, R; Schleiermacher, G; Janoueix-Lerosey, I; Laureys, G; Powel, R; Nittner, D; Marine, J-C; Ringnér, M; Speleman, F; Vandesompele, J

    2010-06-17

    Different classes of non-coding RNAs, including microRNAs, have recently been implicated in the process of tumourigenesis. In this study, we examined the expression and putative functions of a novel class of non-coding RNAs known as transcribed ultraconserved regions (T-UCRs) in neuroblastoma. Genome-wide expression profiling revealed correlations between specific T-UCR expression levels and important clinicogenetic parameters such as MYCN amplification status. A functional genomics approach based on the integration of multi-level transcriptome data was adapted to gain insights into T-UCR functions. Assignments of T-UCRs to cellular processes such as TP53 response, differentiation and proliferation were verified using various cellular model systems. For the first time, our results define a T-UCR expression landscape in neuroblastoma and suggest widespread T-UCR involvement in diverse cellular processes that are deregulated in the process of tumourigenesis. PMID:20383195

  20. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities.

    PubMed

    Craig, David W; O'Shaughnessy, Joyce A; Kiefer, Jeffrey A; Aldrich, Jessica; Sinari, Shripad; Moses, Tracy M; Wong, Shukmei; Dinh, Jennifer; Christoforides, Alexis; Blum, Joanne L; Aitelli, Cristi L; Osborne, Cynthia R; Izatt, Tyler; Kurdoglu, Ahmet; Baker, Angela; Koeman, Julie; Barbacioru, Catalin; Sakarya, Onur; De La Vega, Francisco M; Siddiqui, Asim; Hoang, Linh; Billings, Paul R; Salhia, Bodour; Tolcher, Anthony W; Trent, Jeffrey M; Mousses, Spyro; Von Hoff, Daniel; Carpten, John D

    2013-01-01

    Triple-negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first-line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors, particularly those that may inform targeted therapies. Genes mutated in multiple tumors included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Notable genes involved in focal structural events were CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 was detected in 2 of 6 African Americans. RNA sequencing revealed consistent overexpression of the FOXM1 gene when tumor gene expression was compared with nonmalignant breast samples. Using an outlier analysis of gene expression comparing one cancer with all the others, we detected expression patterns unique to each patient's tumor. Integrative DNA/RNA analysis provided evidence for deregulation of mutated genes, including the monoallelic expression of TP53 mutations. Finally, molecular alterations in several cancers supported targeted therapeutic intervention on clinical trials with known inhibitors, particularly for alterations in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways. In conclusion, whole genome and transcriptome profiling of mTNBC have provided insights into somatic events occurring in this difficult to treat cancer. These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials in this irremediable cancer. PMID:23171949

  1. Identification of Candidate Genes in Rice for Resistance to Sheath Blight Disease by Whole Genome Sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent advances in whole genome sequencing have allowed identification of genes for disease susceptibility in humans. The objective of our research was to exploit whole genome sequences of 13 rice (Oryza sativa L.) inbred lines to identify non-synonymous SNPs (nsSNPs) and candidate genes for resista...

  2. Draft Genome Sequence of Lactobacillus reuteri Strain CRL 1098, an Interesting Candidate for Functional Food Development

    PubMed Central

    Torres, Andrea C.; Suárez, Nadia E.; Font, Graciela; Saavedra, Lucila

    2016-01-01

    We report here the draft genome sequence of Lactobacillus reuteri strain CRL 1098. This strain represents an interesting candidate for functional food development because of its proven probiotic properties. The draft genome sequence is composed of 1,969,471 bp assembled into 45 contigs and an average G+C content of 38.8%. PMID:27563038

  3. Comparative Phylogenomics Uncovers the Impact of Symbiotic Associations on Host Genome Evolution

    PubMed Central

    Delaux, Pierre-Marc; Varala, Kranthi; Edger, Patrick P.; Coruzzi, Gloria M.; Pires, J. Chris; Ané, Jean-Michel

    2014-01-01

    Mutualistic symbioses between eukaryotes and beneficial microorganisms of their microbiome play an essential role in nutrition, protection against disease, and development of the host. However, the impact of beneficial symbionts on the evolution of host genomes remains poorly characterized. Here we used the independent loss of the most widespread plant–microbe symbiosis, arbuscular mycorrhization (AM), as a model to address this question. Using a large phenotypic approach and phylogenetic analyses, we present evidence that loss of AM symbiosis correlates with the loss of many symbiotic genes in the Arabidopsis lineage (Brassicales). Then, by analyzing the genome and/or transcriptomes of nine other phylogenetically divergent non-host plants, we show that this correlation occurred in a convergent manner in four additional plant lineages, demonstrating the existence of an evolutionary pattern specific to symbiotic genes. Finally, we use a global comparative phylogenomic approach to track this evolutionary pattern among land plants. Based on this approach, we identify a set of 174 highly conserved genes and demonstrate enrichment in symbiosis-related genes. Our findings are consistent with the hypothesis that beneficial symbionts maintain purifying selection on host gene networks during the evolution of entire lineages. PMID:25032823

  4. Genomic profiling of lower-grade gliomas uncovers cohesive disease groups: implications for diagnosis and treatment.

    PubMed

    Zhang, Chang-Ming; Brat, Daniel J

    2016-01-01

    Lower-grade gliomas (including low- and intermediate-grade gliomas, World Health Organization grades II and III) are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas, oligodendrogliomas, or oligoastrocytomas. Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century, it suffers from high intra- and inter-observer variability and does not adequately predict clinical outcomes. Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas, lower-grade gliomas have been found to segregate into three cohesive, clinically relevant molecular classes. Molecular classes were closely aligned with the status of isocitrate dehydrogenase (IDH) mutations, tumor protein 53 mutations and the co-deletion of chromosome arms 1p and 19q, but were not closely aligned with histologic classes. These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification. PMID:26758195

  5. Genome Reduction Uncovers a Large Dispensable Genome and Adaptive Role for Copy Number Variation in Asexually Propagated Solanum tuberosum[OPEN

    PubMed Central

    Hardigan, Michael A.; Crisovan, Emily; Hamilton, John P.; Laimbeer, Parker; Leisner, Courtney P.; Manrique-Carpintero, Norma C.; Newton, Linsey; Pham, Gina M.; Vaillancourt, Brieanne; Zeng, Zixian; Jiang, Jiming

    2016-01-01

    Clonally reproducing plants have the potential to bear a significantly greater mutational load than sexually reproducing species. To investigate this possibility, we examined the breadth of genome-wide structural variation in a panel of monoploid/doubled monoploid clones generated from native populations of diploid potato (Solanum tuberosum), a highly heterozygous asexually propagated plant. As rare instances of purely homozygous clones, they provided an ideal set for determining the degree of structural variation tolerated by this species and deriving its minimal gene complement. Extensive copy number variation (CNV) was uncovered, impacting 219.8 Mb (30.2%) of the potato genome with nearly 30% of genes subject to at least partial duplication or deletion, revealing the highly heterogeneous nature of the potato genome. Dispensable genes (>7000) were associated with limited transcription and/or a recent evolutionary history, with lower deletion frequency observed in genes conserved across angiosperms. Association of CNV with plant adaptation was highlighted by enrichment in gene clusters encoding functions for environmental stress response, with gene duplication playing a part in species-specific expansions of stress-related gene families. This study revealed unique impacts of CNV in a species with asexual reproductive habits and how CNV may drive adaption through evolution of key stress pathways. PMID:26772996

  6. Translational Genomics in Legumes Allowed Placing In Silico 5460 Unigenes on the Pea Functional Map and Identified Candidate Genes in Pisum sativum L.

    PubMed Central

    Bordat, Amandine; Savois, Vincent; Nicolas, Marie; Salse, Jérome; Chauveau, Aurélie; Bourgeois, Michael; Potier, Jean; Houtin, Hervé; Rond, Céline; Murat, Florent; Marget, Pascal; Aubert, Grégoire; Burstin, Judith

    2011-01-01

    To identify genes involved in phenotypic traits, translational genomics from highly characterized model plants to poorly characterized crop plants provides a valuable source of markers to saturate a zone of interest as well as functionally characterized candidate genes. In this paper, an integrated view of the pea genetic map was developed. A series of gene markers were mapped and their best reciprocal homologs were identified on M. truncatula, L. japonicus, soybean, and poplar pseudomolecules. Based on the syntenic relationships uncovered between pea and M. truncatula, 5460 pea Unigenes were tentatively placed on the consensus map. A new bioinformatics tool, http://www.thelegumeportal.net/pea_mtr_translational_toolkit, was developed that allows, for any gene sequence, to search its putative position on the pea consensus map and hence to search for candidate genes among neighboring Unigenes. As an example, a promising candidate gene for the hypernodulation mutation nod3 in pea was proposed based on the map position of the likely homolog of Pub1, a M. truncatula gene involved in nodulation regulation. A broader view of pea genome evolution was obtained by revealing syntenic relationships between pea and sequenced genomes. Blocks of synteny were identified which gave new insights into the evolution of chromosome structure in Papillionoids and Eudicots. The power of the translational genomics approach was underlined. PMID:22384322

  7. PAR-CLIP analysis uncovers AUF1 impact on target RNA fate and genome integrity

    PubMed Central

    Yoon, Je-Hyun; De, Supriyo; Srikantan, Subramanya; Abdelmohsen, Kotb; Grammatikakis, Ioannis; Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon; White, Elizabeth J.F.; Martindale, Jennifer L.; Yang, Xiaoling; Kang, Min-Ju; Wood, William H.; Hooten, Nicole Noren; Evans, Michele K.; Becker, Kevin G.; Tripathi, Vidisha; Prasanth, Kannanganattu V.; Wilson, Gerald M.; Tuschl, Thomas; Ingolia, Nicholas T.; Hafner, Markus; Gorospe, Myriam

    2015-01-01

    Post-transcriptional gene regulation is robustly regulated by RNA-binding proteins (RBPs). Here we describe the collection of RNAs regulated by AUF1 (AU-binding factor 1), an RBP linked to cancer, inflammation and aging. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) analysis reveals that AUF1 primarily recognizes U-/GU-rich sequences in mRNAs and noncoding RNAs and influences target transcript fate in three main directions. First, AUF1 lowers the steady-state levels of numerous target RNAs, including long noncoding RNA NEAT1, in turn affecting the organization of nuclear paraspeckles. Second, AUF1 does not change the abundance of many target RNAs, but ribosome profiling reveals that AUF1 promotes the translation of numerous mRNAs in this group. Third, AUF1 unexpectedly enhances the steady-state levels of several target mRNAs encoding DNA-maintenance proteins. Through its actions on target RNAs, AUF1 preserves genomic integrity, in agreement with the AUF1-elicited prevention of premature cellular senescence. PMID:25366541

  8. QTL Mapping in Three Rice Populations Uncovers Major Genomic Regions Associated with African Rice Gall Midge Resistance.

    PubMed

    Yao, Nasser; Lee, Cheng-Ruei; Semagn, Kassa; Sow, Mounirou; Nwilene, Francis; Kolade, Olufisayo; Bocco, Roland; Oyetunji, Olumoye; Mitchell-Olds, Thomas; Ndjiondjop, Marie-Noëlle

    2016-01-01

    African rice gall midge (AfRGM) is one of the most destructive pests of irrigated and lowland African ecologies. This study aimed to identify the quantitative trait loci (QTL) associated with AfRGM pest incidence and resistance in three independent bi-parental rice populations (ITA306xBW348-1, ITA306xTOG7106 and ITA306xTOS14519), and to conduct meta QTL (mQTL) analysis to explore whether any genomic regions are conserved across different genetic backgrounds. Composite interval mapping (CIM) conducted on the three populations independently uncovered a total of 28 QTLs associated with pest incidence (12) and pest severity (16). The number of QTLs per population associated with AfRGM resistance varied from three in the ITA306xBW348-1 population to eight in the ITA306xTOG7106 population. Each QTL individually explained 1.3 to 34.1% of the phenotypic variance. The major genomic region for AfRGM resistance had a LOD score and R2 of 60.0 and 34.1% respectively, and mapped at 111 cM on chromosome 4 (qAfrGM4) in the ITA306xTOS14519 population. The meta-analysis reduced the number of QTLs from 28 to 17 mQTLs, each explaining 1.3 to 24.5% of phenotypic variance, and narrowed the confidence intervals by 2.2 cM. There was only one minor effect mQTL on chromosome 1 that was common in the TOS14519 and TOG7106 genetic backgrounds; all other mQTLs were background specific. We are currently fine-mapping and validating the major effect genomic region on chromosome 4 (qAfRGM4). This is the first report in mapping the genomic regions associated with the AfRGM resistance, and will be highly useful for rice breeders. PMID:27508500

  9. QTL Mapping in Three Rice Populations Uncovers Major Genomic Regions Associated with African Rice Gall Midge Resistance

    PubMed Central

    Semagn, Kassa; Sow, Mounirou; Nwilene, Francis; Kolade, Olufisayo; Bocco, Roland; Oyetunji, Olumoye; Mitchell-Olds, Thomas; Ndjiondjop, Marie-Noëlle

    2016-01-01

    African rice gall midge (AfRGM) is one of the most destructive pests of irrigated and lowland African ecologies. This study aimed to identify the quantitative trait loci (QTL) associated with AfRGM pest incidence and resistance in three independent bi-parental rice populations (ITA306xBW348-1, ITA306xTOG7106 and ITA306xTOS14519), and to conduct meta QTL (mQTL) analysis to explore whether any genomic regions are conserved across different genetic backgrounds. Composite interval mapping (CIM) conducted on the three populations independently uncovered a total of 28 QTLs associated with pest incidence (12) and pest severity (16). The number of QTLs per population associated with AfRGM resistance varied from three in the ITA306xBW348-1 population to eight in the ITA306xTOG7106 population. Each QTL individually explained 1.3 to 34.1% of the phenotypic variance. The major genomic region for AfRGM resistance had a LOD score and R2 of 60.0 and 34.1% respectively, and mapped at 111 cM on chromosome 4 (qAfrGM4) in the ITA306xTOS14519 population. The meta-analysis reduced the number of QTLs from 28 to 17 mQTLs, each explaining 1.3 to 24.5% of phenotypic variance, and narrowed the confidence intervals by 2.2 cM. There was only one minor effect mQTL on chromosome 1 that was common in the TOS14519 and TOG7106 genetic backgrounds; all other mQTLs were background specific. We are currently fine-mapping and validating the major effect genomic region on chromosome 4 (qAfRGM4). This is the first report in mapping the genomic regions associated with the AfRGM resistance, and will be highly useful for rice breeders. PMID:27508500

  10. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice

    PubMed Central

    Miyata, Haruhiko; Castaneda, Julio M.; Fujihara, Yoshitaka; Yu, Zhifeng; Archambeault, Denise R.; Isotani, Ayako; Kiyozumi, Daiji; Kriseman, Maya L.; Mashiko, Daisuke; Matsumura, Takafumi; Matzuk, Ryan M.; Mori, Masashi; Noda, Taichi; Oji, Asami; Okabe, Masaru; Prunskaite-Hyyrylainen, Renata; Ramirez-Solis, Ramiro; Satouh, Yuhkoh; Zhang, Qian; Ikawa, Masahito; Matzuk, Martin M.

    2016-01-01

    Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly in the male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201–12206], the functions of the majority of these testis-enriched genes during spermatogenesis and fertilization were largely unknown. Since the study by Schultz et al., functional analysis of hundreds of reproductive-tract–enriched genes have been performed, but there remain many testis-enriched genes for which their relevance to reproduction remain unexplored or unreported. Historically, a gene knockout is the “gold standard” to determine whether a gene’s function is essential in vivo. Although knockout mice without apparent phenotypes are rarely published, these knockout mouse lines and their phenotypic information need to be shared to prevent redundant experiments. Herein, we used bioinformatic and experimental approaches to uncover mouse testis-enriched genes that are evolutionarily conserved in humans. We then used gene-disruption approaches, including Knockout Mouse Project resources (targeting vectors and mice) and CRISPR/Cas9, to mutate and quickly analyze the fertility of these mutant mice. We discovered that 54 mutant mouse lines were fertile. Thus, despite evolutionary conservation of these genes in vertebrates and in some cases in all eukaryotes, our results indicate that these genes are not individually essential for male mouse fertility. Our phenotypic data are highly relevant in this fiscally tight funding period and postgenomic age when large numbers of genomes are being analyzed for disease association, and will prevent unnecessary expenditures and duplications of effort by others. PMID:27357688

  11. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice.

    PubMed

    Miyata, Haruhiko; Castaneda, Julio M; Fujihara, Yoshitaka; Yu, Zhifeng; Archambeault, Denise R; Isotani, Ayako; Kiyozumi, Daiji; Kriseman, Maya L; Mashiko, Daisuke; Matsumura, Takafumi; Matzuk, Ryan M; Mori, Masashi; Noda, Taichi; Oji, Asami; Okabe, Masaru; Prunskaite-Hyyrylainen, Renata; Ramirez-Solis, Ramiro; Satouh, Yuhkoh; Zhang, Qian; Ikawa, Masahito; Matzuk, Martin M

    2016-07-12

    Gene-expression analysis studies from Schultz et al. estimate that more than 2,300 genes in the mouse genome are expressed predominantly in the male germ line. As of their 2003 publication [Schultz N, Hamra FK, Garbers DL (2003) Proc Natl Acad Sci USA 100(21):12201-12206], the functions of the majority of these testis-enriched genes during spermatogenesis and fertilization were largely unknown. Since the study by Schultz et al., functional analysis of hundreds of reproductive-tract-enriched genes have been performed, but there remain many testis-enriched genes for which their relevance to reproduction remain unexplored or unreported. Historically, a gene knockout is the "gold standard" to determine whether a gene's function is essential in vivo. Although knockout mice without apparent phenotypes are rarely published, these knockout mouse lines and their phenotypic information need to be shared to prevent redundant experiments. Herein, we used bioinformatic and experimental approaches to uncover mouse testis-enriched genes that are evolutionarily conserved in humans. We then used gene-disruption approaches, including Knockout Mouse Project resources (targeting vectors and mice) and CRISPR/Cas9, to mutate and quickly analyze the fertility of these mutant mice. We discovered that 54 mutant mouse lines were fertile. Thus, despite evolutionary conservation of these genes in vertebrates and in some cases in all eukaryotes, our results indicate that these genes are not individually essential for male mouse fertility. Our phenotypic data are highly relevant in this fiscally tight funding period and postgenomic age when large numbers of genomes are being analyzed for disease association, and will prevent unnecessary expenditures and duplications of effort by others. PMID:27357688

  12. Genome-wide screen uncovers novel pathways for tRNA processing and nuclear–cytoplasmic dynamics

    PubMed Central

    Wu, Jingyan; Bao, Alicia; Chatterjee, Kunal; Wan, Yao; Hopper, Anita K.

    2015-01-01

    Transfer ribonucleic acids (tRNAs) are essential for protein synthesis. However, key gene products involved in tRNA biogenesis and subcellular movement remain to be discovered. We conducted the first comprehensive unbiased analysis of the role of nearly an entire proteome in tRNA biology and describe 162 novel and 12 previously known Saccharomyces cerevisiae gene products that function in tRNA processing, turnover, and subcellular movement. tRNA nuclear export is of particular interest because it is essential, but the known tRNA exporters (Los1 [exportin-t] and Msn5 [exportin-5]) are unessential. We report that mutations of CRM1 (Exportin-1), MEX67/MTR2 (TAP/p15), and five nucleoporins cause accumulation of unspliced tRNA, a hallmark of defective tRNA nuclear export. CRM1 mutation genetically interacts with los1Δ and causes altered tRNA nuclear–cytoplasmic distribution. The data implicate roles for the protein and mRNA nuclear export machineries in tRNA nuclear export. Mutations of genes encoding actin cytoskeleton components and mitochondrial outer membrane proteins also cause accumulation of unspliced tRNA, likely due to defective splicing on mitochondria. Additional gene products, such as chromatin modification enzymes, have unanticipated effects on pre-tRNA end processing. Thus, this genome-wide screen uncovered putative novel pathways for tRNA nuclear export and extensive links between tRNA biology and other aspects of cell physiology. PMID:26680305

  13. Exploring novel candidate genes from the Mouse Genome Informatics database: Potential implications for avian migration research.

    PubMed

    Contina, Andrea; Bridge, Eli S; Kelly, Jeffrey F

    2016-07-01

    To search for genes associated with migratory phenotypes in songbirds, we selected candidate genes through annotations from the Mouse Genome Informatics database and assembled an extensive candidate-gene library. Then, we implemented a next-generation sequencing approach to obtain DNA sequences from the Painted Bunting genome. We focused on those sequences that were conserved across avian species and that aligned with candidate genes in our mouse library. We genotyped short sequence repeats from the following candidate genes: ADRA1d, ANKRD17, CISH and MYH7. We studied the possible correlations between allelic variations occurring in these novel candidate migration genes and avian migratory phenotypes available from the published literature. We found that allele variation at MYH7 correlated with a calculated index of speed of migration (km/day) across 11 species of songbirds. We highlight the potential of the Mouse Genome Informatics database in providing new candidate genes that might play a crucial role in regulating migration in birds and possibly in other taxa. Our research effort shows the benefits and limitations of working with extensive genomic datasets and offers a snapshot of the challenges related to cross-species validation in behavioral and molecular ecology studies. PMID:27061206

  14. Genome-wide identification of CCA1 targets uncovers an expanded clock network in Arabidopsis

    PubMed Central

    Nagel, Dawn H.; Doherty, Colleen J.; Pruneda-Paz, Jose L.; Schmitz, Robert J.; Ecker, Joseph R.; Kay, Steve A.

    2015-01-01

    The circadian clock in Arabidopsis exerts a critical role in timing multiple biological processes and stress responses through the regulation of up to 80% of the transcriptome. As a key component of the clock, the Myb-like transcription factor CIRCADIAN CLOCK ASSOCIATED1 (CCA1) is able to initiate and set the phase of clock-controlled rhythms and has been shown to regulate gene expression by binding directly to the evening element (EE) motif found in target gene promoters. However, the precise molecular mechanisms underlying clock regulation of the rhythmic transcriptome, specifically how clock components connect to clock output pathways, is poorly understood. In this study, using ChIP followed by deep sequencing of CCA1 in constant light (LL) and diel (LD) conditions, more than 1,000 genomic regions occupied by CCA1 were identified. CCA1 targets are enriched for a myriad of biological processes and stress responses, providing direct links to clock-controlled pathways and suggesting that CCA1 plays an important role in regulating a large subset of the rhythmic transcriptome. Although many of these target genes are evening expressed and contain the EE motif, a significant subset is morning phased and enriched for previously unrecognized motifs associated with CCA1 function. Furthermore, this work revealed several CCA1 targets that do not cycle in either LL or LD conditions. Together, our results emphasize an expanded role for the clock in regulating a diverse category of genes and key pathways in Arabidopsis and provide a comprehensive resource for future functional studies. PMID:26261339

  15. Novel Genes Affecting the Interaction between the Cabbage Whitefly and Arabidopsis Uncovered by Genome-Wide Association Mapping

    PubMed Central

    Broekgaarden, Colette; Bucher, Johan; Bac-Molenaar, Johanna; Keurentjes, Joost J. B.; Kruijer, Willem; Voorrips, Roeland E.; Vosman, Ben

    2015-01-01

    Plants have evolved a variety of ways to defend themselves against biotic attackers. This has resulted in the presence of substantial variation in defense mechanisms among plants, even within a species. Genome-wide association (GWA) mapping is a useful tool to study the genetic architecture of traits, but has so far only had limited exploitation in studies of plant defense. Here, we study the genetic architecture of defense against the phloem-feeding insect cabbage whitefly (Aleyrodes proletella) in Arabidopsis thaliana. We determined whitefly performance, i.e. the survival and reproduction of whitefly females, on 360 worldwide selected natural accessions and subsequently performed GWA mapping using 214,051 SNPs. Substantial variation for whitefly adult survival and oviposition rate (number of eggs laid per female per day) was observed between the accessions. We identified 39 candidate SNPs for either whitefly adult survival or oviposition rate, all with relatively small effects, underpinning the complex architecture of defense traits. Among the corresponding candidate genes, i.e. genes in linkage disequilibrium (LD) with candidate SNPs, none have previously been identified as a gene playing a role in the interaction between plants and phloem-feeding insects. Whitefly performance on knock-out mutants of a number of candidate genes was significantly affected, validating the potential of GWA mapping for novel gene discovery in plant-insect interactions. Our results show that GWA analysis is a very useful tool to gain insight into the genetic architecture of plant defense against herbivorous insects, i.e. we identified and validated several genes affecting whitefly performance that have not previously been related to plant defense against herbivorous insects. PMID:26699853

  16. Whole genome approaches to identify early meiotic gene candidates in cereals.

    PubMed

    Bovill, William D; Deveshwar, Priyanka; Kapoor, Sanjay; Able, Jason A

    2009-05-01

    Early events during meiotic prophase I underpin not only viability but the variation of a species from generation to generation. Understanding and manipulating processes such as chromosome pairing and recombination are integral for improving plant breeding. This study uses comparative genetics, quantitative trait locus (QTL) analysis and a transcriptomics-based approach to identify genes that might have a role in genome-wide recombination control. Comparative genetics and the analysis of the yeast and Arabidopsis sequenced genomes has allowed the identification of early meiotic candidates that are conserved in wheat, rice and barley. Secondly, scoring recombination frequency as a phenotype for QTL analysis across wheat, rice and barley mapping populations has enabled us to identify genomic regions and candidate genes that could be involved in genome-wide recombination. Transcriptome data for candidate genes indicate that they are expressed in meiotic tissues. Candidates identified included a non-annotated expressed protein, a DNA topoisomerase 2-like candidate, RecG, RuvB and RAD54 homologues. PMID:18836753

  17. Candidate fire blight resistance genes in Malus identified with the use of genomic tools and approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The goal of this research is to utilize current advances in Rosaceae genomics to identify DNA markers for use in marker-assisted selection of durable resistance to fire blight. Candidate fire blight resistance genes were selected and ranked based upon differential expression after inoculation with ...

  18. SEQUENCING OF CUCUMBER (CUCUMIS SATIVUS L.) CHLOROPLAST GENOMES IDENTIFIES PUTATIVE CANDIDATE GENES FOR CHILLING TOLERANCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chilling injury in cucumber (Cucumis sativus L.) is conditioned by maternal factors and the sequencing of its chloroplast (cp) genome could lead to the identification of economically important candidate genes. Complete sequencing of cucumber cpDNA was facilitated by the development of 414 consensus...

  19. Analysis of the first genome fragment from the marine sponge-associated, novel candidate phylum Poribacteria by environmental genomics.

    PubMed

    Fieseler, Lars; Quaiser, Achim; Schleper, Christa; Hentschel, Ute

    2006-04-01

    The novel candidate phylum Poribacteria is specifically associated with several marine demosponge genera. Because no representatives of Poribacteria have been cultivated, an environmental genomic approach was used to gain insights into genomic properties and possibly physiological/functional features of this elusive candidate division. In a large-insert library harbouring an estimated 1.1 Gb of microbial community DNA from Aplysina aerophoba, a Poribacteria-positive 16S rRNA gene locus was identified. Sequencing and sequence annotation of the 39 kb size insert revealed 27 open reading frames (ORFs) and two genes for stable RNAs. The fragment exhibited an overall G+C content of 50.5% and a coding density of 86.1%. The 16S rRNA gene was unlinked from a conventional rrn operon. Its flanking regions did not show any synteny to other 16S rRNA encoding loci from microorganisms with unlinked rrn operons. Two of the predicted hypothetical proteins were highly similar to homologues from Rhodopirellula baltica. Furthermore, a novel kind of molybdenum containing oxidoreductase was predicted as well as a series of eight ORFs encoding for unusual transporters, channel or pore forming proteins. This environmental genomics approach provides, for the first time, genomic and, by inference, functional information on the so far uncultivated, sponge-associated candidate division Poribacteria. PMID:16584473

  20. Small Genomes and Sparse Metabolisms of Sediment-Associated Bacteria from Four Candidate Phyla

    PubMed Central

    Kantor, Rose S.; Wrighton, Kelly C.; Handley, Kim M.; Sharon, Itai; Hug, Laura A.; Castelle, Cindy J.; Thomas, Brian C.; Banfield, Jillian F.

    2013-01-01

    ABSTRACT Cultivation-independent surveys of microbial diversity have revealed many bacterial phyla that lack cultured representatives. These lineages, referred to as candidate phyla, have been detected across many environments. Here, we deeply sequenced microbial communities from acetate-stimulated aquifer sediment to recover the complete and essentially complete genomes of single representatives of the candidate phyla SR1, WWE3, TM7, and OD1. All four of these genomes are very small, 0.7 to 1.2 Mbp, and have large inventories of novel proteins. Additionally, all lack identifiable biosynthetic pathways for several key metabolites. The SR1 genome uses the UGA codon to encode glycine, and the same codon is very rare in the OD1 genome, suggesting that the OD1 organism could also transition to alternate coding. Interestingly, the relative abundance of the members of SR1 increased with the appearance of sulfide in groundwater, a pattern mirrored by a member of the phylum Tenericutes. All four genomes encode type IV pili, which may be involved in interorganism interaction. On the basis of these results and other recently published research, metabolic dependence on other organisms may be widely distributed across multiple bacterial candidate phyla. PMID:24149512

  1. Identification of candidate genes for drought tolerance by whole-genome resequencing in maize

    PubMed Central

    2014-01-01

    Background Drought stress is one of the major limiting factors for maize production. With the availability of maize B73 reference genome and whole-genome resequencing of 15 maize inbreds, common variants (CV) and clustering analyses were applied to identify non-synonymous SNPs (nsSNPs) and corresponding candidate genes for drought tolerance. Results A total of 524 nsSNPs that were associated with 271 candidate genes involved in plant hormone regulation, carbohydrate and sugar metabolism, signaling molecules regulation, redox reaction and acclimation of photosynthesis to environment were detected by CV and cluster analyses. Most of the nsSNPs identified were clustered in bin 1.07 region that harbored six previously reported QTL with relatively high phenotypic variation explained for drought tolerance. Genes Ontology (GO) analysis of candidate genes revealed that there were 35 GO terms related to biotic stimulus and membrane-bounded organelle, showing significant differences between the candidate genes and the reference B73 background. Changes of expression level in these candidate genes for drought tolerance were detected using RNA sequencing for fertilized ovary, basal leaf meristem tissue and roots collected under drought stressed and well-watered conditions. The results indicated that 70% of candidate genes showed significantly expression changes under two water treatments and our strategies for mining candidate genes are feasible and relatively efficient. Conclusions Our results successfully revealed candidate nsSNPs and associated genes for drought tolerance by comparative sequence analysis of 16 maize inbred lines. Both methods we applied were proved to be efficient for identifying candidate genes for complex traits through the next-generation sequencing technologies (NGS). These selected genes will not only facilitate understanding of genetic basis of drought stress response, but also accelerate genetic improvement through marker-assisted selection in maize

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

    PubMed Central

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

    2014-01-01

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

  3. Predicting candidate genomic sequences that correspond to synthetic functional RNA motifs

    PubMed Central

    Laserson, Uri; Gan, Hin Hark; Schlick, Tamar

    2005-01-01

    Riboswitches and RNA interference are important emerging mechanisms found in many organisms to control gene expression. To enhance our understanding of such RNA roles, finding small regulatory motifs in genomes presents a challenge on a wide scale. Many simple functional RNA motifs have been found by in vitro selection experiments, which produce synthetic target-binding aptamers as well as catalytic RNAs, including the hammerhead ribozyme. Motivated by the prediction of Piganeau and Schroeder [(2003) Chem. Biol., 10, 103–104] that synthetic RNAs may have natural counterparts, we develop and apply an efficient computational protocol for identifying aptamer-like motifs in genomes. We define motifs from the sequence and structural information of synthetic aptamers, search for sequences in genomes that will produce motif matches, and then evaluate the structural stability and statistical significance of the potential hits. Our application to aptamers for streptomycin, chloramphenicol, neomycin B and ATP identifies 37 candidate sequences (in coding and non-coding regions) that fold to the target aptamer structures in bacterial and archaeal genomes. Further energetic screening reveals that several candidates exhibit energetic properties and sequence conservation patterns that are characteristic of functional motifs. Besides providing candidates for experimental testing, our computational protocol offers an avenue for expanding natural RNA's functional repertoire. PMID:16254081

  4. An Arrayed RNA Interference Genome-Wide Screen Identifies Candidate Genes Involved in the MicroRNA 21 Biogenesis Pathway

    PubMed Central

    Shum, David; Bhinder, Bhavneet; Ramirez, Christina N.; Radu, Constantin; Calder, Paul A.; Beauchamp, Lesslie; Farazi, T.; Landthaler, M.; Tuschi, T.; Magdaleno, Susan

    2013-01-01

    Abstract MicroRNAs (miRNAs) are evolutionary conserved noncoding molecules that regulate gene expression. They influence a number of diverse biological functions, such as development and differentiation. However, their dysregulation has been shown to be associated with disease states, such as cancer. Genes and pathways regulating their biogenesis remain unknown and are highly sought after. For this purpose, we have validated a multiplexed high-content assay strategy to screen for such modulators. Here, we describe its implementation that makes use of a cell-based gain-of-function reporter assay monitoring enhanced green fluorescent protein expression under the control of miRNA 21 (miR-21); combined with measures of both cell metabolic activities through the use of Alamar Blue and cell death through imaged Hoechst-stained nuclei. The strategy was validated using a panel of known genes and enabled us to successfully progress to and complete an arrayed genome-wide short interfering RNA (siRNA) screen against the Ambion Silencer Select v4.0 library containing 64,755 siRNA duplexes covering 21,565 genes. We applied a high-stringency hit analysis method, referred to as the Bhinder–Djaballah analysis method, leading to the nomination of 1,273 genes as candidate inhibitors of the miR-21 biogenesis pathway; after several iterations eliminating those genes with only one active duplex and those enriched in seed sequence mediated off-target effects. Biological classifications revealed four major control junctions among them vesicular transport via clathrin-mediated endocytosis. Altogether, our screen has uncovered a number of novel candidate regulators that are potentially good druggable targets allowing for the discovery and development of small molecules for regulating miRNA function. PMID:23153064

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

    PubMed Central

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

    2014-01-01

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

  6. Triad pattern algorithm for predicting strong promoter candidates in bacterial genomes

    PubMed Central

    Dekhtyar, Michael; Morin, Amelie; Sakanyan, Vehary

    2008-01-01

    Background Bacterial promoters, which increase the efficiency of gene expression, differ from other promoters by several characteristics. This difference, not yet widely exploited in bioinformatics, looks promising for the development of relevant computational tools to search for strong promoters in bacterial genomes. Results We describe a new triad pattern algorithm that predicts strong promoter candidates in annotated bacterial genomes by matching specific patterns for the group I σ70 factors of Escherichia coli RNA polymerase. It detects promoter-specific motifs by consecutively matching three patterns, consisting of an UP-element, required for interaction with the α subunit, and then optimally-separated patterns of -35 and -10 boxes, required for interaction with the σ70 subunit of RNA polymerase. Analysis of 43 bacterial genomes revealed that the frequency of candidate sequences depends on the A+T content of the DNA under examination. The accuracy of in silico prediction was experimentally validated for the genome of a hyperthermophilic bacterium, Thermotoga maritima, by applying a cell-free expression assay using the predicted strong promoters. In this organism, the strong promoters govern genes for translation, energy metabolism, transport, cell movement, and other as-yet unidentified functions. Conclusion The triad pattern algorithm developed for predicting strong bacterial promoters is well suited for analyzing bacterial genomes with an A+T content of less than 62%. This computational tool opens new prospects for investigating global gene expression, and individual strong promoters in bacteria of medical and/or economic significance. PMID:18471287

  7. Candidate targets of balancing selection in the genome of Staphylococcus aureus.

    PubMed

    Thomas, Jonathan C; Godfrey, Paul A; Feldgarden, Michael; Robinson, D Ashley

    2012-04-01

    Signatures of balancing selection can highlight polymorphisms and functions that are important to the long-term fitness of a species. We performed a first genome-wide scan for balancing selection in a bacterial species, Staphylococcus aureus, which is a common cause of serious antimicrobial-resistant infections of humans. Using a sliding window approach, the genomes of 16 strains of S. aureus, including 5 new genome sequences presented here, and 1 outgroup strain of S. epidermidis were scanned for signatures of balancing selection. A total of 195 short windows were investigated based on their extreme values of both Tajima's D (>2.03) and π/K ratios (>0.12) relative to the rest of the genome. To test the unusualness of these windows, an Approximate Bayesian Computation framework was used to select a null demographic model that better accounted for the observed data than did the standard neutral model. A total of 186 windows were demonstrated to be unusual under the null model and, thus, represented candidate loci under balancing selection. These 186 candidate windows were located within 99 candidate genes that were spread across 62 different loci. Nearly all the signal (97.2%) was located within coding sequences; balancing selection on gene regulation apparently occurs through the targeting of global regulators such as agr and gra/aps. The agr locus had some of the strongest signatures of balancing selection, which provides new insight into the causes of diversity at this locus. The list of candidate genes included multiple virulence-associated genes and was significantly enriched for functions in amino acid and inorganic ion transport and metabolism and in defense mechanisms against innate immunity and antimicrobials, highlighting these particular functions as important to the fitness of this pathogen. PMID:22114360

  8. Candidate Targets of Balancing Selection in the Genome of Staphylococcus aureus

    PubMed Central

    Thomas, Jonathan C.; Godfrey, Paul A.; Feldgarden, Michael; Robinson, D. Ashley

    2012-01-01

    Signatures of balancing selection can highlight polymorphisms and functions that are important to the long-term fitness of a species. We performed a first genome-wide scan for balancing selection in a bacterial species, Staphylococcus aureus, which is a common cause of serious antimicrobial-resistant infections of humans. Using a sliding window approach, the genomes of 16 strains of S. aureus, including 5 new genome sequences presented here, and 1 outgroup strain of S. epidermidis were scanned for signatures of balancing selection. A total of 195 short windows were investigated based on their extreme values of both Tajima's D (>2.03) and π/K ratios (>0.12) relative to the rest of the genome. To test the unusualness of these windows, an Approximate Bayesian Computation framework was used to select a null demographic model that better accounted for the observed data than did the standard neutral model. A total of 186 windows were demonstrated to be unusual under the null model and, thus, represented candidate loci under balancing selection. These 186 candidate windows were located within 99 candidate genes that were spread across 62 different loci. Nearly all the signal (97.2%) was located within coding sequences; balancing selection on gene regulation apparently occurs through the targeting of global regulators such as agr and gra/aps. The agr locus had some of the strongest signatures of balancing selection, which provides new insight into the causes of diversity at this locus. The list of candidate genes included multiple virulence-associated genes and was significantly enriched for functions in amino acid and inorganic ion transport and metabolism and in defense mechanisms against innate immunity and antimicrobials, highlighting these particular functions as important to the fitness of this pathogen. PMID:22114360

  9. Direct Estimate of the Spontaneous Mutation Rate Uncovers the Effects of Drift and Recombination in the Chlamydomonas reinhardtii Plastid Genome.

    PubMed

    Ness, Rob W; Kraemer, Susanne A; Colegrave, Nick; Keightley, Peter D

    2016-03-01

    Plastids perform crucial cellular functions, including photosynthesis, across a wide variety of eukaryotes. Since endosymbiosis, plastids have maintained independent genomes that now display a wide diversity of gene content, genome structure, gene regulation mechanisms, and transmission modes. The evolution of plastid genomes depends on an input of de novo mutation, but our knowledge of mutation in the plastid is limited to indirect inference from patterns of DNA divergence between species. Here, we use a mutation accumulation experiment, where selection acting on mutations is rendered ineffective, combined with whole-plastid genome sequencing to directly characterize de novo mutation in Chlamydomonas reinhardtii. We show that the mutation rates of the plastid and nuclear genomes are similar, but that the base spectra of mutations differ significantly. We integrate our measure of the mutation rate with a population genomic data set of 20 individuals, and show that the plastid genome is subject to substantially stronger genetic drift than the nuclear genome. We also show that high levels of linkage disequilibrium in the plastid genome are not due to restricted recombination, but are instead a consequence of increased genetic drift. One likely explanation for increased drift in the plastid genome is that there are stronger effects of genetic hitchhiking. The presence of recombination in the plastid is consistent with laboratory studies in C. reinhardtii and demonstrates that although the plastid genome is thought to be uniparentally inherited, it recombines in nature at a rate similar to the nuclear genome. PMID:26615203

  10. Comparative Genomics Analysis of Mycobacterium ulcerans for the Identification of Putative Essential Genes and Therapeutic Candidates

    PubMed Central

    Tahir, Shifa; Tong, Yigang

    2012-01-01

    Mycobacterium ulcerans, the causative agent of Buruli ulcer, is the third most common mycobacterial disease after tuberculosis and leprosy. The present treatment options are limited and emergence of treatment resistant isolates represents a serious concern and a need for better therapeutics. Conventional drug discovery methods are time consuming and labor-intensive. Unfortunately, the slow growing nature of M. ulcerans in experimental conditions is also a barrier for drug discovery and development. In contrast, recent advancements in complete genome sequencing, in combination with cheminformatics and computational biology, represent an attractive alternative approach for the identification of therapeutic candidates worthy of experimental research. A computational, comparative genomics workflow was defined for the identification of novel therapeutic candidates against M. ulcerans, with the aim that a selected target should be essential to the pathogen, and have no homology in the human host. Initially, a total of 424 genes were predicted as essential from the M. ulcerans genome, via homology searching of essential genome content from 20 different bacteria. Metabolic pathway analysis showed that the most essential genes are associated with carbohydrate and amino acid metabolism. Among these, 236 proteins were identified as non-host and essential, and could serve as potential drug and vaccine candidates. Several drug target prioritization parameters including druggability were also calculated. Enzymes from several pathways are discussed as potential drug targets, including those from cell wall synthesis, thiamine biosynthesis, protein biosynthesis, and histidine biosynthesis. It is expected that our data will facilitate selection of M. ulcerans proteins for successful entry into drug design pipelines. PMID:22912793

  11. Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome.

    PubMed

    Hino-Fukuyo, Naomi; Kikuchi, Atsuo; Arai-Ichinoi, Natsuko; Niihori, Tetsuya; Sato, Ryo; Suzuki, Tasuku; Kudo, Hiroki; Sato, Yuko; Nakayama, Tojo; Kakisaka, Yosuke; Kubota, Yuki; Kobayashi, Tomoko; Funayama, Ryo; Nakayama, Keiko; Uematsu, Mitsugu; Aoki, Yoko; Haginoya, Kazuhiro; Kure, Shigeo

    2015-06-01

    West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50% of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22%, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36%, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21%, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14%, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome. PMID:25877686

  12. In vivo function and comparative genomic analyses of the Drosophila gut microbiota identify candidate symbiosis factors

    PubMed Central

    Newell, Peter D.; Chaston, John M.; Wang, Yiping; Winans, Nathan J.; Sannino, David R.; Wong, Adam C. N.; Dobson, Adam J.; Kagle, Jeanne; Douglas, Angela E.

    2014-01-01

    Symbiosis is often characterized by co-evolutionary changes in the genomes of the partners involved. An understanding of these changes can provide insight into the nature of the relationship, including the mechanisms that initiate and maintain an association between organisms. In this study we examined the genome sequences of bacteria isolated from the Drosophila melanogaster gut with the objective of identifying genes that are important for function in the host. We compared microbiota isolates with con-specific or closely related bacterial species isolated from non-fly environments. First the phenotype of germ-free Drosophila (axenic flies) was compared to that of flies colonized with specific bacteria (gnotobiotic flies) as a measure of symbiotic function. Non-fly isolates were functionally distinct from bacteria isolated from flies, conferring slower development and an altered nutrient profile in the host, traits known to be microbiota-dependent. Comparative genomic methods were next employed to identify putative symbiosis factors: genes found in bacteria that restore microbiota-dependent traits to gnotobiotic flies, but absent from those that do not. Factors identified include riboflavin synthesis and stress resistance. We also used a phylogenomic approach to identify protein coding genes for which fly-isolate sequences were more similar to each other than to other sequences, reasoning that these genes may have a shared function unique to the fly environment. This method identified genes in Acetobacter species that cluster in two distinct genomic loci: one predicted to be involved in oxidative stress detoxification and another encoding an efflux pump. In summary, we leveraged genomic and in vivo functional comparisons to identify candidate traits that distinguish symbiotic bacteria. These candidates can serve as the basis for further work investigating the genetic requirements of bacteria for function and persistence in the Drosophila gut. PMID:25408687

  13. Genome-Wide Prediction of Vaccine Candidates for Leishmania major: An Integrated Approach

    PubMed Central

    Singh, Satarudra Prakash; Roopendra, Kriti; Mishra, Bhartendu Nath

    2015-01-01

    Despite the wealth of information regarding genetics of the causative parasite and experimental immunology of the cutaneous leishmaniasis, there is currently no licensed vaccine against it. In the current study, a two-level data mining strategy was employed, to screen the Leishmania major genome for promising vaccine candidates. First, we screened a set of 25 potential antigens from 8312 protein coding sequences, based on presence of signal peptides, GPI anchors, and consensus antigenicity predictions. Second, we conducted a comprehensive immunogenic analysis of the 25 antigens based on epitopes predicted by NetCTL tool. Interestingly, results revealed that candidate antigen number 1 (LmjF.03.0550) had greater number of potential T cell epitopes, as compared to five well-characterized control antigens (CSP-Plasmodium falciparum, M1 and NP-Influenza A virus, core protein-Hepatitis B virus, and PSTA1-Mycobacterium tuberculosis). In order to determine an optimal set of epitopes among the highest scoring predicted epitopes, the OptiTope tool was employed for populations susceptible to cutaneous leishmaniasis. The epitope (127SLWSLLAGV) from antigen number 1, found to bind with the most prevalent allele HLA-A⁎0201 (25% frequency in Southwest Asia), was predicted as most immunogenic for all the target populations. Thus, our study reasserts the potential of genome-wide screening of pathogen antigens and epitopes, for identification of promising vaccine candidates. PMID:26681959

  14. Complete Genome Sequence of the Bacterium Aalborg_AAW-1, Representing a Novel Family within the Candidate Phylum SR1

    PubMed Central

    Dueholm, Morten Simonsen; Albertsen, Mads; Stokholm-Bjerregaard, Mikkel; McIlroy, Simon J.; Karst, Søren M.

    2015-01-01

    Here, we present the complete genome sequence of the candidate phylum SR1 bacterium Aalborg_AAW-1. Its 16S rRNA gene is only 85.5% similar to that of the closest relative, RAAC1_SR1, and the genome of Aalborg_AAW-1 consequently represents the first of a novel family within the candidate phylum SR1. PMID:26067967

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  17. Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra.

    PubMed

    Noureddine, Maher A; Li, Yi-Ju; van der Walt, Joelle M; Walters, Robert; Jewett, Rita M; Xu, Hong; Wang, Tianyuan; Walter, Jeffrey W; Scott, Burton L; Hulette, Christine; Schmechel, Don; Stenger, Judith E; Dietrich, Fred; Vance, Jeffery M; Hauser, Michael A

    2005-10-01

    Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671-677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239-2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P<0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. PMID:15966006

  18. Comparative and Transcriptome Analyses Uncover Key Aspects of Coding- and Long Noncoding RNAs in Flatworm Mitochondrial Genomes.

    PubMed

    Ross, Eric; Blair, David; Guerrero-Hernández, Carlos; Sánchez Alvarado, Alejandro

    2016-01-01

    Exploiting the conservation of various features of mitochondrial genomes has been instrumental in resolving phylogenetic relationships. Despite extensive sequence evidence, it has not previously been possible to conclusively resolve some key aspects of flatworm mitochondrial genomes, including generally conserved traits, such as start codons, noncoding regions, the full complement of tRNAs, and whether ATP8 is, or is not, encoded by this extranuclear genome. In an effort to address these difficulties, we sought to determine the mitochondrial transcriptomes and genomes of sexual and asexual taxa of freshwater triclads, a group previously poorly represented in flatworm mitogenomic studies. We have discovered evidence for an alternative start codon, an extended cox1 gene, a previously undescribed conserved open reading frame, long noncoding RNAs, and a highly conserved gene order across the large evolutionary distances represented within the triclads. Our findings contribute to the expansion and refinement of mitogenomics to address evolutionary issues in this diverse group of animals. PMID:26921295

  19. Comparative and Transcriptome Analyses Uncover Key Aspects of Coding- and Long Noncoding RNAs in Flatworm Mitochondrial Genomes

    PubMed Central

    Ross, Eric; Blair, David; Guerrero-Hernández, Carlos; Alvarado, Alejandro Sánchez

    2016-01-01

    Exploiting the conservation of various features of mitochondrial genomes has been instrumental in resolving phylogenetic relationships. Despite extensive sequence evidence, it has not previously been possible to conclusively resolve some key aspects of flatworm mitochondrial genomes, including generally conserved traits, such as start codons, noncoding regions, the full complement of tRNAs, and whether ATP8 is, or is not, encoded by this extranuclear genome. In an effort to address these difficulties, we sought to determine the mitochondrial transcriptomes and genomes of sexual and asexual taxa of freshwater triclads, a group previously poorly represented in flatworm mitogenomic studies. We have discovered evidence for an alternative start codon, an extended cox1 gene, a previously undescribed conserved open reading frame, long noncoding RNAs, and a highly conserved gene order across the large evolutionary distances represented within the triclads. Our findings contribute to the expansion and refinement of mitogenomics to address evolutionary issues in this diverse group of animals. PMID:26921295

  20. GENETIC CHARACTERIZATION OF GONATOCERUS TUBERCULIFEMUR FROM SOUTH AMERICA UNCOVERS DIVERGENT CLADES: PROSPECTIVE EGG PARASITOID CANDIDATE AGENT FOR THE GLASSY-WINGED SHARPSHOOTER IN CALIFORNIA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We genetically characterized the prospective South American egg parasitoid candidate agent, Gonatocerus tuberculifemur, of the glassy-winged sharsphooter (GWSS), Homalodisca vitripennis (Germar) [=H. coagulata (Say)] for a neoclassical biological control program in California. Two molecular methods...

  1. Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis.

    PubMed

    Horpaopan, Sukanya; Spier, Isabel; Zink, Alexander M; Altmüller, Janine; Holzapfel, Stefanie; Laner, Andreas; Vogt, Stefanie; Uhlhaas, Siegfried; Heilmann, Stefanie; Stienen, Dietlinde; Pasternack, Sandra M; Keppler, Kathleen; Adam, Ronja; Kayser, Katrin; Moebus, Susanne; Draaken, Markus; Degenhardt, Franziska; Engels, Hartmut; Hofmann, Andrea; Nöthen, Markus M; Steinke, Verena; Perez-Bouza, Alberto; Herms, Stefan; Holinski-Feder, Elke; Fröhlich, Holger; Thiele, Holger; Hoffmann, Per; Aretz, Stefan

    2015-03-15

    To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (β-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant. PMID:25219767

  2. Genomic Analysis of Differentiation between Soil Types Reveals Candidate Genes for Local Adaptation in Arabidopsis lyrata

    PubMed Central

    Turner, Thomas L.; von Wettberg, Eric J.; Nuzhdin, Sergey V.

    2008-01-01

    Serpentine soil, which is naturally high in heavy metal content and has low calcium to magnesium ratios, comprises a difficult environment for most plants. An impressive number of species are endemic to serpentine, and a wide range of non-endemic plant taxa have been shown to be locally adapted to these soils. Locating genomic polymorphisms which are differentiated between serpentine and non-serpentine populations would provide candidate loci for serpentine adaptation. We have used the Arabidopsis thaliana tiling array, which has 2.85 million probes throughout the genome, to measure genetic differentiation between populations of Arabidopsis lyrata growing on granitic soils and those growing on serpentinic soils. The significant overrepresentation of genes involved in ion transport and other functions provides a starting point for investigating the molecular basis of adaptation to soil ion content, water retention, and other ecologically and economically important variables. One gene in particular, calcium-exchanger 7, appears to be an excellent candidate gene for adaptation to low Ca∶Mg ratio in A. lyrata. PMID:18784841

  3. Identification of a strawberry flavor gene candidate using an integrated genetic-genomic-analytical chemistry approach

    PubMed Central

    2014-01-01

    Background There is interest in improving the flavor of commercial strawberry (Fragaria × ananassa) varieties. Fruit flavor is shaped by combinations of sugars, acids and volatile compounds. Many efforts seek to use genomics-based strategies to identify genes controlling flavor, and then designing durable molecular markers to follow these genes in breeding populations. In this report, fruit from two cultivars, varying for presence-absence of volatile compounds, along with segregating progeny, were analyzed using GC/MS and RNAseq. Expression data were bulked in silico according to presence/absence of a given volatile compound, in this case γ-decalactone, a compound conferring a peach flavor note to fruits. Results Computationally sorting reads in segregating progeny based on γ-decalactone presence eliminated transcripts not directly relevant to the volatile, revealing transcripts possibly imparting quantitative contributions. One candidate encodes an omega-6 fatty acid desaturase, an enzyme known to participate in lactone production in fungi, noted here as FaFAD1. This candidate was induced by ripening, was detected in certain harvests, and correlated with γ-decalactone presence. The FaFAD1 gene is present in every genotype where γ-decalactone has been detected, and it was invariably missing in non-producers. A functional, PCR-based molecular marker was developed that cosegregates with the phenotype in F1 and BC1 populations, as well as in many other cultivars and wild Fragaria accessions. Conclusions Genetic, genomic and analytical chemistry techniques were combined to identify FaFAD1, a gene likely controlling a key flavor volatile in strawberry. The same data may now be re-sorted based on presence/absence of any other volatile to identify other flavor-affecting candidates, leading to rapid generation of gene-specific markers. PMID:24742080

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

    PubMed Central

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

    2015-01-01

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

  5. Identification of Candidate Adherent-Invasive E. coli Signature Transcripts by Genomic/Transcriptomic Analysis

    PubMed Central

    Zhang, Yuanhao; Rowehl, Leahana; Krumsiek, Julia M.; Orner, Erika P.; Shaikh, Nurmohammad; Tarr, Phillip I.; Sodergren, Erica; Weinstock, George M.; Boedeker, Edgar C.; Xiong, Xuejian; Parkinson, John; Frank, Daniel N.; Li, Ellen; Gathungu, Grace

    2015-01-01

    Adherent-invasive Escherichia coli (AIEC) strains are detected more frequently within mucosal lesions of patients with Crohn’s disease (CD). The AIEC phenotype consists of adherence and invasion of intestinal epithelial cells and survival within macrophages of these bacteria in vitro. Our aim was to identify candidate transcripts that distinguish AIEC from non-invasive E. coli (NIEC) strains and might be useful for rapid and accurate identification of AIEC by culture-independent technology. We performed comparative RNA-Sequence (RNASeq) analysis using AIEC strain LF82 and NIEC strain HS during exponential and stationary growth. Differential expression analysis of coding sequences (CDS) homologous to both strains demonstrated 224 and 241 genes with increased and decreased expression, respectively, in LF82 relative to HS. Transition metal transport and siderophore metabolism related pathway genes were up-regulated, while glycogen metabolic and oxidation-reduction related pathway genes were down-regulated, in LF82. Chemotaxis related transcripts were up-regulated in LF82 during the exponential phase, but flagellum-dependent motility pathway genes were down-regulated in LF82 during the stationary phase. CDS that mapped only to the LF82 genome accounted for 747 genes. We applied an in silico subtractive genomics approach to identify CDS specific to AIEC by incorporating the genomes of 10 other previously phenotyped NIEC. From this analysis, 166 CDS mapped to the LF82 genome and lacked homology to any of the 11 human NIEC strains. We compared these CDS across 13 AIEC, but none were homologous in each. Four LF82 gene loci belonging to clustered regularly interspaced short palindromic repeats region (CRISPR)—CRISPR-associated (Cas) genes were identified in 4 to 6 AIEC and absent from all non-pathogenic bacteria. As previously reported, AIEC strains were enriched for pdu operon genes. One CDS, encoding an excisionase, was shared by 9 AIEC strains. Reverse transcription

  6. First genomic insights into members of a candidate bacterial phylum responsible for wastewater bulking

    PubMed Central

    Ohashi, Akiko; Parks, Donovan H.; Yamauchi, Toshihiro; Tyson, Gene W.

    2015-01-01

    Filamentous cells belonging to the candidate bacterial phylum KSB3 were previously identified as the causative agent of fatal filament overgrowth (bulking) in a high-rate industrial anaerobic wastewater treatment bioreactor. Here, we obtained near complete genomes from two KSB3 populations in the bioreactor, including the dominant bulking filament, using differential coverage binning of metagenomic data. Fluorescence in situ hybridization with 16S rRNA-targeted probes specific for the two populations confirmed that both are filamentous organisms. Genome-based metabolic reconstruction and microscopic observation of the KSB3 filaments in the presence of sugar gradients indicate that both filament types are Gram-negative, strictly anaerobic fermenters capable of non-flagellar based gliding motility, and have a strikingly large number of sensory and response regulator genes. We propose that the KSB3 filaments are highly sensitive to their surroundings and that cellular processes, including those causing bulking, are controlled by external stimuli. The obtained genomes lay the foundation for a more detailed understanding of environmental cues used by KSB3 filaments, which may lead to more robust treatment options to prevent bulking. PMID:25650158

  7. Genome-wide comparative diversity uncovers multiple targets of selection for improvement in hexaploid wheat landrace and cultivars

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Domesticated crops have experienced strong human-driven selection aimed at the development of improved varieties adapted to local conditions. To detect regions of the wheat genome subject to selection during improvement, we developed a high-throughput array to interrogate 9,000 gene-associated DNA m...

  8. Single-Cell-Genomics-Facilitated Read Binning of Candidate Phylum EM19 Genomes from Geothermal Spring Metagenomes.

    PubMed

    Becraft, Eric D; Dodsworth, Jeremy A; Murugapiran, Senthil K; Ohlsson, J Ingemar; Briggs, Brandon R; Kanbar, Jad; De Vlaminck, Iwijn; Quake, Stephen R; Dong, Hailiang; Hedlund, Brian P; Swingley, Wesley D

    2016-02-01

    The vast majority of microbial life remains uncatalogued due to the inability to cultivate these organisms in the laboratory. This "microbial dark matter" represents a substantial portion of the tree of life and of the populations that contribute to chemical cycling in many ecosystems. In this work, we leveraged an existing single-cell genomic data set representing the candidate bacterial phylum "Calescamantes" (EM19) to calibrate machine learning algorithms and define metagenomic bins directly from pyrosequencing reads derived from Great Boiling Spring in the U.S. Great Basin. Compared to other assembly-based methods, taxonomic binning with a read-based machine learning approach yielded final assemblies with the highest predicted genome completeness of any method tested. Read-first binning subsequently was used to extract Calescamantes bins from all metagenomes with abundant Calescamantes populations, including metagenomes from Octopus Spring and Bison Pool in Yellowstone National Park and Gongxiaoshe Spring in Yunnan Province, China. Metabolic reconstruction suggests that Calescamantes are heterotrophic, facultative anaerobes, which can utilize oxidized nitrogen sources as terminal electron acceptors for respiration in the absence of oxygen and use proteins as their primary carbon source. Despite their phylogenetic divergence, the geographically separate Calescamantes populations were highly similar in their predicted metabolic capabilities and core gene content, respiring O2, or oxidized nitrogen species for energy conservation in distant but chemically similar hot springs. PMID:26637598

  9. Single-Cell-Genomics-Facilitated Read Binning of Candidate Phylum EM19 Genomes from Geothermal Spring Metagenomes

    PubMed Central

    Becraft, Eric D.; Dodsworth, Jeremy A.; Murugapiran, Senthil K.; Ohlsson, J. Ingemar; Briggs, Brandon R.; Kanbar, Jad; De Vlaminck, Iwijn; Quake, Stephen R.; Dong, Hailiang; Hedlund, Brian P.

    2015-01-01

    The vast majority of microbial life remains uncatalogued due to the inability to cultivate these organisms in the laboratory. This “microbial dark matter” represents a substantial portion of the tree of life and of the populations that contribute to chemical cycling in many ecosystems. In this work, we leveraged an existing single-cell genomic data set representing the candidate bacterial phylum “Calescamantes” (EM19) to calibrate machine learning algorithms and define metagenomic bins directly from pyrosequencing reads derived from Great Boiling Spring in the U.S. Great Basin. Compared to other assembly-based methods, taxonomic binning with a read-based machine learning approach yielded final assemblies with the highest predicted genome completeness of any method tested. Read-first binning subsequently was used to extract Calescamantes bins from all metagenomes with abundant Calescamantes populations, including metagenomes from Octopus Spring and Bison Pool in Yellowstone National Park and Gongxiaoshe Spring in Yunnan Province, China. Metabolic reconstruction suggests that Calescamantes are heterotrophic, facultative anaerobes, which can utilize oxidized nitrogen sources as terminal electron acceptors for respiration in the absence of oxygen and use proteins as their primary carbon source. Despite their phylogenetic divergence, the geographically separate Calescamantes populations were highly similar in their predicted metabolic capabilities and core gene content, respiring O2, or oxidized nitrogen species for energy conservation in distant but chemically similar hot springs. PMID:26637598

  10. Candidate gene association mapping of Sclerotinia stalk rot resistance in sunflower (Helianthus annuus L.) uncovers the importance of COI1 homologs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sclerotinia stalk rot is one of the most destructive diseases of sunflower (Helianthus annuus L.) worldwide. Markers based on the Sclerotinia disease resistance gene will enable efficient marker-assisted selection (MAS). We sequenced eight candidate genes homologus to Arabidopsis thaliana defense ge...

  11. Uncovering the Genome-Wide Transcriptional Responses of the Filamentous Fungus Aspergillus niger to Lignocellulose Using RNA Sequencing

    PubMed Central

    Gaddipati, Sanyasi; Kokolski, Matthew; Malla, Sunir; Blythe, Martin J.; Ibbett, Roger; Campbell, Maria; Liddell, Susan; Aboobaker, Aziz; Tucker, Gregory A.; Archer, David B.

    2012-01-01

    A key challenge in the production of second generation biofuels is the conversion of lignocellulosic substrates into fermentable sugars. Enzymes, particularly those from fungi, are a central part of this process, and many have been isolated and characterised. However, relatively little is known of how fungi respond to lignocellulose and produce the enzymes necessary for dis-assembly of plant biomass. We studied the physiological response of the fungus Aspergillus niger when exposed to wheat straw as a model lignocellulosic substrate. Using RNA sequencing we showed that, 24 hours after exposure to straw, gene expression of known and presumptive plant cell wall–degrading enzymes represents a huge investment for the cells (about 20% of the total mRNA). Our results also uncovered new esterases and surface interacting proteins that might form part of the fungal arsenal of enzymes for the degradation of plant biomass. Using transcription factor deletion mutants (xlnR and creA) to study the response to both lignocellulosic substrates and low carbon source concentrations, we showed that a subset of genes coding for degradative enzymes is induced by starvation. Our data support a model whereby this subset of enzymes plays a scouting role under starvation conditions, testing for available complex polysaccharides and liberating inducing sugars, that triggers the subsequent induction of the majority of hydrolases. We also showed that antisense transcripts are abundant and that their expression can be regulated by growth conditions. PMID:22912594

  12. Comparative Chloroplast Genome Analyses of Streptophyte Green Algae Uncover Major Structural Alterations in the Klebsormidiophyceae, Coleochaetophyceae and Zygnematophyceae.

    PubMed

    Lemieux, Claude; Otis, Christian; Turmel, Monique

    2016-01-01

    The Streptophyta comprises all land plants and six main lineages of freshwater green algae: Mesostigmatophyceae, Chlorokybophyceae, Klebsormidiophyceae, Charophyceae, Coleochaetophyceae and Zygnematophyceae. Previous comparisons of the chloroplast genome from nine streptophyte algae (including four zygnematophyceans) revealed that, although land plant chloroplast DNAs (cpDNAs) inherited most of their highly conserved structural features from green algal ancestors, considerable cpDNA changes took place during the evolution of the Zygnematophyceae, the sister group of land plants. To gain deeper insights into the evolutionary dynamics of the chloroplast genome in streptophyte algae, we sequenced the cpDNAs of nine additional taxa: two klebsormidiophyceans (Entransia fimbriata and Klebsormidium sp. SAG 51.86), one coleocheatophycean (Coleochaete scutata) and six zygnematophyceans (Cylindrocystis brebissonii, Netrium digitus, Roya obtusa, Spirogyra maxima, Cosmarium botrytis and Closterium baillyanum). Our comparative analyses of these genomes with their streptophyte algal counterparts indicate that the large inverted repeat (IR) encoding the rDNA operon experienced loss or expansion/contraction in all three sampled classes and that genes were extensively shuffled in both the Klebsormidiophyceae and Zygnematophyceae. The klebsormidiophycean genomes boast greatly expanded IRs, with the Entransia 60,590-bp IR being the largest known among green algae. The 206,025-bp Entransia cpDNA, which is one of the largest genome among streptophytes, encodes 118 standard genes, i.e., four additional genes compared to its Klebsormidium flaccidum homolog. We inferred that seven of the 21 group II introns usually found in land plants were already present in the common ancestor of the Klebsormidiophyceae and its sister lineages. At 107,236 bp and with 117 standard genes, the Coleochaete IR-less genome is both the smallest and most compact among the streptophyte algal cpDNAs analyzed thus

  13. Comparative Chloroplast Genome Analyses of Streptophyte Green Algae Uncover Major Structural Alterations in the Klebsormidiophyceae, Coleochaetophyceae and Zygnematophyceae

    PubMed Central

    Lemieux, Claude; Otis, Christian; Turmel, Monique

    2016-01-01

    The Streptophyta comprises all land plants and six main lineages of freshwater green algae: Mesostigmatophyceae, Chlorokybophyceae, Klebsormidiophyceae, Charophyceae, Coleochaetophyceae and Zygnematophyceae. Previous comparisons of the chloroplast genome from nine streptophyte algae (including four zygnematophyceans) revealed that, although land plant chloroplast DNAs (cpDNAs) inherited most of their highly conserved structural features from green algal ancestors, considerable cpDNA changes took place during the evolution of the Zygnematophyceae, the sister group of land plants. To gain deeper insights into the evolutionary dynamics of the chloroplast genome in streptophyte algae, we sequenced the cpDNAs of nine additional taxa: two klebsormidiophyceans (Entransia fimbriata and Klebsormidium sp. SAG 51.86), one coleocheatophycean (Coleochaete scutata) and six zygnematophyceans (Cylindrocystis brebissonii, Netrium digitus, Roya obtusa, Spirogyra maxima, Cosmarium botrytis and Closterium baillyanum). Our comparative analyses of these genomes with their streptophyte algal counterparts indicate that the large inverted repeat (IR) encoding the rDNA operon experienced loss or expansion/contraction in all three sampled classes and that genes were extensively shuffled in both the Klebsormidiophyceae and Zygnematophyceae. The klebsormidiophycean genomes boast greatly expanded IRs, with the Entransia 60,590-bp IR being the largest known among green algae. The 206,025-bp Entransia cpDNA, which is one of the largest genome among streptophytes, encodes 118 standard genes, i.e., four additional genes compared to its Klebsormidium flaccidum homolog. We inferred that seven of the 21 group II introns usually found in land plants were already present in the common ancestor of the Klebsormidiophyceae and its sister lineages. At 107,236 bp and with 117 standard genes, the Coleochaete IR-less genome is both the smallest and most compact among the streptophyte algal cpDNAs analyzed thus

  14. Genome-wide comparative diversity uncovers multiple targets of selection for improvement in hexaploid wheat landraces and cultivars

    PubMed Central

    Cavanagh, Colin R.; Chao, Shiaoman; Wang, Shichen; Huang, Bevan Emma; Stephen, Stuart; Kiani, Seifollah; Forrest, Kerrie; Saintenac, Cyrille; Brown-Guedira, Gina L.; Akhunova, Alina; See, Deven; Bai, Guihua; Pumphrey, Michael; Tomar, Luxmi; Wong, Debbie; Kong, Stephan; Reynolds, Matthew; da Silva, Marta Lopez; Bockelman, Harold; Talbert, Luther; Anderson, James A.; Dreisigacker, Susanne; Baenziger, Stephen; Carter, Arron; Korzun, Viktor; Morrell, Peter Laurent; Dubcovsky, Jorge; Morell, Matthew K.; Sorrells, Mark E.; Hayden, Matthew J.; Akhunov, Eduard

    2013-01-01

    Domesticated crops experience strong human-mediated selection aimed at developing high-yielding varieties adapted to local conditions. To detect regions of the wheat genome subject to selection during improvement, we developed a high-throughput array to interrogate 9,000 gene-associated single-nucleotide polymorphisms (SNP) in a worldwide sample of 2,994 accessions of hexaploid wheat including landraces and modern cultivars. Using a SNP-based diversity map we characterized the impact of crop improvement on genomic and geographic patterns of genetic diversity. We found evidence of a small population bottleneck and extensive use of ancestral variation often traceable to founders of cultivars from diverse geographic regions. Analyzing genetic differentiation among populations and the extent of haplotype sharing, we identified allelic variants subjected to selection during improvement. Selective sweeps were found around genes involved in the regulation of flowering time and phenology. An introgression of a wild relative-derived gene conferring resistance to a fungal pathogen was detected by haplotype-based analysis. Comparing selective sweeps identified in different populations, we show that selection likely acts on distinct targets or multiple functionally equivalent alleles in different portions of the geographic range of wheat. The majority of the selected alleles were present at low frequency in local populations, suggesting either weak selection pressure or temporal variation in the targets of directional selection during breeding probably associated with changing agricultural practices or environmental conditions. The developed SNP chip and map of genetic variation provide a resource for advancing wheat breeding and supporting future population genomic and genome-wide association studies in wheat. PMID:23630259

  15. Low Frequency Variants, Collapsed Based on Biological Knowledge, Uncover Complexity of Population Stratification in 1000 Genomes Project Data

    PubMed Central

    Moore, Carrie B.; Wallace, John R.; Wolfe, Daniel J.; Frase, Alex T.; Pendergrass, Sarah A.; Weiss, Kenneth M.; Ritchie, Marylyn D.

    2013-01-01

    Analyses investigating low frequency variants have the potential for explaining additional genetic heritability of many complex human traits. However, the natural frequencies of rare variation between human populations strongly confound genetic analyses. We have applied a novel collapsing method to identify biological features with low frequency variant burden differences in thirteen populations sequenced by the 1000 Genomes Project. Our flexible collapsing tool utilizes expert biological knowledge from multiple publicly available database sources to direct feature selection. Variants were collapsed according to genetically driven features, such as evolutionary conserved regions, regulatory regions genes, and pathways. We have conducted an extensive comparison of low frequency variant burden differences (MAF<0.03) between populations from 1000 Genomes Project Phase I data. We found that on average 26.87% of gene bins, 35.47% of intergenic bins, 42.85% of pathway bins, 14.86% of ORegAnno regulatory bins, and 5.97% of evolutionary conserved regions show statistically significant differences in low frequency variant burden across populations from the 1000 Genomes Project. The proportion of bins with significant differences in low frequency burden depends on the ancestral similarity of the two populations compared and types of features tested. Even closely related populations had notable differences in low frequency burden, but fewer differences than populations from different continents. Furthermore, conserved or functionally relevant regions had fewer significant differences in low frequency burden than regions under less evolutionary constraint. This degree of low frequency variant differentiation across diverse populations and feature elements highlights the critical importance of considering population stratification in the new era of DNA sequencing and low frequency variant genomic analyses. PMID:24385916

  16. A systematic, functional genomics, and reverse vaccinology approach to the identification of vaccine candidates in the cattle tick, Rhipicephalus microplus.

    PubMed

    Maritz-Olivier, Christine; van Zyl, Willem; Stutzer, Christian

    2012-06-01

    In the post-genomic era, reverse vaccinology is proving promising in the development of vaccines against bacterial and viral diseases, with limited application in ectoparasite vaccine design. In this study, we present a systematic approach using a combination of functional genomics (DNA microarrays) techniques and a pipeline incorporating in silico prediction of subcellular localization and protective antigenicity using VaxiJen for the identification of novel anti-tick vaccine candidates. A total of 791 candidates were identified using this approach, of which 176 are membrane-associated and 86 secreted soluble proteins. A preliminary analysis on the antigenicity of selected membrane proteins using anti-gut antisera yielded candidates with an IgG binding capacity greater than previously identified epitopes of Bm86. Subsequent vaccination trials using recombinant proteins will not only validate this approach, but will also improve subsequent reverse vaccinology approaches for the identification of novel anti-tick vaccine candidates. PMID:22521592

  17. A Genome-Wide Association Study Uncovers a Genetic Locus Associated with Thoracic-to-Hip Ratio in Koreans

    PubMed Central

    Cha, Seongwon; Park, Ah Yeon; Kang, Changsoo

    2015-01-01

    The thoracic-to-hip circumference ratio (THR) is an anthropometric marker recently described as a predictor of type 2 diabetes. In this study, we performed a genome-wide association study (GWAS) followed by confirmatory analyses to identify genetic markers associated with THR. A total of 7,240 Korean subjects (4,988 for the discovery stage and 2,252 for the confirmatory analyses) were recruited for this study, and genome-wide single nucleotide polymorphism (SNP) genotyping of the initial 4,988 individuals was performed using Affymetrix Human SNP array 5.0. Linear regression analysis was then performed to adjust for the effects of age, sex, and current diabetes medication status on the THR of the study subjects. In the initial discovery stage, there was a statistically nominal association between minor alleles of SNP markers on chromosomes 4, 8, 10, and 12, and THR changes (p < 5.0 × 10−6). The subsequent confirmatory analyses of these markers, however, only detected a significant association between two SNPs in the HECTD4 gene and decreased THRs. Notably, this association was detected in male (rs11066280: p = 1.14 × 10−2; rs2074356: p = 1.10 × 10−2), but not in female subjects. Meanwhile, the combined results from the two analyses (initial and confirmatory) indicated that minor alleles of these two intronic variants exhibited a significant genome-wide association with decreased THR in the male subjects (n = 3,155; rs11066280: effect size = −0.008624, p = 6.19 × 10−9; rs2074356: effect size = −0.008762, p = 1.89 × 10−8). Furthermore, minor alleles of these two SNPs exhibited protective effects on patients’ risks for developing type 2 diabetes. In conclusion, we have identified two genetic variations in HECTD4 that are associated with THR, particularly in men. PMID:26675016

  18. A genome-wide RNA interference screen uncovers two p24 proteins as regulators of Wingless secretion.

    PubMed

    Port, Fillip; Hausmann, George; Basler, Konrad

    2011-11-01

    Wnt proteins are secreted, lipid-modified glycoproteins that control animal development and adult tissue homeostasis. Secretion of Wnt proteins is at least partly regulated by a dedicated machinery. Here, we report a genome-wide RNA interference screen for genes involved in the secretion of Wingless (Wg), a Drosophila Wnt. We identify three new genes required for Wg secretion. Of these, Emp24 and Eclair are required for proper export of Wg from the endoplasmic reticulum (ER). We propose that Emp24 and Eca act as specific cargo receptors for Wg to concentrate it in forming vesicles at sites of ER export. PMID:21886182

  19. Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage.

    PubMed

    Hauser, Michael A; Li, Yi-Ju; Takeuchi, Satoshi; Walters, Robert; Noureddine, Maher; Maready, Melinda; Darden, Tiffany; Hulette, Christine; Martin, Eden; Hauser, Elizabeth; Xu, Hong; Schmechel, Don; Stenger, Judith E; Dietrich, Fred; Vance, Jeffery

    2003-03-15

    We present a multifactorial, multistep approach called genomic convergence that combines gene expression with genomic linkage analysis to identify and prioritize candidate susceptibility genes for Parkinson's disease (PD). To initiate this process, we used serial analysis of gene expression (SAGE) to identify genes expressed in two normal substantia nigras (SN) and adjacent midbrain tissue. This identified over 3700 transcripts, including the three most abundant SAGE tags, which did not correspond to any known genes or ESTs. We developed high-throughput bioinformatics methods to map the genes corresponding to these tags and identified 402 SN genes that lay within five large genomic linkage regions, previously identified in 174 multiplex PD families. These genes represent excellent candidates for PD susceptibility alleles and further genomic convergence and analyses. PMID:12620972

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  2. Using Biological Knowledge to Uncover the Mystery in the Search for Epistasis in Genome-Wide Association Studies

    PubMed Central

    Ritchie, Marylyn D.

    2011-01-01

    The search for the missing heritability in genome-wide association studies (GWAS) has become an important focus for the human genetics community. One suspected location of these genetic effects is in gene-gene interactions, or epistasis. The computational burden of exploring gene-gene interactions in the wealth of data generated in GWAS, along with small to moderate sample sizes, have led to epistasis being an afterthought, rather than a primary focus of GWAS analyses. In this review, we discuss some potential approaches to filter a GWAS dataset to a smaller, more manageable dataset where searching for epistasis is considerably more feasible. We describe a number of alternative approaches, but primarily focus on the use of prior biological knowledge from databases in the public domain to guide the search for epistasis. The manner in which prior knowledge is incorporated into a GWA study can be many and these data can be extracted from a variety of database sources. We discuss a number of these approaches and propose that a comprehensive approach will likely be most fruitful for searching for epistasis in large-scale genomic studies of the current state-of-the-art and into the future. PMID:21158748

  3. Global Genome and Transcriptome Analyses of Magnaporthe oryzae Epidemic Isolate 98-06 Uncover Novel Effectors and Pathogenicity-Related Genes, Revealing Gene Gain and Lose Dynamics in Genome Evolution

    PubMed Central

    Dong, Yanhan; Li, Ying; Zhao, Miaomiao; Jing, Maofeng; Liu, Xinyu; Liu, Muxing; Guo, Xianxian; Zhang, Xing; Chen, Yue; Liu, Yongfeng; Liu, Yanhong; Ye, Wenwu; Zhang, Haifeng; Wang, Yuanchao; Zheng, Xiaobo; Wang, Ping; Zhang, Zhengguang

    2015-01-01

    Genome dynamics of pathogenic organisms are driven by pathogen and host co-evolution, in which pathogen genomes are shaped to overcome stresses imposed by hosts with various genetic backgrounds through generation of a variety of isolates. This same principle applies to the rice blast pathogen Magnaporthe oryzae and the rice host; however, genetic variations among different isolates of M. oryzae remain largely unknown, particularly at genome and transcriptome levels. Here, we applied genomic and transcriptomic analytical tools to investigate M. oryzae isolate 98-06 that is the most aggressive in infection of susceptible rice cultivars. A unique 1.4 Mb of genomic sequences was found in isolate 98-06 in comparison to reference strain 70-15. Genome-wide expression profiling revealed the presence of two critical expression patterns of M. oryzae based on 64 known pathogenicity-related (PaR) genes. In addition, 134 candidate effectors with various segregation patterns were identified. Five tested proteins could suppress BAX-mediated programmed cell death in Nicotiana benthamiana leaves. Characterization of isolate-specific effector candidates Iug6 and Iug9 and PaR candidate Iug18 revealed that they have a role in fungal propagation and pathogenicity. Moreover, Iug6 and Iug9 are located exclusively in the biotrophic interfacial complex (BIC) and their overexpression leads to suppression of defense-related gene expression in rice, suggesting that they might participate in biotrophy by inhibiting the SA and ET pathways within the host. Thus, our studies identify novel effector and PaR proteins involved in pathogenicity of the highly aggressive M. oryzae field isolate 98-06, and reveal molecular and genomic dynamics in the evolution of M. oryzae and rice host interactions. PMID:25837042

  4. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing.

    PubMed

    de Jonge, Ronnie; van Esse, H Peter; Maruthachalam, Karunakaran; Bolton, Melvin D; Santhanam, Parthasarathy; Saber, Mojtaba Keykha; Zhang, Zhao; Usami, Toshiyuki; Lievens, Bart; Subbarao, Krishna V; Thomma, Bart P H J

    2012-03-27

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, and plants in turn use immune receptors to try to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and Verticillium albo-atrum, but the corresponding Verticillium effector remained unknown thus far. By high-throughput population genome sequencing, a single 50-Kb sequence stretch was identified that only occurs in race 1 strains, and subsequent transcriptome sequencing of Verticillium-infected Nicotiana benthamiana plants revealed only a single highly expressed ORF in this region, designated Ave1 (for Avirulence on Ve1 tomato). Functional analyses confirmed that Ave1 activates Ve1-mediated resistance and demonstrated that Ave1 markedly contributes to fungal virulence, not only on tomato but also on Arabidopsis. Interestingly, Ave1 is homologous to a widespread family of plant natriuretic peptides. Besides plants, homologous proteins were only found in the bacterial plant pathogen Xanthomonas axonopodis and the plant pathogenic fungi Colletotrichum higginsianum, Cercospora beticola, and Fusarium oxysporum f. sp. lycopersici. The distribution of Ave1 homologs, coincident with the presence of Ave1 within a flexible genomic region, strongly suggests that Verticillium acquired Ave1 from plants through horizontal gene transfer. Remarkably, by transient expression we show that also the Ave1 homologs from F. oxysporum and C. beticola can activate Ve1-mediated resistance. In line with this observation, Ve1 was found to mediate resistance toward F. oxysporum in tomato, showing that this immune receptor is involved in resistance against multiple fungal pathogens. PMID:22416119

  5. Tomato immune receptor Ve1 recognizes effector of multiple fungal pathogens uncovered by genome and RNA sequencing

    PubMed Central

    de Jonge, Ronnie; Peter van Esse, H.; Maruthachalam, Karunakaran; Bolton, Melvin D.; Santhanam, Parthasarathy; Saber, Mojtaba Keykha; Zhang, Zhao; Usami, Toshiyuki; Lievens, Bart; Subbarao, Krishna V.; Thomma, Bart P. H. J.

    2012-01-01

    Fungal plant pathogens secrete effector molecules to establish disease on their hosts, and plants in turn use immune receptors to try to intercept these effectors. The tomato immune receptor Ve1 governs resistance to race 1 strains of the soil-borne vascular wilt fungi Verticillium dahliae and Verticillium albo-atrum, but the corresponding Verticillium effector remained unknown thus far. By high-throughput population genome sequencing, a single 50-Kb sequence stretch was identified that only occurs in race 1 strains, and subsequent transcriptome sequencing of Verticillium-infected Nicotiana benthamiana plants revealed only a single highly expressed ORF in this region, designated Ave1 (for Avirulence on Ve1 tomato). Functional analyses confirmed that Ave1 activates Ve1-mediated resistance and demonstrated that Ave1 markedly contributes to fungal virulence, not only on tomato but also on Arabidopsis. Interestingly, Ave1 is homologous to a widespread family of plant natriuretic peptides. Besides plants, homologous proteins were only found in the bacterial plant pathogen Xanthomonas axonopodis and the plant pathogenic fungi Colletotrichum higginsianum, Cercospora beticola, and Fusarium oxysporum f. sp. lycopersici. The distribution of Ave1 homologs, coincident with the presence of Ave1 within a flexible genomic region, strongly suggests that Verticillium acquired Ave1 from plants through horizontal gene transfer. Remarkably, by transient expression we show that also the Ave1 homologs from F. oxysporum and C. beticola can activate Ve1-mediated resistance. In line with this observation, Ve1 was found to mediate resistance toward F. oxysporum in tomato, showing that this immune receptor is involved in resistance against multiple fungal pathogens. PMID:22416119

  6. Genome sequencing of a virulent avian Pasteurella multocida strain GX-Pm reveals the candidate genes involved in the pathogenesis.

    PubMed

    Yu, Chengjie; Sizhu, Suolang; Luo, Qingping; Xu, Xuewen; Fu, Lei; Zhang, Anding

    2016-04-01

    Pasteurella multocida (P. multocida) was first shown to be the causative agent of fowl cholera by Louis Pasteur in 1881. First genomic study was performed on an avirulent avian strain Pm70, and until 2013, two genomes of virulent avian strains X73 and P1059 were sequenced. Comparative genome study supplied important information for further study on the pathogenesis of fowl cholera. In the previous study, a capsular serotype A strain GX-Pm was isolated from the liver of a chicken, which died during an outbreak of fowl cholera in 2011. The strain showed multiple drug resistance and was highly virulent to chickens. Therefore, the present study performed the genome sequencing and a comparative genomic analysis to reveal the candidate genes involved in virulence of P. multocida. Sequenced draft genome sequence of GX-Pm was 2,292,886 bp, contained 2941 protein-coding genes, 5 genomic islands, 4 IS elements and 2 prophage regions. Notability, all the predicted drug-resistance genes were included in predicted genomic islands. A comparative genome study on virulent avian strains P1059, X73 and GX-Pm with the avirulent avian strain Pm 70 indicated that 475 unique genes were only identified in either of virulent strains but absent in the avirulent strain. Among these genes, 20 genes were contained within genomes of all three virulent strains, including a few of putative virulence genes. Further characterization of the pathogenic functions of these genes would benefit the understanding of pathogenesis of fowl cholera. PMID:27033902

  7. Whole-Genome Sequencing of Staphylococcus haemolyticus Uncovers the Extreme Plasticity of Its Genome and the Evolution of Human-Colonizing Staphylococcal Species

    PubMed Central

    Takeuchi, Fumihiko; Watanabe, Shinya; Baba, Tadashi; Yuzawa, Harumi; Ito, Teruyo; Morimoto, Yuh; Kuroda, Makoto; Cui, Longzhu; Takahashi, Mikio; Ankai, Akiho; Baba, Shin-ichi; Fukui, Shigehiro; Lee, Jean C.; Hiramatsu, Keiichi

    2005-01-01

    Staphylococcus haemolyticus is an opportunistic bacterial pathogen that colonizes human skin and is remarkable for its highly antibiotic-resistant phenotype. We determined the complete genome sequence of S.haemolyticus to better understand its pathogenicity and evolutionary relatedness to the other staphylococcal species. A large proportion of the open reading frames in the genomes of S.haemolyticus, Staphylococcus aureus, and Staphylococcus epidermidis were conserved in their sequence and order on the chromosome. We identified a region of the bacterial chromosome just downstream of the origin of replication that showed little homology among the species but was conserved among strains within a species. This novel region, designated the “oriC environ,” likely contributes to the evolution and differentiation of the staphylococcal species, since it was enriched for species-specific nonessential genes that contribute to the biological features of each staphylococcal species. A comparative analysis of the genomes of S.haemolyticus, S.aureus, and S.epidermidis elucidated differences in their biological and genetic characteristics and pathogenic potentials. We identified as many as 82 insertion sequences in the S.haemolyticus chromosome that probably mediated frequent genomic rearrangements, resulting in phenotypic diversification of the strain. Such rearrangements could have brought genomic plasticity to this species and contributed to its acquisition of antibiotic resistance. PMID:16237012

  8. Complete mitochondrial genome of Dendronephthya putteri (Octocorallia, Alcyonacea) and useful candidate for developing DNA barcode markers of Dendronephthya species.

    PubMed

    Kwak, Hyeon Sook; Choi, Eun Hwa; Jang, Kuem Hee; Ryu, Shi Hyun; Kim, Young Shin; Hwang, Ui Wook

    2015-08-01

    The mitochondrial genome of Dendronephthya putteri (Octocorallia, Alcyonacea) which is an endangered species was completely sequenced. It is 18,853 bp in length and identical to those of Dendronephthya species in its gene arrangement and genome organization. Nucleotide sequence comparison of the mitochondrial genomes of the two D. putteri individuals obtained from this study and the previously reported one (GenBank accession number JQ290079) showed that they are identical perfectly. We found useful candidate for DNA barcode markers for D. putteri species identification. PMID:24083972

  9. Genetic diversity and breeding history of Winter Mushroom (Flammulina velutipes) in China uncovered by genomic SSR markers.

    PubMed

    Liu, Xiao Bin; Feng, Bang; Li, Jing; Yan, Chen; Yang, Zhu L

    2016-10-10

    Flammulina velutipes is one of the most widely cultivated mushroom species in China. However, its genetic background remains poorly understood due to the limited sampling and poor molecular markers used. In this study, 124 F. velutipes strains were employed, including 110 cultivars and 14 wild strains, and 25 new SSR markers were developed based on the genome of F. velutipes. A total of 153 alleles were detected in 124 strains to investigate the improper cultivar naming, genetic diversity and breeding history of F. velutipes in China. Our fingerprinting analyses indicated that 65 strains can be differentiated from the total of 124 strains, and over 53% of the strains are labeled with improper commercial names. The genetic diversities of wild strains are higher than those of the cultivars, suggesting that wild strains may harbor a large "arsenal" gene pool in nature available for strain breeding. The white cultivars in China were originally introduced from Japan, while the yellow cultivars were directly domesticated from wild strains isolated from southeastern China or hybridized between the white cultivars and yellow strains. PMID:27393649

  10. Genome-wide transcriptomic analysis uncovers the molecular basis underlying early flowering and apetalous characteristic in Brassica napus L.

    PubMed

    Yu, Kunjiang; Wang, Xiaodong; Chen, Feng; Chen, Song; Peng, Qi; Li, Hongge; Zhang, Wei; Hu, Maolong; Chu, Pu; Zhang, Jiefu; Guan, Rongzhan

    2016-01-01

    Floral transition and petal onset, as two main aspects of flower development, are crucial to rapeseed evolutionary success and yield formation. Currently, very little is known regarding the genetic architecture that regulates flowering time and petal morphogenesis in Brassica napus. In the present study, a genome-wide transcriptomic analysis was performed with an absolutely apetalous and early flowering line, APL01, and a normally petalled line, PL01, using high-throughput RNA sequencing. In total, 13,205 differential expressed genes were detected, of which 6111 genes were significantly down-regulated, while 7094 genes were significantly up-regulated in the young inflorescences of APL01 compared with PL01. The expression levels of a vast number of genes involved in protein biosynthesis were altered in response to the early flowering and apetalous character. Based on the putative rapeseed flowering genes, an early flowering network, mainly comprised of vernalization and photoperiod pathways, was built. Additionally, 36 putative upstream genes possibly governing the apetalous character of line APL01 were identified, and six genes potentially regulating petal origination were obtained by combining with three petal-related quantitative trait loci. These findings will facilitate understanding of the molecular mechanisms underlying floral transition and petal initiation in B. napus. PMID:27460760

  11. A genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection.

    PubMed

    López-Saavedra, Ana; Gómez-Cabello, Daniel; Domínguez-Sánchez, María Salud; Mejías-Navarro, Fernando; Fernández-Ávila, María Jesús; Dinant, Christoffel; Martínez-Macías, María Isabel; Bartek, Jiri; Huertas, Pablo

    2016-01-01

    There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double-strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome-wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio. Here we report that two distinct sets of genes are involved in the control of the balance between NHEJ and HR: those that are required to facilitate recombination and those that favour NHEJ. This last category includes CCAR2/DBC1, which we show inhibits recombination by limiting the initiation and the extent of DNA end resection, thereby acting as an antagonist of CtIP. PMID:27503537

  12. A genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection

    PubMed Central

    López-Saavedra, Ana; Gómez-Cabello, Daniel; Domínguez-Sánchez, María Salud; Mejías-Navarro, Fernando; Fernández-Ávila, María Jesús; Dinant, Christoffel; Martínez-Macías, María Isabel; Bartek, Jiri; Huertas, Pablo

    2016-01-01

    There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double-strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome-wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio. Here we report that two distinct sets of genes are involved in the control of the balance between NHEJ and HR: those that are required to facilitate recombination and those that favour NHEJ. This last category includes CCAR2/DBC1, which we show inhibits recombination by limiting the initiation and the extent of DNA end resection, thereby acting as an antagonist of CtIP. PMID:27503537

  13. Genome-wide transcriptomic analysis uncovers the molecular basis underlying early flowering and apetalous characteristic in Brassica napus L

    PubMed Central

    Yu, Kunjiang; Wang, Xiaodong; Chen, Feng; Chen, Song; Peng, Qi; Li, Hongge; Zhang, Wei; Hu, Maolong; Chu, Pu; Zhang, Jiefu; Guan, Rongzhan

    2016-01-01

    Floral transition and petal onset, as two main aspects of flower development, are crucial to rapeseed evolutionary success and yield formation. Currently, very little is known regarding the genetic architecture that regulates flowering time and petal morphogenesis in Brassica napus. In the present study, a genome-wide transcriptomic analysis was performed with an absolutely apetalous and early flowering line, APL01, and a normally petalled line, PL01, using high-throughput RNA sequencing. In total, 13,205 differential expressed genes were detected, of which 6111 genes were significantly down-regulated, while 7094 genes were significantly up-regulated in the young inflorescences of APL01 compared with PL01. The expression levels of a vast number of genes involved in protein biosynthesis were altered in response to the early flowering and apetalous character. Based on the putative rapeseed flowering genes, an early flowering network, mainly comprised of vernalization and photoperiod pathways, was built. Additionally, 36 putative upstream genes possibly governing the apetalous character of line APL01 were identified, and six genes potentially regulating petal origination were obtained by combining with three petal-related quantitative trait loci. These findings will facilitate understanding of the molecular mechanisms underlying floral transition and petal initiation in B. napus. PMID:27460760

  14. The Eukaryotic Flagellum Makes the Day: Novel and Unforeseen Roles Uncovered After Post-Genomics and Proteomics Data

    PubMed Central

    Diniz, Michely C; Pacheco, Ana Carolina L; Farias, Kaio M; de Oliveira, Diana M

    2012-01-01

    This review will summarize and discuss the current biological understanding of the motile eukaryotic flagellum, as posed out by recent advances enabled by post-genomics and proteomics approaches. The organelle, which is crucial for motility, survival, differentiation, reproduction, division and feeding, among other activities, of many eukaryotes, is a great example of a natural nanomachine assembled mostly by proteins (around 350-650 of them) that have been conserved throughout eukaryotic evolution. Flagellar proteins are discussed in terms of their arrangement on to the axoneme, the canonical “9+2” microtubule pattern, and also motor and sensorial elements that have been detected by recent proteomic analyses in organisms such as Chlamydomonas reinhardtii, sea urchin, and trypanosomatids. Such findings can be remarkably matched up to important discoveries in vertebrate and mammalian types as diverse as sperm cells, ciliated kidney epithelia, respiratory and oviductal cilia, and neuro-epithelia, among others. Here we will focus on some exciting work regarding eukaryotic flagellar proteins, particularly using the flagellar proteome of C. reinhardtii as a reference map for exploring motility in function, dysfunction and pathogenic flagellates. The reference map for the eukaryotic flagellar proteome consists of 652 proteins that include known structural and intraflagellar transport (IFT) proteins, less well-characterized signal transduction proteins and flagellar associated proteins (FAPs), besides almost two hundred unannotated conserved proteins, which lately have been the subject of intense investigation and of our present examination. PMID:22708495

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  16. Mass Spectrometry Uncovers Molecular Reactivities of Coordination and Organometallic Gold(III) Drug Candidates in Competitive Experiments That Correlate with Their Biological Effects.

    PubMed

    Meier, Samuel M; Gerner, Christopher; Keppler, Bernhard K; Cinellu, Maria Agostina; Casini, Angela

    2016-05-01

    The reactivity of three cytotoxic organometallic gold(III) complexes with cyclometalated C,N,N and C,N ligands (either six- or five-membered metallacycles), as well as that of two representative gold(III) complexes with N-donor ligands, with biological nucleophiles has been studied by ESI-MS on ion trap and time-of-flight instruments. Specifically, the gold compounds were reacted with mixtures of nucleophiles containing l-histidine (imine), l-methionine (thioether), l-cysteine (thiol), l-glutamic acid (carboxylic acid), methylseleno-l-cysteine (selenoether), and in situ generated seleno-l-cysteine (selenol) to judge the preference of the gold compounds for binding to selenium-containing amino acid residues. Moreover, the gold compounds' reactivity was studied with proteins and nucleic acid building blocks. These experiments revealed profound differences between the coordination and organometallic families and even within the family of organometallics, which allowed insights to be gained into the compounds mechanisms of action. In particular, interactions with seleno-l-cysteine appear to reflect well the compounds' inhibition properties of the seleno-enzyme thioredoxin reductase and to a certain extent their antiproliferative effects in vitro. Therefore, mass spectrometry is successfully applied for linking the molecular reactivity and target preferences of metal-based drug candidates to their biological effects. Finally, this experimental setup is applicable to any other metallodrug that undergoes ligand substitution reactions and/or redox changes as part of its mechanism of action. PMID:26866307

  17. 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. PMID:23696811

  18. 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

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

    PubMed

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

    2009-01-01

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

  20. On the identification of potential regulatory variants within genome wide association candidate SNP sets

    PubMed Central

    2014-01-01

    Background Genome wide association studies (GWAS) are a population-scale approach to the identification of segments of the genome in which genetic variations may contribute to disease risk. Current methods focus on the discovery of single nucleotide polymorphisms (SNPs) associated with disease traits. As there are many SNPs within identified risk loci, and the majority of these are situated within non-coding regions, a key challenge is to identify and prioritize variants affecting regulatory sequences that are likely to contribute to the phenotype assessed. Methods We focused investigation on SNPs within lung and breast cancer GWAS loci that reached genome-wide significance for potential roles in gene regulation with a specific focus on SNPs likely to disrupt transcription factor binding sites. Within risk loci, the regulatory potential of sub-regions was classified using relevant open chromatin and epigenetic high throughput sequencing data sets from the ENCODE project in available cancer and normal cell lines. Furthermore, transcription factor affinity altering variants were predicted by comparison of position weight matrix scores between disease and reference alleles. Lastly, ChIP-seq data of transcription associated factors and topological domains were included as binding evidence and potential gene target inference. Results The sets of SNPs, including both the disease-associated markers and those in high linkage disequilibrium with them, were significantly over-represented in regulatory sequences of cancer and/or normal cells; however, over-representation was generally not restricted to disease-relevant tissue specific regions. The calculated regulatory potential, allelic binding affinity scores and ChIP-seq binding evidence were the three criteria used to prioritize candidates. Fitting all three criteria, we highlighted breast cancer susceptibility SNPs and a borderline lung cancer relevant SNP located in cancer-specific enhancers overlapping multiple

  1. Application of Genomic and Quantitative Genetic Tools to Identify Candidate Resistance Genes for Brown Rot Resistance in Peach

    PubMed Central

    Martínez-García, Pedro J.; Parfitt, Dan E.; Bostock, Richard M.; Fresnedo-Ramírez, Jonathan; Vazquez-Lobo, Alejandra; Ogundiwin, Ebenezer A.; Gradziel, Thomas M.; Crisosto, Carlos H.

    2013-01-01

    The availability of a complete peach genome assembly and three different peach genome sequences created by our group provide new opportunities for application of genomic data and can improve the power of the classical Quantitative Trait Loci (QTL) approaches to identify candidate genes for peach disease resistance. Brown rot caused by Monilinia spp., is the most important fungal disease of stone fruits worldwide. Improved levels of peach fruit rot resistance have been identified in some cultivars and advanced selections developed in the UC Davis and USDA breeding programs. Whole genome sequencing of the Pop-DF parents lead to discovery of high-quality SNP markers for QTL genome scanning in this experimental population. Pop-DF created by crossing a brown rot moderately resistant cultivar ‘Dr. Davis’ and a brown rot resistant introgression line, ‘F8,1–42’, derived from an initial almond × peach interspecific hybrid, was evaluated for brown rot resistance in fruit of harvest maturity over three seasons. Using the SNP linkage map of Pop-DF and phenotypic data collected with inoculated fruit, a genome scan for QTL identified several SNP markers associated with brown rot resistance. Two of these QTLs were placed on linkage group 1, covering a large (physical) region on chromosome 1. The genome scan for QTL and SNP effects predicted several candidate genes associated with disease resistance responses in other host-pathogen systems. Two potential candidate genes, ppa011763m and ppa026453m, may be the genes primarily responsible for M. fructicola recognition in peach, activating both PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI) responses. Our results provide a foundation for further genetic dissection, marker assisted breeding for brown rot resistance, and development of peach cultivars resistant to brown rot. PMID:24244329

  2. Genome-wide association links candidate genes to resistance to Plum Pox Virus in apricot (Prunus armeniaca).

    PubMed

    Mariette, Stéphanie; Wong Jun Tai, Fabienne; Roch, Guillaume; Barre, Aurélien; Chague, Aurélie; Decroocq, Stéphane; Groppi, Alexis; Laizet, Yec'han; Lambert, Patrick; Tricon, David; Nikolski, Macha; Audergon, Jean-Marc; Abbott, Albert G; Decroocq, Véronique

    2016-01-01

    In fruit tree species, many important traits have been characterized genetically by using single-family descent mapping in progenies segregating for the traits. However, most mapped loci have not been sufficiently resolved to the individual genes due to insufficient progeny sizes for high resolution mapping and the previous lack of whole-genome sequence resources of the study species. To address this problem for Plum Pox Virus (PPV) candidate resistance gene identification in Prunus species, we implemented a genome-wide association (GWA) approach in apricot. This study exploited the broad genetic diversity of the apricot (Prunus armeniaca) germplasm containing resistance to PPV, next-generation sequence-based genotyping, and the high-quality peach (Prunus persica) genome reference sequence for single nucleotide polymorphism (SNP) identification. The results of this GWA study validated previously reported PPV resistance quantitative trait loci (QTL) intervals, highlighted other potential resistance loci, and resolved each to a limited set of candidate genes for further study. This work substantiates the association genetics approach for resolution of QTL to candidate genes in apricot and suggests that this approach could simplify identification of other candidate genes for other marked trait intervals in this germplasm. PMID:26356603

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

    PubMed Central

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

    2012-01-01

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

  4. Comparative Genomics of Candidate Phylum TM6 Suggests That Parasitism Is Widespread and Ancestral in This Lineage

    PubMed Central

    Yeoh, Yun Kit; Sekiguchi, Yuji; Parks, Donovan H.; Hugenholtz, Philip

    2016-01-01

    Candidate phylum TM6 is a major bacterial lineage recognized through culture-independent rRNA surveys to be low abundance members in a wide range of habitats; however, they are poorly characterized due to a lack of pure culture representatives. Two recent genomic studies of TM6 bacteria revealed small genomes and limited gene repertoire, consistent with known or inferred dependence on eukaryotic hosts for their metabolic needs. Here, we obtained additional near-complete genomes of TM6 populations from agricultural soil and upflow anaerobic sludge blanket reactor metagenomes which, together with the two publicly available TM6 genomes, represent seven distinct family level lineages in the TM6 phylum. Genome-based phylogenetic analysis confirms that TM6 is an independent phylum level lineage in the bacterial domain, possibly affiliated with the Patescibacteria superphylum. All seven genomes are small (1.0–1.5 Mb) and lack complete biosynthetic pathways for various essential cellular building blocks including amino acids, lipids, and nucleotides. These and other features identified in the TM6 genomes such as a degenerated cell envelope, ATP/ADP translocases for parasitizing host ATP pools, and protein motifs to facilitate eukaryotic host interactions indicate that parasitism is widespread in this phylum. Phylogenetic analysis of ATP/ADP translocase genes suggests that the ancestral TM6 lineage was also parasitic. We propose the name Dependentiae (phyl. nov.) to reflect dependence of TM6 bacteria on host organisms. PMID:26615204

  5. Comparative Genomics of Candidate Phylum TM6 Suggests That Parasitism Is Widespread and Ancestral in This Lineage.

    PubMed

    Yeoh, Yun Kit; Sekiguchi, Yuji; Parks, Donovan H; Hugenholtz, Philip

    2016-04-01

    Candidate phylum TM6 is a major bacterial lineage recognized through culture-independent rRNA surveys to be low abundance members in a wide range of habitats; however, they are poorly characterized due to a lack of pure culture representatives. Two recent genomic studies of TM6 bacteria revealed small genomes and limited gene repertoire, consistent with known or inferred dependence on eukaryotic hosts for their metabolic needs. Here, we obtained additional near-complete genomes of TM6 populations from agricultural soil and upflow anaerobic sludge blanket reactor metagenomes which, together with the two publicly available TM6 genomes, represent seven distinct family level lineages in the TM6 phylum. Genome-based phylogenetic analysis confirms that TM6 is an independent phylum level lineage in the bacterial domain, possibly affiliated with the Patescibacteria superphylum. All seven genomes are small (1.0-1.5 Mb) and lack complete biosynthetic pathways for various essential cellular building blocks including amino acids, lipids, and nucleotides. These and other features identified in the TM6 genomes such as a degenerated cell envelope, ATP/ADP translocases for parasitizing host ATP pools, and protein motifs to facilitate eukaryotic host interactions indicate that parasitism is widespread in this phylum. Phylogenetic analysis of ATP/ADP translocase genes suggests that the ancestral TM6 lineage was also parasitic. We propose the name Dependentiae (phyl. nov.) to reflect dependence of TM6 bacteria on host organisms. PMID:26615204

  6. Short communication: The effect of genotyping cows to improve the reliability of genomic predictions for selection candidates.

    PubMed

    Edel, C; Pimentel, E C G; Plieschke, L; Emmerling, R; Götz, K-U

    2016-03-01

    In this study we investigate the potential of enlarging the reference population for genomic prediction in dairy cattle by routinely genotyping a random sample of the first-crop daughters of every AI bull in the breeding program. We analyzed small nuclear pedigrees, each consisting of a genotyped selection candidate and 3 generations of genotyped male ancestors. Genotypes were taken from the genomic routine evaluation of Fleckvieh cattle in Germany and Austria. The phenotypic information of a daughter of any one male in each of these pedigrees was either considered to be part of the daughter yield deviation of the corresponding sire, or was assumed to be an individually observed genotyped daughter of this sire. Daughter genotypes in this case were simulated from phased haplotypes of their sires and random maternal gametes drawn from a haplotype library. We measured the gain from genotyping daughters as the increase in model-based theoretical reliability of the genomic prediction for a putative selection candidate. We expressed the improvements as a marginal increase, corresponding to an increase in reliability at a reliability baseline level of zero, to simplify comparisons. Results were encouraging with 2 to 40% of marginal reliability increase for selection candidates depending on the assumed heritability of the trait and the number of daughters modeled to be genotyped in the design. PMID:26723131

  7. Quantitative Trait Locus Mapping and Candidate Gene Analysis for Plant Architecture Traits Using Whole Genome Re-Sequencing in Rice

    PubMed Central

    Lim, Jung-Hyun; Yang, Hyun-Jung; Jung, Ki-Hong; Yoo, Soo-Cheul; Paek, Nam-Chon

    2014-01-01

    Plant breeders have focused on improving plant architecture as an effective means to increase crop yield. Here, we identify the main-effect quantitative trait loci (QTLs) for plant shape-related traits in rice (Oryza sativa) and find candidate genes by applying whole genome re-sequencing of two parental cultivars using next-generation sequencing. To identify QTLs influencing plant shape, we analyzed six traits: plant height, tiller number, panicle diameter, panicle length, flag leaf length, and flag leaf width. We performed QTL analysis with 178 F7 recombinant in-bred lines (RILs) from a cross of japonica rice line ‘SNUSG1’ and indica rice line ‘Milyang23’. Using 131 molecular markers, including 28 insertion/deletion markers, we identified 11 main- and 16 minor-effect QTLs for the six traits with a threshold LOD value > 2.8. Our sequence analysis identified fifty-four candidate genes for the main-effect QTLs. By further comparison of coding sequences and meta-expression profiles between japonica and indica rice varieties, we finally chose 15 strong candidate genes for the 11 main-effect QTLs. Our study shows that the whole-genome sequence data substantially enhanced the efficiency of polymorphic marker development for QTL fine-mapping and the identification of possible candidate genes. This yields useful genetic resources for breeding high-yielding rice cultivars with improved plant architecture. PMID:24599000

  8. Genome analysis of a clinical isolate of Shewanella sp. uncovered an active hybrid integrative and conjugative element carrying an integron platform inserted in a novel genomic locus.

    PubMed

    Parmeciano Di Noto, Gisela; Jara, Eugenio; Iriarte, Andrés; Centrón, Daniela; Quiroga, Cecilia

    2016-08-01

    Shewanella spp. are currently considered to be emerging pathogens that can code for a blaOXA carbapenemase in their chromosome. Complete genome analysis of the clinical isolate Shewanella sp. Sh95 revealed that this strain is a novel species, which shares a lineage with marine isolates. Characterization of its resistome showed that it codes for genes drfA15, qacH and blaOXA-48. We propose that Shewanella sp. Sh95 acts as reservoir of blaOXA-48. Moreover, analysis of mobilome showed that it contains a novel integrative and conjugative element (ICE), named ICESh95. Comparative analysis between the close relatives ICESpuPO1 from Shewanella sp. W3-18-1 and ICE SXTMO10 from Vibrio cholerae showed that ICESh95 encompassed two new regions, a type III restriction modification system and a multidrug resistance integron. The integron platform contained a novel arrangement formed by gene cassettes drfA15 and qacH, and a class C-attC group II intron. Furthermore, insertion of ICESh95 occurred at a unique target site, which correlated with the presence of a different xis/int module. Mobility of ICESh95 was assessed and demonstrated its ability to self-transfer with high efficiency to different species of bacteria. Our results show that ICESh95 is a self-transmissible, mobile element, which can contribute to the dissemination of antimicrobial resistance; this is clearly a threat when natural bacteria from water ecosystems, such as Shewanella, act as vectors in its propagation. PMID:27215217

  9. A whole-genome RNAi screen uncovers a novel role for human potassium channels in cell killing by the parasite Entamoeba histolytica

    PubMed Central

    Marie, Chelsea; Verkerke, Hans P.; Theodorescu, Dan; Petri, William A.

    2015-01-01

    The parasite Entamoeba histolytica kills human cells resulting in ulceration, inflammation and invasion of the colonic epithelium. We used the cytotoxic properties of ameba to select a genome-wide RNAi library to reveal novel host factors that control susceptibility to amebic killing. We identified 281 candidate susceptibility genes and bioinformatics analyses revealed that ion transporters were significantly enriched among susceptibility genes. Potassium (K+) channels were the most common transporter identified. Their importance was further supported by colon biopsy of humans with amebiasis that demonstrated suppressed K+ channel expression. Inhibition of human K+ channels by genetic silencing, pharmacologic inhibitors and with excess K+ protected diverse cell types from E. histolytica-induced death. Contact with E. histolytica parasites triggered K+ channel activation and K+ efflux by intestinal epithelial cells, which preceded cell killing. Specific inhibition of Ca2+-dependent K+ channels was highly effective in preventing amebic cytotoxicity in intestinal epithelial cells and macrophages. Blockade of K+ efflux also inhibited caspase-1 activation, IL-1β secretion and pyroptotic death in THP-1 macrophages. We concluded that K+ channels are host mediators of amebic cytotoxicity in multiple cells types and of inflammasome activation in macrophages. PMID:26346926

  10. Complete Chloroplast Genome Sequence of an Orchid Model Plant Candidate: Erycina pusilla Apply in Tropical Oncidium Breeding

    PubMed Central

    Pan, I-Chun; Liao, Der-Chih; Wu, Fu-Huei; Daniell, Henry; Singh, Nameirakpam Dolendro; Chang, Chen; Shih, Ming-Che; Chan, Ming-Tsair; Lin, Choun-Sea

    2012-01-01

    Oncidium is an important ornamental plant but the study of its functional genomics is difficult. Erycina pusilla is a fast-growing Oncidiinae species. Several characteristics including low chromosome number, small genome size, short growth period, and its ability to complete its life cycle in vitro make E. pusilla a good model candidate and parent for hybridization for orchids. Although genetic information remains limited, systematic molecular analysis of its chloroplast genome might provide useful genetic information. By combining bacterial artificial chromosome (BAC) clones and next-generation sequencing (NGS), the chloroplast (cp) genome of E. pusilla was sequenced accurately, efficiently and economically. The cp genome of E. pusilla shares 89 and 84% similarity with Oncidium Gower Ramsey and Phalanopsis aphrodite, respectively. Comparing these 3 cp genomes, 5 regions have been identified as showing diversity. Using PCR analysis of 19 species belonging to the Epidendroideae subfamily, a conserved deletion was found in the rps15-trnN region of the Cymbidieae tribe. Because commercial Oncidium varieties in Taiwan are limited, identification of potential parents using molecular breeding method has become very important. To demonstrate the relationship between taxonomic position and hybrid compatibility of E. pusilla, 4 DNA regions of 36 tropically adapted Oncidiinae varieties have been analyzed. The results indicated that trnF-ndhJ and trnH-psbA were suitable for phylogenetic analysis. E. pusilla proved to be phylogenetically closer to Rodriguezia and Tolumnia than Oncidium, despite its similar floral appearance to Oncidium. These results indicate the hybrid compatibility of E. pusilla, its cp genome providing important information for Oncidium breeding. PMID:22496851

  11. The Candidate Phylum Poribacteria by Single-Cell Genomics: New Insights into Phylogeny, Cell-Compartmentation, Eukaryote-Like Repeat Proteins, and Other Genomic Features

    PubMed Central

    Kamke, Janine; Rinke, Christian; Schwientek, Patrick; Mavromatis, Kostas; Ivanova, Natalia; Sczyrba, Alexander; Woyke, Tanja; Hentschel, Ute

    2014-01-01

    The candidate phylum Poribacteria is one of the most dominant and widespread members of the microbial communities residing within marine sponges. Cell compartmentalization had been postulated along with their discovery about a decade ago and their phylogenetic association to the Planctomycetes, Verrucomicrobia, Chlamydiae superphylum was proposed soon thereafter. In the present study we revised these features based on genomic data obtained from six poribacterial single cells. We propose that Poribacteria form a distinct monophyletic phylum contiguous to the PVC superphylum together with other candidate phyla. Our genomic analyses supported the possibility of cell compartmentalization in form of bacterial microcompartments. Further analyses of eukaryote-like protein domains stressed the importance of such proteins with features including tetratricopeptide repeats, leucin rich repeats as well as low density lipoproteins receptor repeats, the latter of which are reported here for the first time from a sponge symbiont. Finally, examining the most abundant protein domain family on poribacterial genomes revealed diverse phyH family proteins, some of which may be related to dissolved organic posphorus uptake. PMID:24498082

  12. Phylogeography, Salinity Adaptations and Metabolic Potential of the Candidate Division KB1 Bacteria Based on a Partial Single Cell Genome.

    PubMed

    Nigro, Lisa M; Hyde, Andrew S; MacGregor, Barbara J; Teske, Andreas

    2016-01-01

    Deep-sea hypersaline anoxic basins and other hypersaline environments contain abundant and diverse microbial life that has adapted to these extreme conditions. The bacterial Candidate Division KB1 represents one of several uncultured groups that have been consistently observed in hypersaline microbial diversity studies. Here we report the phylogeography of KB1, its phylogenetic relationships to Candidate Division OP1 Bacteria, and its potential metabolic and osmotic stress adaptations based on a partial single cell amplified genome of KB1 from Orca Basin, the largest hypersaline seafloor brine basin in the Gulf of Mexico. Our results are consistent with the hypothesis - previously developed based on (14)C incorporation experiments with mixed-species enrichments from Mediterranean seafloor brines - that KB1 has adapted its proteins to elevated intracellular salinity, but at the same time KB1 apparently imports glycine betaine; this compatible solute is potentially not limited to osmoregulation but could also serve as a carbon and energy source. PMID:27597842

  13. Integrative Analysis of Metabolomic, Proteomic and Genomic Data to Reveal Functional Pathways and Candidate Genes for Drip Loss in Pigs.

    PubMed

    Welzenbach, Julia; Neuhoff, Christiane; Heidt, Hanna; Cinar, Mehmet Ulas; Looft, Christian; Schellander, Karl; Tholen, Ernst; Große-Brinkhaus, Christine

    2016-01-01

    The aim of this study was to integrate multi omics data to characterize underlying functional pathways and candidate genes for drip loss in pigs. The consideration of different omics levels allows elucidating the black box of phenotype expression. Metabolite and protein profiling was applied in Musculus longissimus dorsi samples of 97 Duroc × Pietrain pigs. In total, 126 and 35 annotated metabolites and proteins were quantified, respectively. In addition, all animals were genotyped with the porcine 60 k Illumina beadchip. An enrichment analysis resulted in 10 pathways, amongst others, sphingolipid metabolism and glycolysis/gluconeogenesis, with significant influence on drip loss. Drip loss and 22 metabolic components were analyzed as intermediate phenotypes within a genome-wide association study (GWAS). We detected significantly associated genetic markers and candidate genes for drip loss and for most of the metabolic components. On chromosome 18, a region with promising candidate genes was identified based on SNPs associated with drip loss, the protein "phosphoglycerate mutase 2" and the metabolite glycine. We hypothesize that association studies based on intermediate phenotypes are able to provide comprehensive insights in the genetic variation of genes directly involved in the metabolism of performance traits. In this way, the analyses contribute to identify reliable candidate genes. PMID:27589727

  14. Genome-Wide Linkage Analysis of Global Gene Expression in Loin Muscle Tissue Identifies Candidate Genes in Pigs

    PubMed Central

    Steibel, Juan Pedro; Bates, Ronald O.; Rosa, Guilherme J. M.; Tempelman, Robert J.; Rilington, Valencia D.; Ragavendran, Ashok; Raney, Nancy E.; Ramos, Antonio Marcos; Cardoso, Fernando F.; Edwards, David B.; Ernst, Catherine W.

    2011-01-01

    Background Nearly 6,000 QTL have been reported for 588 different traits in pigs, more than in any other livestock species. However, this effort has translated into only a few confirmed causative variants. A powerful strategy for revealing candidate genes involves expression QTL (eQTL) mapping, where the mRNA abundance of a set of transcripts is used as the response variable for a QTL scan. Methodology/Principal Findings We utilized a whole genome expression microarray and an F2 pig resource population to conduct a global eQTL analysis in loin muscle tissue, and compared results to previously inferred phenotypic QTL (pQTL) from the same experimental cross. We found 62 unique eQTL (FDR <10%) and identified 3 gene networks enriched with genes subject to genetic control involved in lipid metabolism, DNA replication, and cell cycle regulation. We observed strong evidence of local regulation (40 out of 59 eQTL with known genomic position) and compared these eQTL to pQTL to help identify potential candidate genes. Among the interesting associations, we found aldo-keto reductase 7A2 (AKR7A2) and thioredoxin domain containing 12 (TXNDC12) eQTL that are part of a network associated with lipid metabolism and in turn overlap with pQTL regions for marbling, % intramuscular fat (% fat) and loin muscle area on Sus scrofa (SSC) chromosome 6. Additionally, we report 13 genomic regions with overlapping eQTL and pQTL involving 14 local eQTL. Conclusions/Significance Results of this analysis provide novel candidate genes for important complex pig phenotypes. PMID:21346809

  15. The genomic architecture and association genetics of adaptive characters using a candidate SNP approach in boreal black spruce

    PubMed Central

    2013-01-01

    Background The genomic architecture of adaptive traits remains poorly understood in non-model plants. Various approaches can be used to bridge this gap, including the mapping of quantitative trait loci (QTL) in pedigrees, and genetic association studies in non-structured populations. Here we present results on the genomic architecture of adaptive traits in black spruce, which is a widely distributed conifer of the North American boreal forest. As an alternative to the usual candidate gene approach, a candidate SNP approach was developed for association testing. Results A genetic map containing 231 gene loci was used to identify QTL that were related to budset timing and to tree height assessed over multiple years and sites. Twenty-two unique genomic regions were identified, including 20 that were related to budset timing and 6 that were related to tree height. From results of outlier detection and bulk segregant analysis for adaptive traits using DNA pool sequencing of 434 genes, 52 candidate SNPs were identified and subsequently tested in genetic association studies for budset timing and tree height assessed over multiple years and sites. A total of 34 (65%) SNPs were significantly associated with budset timing, or tree height, or both. Although the percentages of explained variance (PVE) by individual SNPs were small, several significant SNPs were shared between sites and among years. Conclusions The sharing of genomic regions and significant SNPs between budset timing and tree height indicates pleiotropic effects. Significant QTLs and SNPs differed quite greatly among years, suggesting that different sets of genes for the same characters are involved at different stages in the tree’s life history. The functional diversity of genes carrying significant SNPs and low observed PVE further indicated that a large number of polymorphisms are involved in adaptive genetic variation. Accordingly, for undomesticated species such as black spruce with natural populations

  16. Single-cell genomics reveals the lifestyle of Poribacteria, a candidate phylum symbiotically associated with marine sponges.

    PubMed

    Siegl, Alexander; Kamke, Janine; Hochmuth, Thomas; Piel, Jörn; Richter, Michael; Liang, Chunguang; Dandekar, Thomas; Hentschel, Ute

    2011-01-01

    In this study, we present a single-cell genomics approach for the functional characterization of the candidate phylum Poribacteria, members of which are nearly exclusively found in marine sponges. The microbial consortia of the Mediterranean sponge Aplysina aerophoba were singularized by fluorescence-activated cell sorting, and individual microbial cells were subjected to phi29 polymerase-mediated 'whole-genome amplification'. Pyrosequencing of a single amplified genome (SAG) derived from a member of the Poribacteria resulted in nearly 1.6 Mb of genomic information distributed among 554 contigs analyzed in this study. Approximately two-third of the poribacterial genome was sequenced. Our findings shed light on the functional properties and lifestyle of a possibly ancient bacterial symbiont of marine sponges. The Poribacteria are mixotrophic bacteria with autotrophic CO(2)-fixation capacities through the Wood-Ljungdahl pathway. The cell wall is of Gram-negative origin. The Poribacteria produce at least two polyketide synthases (PKSs), one of which is the sponge-specific Sup-type PKS. Several putative symbiosis factors such as adhesins (bacterial Ig-like domains, lamininin G domain proteins), adhesin-related proteins (ankyrin, fibronectin type III) and tetratrico peptide repeat domain-encoding proteins were identified, which might be involved in mediating sponge-microbe interactions. The discovery of genes coding for 24-isopropyl steroids implies that certain fossil biomarkers used to date the origins of metazoan life on earth may possibly be of poribacterial origin. Single-cell genomic approaches, such as those shown herein, contribute to a better understanding of beneficial microbial consortia, of which most members are, because of the lack of cultivation, inaccessible by conventional techniques. PMID:20613790

  17. Phylogeny and physiology of candidate phylum 'Atribacteria' (OP9/JS1) inferred from cultivation-independent genomics.

    PubMed

    Nobu, Masaru K; Dodsworth, Jeremy A; Murugapiran, Senthil K; Rinke, Christian; Gies, Esther A; Webster, Gordon; Schwientek, Patrick; Kille, Peter; Parkes, R John; Sass, Henrik; Jørgensen, Bo B; Weightman, Andrew J; Liu, Wen-Tso; Hallam, Steven J; Tsiamis, George; Woyke, Tanja; Hedlund, Brian P

    2016-02-01

    The 'Atribacteria' is a candidate phylum in the Bacteria recently proposed to include members of the OP9 and JS1 lineages. OP9 and JS1 are globally distributed, and in some cases abundant, in anaerobic marine sediments, geothermal environments, anaerobic digesters and reactors and petroleum reservoirs. However, the monophyly of OP9 and JS1 has been questioned and their physiology and ecology remain largely enigmatic due to a lack of cultivated representatives. Here cultivation-independent genomic approaches were used to provide a first comprehensive view of the phylogeny, conserved genomic features and metabolic potential of members of this ubiquitous candidate phylum. Previously available and heretofore unpublished OP9 and JS1 single-cell genomic data sets were used as recruitment platforms for the reconstruction of atribacterial metagenome bins from a terephthalate-degrading reactor biofilm and from the monimolimnion of meromictic Sakinaw Lake. The single-cell genomes and metagenome bins together comprise six species- to genus-level groups that represent most major lineages within OP9 and JS1. Phylogenomic analyses of these combined data sets confirmed the monophyly of the 'Atribacteria' inclusive of OP9 and JS1. Additional conserved features within the 'Atribacteria' were identified, including a gene cluster encoding putative bacterial microcompartments that may be involved in aldehyde and sugar metabolism, energy conservation and carbon storage. Comparative analysis of the metabolic potential inferred from these data sets revealed that members of the 'Atribacteria' are likely to be heterotrophic anaerobes that lack respiratory capacity, with some lineages predicted to specialize in either primary fermentation of carbohydrates or secondary fermentation of organic acids, such as propionate. PMID:26090992

  18. Self-Confirmation and Ascertainment of the Candidate Genomic Regions of Complex Trait Loci - A None-Experimental Solution.

    PubMed

    Wang, Lishi; Jiao, Yan; Wang, Yongjun; Zhang, Mengchen; Gu, Weikuan

    2016-01-01

    Over the past half century, thousands of quantitative trait loci (QTL) have been identified by using animal models and plant populations. However, the none-reliability and imprecision of the genomic regions of these loci have remained the major hurdle for the identification of the causal genes for the correspondent traits. We used a none-experimental strategy of strain number reduction for testing accuracy and ascertainment of the candidate region for QTL. We tested the strategy in over 400 analyses with data from 47 studies. These studies include: 1) studies with recombinant inbred (RI) strains of mice. We first tested two previously mapped QTL with well-defined genomic regions; We then tested additional four studies with known QTL regions; and finally we examined the reliability of QTL in 38 sets of data which are produced from relatively large numbers of RI strains, derived from C57BL/6J (B6) X DBA/2J (D2), known as BXD RI mouse strains; 2) studies with RI strains of rats and plants; and 3) studies using F2 populations in mice, rats and plants. In these cases, our method identified the reliability of mapped QTL and localized the candidate genes into the defined genomic regions. Our data also suggests that LRS score produced by permutation tests does not necessarily confirm the reliability of the QTL. Number of strains are not the reliable indicators for the accuracy of QTL either. Our strategy determines the reliability and accuracy of the genomic region of a QTL without any additional experimental study such as congenic breeding. PMID:27203862

  19. Self-Confirmation and Ascertainment of the Candidate Genomic Regions of Complex Trait Loci – A None-Experimental Solution

    PubMed Central

    Wang, Lishi; Jiao, Yan; Wang, Yongjun; Zhang, Mengchen; Gu, Weikuan

    2016-01-01

    Over the past half century, thousands of quantitative trait loci (QTL) have been identified by using animal models and plant populations. However, the none-reliability and imprecision of the genomic regions of these loci have remained the major hurdle for the identification of the causal genes for the correspondent traits. We used a none-experimental strategy of strain number reduction for testing accuracy and ascertainment of the candidate region for QTL. We tested the strategy in over 400 analyses with data from 47 studies. These studies include: 1) studies with recombinant inbred (RI) strains of mice. We first tested two previously mapped QTL with well-defined genomic regions; We then tested additional four studies with known QTL regions; and finally we examined the reliability of QTL in 38 sets of data which are produced from relatively large numbers of RI strains, derived from C57BL/6J (B6) X DBA/2J (D2), known as BXD RI mouse strains; 2) studies with RI strains of rats and plants; and 3) studies using F2 populations in mice, rats and plants. In these cases, our method identified the reliability of mapped QTL and localized the candidate genes into the defined genomic regions. Our data also suggests that LRS score produced by permutation tests does not necessarily confirm the reliability of the QTL. Number of strains are not the reliable indicators for the accuracy of QTL either. Our strategy determines the reliability and accuracy of the genomic region of a QTL without any additional experimental study such as congenic breeding. PMID:27203862

  20. The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color

    PubMed Central

    2013-01-01

    Background Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results We describe the sequencing and assembly of the genome of Theobroma cacao L. cultivar Matina 1-6. The genome of the Matina 1-6 cultivar is 445 Mbp, which is significantly larger than a sequenced Criollo cultivar, and more typical of other cultivars. The chromosome-scale assembly, version 1.1, contains 711 scaffolds covering 346.0 Mbp, with a contig N50 of 84.4 kbp, a scaffold N50 of 34.4 Mbp, and an evidence-based gene set of 29,408 loci. Version 1.1 has 10x the scaffold N50 and 4x the contig N50 as Criollo, and includes 111 Mb more anchored sequence. The version 1.1 assembly has 4.4% gap sequence, while Criollo has 10.9%. Through a combination of haplotype, association mapping and gene expression analyses, we leverage this robust reference genome to identify a promising candidate gene responsible for pod color variation. We demonstrate that green/red pod color in cacao is likely regulated by the R2R3 MYB transcription factor TcMYB113, homologs of which determine pigmentation in Rosaceae, Solanaceae, and Brassicaceae. One SNP within the target site for a highly conserved trans-acting siRNA in dicots, found within TcMYB113, seems to affect transcript levels of this gene and therefore pod color variation. Conclusions We report a high-quality sequence and annotation of Theobroma cacao L. and demonstrate its utility in identifying candidate genes regulating traits. PMID:23731509

  1. Integrative Transcriptome, Genome and Quantitative Trait Loci Resources Identify Single Nucleotide Polymorphisms in Candidate Genes for Growth Traits in Turbot.

    PubMed

    Robledo, Diego; Fernández, Carlos; Hermida, Miguel; Sciara, Andrés; Álvarez-Dios, José Antonio; Cabaleiro, Santiago; Caamaño, Rubén; Martínez, Paulino; Bouza, Carmen

    2016-01-01

    Growth traits represent a main goal in aquaculture breeding programs and may be related to adaptive variation in wild fisheries. Integrating quantitative trait loci (QTL) mapping and next generation sequencing can greatly help to identify variation in candidate genes, which can result in marker-assisted selection and better genetic structure information. Turbot is a commercially important flatfish in Europe and China, with available genomic information on QTLs and genome mapping. Muscle and liver RNA-seq from 18 individuals was carried out to obtain gene sequences and markers functionally related to growth, resulting in a total of 20,447 genes and 85,344 single nucleotide polymorphisms (SNPs). Many growth-related genes and SNPs were identified and placed in the turbot genome and genetic map to explore their co-localization with growth-QTL markers. Forty-five SNPs on growth-related genes were selected based on QTL co-localization and relevant function for growth traits. Forty-three SNPs were technically feasible and validated in a wild Atlantic population, where 91% were polymorphic. The integration of functional and structural genomic resources in turbot provides a practical approach for QTL mining in this species. Validated SNPs represent a useful set of growth-related gene markers for future association, functional and population studies in this flatfish species. PMID:26901189

  2. Integrative Transcriptome, Genome and Quantitative Trait Loci Resources Identify Single Nucleotide Polymorphisms in Candidate Genes for Growth Traits in Turbot

    PubMed Central

    Robledo, Diego; Fernández, Carlos; Hermida, Miguel; Sciara, Andrés; Álvarez-Dios, José Antonio; Cabaleiro, Santiago; Caamaño, Rubén; Martínez, Paulino; Bouza, Carmen

    2016-01-01

    Growth traits represent a main goal in aquaculture breeding programs and may be related to adaptive variation in wild fisheries. Integrating quantitative trait loci (QTL) mapping and next generation sequencing can greatly help to identify variation in candidate genes, which can result in marker-assisted selection and better genetic structure information. Turbot is a commercially important flatfish in Europe and China, with available genomic information on QTLs and genome mapping. Muscle and liver RNA-seq from 18 individuals was carried out to obtain gene sequences and markers functionally related to growth, resulting in a total of 20,447 genes and 85,344 single nucleotide polymorphisms (SNPs). Many growth-related genes and SNPs were identified and placed in the turbot genome and genetic map to explore their co-localization with growth-QTL markers. Forty-five SNPs on growth-related genes were selected based on QTL co-localization and relevant function for growth traits. Forty-three SNPs were technically feasible and validated in a wild Atlantic population, where 91% were polymorphic. The integration of functional and structural genomic resources in turbot provides a practical approach for QTL mining in this species. Validated SNPs represent a useful set of growth-related gene markers for future association, functional and population studies in this flatfish species. PMID:26901189

  3. Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies

    PubMed Central

    Rodriguez-Fontenla, Cristina; Calaza, Manuel; Evangelou, Evangelos; Valdes, Ana M; Arden, Nigel; Blanco, Francisco J; Carr, Andrew; Chapman, Kay; Deloukas, Panos; Doherty, Michael; Esko, Tõnu; Garcés Aletá, Carlos M; Gomez-Reino Carnota, Juan J; Helgadottir, Hafdis; Hofman, Albert; Jonsdottir, Ingileif; Kerkhof, Hanneke J M; Kloppenburg, Margreet; McCaskie, Andrew; Ntzani, Evangelia E; Ollier, William E R; Oreiro, Natividad; Panoutsopoulou, Kalliope; Ralston, Stuart H; Ramos, Yolande F; Riancho, Jose A; Rivadeneira, Fernando; Slagboom, P Eline; Styrkarsdottir, Unnur; Thorsteinsdottir, Unnur; Thorleifsson, Gudmar; Tsezou, Aspasia; Uitterlinden, André G; Wallis, Gillian A; Wilkinson, J Mark; Zhai, Guangju; Zhu, Yanyan; Felson, David T; Ioannidis, John P A; Loughlin, John; Metspalu, Andres; Meulenbelt, Ingrid; Stefansson, Kari; van Meurs, Joyce B; Zeggini, Eleftheria; Spector, Timothy D; Gonzalez, Antonio

    2014-01-01

    Objective To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant. Results SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated. PMID:24757145

  4. Identification of candidate transcription factor binding sites in the cattle genome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A resource that provides candidate transcription factor binding sites does not currently exist for cattle. Such data is necessary, as predicted sites may serve as excellent starting locations for future 'omics studies to develop transcriptional regulation hypotheses. In order to generate this resour...

  5. Identification of candidate genes in Populus cell wall biosynthesis using text-mining, co-expression network and comparative genomics

    SciTech Connect

    Yang, Xiaohan; Ye, Chuyu; Bisaria, Anjali; Tuskan, Gerald A; Kalluri, Udaya C

    2011-01-01

    Populus is an important bioenergy crop for bioethanol production. A greater understanding of cell wall biosynthesis processes is critical in reducing biomass recalcitrance, a major hindrance in efficient generation of ethanol from lignocellulosic biomass. Here, we report the identification of candidate cell wall biosynthesis genes through the development and application of a novel bioinformatics pipeline. As a first step, via text-mining of PubMed publications, we obtained 121 Arabidopsis genes that had the experimental evidences supporting their involvement in cell wall biosynthesis or remodeling. The 121 genes were then used as bait genes to query an Arabidopsis co-expression database and additional genes were identified as neighbors of the bait genes in the network, increasing the number of genes to 548. The 548 Arabidopsis genes were then used to re-query the Arabidopsis co-expression database and re-construct a network that captured additional network neighbors, expanding to a total of 694 genes. The 694 Arabidopsis genes were computationally divided into 22 clusters. Queries of the Populus genome using the Arabidopsis genes revealed 817 Populus orthologs. Functional analysis of gene ontology and tissue-specific gene expression indicated that these Arabidopsis and Populus genes are high likelihood candidates for functional genomics in relation to cell wall biosynthesis.

  6. Identification of a strawberry flavor gene candidate using an integrated genetic-genomic-analytical chemistry approach

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: There is interest in improving the flavor of commercial strawberry (Fragaria × ananassa) varieties. Fruit flavor is shaped by combinations of sugars, acids and volatile compounds. Many efforts seek to use genomics-based strategies to identify genes controlling flavor, and then designing ...

  7. Whole genome analysis using Bayesian models to identify candidate genes for immune response to vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study identified genome regions associated with variation in immune response to vaccination against bovine viral diarrhea virus type 2 (BVDV 2) in American Angus calves. Calves were born in the spring or fall of 2006-2008 (n = 620). Two doses of modified live vaccine were administered three wee...

  8. Natural bone fragmentation in the blind cave-dwelling fish, Astyanax mexicanus: candidate gene identification through integrative comparative genomics.

    PubMed

    Gross, Joshua B; Stahl, Bethany A; Powers, Amanda K; Carlson, Brian M

    2016-01-01

    Animals that colonize dark and nutrient-poor subterranean environments evolve numerous extreme phenotypes. These include dramatic changes to the craniofacial complex, many of which are under genetic control. These phenotypes can demonstrate asymmetric genetic signals wherein a QTL is detected on one side of the face but not the other. The causative gene(s) underlying QTL are difficult to identify with limited genomic resources. We approached this task by searching for candidate genes mediating fragmentation of the third suborbital bone (SO3) directly inferior to the orbit of the eye. We integrated positional genomic information using emerging Astyanax resources, and linked these intervals to homologous (syntenic) regions of the Danio rerio genome. We identified a discrete, approximately 6 Mb, conserved region wherein the gene causing SO3 fragmentation likely resides. We interrogated this interval for genes demonstrating significant differential expression using mRNA-seq analysis of cave and surface morphs across life history. We then assessed genes with known roles in craniofacial evolution and development based on GO term annotation. Finally, we screened coding sequence alterations in this region, identifying two key genes: transforming growth factor β3 (tgfb3) and bone morphogenetic protein 4 (bmp4). Of these candidates, tgfb3 is most promising as it demonstrates significant differential expression across multiple stages of development, maps close (<1 Mb) to the fragmentation critical locus, and is implicated in a variety of other animal systems (including humans) in non-syndromic clefting and malformations of the cranial sutures. Both abnormalities are analogous to the failure-to-fuse phenotype that we observe in SO3 fragmentation. This integrative approach will enable discovery of the causative genetic lesions leading to complex craniofacial features analogous to human craniofacial disorders. This work underscores the value of cave-dwelling fish as a

  9. Candidate Luminal B Breast Cancer Genes Identified by Genome, Gene Expression and DNA Methylation Profiling

    PubMed Central

    Addou-Klouche, Lynda; Finetti, Pascal; Saade, Marie-Rose; Manai, Marwa; Carbuccia, Nadine; Bekhouche, Ismahane; Letessier, Anne; Charafe-Jauffret, Emmanuelle; Jacquemier, Jocelyne; Spicuglia, Salvatore; de The, Hugues; Viens, Patrice; Bertucci, François; Birnbaum, Daniel; Chaffanet, Max

    2014-01-01

    Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype. PMID:24416132

  10. An Integrated Genomic Strategy Delineates Candidate Mediator Genes Regulating Grain Size and Weight in Rice

    PubMed Central

    Malik, Naveen; Dwivedi, Nidhi; Singh, Ashok K.; Parida, Swarup K.; Agarwal, Pinky; Thakur, Jitendra K.; Tyagi, Akhilesh K.

    2016-01-01

    The present study deployed a Mediator (MED) genes-mediated integrated genomic strategy for understanding the complex genetic architecture of grain size/weight quantitative trait in rice. The targeted multiplex amplicon resequencing of 55 MED genes annotated from whole rice genome in 384 accessions discovered 3971 SNPs, which were structurally and functionally annotated in diverse coding and non-coding sequence-components of genes. Association analysis, using the genotyping information of 3971 SNPs in a structured population of 384 accessions (with 50–100 kb linkage disequilibrium decay), detected 10 MED gene-derived SNPs significantly associated (46% combined phenotypic variation explained) with grain length, width and weight in rice. Of these, one strong grain weight-associated non-synonymous SNP (G/A)-carrying OsMED4_2 gene was validated successfully in low- and high-grain weight parental accessions and homozygous individuals of a rice mapping population. The seed-specific expression, including differential up/down-regulation of three grain size/weight-associated MED genes (including OsMED4_2) in six low and high-grain weight rice accessions was evident. Altogether, combinatorial genomic approach involving haplotype-based association analysis delineated diverse functionally relevant natural SNP-allelic variants in 10 MED genes, including three potential novel SNP haplotypes in an OsMED4_2 gene governing grain size/weight differentiation in rice. These molecular tags have potential to accelerate genomics-assisted crop improvement in rice. PMID:27000976

  11. Genome-wide scans for candidate genes involved in the aquatic adaptation of dolphins.

    PubMed

    Sun, Yan-Bo; Zhou, Wei-Ping; Liu, He-Qun; Irwin, David M; Shen, Yong-Yi; Zhang, Ya-Ping

    2013-01-01

    Since their divergence from the terrestrial artiodactyls, cetaceans have fully adapted to an aquatic lifestyle, which represents one of the most dramatic transformations in mammalian evolutionary history. Numerous morphological and physiological characters of cetaceans have been acquired in response to this drastic habitat transition, such as thickened blubber, echolocation, and ability to hold their breath for a long period of time. However, knowledge about the molecular basis underlying these adaptations is still limited. The sequence of the genome of Tursiops truncates provides an opportunity for a comparative genomic analyses to examine the molecular adaptation of this species. Here, we constructed 11,838 high-quality orthologous gene alignments culled from the dolphin and four other terrestrial mammalian genomes and screened for positive selection occurring in the dolphin lineage. In total, 368 (3.1%) of the genes were identified as having undergone positive selection by the branch-site model. Functional characterization of these genes showed that they are significantly enriched in the categories of lipid transport and localization, ATPase activity, sense perception of sound, and muscle contraction, areas that are potentially related to cetacean adaptations. In contrast, we did not find a similar pattern in the cow, a closely related species. We resequenced some of the positively selected sites (PSSs), within the positively selected genes, and showed that most of our identified PSSs (50/52) could be replicated. The results from this study should have important implications for our understanding of cetacean evolution and their adaptations to the aquatic environment. PMID:23246795

  12. Genome Sequence of Brucella abortus Vaccine Strain S19 Compared to Virulent Strains Yields Candidate Virulence Genes

    PubMed Central

    Crasta, Oswald R.; Folkerts, Otto; Fei, Zhangjun; Mane, Shrinivasrao P.; Evans, Clive; Martino-Catt, Susan; Bricker, Betsy; Yu, GongXin; Du, Lei; Sobral, Bruno W.

    2008-01-01

    The Brucella abortus strain S19, a spontaneously attenuated strain, has been used as a vaccine strain in vaccination of cattle against brucellosis for six decades. Despite many studies, the physiological and molecular mechanisms causing the attenuation are not known. We have applied pyrosequencing technology together with conventional sequencing to rapidly and comprehensively determine the complete genome sequence of the attenuated Brucella abortus vaccine strain S19. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with the published genome sequences of two virulent and closely related strains of B. abortus, 9–941 and 2308. The two S19 chromosomes are 2,122,487 and 1,161,449 bp in length. A total of 3062 genes were identified and annotated. Pairwise and reciprocal genome comparisons resulted in a total of 263 genes that were non-identical between the S19 genome and any of the two virulent strains. Amongst these, 45 genes were consistently different between the attenuated strain and the two virulent strains but were identical amongst the virulent strains, which included only two of the 236 genes that have been implicated as virulence factors in literature. The functional analyses of the differences have revealed a total of 24 genes that may be associated with the loss of virulence in S19. Of particular relevance are four genes with more than 60bp consistent difference in S19 compared to both the virulent strains, which, in the virulent strains, encode an outer membrane protein and three proteins involved in erythritol uptake or metabolism. PMID:18478107

  13. Genome sequence of Brucella abortus vaccine strain S19 compared to virulent strains yields candidate virulence genes.

    PubMed

    Crasta, Oswald R; Folkerts, Otto; Fei, Zhangjun; Mane, Shrinivasrao P; Evans, Clive; Martino-Catt, Susan; Bricker, Betsy; Yu, GongXin; Du, Lei; Sobral, Bruno W

    2008-01-01

    The Brucella abortus strain S19, a spontaneously attenuated strain, has been used as a vaccine strain in vaccination of cattle against brucellosis for six decades. Despite many studies, the physiological and molecular mechanisms causing the attenuation are not known. We have applied pyrosequencing technology together with conventional sequencing to rapidly and comprehensively determine the complete genome sequence of the attenuated Brucella abortus vaccine strain S19. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with the published genome sequences of two virulent and closely related strains of B. abortus, 9-941 and 2308. The two S19 chromosomes are 2,122,487 and 1,161,449 bp in length. A total of 3062 genes were identified and annotated. Pairwise and reciprocal genome comparisons resulted in a total of 263 genes that were non-identical between the S19 genome and any of the two virulent strains. Amongst these, 45 genes were consistently different between the attenuated strain and the two virulent strains but were identical amongst the virulent strains, which included only two of the 236 genes that have been implicated as virulence factors in literature. The functional analyses of the differences have revealed a total of 24 genes that may be associated with the loss of virulence in S19. Of particular relevance are four genes with more than 60 bp consistent difference in S19 compared to both the virulent strains, which, in the virulent strains, encode an outer membrane protein and three proteins involved in erythritol uptake or metabolism. PMID:18478107

  14. Population Genomic Scan for Candidate Signatures of Balancing Selection to Guide Antigen Characterization in Malaria Parasites

    PubMed Central

    Amambua-Ngwa, Alfred; Tetteh, Kevin K. A.; Manske, Magnus; Gomez-Escobar, Natalia; Stewart, Lindsay B.; Deerhake, M. Elizabeth; Cheeseman, Ian H.; Newbold, Christopher I.; Holder, Anthony A.; Knuepfer, Ellen; Janha, Omar; Jallow, Muminatou; Campino, Susana; MacInnis, Bronwyn; Kwiatkowski, Dominic P.; Conway, David J.

    2012-01-01

    Acquired immunity in vertebrates maintains polymorphisms in endemic pathogens, leading to identifiable signatures of balancing selection. To comprehensively survey for genes under such selection in the human malaria parasite Plasmodium falciparum, we generated paired-end short-read sequences of parasites in clinical isolates from an endemic Gambian population, which were mapped to the 3D7 strain reference genome to yield high-quality genome-wide coding sequence data for 65 isolates. A minority of genes did not map reliably, including the hypervariable var, rifin, and stevor families, but 5,056 genes (90.9% of all in the genome) had >70% sequence coverage with minimum read depth of 5 for at least 50 isolates, of which 2,853 genes contained 3 or more single nucleotide polymorphisms (SNPs) for analysis of polymorphic site frequency spectra. Against an overall background of negatively skewed frequencies, as expected from historical population expansion combined with purifying selection, the outlying minority of genes with signatures indicating exceptionally intermediate frequencies were identified. Comparing genes with different stage-specificity, such signatures were most common in those with peak expression at the merozoite stage that invades erythrocytes. Members of clag, PfMC-2TM, surfin, and msp3-like gene families were highly represented, the strongest signature being in the msp3-like gene PF10_0355. Analysis of msp3-like transcripts in 45 clinical and 11 laboratory adapted isolates grown to merozoite-containing schizont stages revealed surprisingly low expression of PF10_0355. In diverse clonal parasite lines the protein product was expressed in a minority of mature schizonts (<1% in most lines and ∼10% in clone HB3), and eight sub-clones of HB3 cultured separately had an intermediate spectrum of positive frequencies (0.9 to 7.5%), indicating phase variable expression of this polymorphic antigen. This and other identified targets of balancing selection are now

  15. Genomic survey of candidate stress-response genes in the estuarine anemone Nematostella vectensis.

    PubMed

    Reitzel, Adam M; Sullivan, James C; Traylor-Knowles, Nikki; Finnerty, John R

    2008-06-01

    Salt marshes are challenging habitats due to natural variability in key environmental parameters including temperature, salinity, ultraviolet light, oxygen, sulfides, and reactive oxygen species. Compounding this natural variation, salt marshes are often heavily impacted by anthropogenic insults including eutrophication, toxic contamination, and coastal development that alter tidal and freshwater inputs. Commensurate with this environmental variability, estuarine animals generally exhibit broader physiological tolerances than freshwater, marine, or terrestrial species. One factor that determines an organism's physiological tolerance is its ability to upregulate "stress-response genes" in reaction to particular stressors. Comparative studies on diverse organisms have identified a number of evolutionarily conserved genes involved in responding to abiotic and biotic stressors. We used homology-based scans to survey the sequenced genome of Nematostella vectensis, the starlet sea anemone, an estuarine specialist, to identify genes involved in the response to three kinds of insult-physiochemical insults, pathogens, and injury. Many components of the stress-response networks identified in triploblastic animals have clear orthologs in the sea anemone, meaning that they must predate the cnidarian-triploblast split (e.g., xenobiotic receptors, biotransformative genes, ATP-dependent transporters, and genes involved in responding to reactive oxygen species, toxic metals, osmotic shock, thermal stress, pathogen exposure, and wounding). However, in some instances, stress-response genes known from triploblasts appear to be absent from the Nematostella genome (e.g., many metal-complexing genes). This is the first comprehensive examination of the genomic stress-response repertoire of an estuarine animal and a member of the phylum Cnidaria. The molecular markers of stress response identified in Nematostella may prove useful in monitoring estuary health and evaluating coastal

  16. A candidate autonomous version of the wheat MITE Hikkoshi is present in the rice genome.

    PubMed

    Saito, M; Yonemaru, J; Ishikawa, G; Nakamura, T

    2005-06-01

    A miniature inverted-repeat transposable element (MITE), designated as Hikkoshi, was previously identified in the null Wx-A1 allele of Turkish bread wheat lines. This MITE is 165 bp in size and has 12-bp terminal inverted repeats (TIRs) flanked by 8-bp target site duplications (TSDs). Southern and PCR analyses demonstrated the presence of multiple copies of Hikkoshi in the wheat genome. Database searches indicated that Hikkoshi MITEs are also present in barley, rice and maize. A 3.4-kb element that has Hikkoshi-like TIRs flanked by 8-bp TSDs has now been identified in the rice genome. This element shows high similarity to the 5' subterminal region of the wheat Hikkoshi MITE and contains a transposase (TPase) coding region. The TPase has two conserved domains, ZnF_TTF and hATC, and its amino acid sequence shows a high degree of homology to TPases encoded by Tip100 transposable elements belonging to the hAT superfamily. We designated the 3.4-kb element as OsHikkoshi. Several wheat clones deposited in EST databases showed sequence similarity to the TPase ORF of OsHikkoshi. The sequence information from the TPase of OsHikkoshi will thus be useful in isolating the autonomous element of the Hikkoshi system from wheat. PMID:15883824

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

    PubMed Central

    Thomas, Duncan

    2010-01-01

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

  18. Genome-wide association identifies candidate genes that influence the human electroencephalogram

    PubMed Central

    Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Cummins-Oman, Justine S.; Ferrier, Cherisse; Iarikova, Polina; Sankararaman, Sriram; Yamini, Goli; Yuan, Qiaoping; Zhou, Zhifeng; Albaugh, Bernard; White, Kenneth V.; Shen, Pei-Hong; Goldman, David

    2010-01-01

    Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (α), beta (β), and theta (θ) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of θ or α power. SGIP1 was estimated to account for 8.8% of variance in θ power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with θ power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by θ EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism. PMID:20421487

  19. Identification of candidate genes for an early-maturing soybean mutant by genome resequencing analysis.

    PubMed

    Lee, Kyung Jun; Kim, Dong Sub; Kim, Jin-Baek; Jo, Sung-Hwan; Kang, Si-Yong; Choi, Hong-Il; Ha, Bo-Keun

    2016-08-01

    Flowering is indicative of the transition from vegetative to reproductive phase, a critical event in the life cycle of plants. In this study, we performed whole genome resequencing by Illumina HiSeq to identify changes in flowering genes using an early-flowering phenotype of soybean mutant line Josaengserori (JS) derived from Korean landrace, Seoritae (SR), and we obtained mapped reads of 131,769,690 and 167,669,640 bp in JS and SR, respectively. From the whole genome sequencing results between JS and SR, we identified 332,821 polymorphic SNPs and 65,178 indels, respectively. Among these, 30 flowering genes were in SNPs and 25 were in indels. Among 30 flowering genes detected in SNPs, Glyma02g33040, Glyma06g22650, Glyma10g36600, Glyma13g01290, Glyma14g10530, Glyma16g01980, Glyma17g11040, Glyma18g53690, and Glyma20g29300 were non-synonymous substitutions between JS and SR. Changes in Glyma10g36600 (GI), Glya02g33040 (AGL18), Glyma17g11040 (TOC1), and Glyma14g10530 (ELF3) in JS affected the expression of GmFT2a and resulted in early flowering. These results provide insight into the regulatory pathways of flowering in soybean mutants and help to improve our knowledge of soybean mutation breeding. PMID:27033554

  20. Quantitative Trait Locus (QTL) meta-analysis and comparative genomics for candidate gene prediction in perennial ryegrass (Lolium perenne L.)

    PubMed Central

    2012-01-01

    Background In crop species, QTL analysis is commonly used for identification of factors contributing to variation of agronomically important traits. As an important pasture species, a large number of QTLs have been reported for perennial ryegrass based on analysis of biparental mapping populations. Further characterisation of those QTLs is, however, essential for utilisation in varietal improvement programs. Results A bibliographic survey of perennial ryegrass trait-dissection studies identified a total of 560 QTLs from previously published papers, of which 189, 270 and 101 were classified as morphology-, physiology- and resistance/tolerance-related loci, respectively. The collected dataset permitted a subsequent meta-QTL study and implementation of a cross-species candidate gene identification approach. A meta-QTL analysis based on use of the BioMercator software was performed to identify two consensus regions for pathogen resistance traits. Genes that are candidates for causal polymorphism underpinning perennial ryegrass QTLs were identified through in silico comparative mapping using rice databases, and 7 genes were assigned to the p150/112 reference map. Markers linked to the LpDGL1, LpPh1 and LpPIPK1 genes were located close to plant size, leaf extension time and heading date-related QTLs, respectively, suggesting that these genes may be functionally associated with important agronomic traits in perennial ryegrass. Conclusions Functional markers are valuable for QTL meta-analysis and comparative genomics. Enrichment of such genetic markers may permit further detailed characterisation of QTLs. The outcomes of QTL meta-analysis and comparative genomics studies may be useful for accelerated development of novel perennial ryegrass cultivars with desirable traits. PMID:23137269

  1. Evidence of Carbon Fixation Pathway in a Bacterium from Candidate Phylum SBR1093 Revealed with Genomic Analysis

    PubMed Central

    Wang, Zhiping; Guo, Feng; Liu, Lili; Zhang, Tong

    2014-01-01

    Autotrophic CO2 fixation is the most important biotransformation process in the biosphere. Research focusing on the diversity and distribution of relevant autotrophs is significant to our comprehension of the biosphere. In this study, a draft genome of a bacterium from candidate phylum SBR1093 was reconstructed with the metagenome of an industrial activated sludge. Based on comparative genomics, this autotrophy may occur via a newly discovered carbon fixation path, the hydroxypropionate-hydroxybutyrate (HPHB) cycle, which was demonstrated in a previous work to be uniquely possessed by some genera from Archaea. This bacterium possesses all of the thirteen enzymes required for the HPHB cycle; these enzymes share 30∼50% identity with those in the autotrophic species of Archaea that undergo the HPHB cycle and 30∼80% identity with the corresponding enzymes of the mixotrophic species within Bradyrhizobiaceae. Thus, this bacterium might have an autotrophic growth mode in certain conditions. A phylogenetic analysis based on the 16S rRNA gene reveals that the phylotypes within candidate phylum SBR1093 are primarily clustered into 5 clades with a shallow branching pattern. This bacterium is clustered with phylotypes from organically contaminated environments, implying a demand for organics in heterotrophic metabolism. Considering the types of regulators, such as FnR, Fur, and ArsR, this bacterium might be a facultative aerobic mixotroph with potential multi-antibiotic and heavy metal resistances. This is the first report on Bacteria that may perform potential carbon fixation via the HPHB cycle, thus may expand our knowledge of the distribution and importance of the HPHB cycle in the biosphere. PMID:25310003

  2. Genetic‐Genomic Replication to Identify Candidate Mouse Atherosclerosis Modifier Genes

    PubMed Central

    Hsu, Jeffrey; Smith, Jonathan D.

    2013-01-01

    Objective Genetics plays a large role in atherosclerosis susceptibility in humans and mice. We attempted to confirm previously determined mouse atherosclerosis‐associated loci and use bioinformatics and transcriptomics to create a catalog of candidate atherosclerosis modifier genes at these loci. Methods and Results A strain intercross was performed between AKR and DBA/2 mice on the apoE−/− background generating 166 F2 progeny. Using the phenotype log10 of the aortic root lesion area, we identified 3 suggestive atherosclerosis quantitative trait loci (Ath QTLs). When combined with our prior strain intercross, we confirmed 3 significant Ath QTLs on chromosomes 2, 15, and 17, with combined logarithm of odds scores of 5.9, 5.3, and 5.6, respectively, which each met the genome‐wide 5% false discovery rate threshold. We identified all of the protein coding differences between these 2 mouse strains within the Ath QTL intervals. Microarray gene expression profiling was performed on macrophages and endothelial cells from this intercross to identify expression QTLs (eQTLs), the loci that are associated with variation in the expression levels of specific transcripts. Cross tissue eQTLs and macrophage eQTLs that replicated from a prior strain intercross were identified. These bioinformatic and eQTL analyses produced a comprehensive list of candidate genes that may be responsible for the Ath QTLs. Conclusions Replication studies for clinical traits as well as gene expression traits are worthwhile in identifying true versus false genetic associations. We have replicated 3 loci on mouse chromosomes 2, 15, and 17 that are associated with atherosclerosis. We have also identified protein coding differences and multiple replicated eQTLs, which may be useful in the identification of atherosclerosis modifier genes. PMID:23525445

  3. Phylogeography, Salinity Adaptations and Metabolic Potential of the Candidate Division KB1 Bacteria Based on a Partial Single Cell Genome

    PubMed Central

    Nigro, Lisa M.; Hyde, Andrew S.; MacGregor, Barbara J.; Teske, Andreas

    2016-01-01

    Deep-sea hypersaline anoxic basins and other hypersaline environments contain abundant and diverse microbial life that has adapted to these extreme conditions. The bacterial Candidate Division KB1 represents one of several uncultured groups that have been consistently observed in hypersaline microbial diversity studies. Here we report the phylogeography of KB1, its phylogenetic relationships to Candidate Division OP1 Bacteria, and its potential metabolic and osmotic stress adaptations based on a partial single cell amplified genome of KB1 from Orca Basin, the largest hypersaline seafloor brine basin in the Gulf of Mexico. Our results are consistent with the hypothesis – previously developed based on 14C incorporation experiments with mixed-species enrichments from Mediterranean seafloor brines – that KB1 has adapted its proteins to elevated intracellular salinity, but at the same time KB1 apparently imports glycine betaine; this compatible solute is potentially not limited to osmoregulation but could also serve as a carbon and energy source. PMID:27597842

  4. An Arrayed Genome-Scale Lentiviral-Enabled Short Hairpin RNA Screen Identifies Lethal and Rescuer Gene Candidates

    PubMed Central

    Bhinder, Bhavneet; Antczak, Christophe; Ramirez, Christina N.; Shum, David; Liu-Sullivan, Nancy; Radu, Constantin; Frattini, Mark G.

    2013-01-01

    Abstract RNA interference technology is becoming an integral tool for target discovery and validation.; With perhaps the exception of only few studies published using arrayed short hairpin RNA (shRNA) libraries, most of the reports have been either against pooled siRNA or shRNA, or arrayed siRNA libraries. For this purpose, we have developed a workflow and performed an arrayed genome-scale shRNA lethality screen against the TRC1 library in HeLa cells. The resulting targets would be a valuable resource of candidates toward a better understanding of cellular homeostasis. Using a high-stringency hit nomination method encompassing criteria of at least three active hairpins per gene and filtered for potential off-target effects (OTEs), referred to as the Bhinder–Djaballah analysis method, we identified 1,252 lethal and 6 rescuer gene candidates, knockdown of which resulted in severe cell death or enhanced growth, respectively. Cross referencing individual hairpins with the TRC1 validated clone database, 239 of the 1,252 candidates were deemed independently validated with at least three validated clones. Through our systematic OTE analysis, we have identified 31 microRNAs (miRNAs) in lethal and 2 in rescuer genes; all having a seed heptamer mimic in the corresponding shRNA hairpins and likely cause of the OTE observed in our screen, perhaps unraveling a previously unknown plausible essentiality of these miRNAs in cellular viability. Taken together, we report on a methodology for performing large-scale arrayed shRNA screens, a comprehensive analysis method to nominate high-confidence hits, and a performance assessment of the TRC1 library highlighting the intracellular inefficiencies of shRNA processing in general. PMID:23198867

  5. Genome Wide Analysis Indicates Genes for Basement Membrane and Cartilage Matrix Proteins as Candidates for Hip Dysplasia in Labrador Retrievers

    PubMed Central

    Lavrijsen, Ineke C. M.; Leegwater, Peter A. J.; Martin, Alan J.; Harris, Stephen J.; Tryfonidou, Marianna A.; Heuven, Henri C. M.; Hazewinkel, Herman A. W.

    2014-01-01

    Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ2 statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia. PMID:24498183

  6. Genome wide analysis indicates genes for basement membrane and cartilage matrix proteins as candidates for hip dysplasia in Labrador Retrievers.

    PubMed

    Lavrijsen, Ineke C M; Leegwater, Peter A J; Martin, Alan J; Harris, Stephen J; Tryfonidou, Marianna A; Heuven, Henri C M; Hazewinkel, Herman A W

    2014-01-01

    Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ(2) statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001). Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia. PMID:24498183

  7. Cytochrome P450-encoding genes from the Heliconius genome as candidates for cyanogenesis.

    PubMed

    Chauhan, R; Jones, R; Wilkinson, P; Pauchet, Y; Ffrench-Constant, R H

    2013-10-01

    Cytochrome P450s are important both in the metabolism of xenobiotics and the production of compounds such as cyanogenic glucosides, which insects use in their defence. In the present study, we use transcriptomic and genomic information to isolate and name P450-encoding genes from the butterfly Heliconius melpomene. We classify each of the putative genes into its appropriate superfamily and compare the distribution of P450s across sequenced insects. We also identify homologues of two P450s known to be involved in cyanogenesis in the six-spot Burnet moth, Zygaena filipendulae. Classification of Heliconius P450s should be an important step in the dissection of their role in the exploitation of their host plant, the passion vine Passiflora. PMID:23834845

  8. Evaluation of the Potential Impact of Ebola Virus Genomic Drift on the Efficacy of Sequence-Based Candidate Therapeutics

    PubMed Central

    Sanchez-Lockhart, Mariano; Andersen, Kristian G.; Gire, Stephen; Park, Daniel J.; Sealfon, Rachel; Lin, Aaron E.; Wohl, Shirlee; Sabeti, Pardis C.

    2015-01-01

    ABSTRACT  Until recently, Ebola virus (EBOV) was a rarely encountered human pathogen that caused disease among small populations with extraordinarily high lethality. At the end of 2013, EBOV initiated an unprecedented disease outbreak in West Africa that is still ongoing and has already caused thousands of deaths. Recent studies revealed the genomic changes this particular EBOV variant undergoes over time during human-to-human transmission. Here we highlight the genomic changes that might negatively impact the efficacy of currently available EBOV sequence-based candidate therapeutics, such as small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and antibodies. Ten of the observed mutations modify the sequence of the binding sites of monoclonal antibody (MAb) 13F6, MAb 1H3, MAb 6D8, MAb 13C6, and siRNA EK-1, VP24, and VP35 targets and might influence the binding efficacy of the sequence-based therapeutics, suggesting that their efficacy should be reevaluated against the currently circulating strain. PMID:25604787

  9. Genome-wide association study identifies loci and candidate genes for meat quality traits in Simmental beef cattle.

    PubMed

    Xia, Jiangwei; Qi, Xin; Wu, Yang; Zhu, Bo; Xu, Lingyang; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Gao, Huijiang

    2016-06-01

    Improving meat quality is the best way to enhance profitability and strengthen competitiveness in beef industry. Identification of genetic variants that control beef quality traits can help breeders design optimal breeding programs to achieve this goal. We carried out a genome-wide association study for meat quality traits in 1141 Simmental cattle using the Illumina Bovine HD 770K SNP array to identify the candidate genes and genomic regions associated with meat quality traits for beef cattle, including fat color, meat color, marbling score, longissimus muscle area, and shear force. In our study, we identified twenty significant single-nucleotide polymorphisms (SNPs) (p < 1.47 × 10(-6)) associated with these five meat quality traits. Notably, we observed several SNPs were in or near eleven genes which have been reported previously, including TMEM236, SORL1, TRDN, S100A10, AP2S1, KCTD16, LOC506594, DHX15, LAMA4, PREX1, and BRINP3. We identified a haplotype block on BTA13 containing five significant SNPs associated with fat color trait. We also found one of 19 SNPs was associated with multiple traits (shear force and longissimus muscle area) on BTA7. Our results offer valuable insights to further explore the potential mechanism of meat quality traits in Simmental beef cattle. PMID:27126640

  10. Evaluation of the potential impact of Ebola virus genomic drift on the efficacy of sequence-based candidate therapeutics.

    PubMed

    Kugelman, Jeffrey R; Sanchez-Lockhart, Mariano; Andersen, Kristian G; Gire, Stephen; Park, Daniel J; Sealfon, Rachel; Lin, Aaron E; Wohl, Shirlee; Sabeti, Pardis C; Kuhn, Jens H; Palacios, Gustavo F

    2015-01-01

    Until recently, Ebola virus (EBOV) was a rarely encountered human pathogen that caused disease among small populations with extraordinarily high lethality. At the end of 2013, EBOV initiated an unprecedented disease outbreak in West Africa that is still ongoing and has already caused thousands of deaths. Recent studies revealed the genomic changes this particular EBOV variant undergoes over time during human-to-human transmission. Here we highlight the genomic changes that might negatively impact the efficacy of currently available EBOV sequence-based candidate therapeutics, such as small interfering RNAs (siRNAs), phosphorodiamidate morpholino oligomers (PMOs), and antibodies. Ten of the observed mutations modify the sequence of the binding sites of monoclonal antibody (MAb) 13F6, MAb 1H3, MAb 6D8, MAb 13C6, and siRNA EK-1, VP24, and VP35 targets and might influence the binding efficacy of the sequence-based therapeutics, suggesting that their efficacy should be reevaluated against the currently circulating strain. PMID:25604787

  11. Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome.

    PubMed

    Woollard, Wesley J; Pullabhatla, Venu; Lorenc, Anna; Patel, Varsha M; Butler, Rosie M; Bayega, Anthony; Begum, Nelema; Bakr, Farrah; Dedhia, Kiran; Fisher, Joshua; Aguilar-Duran, Silvia; Flanagan, Charlotte; Ghasemi, Aria A; Hoffmann, Ricarda M; Castillo-Mosquera, Nubia; Nuttall, Elisabeth A; Paul, Arisa; Roberts, Ceri A; Solomonidis, Emmanouil G; Tarrant, Rebecca; Yoxall, Antoinette; Beyers, Carl Z; Ferreira, Silvia; Tosi, Isabella; Simpson, Michael A; de Rinaldis, Emanuele; Mitchell, Tracey J; Whittaker, Sean J

    2016-06-30

    Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment. PMID:27121473

  12. Comparative mapping in intraspecific populations uncovers a high degree of macrosynteny between A- and B-genome diploid species of peanut

    PubMed Central

    2012-01-01

    Background Cultivated peanut or groundnut (Arachis hypogaea L.) is an important oilseed crop with an allotetraploid genome (AABB, 2n = 4x = 40). Both the low level of genetic variation within the cultivated gene pool and its polyploid nature limit the utilization of molecular markers to explore genome structure and facilitate genetic improvement. Nevertheless, a wealth of genetic diversity exists in diploid Arachis species (2n = 2x = 20), which represent a valuable gene pool for cultivated peanut improvement. Interspecific populations have been used widely for genetic mapping in diploid species of Arachis. However, an intraspecific mapping strategy was essential to detect chromosomal rearrangements among species that could be obscured by mapping in interspecific populations. To develop intraspecific reference linkage maps and gain insights into karyotypic evolution within the genus, we comparatively mapped the A- and B-genome diploid species using intraspecific F2 populations. Exploring genome organization among diploid peanut species by comparative mapping will enhance our understanding of the cultivated tetraploid peanut genome. Moreover, new sources of molecular markers that are highly transferable between species and developed from expressed genes will be required to construct saturated genetic maps for peanut. Results A total of 2,138 EST-SSR (expressed sequence tag-simple sequence repeat) markers were developed by mining a tetraploid peanut EST assembly including 101,132 unigenes (37,916 contigs and 63,216 singletons) derived from 70,771 long-read (Sanger) and 270,957 short-read (454) sequences. A set of 97 SSR markers were also developed by mining 9,517 genomic survey sequences of Arachis. An SSR-based intraspecific linkage map was constructed using an F2 population derived from a cross between K 9484 (PI 298639) and GKBSPSc 30081 (PI 468327) in the B-genome species A. batizocoi. A high degree of macrosynteny was observed when comparing the

  13. EXONSAMPLER: a computer program for genome-wide and candidate gene exon sampling for targeted next-generation sequencing.

    PubMed

    Cosart, Ted; Beja-Pereira, Albano; Luikart, Gordon

    2014-11-01

    The computer program EXONSAMPLER automates the sampling of thousands of exon sequences from publicly available reference genome sequences and gene annotation databases. It was designed to provide exon sequences for the efficient, next-generation gene sequencing method called exon capture. The exon sequences can be sampled by a list of gene name abbreviations (e.g. IFNG, TLR1), or by sampling exons from genes spaced evenly across chromosomes. It provides a list of genomic coordinates (a bed file), as well as a set of sequences in fasta format. User-adjustable parameters for collecting exon sequences include a minimum and maximum acceptable exon length, maximum number of exonic base pairs (bp) to sample per gene, and maximum total bp for the entire collection. It allows for partial sampling of very large exons. It can preferentially sample upstream (5 prime) exons, downstream (3 prime) exons, both external exons, or all internal exons. It is written in the Python programming language using its free libraries. We describe the use of EXONSAMPLER to collect exon sequences from the domestic cow (Bos taurus) genome for the design of an exon-capture microarray to sequence exons from related species, including the zebu cow and wild bison. We collected ~10% of the exome (~3 million bp), including 155 candidate genes, and ~16,000 exons evenly spaced genomewide. We prioritized the collection of 5 prime exons to facilitate discovery and genotyping of SNPs near upstream gene regulatory DNA sequences, which control gene expression and are often under natural selection. PMID:24751285

  14. TMA Uncovers Medicare Mistakes.

    PubMed

    Sorrel, Amy Lynn

    2015-07-01

    The Texas Medical Association recently uncovered some major Medicare mistakes that show just why some physicians talk about leaving the federal program. Investigations and advocacy by TMA staff put Medicare on the path to a fix. PMID:26201065

  15. Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia

    PubMed Central

    2013-01-01

    Background Biliary atresia is a fibroinflammatory obstruction of extrahepatic bile duct that leads to end-stage liver disease in children. Despite advances in understanding the pathogenesis of biliary atresia, very little is known about the role of microRNAs (miRNAs) in onset and progression of the disease. In this study, we aimed to investigate the entire biliary transcriptome to identify miRNAs with potential role in the pathogenesis of bile duct obstruction. Results By profiling the expression levels of miRNA in extrahepatic bile ducts and gallbladder (EHBDs) from a murine model of biliary atresia, we identified 14 miRNAs whose expression was suppressed at the times of duct obstruction and atresia (≥2 fold suppression, P < 0.05, FDR 5%). Next, we obtained 2,216 putative target genes of the 14 miRNAs using in silico target prediction algorithms. By integrating this result with a genome-wide gene expression analysis of the same tissue (≥2 fold increase, P < 0.05, FDR 5%), we identified 26 potential target genes with coordinate expression by the 14 miRNAs. Functional analysis of these target genes revealed a significant relevance of miR-30b/c, -133a/b, -195, -200a, -320 and −365 based on increases in expression of at least 3 target genes in the same tissue and 1st-to-3rd tier links with genes and gene-groups regulating organogenesis and immune response. These miRNAs showed higher expression in EHBDs above livers, a unique expression in cholangiocytes and the subepithelial compartment, and were downregulated in a cholangiocyte cell line after RRV infection. Conclusions Integrative genomics reveals functional relevance of miR-30b/c, -133a/b, -195, -200a, -320 and −365. The coordinate expression of miRNAs and target genes in a temporal-spatial fashion suggests a regulatory role of these miRNAs in pathogenesis of experimental biliary atresia. PMID:24138927

  16. Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

    PubMed Central

    Campbell, Catarina D.; Mohajeri, Kiana; Malig, Maika; Hormozdiari, Fereydoun; Nelson, Benjamin; Du, Gaixin; Patterson, Kristen M.; Eng, Celeste; Torgerson, Dara G.; Hu, Donglei; Herman, Catherine; Chong, Jessica X.; Ko, Arthur; O'Roak, Brian J.; Krumm, Niklas; Vives, Laura; Lee, Choli; Roth, Lindsey A.; Rodriguez-Cintron, William; Rodriguez-Santana, Jose; Brigino-Buenaventura, Emerita; Davis, Adam; Meade, Kelley; LeNoir, Michael A.; Thyne, Shannon; Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.; Shendure, Jay; Abney, Mark; Burchard, Esteban G.; Ober, Carole; Eichler, Evan E.

    2014-01-01

    Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS. PMID:25116239

  17. Genome-Wide Association Study Identifies Candidate Loci Associated with Platelet Count in Koreans

    PubMed Central

    Oh, Ji Hee; Kim, Yun Kyoung; Moon, Sanghoon; Kim, Young Jin

    2014-01-01

    Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction. Here, we performed a genome-wide association study with 352,228 single-nucleotide polymorphisms typed in 8,842 subjects of the Korea Association Resource (KARE) project and replicated the results in 7,861 subjects from an independent population. We identified genetic associations between platelet count and common variants nearby chromosome 4p16.1 (p = 1.46 × 10-10, in the KIAA0232 gene), 6p21 (p = 1.36 × 10-7, in the BAK1 gene), and 12q24.12 (p = 1.11 × 10-15, in the SH2B3 gene). Our results illustrate the value of large-scale discovery and a focus for several novel research avenues. PMID:25705162

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  20. Comparative genomics reveals candidate carotenoid pathway regulators of ripening watermelon fruit

    PubMed Central

    2013-01-01

    Background Many fruits, including watermelon, are proficient in carotenoid accumulation during ripening. While most genes encoding steps in the carotenoid biosynthetic pathway have been cloned, few transcriptional regulators of these genes have been defined to date. Here we describe the identification of a set of putative carotenoid-related transcription factors resulting from fresh watermelon carotenoid and transcriptome analysis during fruit development and ripening. Our goal is to both clarify the expression profiles of carotenoid pathway genes and to identify candidate regulators and molecular targets for crop improvement. Results Total carotenoids progressively increased during fruit ripening up to ~55 μg g-1 fw in red-ripe fruits. Trans-lycopene was the carotenoid that contributed most to this increase. Many of the genes related to carotenoid metabolism displayed changing expression levels during fruit ripening generating a metabolic flux toward carotenoid synthesis. Constitutive low expression of lycopene cyclase genes resulted in lycopene accumulation. RNA-seq expression profiling of watermelon fruit development yielded a set of transcription factors whose expression was correlated with ripening and carotenoid accumulation. Nineteen putative transcription factor genes from watermelon and homologous to tomato carotenoid-associated genes were identified. Among these, six were differentially expressed in the flesh of both species during fruit development and ripening. Conclusions Taken together the data suggest that, while the regulation of a common set of metabolic genes likely influences carotenoid synthesis and accumulation in watermelon and tomato fruits during development and ripening, specific and limiting regulators may differ between climacteric and non-climacteric fruits, possibly related to their differential susceptibility to and use of ethylene during ripening. PMID:24219562

  1. Genome-wide scan for visceral leishmaniasis in mixed-breed dogs identifies candidate genes involved in T helper cells and macrophage signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We conducted a genome-wide scan for visceral leishmaniasis in mixed-breed dogs from a highly endemic area in Brazil using 149,648 single nucleotide polymorphism (SNP) markers genotyped in 20 cases and 28 controls. Using a mixed model approach, we found two candidate loci on canine autosomes 1 and 2....

  2. Bacillus thuringiensis toxin resistance mechanisms among Lepidoptera: progress on genomic approaches to uncover causal mutations in the European corn borer, Ostrinia nubilalis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transgenic plants that expressed Bacillus thuringiensis (Bt) crystalline (Cry) protein toxins can suffer feeding damage from a small number of lepidopteran insect species under field conditions, which has heightened concerns about the durability of pest control tactics. Genomics research has provid...

  3. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions.

    PubMed

    Han, Ying; Hazelett, Dennis J; Wiklund, Fredrik; Schumacher, Fredrick R; Stram, Daniel O; Berndt, Sonja I; Wang, Zhaoming; Rand, Kristin A; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Xu, Jianfeng; Travis, Ruth C; Key, Timothy J; Siddiq, Afshan; Canzian, Federico; Takahashi, Atsushi; Kubo, Michiaki; Stanford, Janet L; Kolb, Suzanne; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Strom, Sara S; Pettaway, Curtis A; Al Olama, Ali Amin; Kote-Jarai, Zsofia; Eeles, Rosalind A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Isaacs, William B; Chen, Constance; Lindstrom, Sara; Le Marchand, Loic; Giovannucci, Edward L; Pomerantz, Mark; Long, Henry; Li, Fugen; Ma, Jing; Stampfer, Meir; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Blot, William J; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anselm J M; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Witte, John S; Casey, Graham; Riboli, Elio; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Gronberg, Henrik; Cook, Michael B; Nakagawa, Hidewaki; Kraft, Peter; Chanock, Stephen J; Easton, Douglas F; Henderson, Brian E; Coetzee, Gerhard A; Conti, David V; Haiman, Christopher A

    2015-10-01

    Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation. PMID:26162851

  4. Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence

    PubMed Central

    Yan, Jia; Aliev, Fazil; Webb, Bradley T; Kendler, Kenneth S; Williamson, Vernell S; Edenberg, Howard J; Agrawal, Arpana; Kos, Mark Z; Almasy, Laura; Nurnberger, John I; Schuckit, Marc A; Kramer, John R; Rice, John P; Kuperman, Samuel; Goate, Alison M; Tischfield, Jay A; Porjesz, Bernice; Dick, Danielle M

    2013-01-01

    Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared to family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying p-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent p-value thresholds of 0.01 to 0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with p < 0.01 to 0.565 for SNPs with p < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk. PMID:23362995

  5. Genetic Predictors of Susceptibility to Cutaneous Fungal Infections: a pilot Genome Wide Association Study to Refine a Candidate Gene Search

    PubMed Central

    Abdel-Rahman, Susan M.; Preuett, Barry L.

    2012-01-01

    Background Trichophyton tonsurans is the foremost fungal pathogen of minority children in the U.S. Despite overwhelming infection rates, it does not appear that this fungus infects children in a non-specific manner. Objective This study was designed to identify genes that may predispose or protect a child from T. tonsurans infection. Methods Children participating in an earlier longitudinal study wherein infection rates could be reliably determined were eligible for inclusion. DNA from a subset (n=40) of these children at the population extremes underwent whole genome genotyping (WGG). Allele frequencies between cases and controls were examined and significant SNPs were used to develop a candidate gene list for which the remainder of the cohort (n=115) were genotyped. Cumulative infection rate was examined by genotype and the ability of selected genotypes to predict the likelihood of infection explored by multivariable analysis. Results 23 genes with a putative mechanistic role in cutaneous infection were selected for evaluation. Of these, 21 demonstrated significant differences in infection rate between genotypes. A risk index assigned to genotypes in the 21 genes accounted for over 60% of the variability observed in infection rate (adjusted r2=0.665, p<0.001). Among these, 8 appeared to account for the majority of variability that was observed (r2=0.603, p<0.001). These included genes involved in: leukocyte activation and migration, extracellular matrix integrity and remodeling, epidermal maintenance and wound repair, and cutaneous permeability. Conclusions Applying WGG to individuals at the extremes of phenotype can help to guide the selection of candidate genes in populations of small cohorts where disease etiology is likely polygenic in nature. PMID:22704677

  6. Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat

    PubMed Central

    Morrissey, Catherine; Grieve, Ian C.; Heinig, Matthias; Atanur, Santosh; Petretto, Enrico; Pravenec, Michal; Hubner, Norbert

    2011-01-01

    The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with “physiological” QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes. PMID:21846806

  7. Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat.

    PubMed

    Morrissey, Catherine; Grieve, Ian C; Heinig, Matthias; Atanur, Santosh; Petretto, Enrico; Pravenec, Michal; Hubner, Norbert; Aitman, Timothy J

    2011-11-01

    The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with "physiological" QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes. PMID:21846806

  8. Genome Wide Screening of Candidate Genes for Improving Piglet Birth Weight Using High and Low Estimated Breeding Value Populations

    PubMed Central

    Zhang, Lifan; Zhou, Xiang; Michal, Jennifer J.; Ding, Bo; Li, Rui; Jiang, Zhihua

    2014-01-01

    Birth weight is an economically important trait in pig production because it directly impacts piglet growth and survival rate. In the present study, we performed a genome wide survey of candidate genes and pathways associated with individual birth weight (IBW) using the Illumina PorcineSNP60 BeadChip on 24 high (HEBV) and 24 low estimated breeding value (LEBV) animals. These animals were selected from a reference population of 522 individuals produced by three sires and six dam lines, which were crossbreds with multiple breeds. After quality-control, 43,257 SNPs (single nucleotide polymorphisms), including 42,243 autosomal SNPs and 1,014 SNPs on chromosome X, were used in the data analysis. A total of 27 differentially selected regions (DSRs), including 1 on Sus scrofa chromosome 1 (SSC1), 1 on SSC4, 2 on SSC5, 4 on SSC6, 2 on SSC7, 5 on SSC8, 3 on SSC9, 1 on SSC14, 3 on SSC18, and 5 on SSCX, were identified to show the genome wide separations between the HEBV and LEBV groups for IBW in piglets. A DSR with the most number of significant SNPs (including 7 top 0.1% and 31 top 5% SNPs) was located on SSC6, while another DSR with the largest genetic differences in FST was found on SSC18. These regions harbor known functionally important genes involved in growth and development, such as TNFRSF9 (tumor necrosis factor receptor superfamily member 9), CA6 (carbonic anhydrase VI) and MDFIC (MyoD family inhibitor domain containing). A DSR rich in imprinting genes appeared on SSC9, which included PEG10 (paternally expressed 10), SGCE (sarcoglycan, epsilon), PPP1R9A (protein phosphatase 1, regulatory subunit 9A) and ASB4 (ankyrin repeat and SOCS box containing 4). More importantly, our present study provided evidence to support six quantitative trait loci (QTL) regions for pig birth weight, six QTL regions for average birth weight (ABW) and three QTL regions for litter birth weight (LBW) reported previously by other groups. Furthermore, gene ontology analysis with 183 genes

  9. Population genomic analysis uncovers African and European admixture in Drosophila melanogaster populations from the south-eastern United States and Caribbean Islands.

    PubMed

    Kao, Joyce Y; Zubair, Asif; Salomon, Matthew P; Nuzhdin, Sergey V; Campo, Daniel

    2015-04-01

    Drosophila melanogaster is postulated to have colonized North America in the past several 100 years in two waves. Flies from Europe colonized the east coast United States while flies from Africa inhabited the Caribbean, which if true, make the south-east US and Caribbean Islands a secondary contact zone for African and European D. melanogaster. This scenario has been proposed based on phenotypes and limited genetic data. In our study, we have sequenced individual whole genomes of flies from populations in the south-east US and Caribbean Islands and examined these populations in conjunction with population sequences from the west coast US, Africa, and Europe. We find that west coast US populations are closely related to the European population, likely reflecting a rapid westward expansion upon first settlements into North America. We also find genomic evidence of African and European admixture in south-east US and Caribbean populations, with a clinal pattern of decreasing proportions of African ancestry with higher latitude. Our genomic analysis of D. melanogaster populations from the south-east US and Caribbean Islands provides more evidence for the Caribbean Islands as the source of previously reported novel African alleles found in other east coast US populations. We also find the border between the south-east US and the Caribbean island to be the admixture hot zone where distinctly African-like Caribbean flies become genomically more similar to European-like south-east US flies. Our findings have important implications for previous studies examining the generation of east coast US clines via selection. PMID:25735402

  10. An Integrated Genomic Approach for Rapid Delineation of Candidate Genes Regulating Agro-Morphological Traits in Chickpea

    PubMed Central

    Saxena, Maneesha S.; Bajaj, Deepak; Das, Shouvik; Kujur, Alice; Kumar, Vinod; Singh, Mohar; Bansal, Kailash C.; Tyagi, Akhilesh K.; Parida, Swarup K.

    2014-01-01

    The identification and fine mapping of robust quantitative trait loci (QTLs)/genes governing important agro-morphological traits in chickpea still lacks systematic efforts at a genome-wide scale involving wild Cicer accessions. In this context, an 834 simple sequence repeat and single-nucleotide polymorphism marker-based high-density genetic linkage map between cultivated and wild parental accessions (Cicer arietinum desi cv. ICC 4958 and Cicer reticulatum wild cv. ICC 17160) was constructed. This inter-specific genetic map comprising eight linkage groups spanned a map length of 949.4 cM with an average inter-marker distance of 1.14 cM. Eleven novel major genomic regions harbouring 15 robust QTLs (15.6–39.8% R2 at 4.2–15.7 logarithm of odds) associated with four agro-morphological traits (100-seed weight, pod and branch number/plant and plant hairiness) were identified and mapped on chickpea chromosomes. Most of these QTLs showed positive additive gene effects with effective allelic contribution from ICC 4958, particularly for increasing seed weight (SW) and pod and branch number. One robust SW-influencing major QTL region (qSW4.2) has been narrowed down by combining QTL mapping with high-resolution QTL region-specific association analysis, differential expression profiling and gene haplotype-based association/LD mapping. This enabled to delineate a strong SW-regulating ABI3VP1 transcription factor (TF) gene at trait-specific QTL interval and consequently identified favourable natural allelic variants and superior high seed weight-specific haplotypes in the upstream regulatory region of this gene showing increased transcript expression during seed development. The genes (TFs) harbouring diverse trait-regulating QTLs, once validated and fine-mapped by our developed rapid integrated genomic approach and through gene/QTL map-based cloning, can be utilized as potential candidates for marker-assisted genetic enhancement of chickpea. PMID:25335477

  11. In Silico Identification and Comparative Genomics of Candidate Genes Involved in Biosynthesis and Accumulation of Seed Oil in Plants

    PubMed Central

    Sharma, Arti; Chauhan, Rajinder Singh

    2012-01-01

    Genes involved in fatty acids biosynthesis, modification and oil body formation are expected to be conserved in structure and function in different plant species. However, significant differences in the composition of fatty acids and total oil contents in seeds have been observed in different plant species. Comparative genomics was performed on 261 genes involved in fatty acids biosynthesis, TAG synthesis, and oil bodies formation in Arabidopsis, Brassica rapa, castor bean and soybean. In silico expression analysis revealed that stearoyl desaturase, FatB, FAD2, oleosin and DGAT are highly abundant in seeds, thereby considered as ideal candidates for mining of favorable alleles in natural population. Gene structure analysis for major genes, ACCase, FatA, FatB, FAD2, FAD3 and DGAT, which are known to play crucial role in oil synthesis revealed that there are uncommon variations (SNPs and INDELs) which lead to varying content and composition of fatty acids in seed oil. The predicted variations can provide good targets for seed oil QTL identification, understanding the molecular mechanism of seed oil accumulation, and genetic modification to enhance seed oil yield in plants. PMID:22312320

  12. In silico identification and comparative genomics of candidate genes involved in biosynthesis and accumulation of seed oil in plants.

    PubMed

    Sharma, Arti; Chauhan, Rajinder Singh

    2012-01-01

    Genes involved in fatty acids biosynthesis, modification and oil body formation are expected to be conserved in structure and function in different plant species. However, significant differences in the composition of fatty acids and total oil contents in seeds have been observed in different plant species. Comparative genomics was performed on 261 genes involved in fatty acids biosynthesis, TAG synthesis, and oil bodies formation in Arabidopsis, Brassica rapa, castor bean and soybean. In silico expression analysis revealed that stearoyl desaturase, FatB, FAD2, oleosin and DGAT are highly abundant in seeds, thereby considered as ideal candidates for mining of favorable alleles in natural population. Gene structure analysis for major genes, ACCase, FatA, FatB, FAD2, FAD3 and DGAT, which are known to play crucial role in oil synthesis revealed that there are uncommon variations (SNPs and INDELs) which lead to varying content and composition of fatty acids in seed oil. The predicted variations can provide good targets for seed oil QTL identification, understanding the molecular mechanism of seed oil accumulation, and genetic modification to enhance seed oil yield in plants. PMID:22312320

  13. Acid-sensing ion channel (ASIC) 4 gene: physical mapping, genomic organisation, and evaluation as a candidate for paroxysmal dystonia.

    PubMed

    Gründer, S; Geisler, H S; Rainier, S; Fink, J K

    2001-09-01

    Acid-sensing ion channels (ASICs) are protongated Na(+) channels. They have been implicated with synaptic transmission, pain perception as well as mechanoperception. ASIC4 is the most recent member of this gene family. It shows expression throughout the central nervous system with strongest expression in pituitary gland. ASIC4 is inactive by itself and its function is unknown. Mutations in ion channel subunits, which are homologues of ASICs lead to neurodegeneration in Caenorhabditis elegans. It has, therefore, been speculated that similar mutations in ASICs may be responsible for neurodegeneration in humans. Here, we show that ASIC4 maps to the long arm of chromosome 2 in close proximity to the locus for paroxysmal dystonic choreoathetosis (PDC), a movement disorder with unknown cause. Ion channel genes have been shown to cause several other paroxysmal neurologic disorders and are important candidate genes for PDC. We established the genomic organisation of the ASIC4 gene and screened a PDC pedigree for mutations in the coding region. Although we identified three polymorphisms in the Cterminal part of the ASIC4 protein, these were not present in each affected subject in the PDC kindred we analysed. Therefore, although the ASIC4 gene is physically mapped to the PDC locus, our data indicates that ASIC4 gene mutation is not the cause of PDC. It remains to be established if mutations in ASIC4 or other ASIC subunits may cause neurological disorders. PMID:11571555

  14. Replication of the results of genome-wide and candidate gene association studies on telomere length in a Korean population

    PubMed Central

    Do, Sook Kyung; Yoo, Seung Soo; Choi, Yi Young; Choi, Jin Eun; Jeon, Hyo-Sung; Lee, Won Kee; Lee, Shin Yup; Lee, Jaehee; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2015-01-01

    Background/Aims: A number of genome-wide and candidate gene association studies have identified polymorphisms associated with telomere length in Caucasian populations. This study was conducted to determine the impacts of 17 polymorphisms identified in Caucasians on telomere length in a Korean population. Methods: Ninety-four healthy individuals were enrolled in this study. Relative telomere length of chromosomes from peripheral blood samples was measured using quantitative polymerase chain reaction. Results: Two polymorphisms, rs10936599 of MYNN and rs412658 of ZNF676, were found to be associated w ith telomere length (under dominant model, p = 0.04; under recessive model, p = 0.001). Three polymorphisms, rs2853669, rs7705526, and rs2736108, at the TERT locus were also associated with telomere length (under recessive model, p = 0.01, p = 0.02, and p = 0.01, respectively). The genotypes of the five polymorphisms associated with short telomere length were considered bad genotypes; telomere length was significantly decreased with increasing number of bad genotypes (p= 1.7 × 10–5). Conclusions: We have identified polymorphisms associated with telomere length in a Korean population. PMID:26354067

  15. Comparative Genomics Uncovers Unique Gene Turnover and Evolutionary Rates in a Gene Family Involved in the Detection of Insect Cuticular Pheromones

    PubMed Central

    Torres-Oliva, Montserrat; Almeida, Francisca C.; Sánchez-Gracia, Alejandro; Rozas, Julio

    2016-01-01

    Chemoreception is an essential process for the survival and reproduction of animals. Many of the proteins responsible for recognizing and transmitting chemical stimuli in insects are encoded by genes that are members of moderately sized multigene families. The members of the CheB family are specialized in gustatory-mediated detection of long-chain hydrocarbon pheromones in Drosophila melanogaster and play a central role in triggering and modulating mating behavior in this species. Here, we present a comprehensive comparative genomic analysis of the CheB family across 12 species of the Drosophila genus. We have identified a total of 102 new CheB genes in the genomes of these species, including a functionally divergent member previously uncharacterized in D. melanogaster. We found that, despite its relatively small repertory size, the CheB family has undergone multiple gain and loss events and various episodes of diversifying selection during the divergence of the surveyed species. Present estimates of gene turnover and coding sequence substitution rates show that this family is evolving faster than any known Drosophila chemosensory family. To date, only other insect gustatory-related genes among these families had shown evolutionary dynamics close to those observed in CheBs. Our findings reveal the high adaptive potential of molecular components of the gustatory system in insects and anticipate a key role of genes involved in this sensory modality in species adaptation and diversification.

  16. Genomic and phenotypic analyses of Carnobacterium jeotgali strain MS3(T), a lactate-producing candidate biopreservative bacterium isolated from salt-fermented shrimp.

    PubMed

    Whon, Tae Woong; Hyun, Dong-Wook; Nam, Young-Do; Kim, Min-Soo; Song, Eun-Ji; Jang, Yu Kyung; Jung, Eun Sung; Shin, Na-Ri; Oh, Sei Joon; Kim, Pil Soo; Kim, Hyun Sik; Lee, Choong Hwan; Bae, Jin-Woo

    2015-05-01

    Carnobacterium jeotgali strain MS3(T) was isolated from traditionally fermented Korean shrimp produced with bay salt. The bacterium belongs to the family Carnobacteriaceae, produces lactic acid and contains gene clusters involved in the production of lactate, butyrate, aromatic compounds and exopolysaccharides. Carnobacterium jeotgali strain MS3(T) was characterized through extensive comparison of the virulence potential, genomic relatedness and sequence similarities of its genome with the genomes of other Carnobacteria and lactic acid bacteria. In addition, links between predicted functions of genes and phenotypic characteristics, such as antibiotic resistance and lactate and butyrate production, were extensively evaluated. Genomic and phenotypic analyses of strain MS3(T) revealed promising features, including minimal virulence genes and lactate production, which make this bacterium a desirable candidate for exploitation by the fermented food industry. PMID:25868912

  17. Comparative genomic analysis of Brucella abortus vaccine strain 104M reveals a set of candidate genes associated with its virulence attenuation

    PubMed Central

    Yu, Dong; Hui, Yiming; Zai, Xiaodong; Xu, Junjie; Liang, Long; Wang, Bingxiang; Yue, Junjie; Li, Shanhu

    2015-01-01

    The Brucella abortus strain 104M, a spontaneously attenuated strain, has been used as a vaccine strain in humans against brucellosis for 6 decades in China. Despite many studies, the molecular mechanisms that cause the attenuation are still unclear. Here, we determined the whole-genome sequence of 104M and conducted a comprehensive comparative analysis against the whole genome sequences of the virulent strain, A13334, and other reference strains. This analysis revealed a highly similar genome structure between 104M and A13334. The further comparative genomic analysis between 104M and A13334 revealed a set of genes missing in 104M. Some of these genes were identified to be directly or indirectly associated with virulence. Similarly, a set of mutations in the virulence-related genes was also identified, which may be related to virulence alteration. This study provides a set of candidate genes associated with virulence attenuation in B.abortus vaccine strain 104M. PMID:26039674

  18. Uncovering the Math Curriculum

    ERIC Educational Resources Information Center

    Burns, Marilyn

    2014-01-01

    Teachers often express to Marulyn Burns their worry about the need to "cover the curriculum." In response, she draws on one of her favorite quotes: "You don't want to cover a subject; you want to uncover it." This quote is from "The Having of Wonderful Ideas and Other Essays on Teaching and Learning" by Eleanor…

  19. Partial Genome Assembly for a Candidate Division OP11 Single Cell from an Anoxic Spring (Zodletone Spring, Oklahoma)▿†

    PubMed Central

    Youssef, Noha H.; Blainey, Paul C.; Quake, Stephen R.; Elshahed, Mostafa S.

    2011-01-01

    Members of candidate division OP11 are widely distributed in terrestrial and marine ecosystems, yet little information regarding their metabolic capabilities and ecological role within such habitats is currently available. Here, we report on the microfluidic isolation, multiple-displacement-amplification, pyrosequencing, and genomic analysis of a single cell (ZG1) belonging to candidate division OP11. Genome analysis of the ∼270-kb partial genome assembly obtained showed that it had no particular similarity to a specific phylum. Four hundred twenty-three open reading frames were identified, 46% of which had no function prediction. In-depth analysis revealed a heterotrophic lifestyle, with genes encoding endoglucanase, amylopullulanase, and laccase enzymes, suggesting a capacity for utilization of cellulose, starch, and, potentially, lignin, respectively. Genes encoding several glycolysis enzymes as well as formate utilization were identified, but no evidence for an electron transport chain was found. The presence of genes encoding various components of lipopolysaccharide biosynthesis indicates a Gram-negative bacterial cell wall. The partial genome also provides evidence for antibiotic resistance (β-lactamase, aminoglycoside phosphotransferase), as well as antibiotic production (bacteriocin) and extracellular bactericidal peptidases. Multiple mechanisms for stress response were identified, as were elements of type I and type IV secretion systems. Finally, housekeeping genes identified within the partial genome were used to demonstrate the OP11 affiliation of multiple hitherto unclassified genomic fragments from multiple database-deposited metagenomic data sets. These results provide the first glimpse into the lifestyle of a member of a ubiquitous, yet poorly understood bacterial candidate division. PMID:21908640

  20. Evolution of Ancient Functions in the Vertebrate Insulin-Like Growth Factor System Uncovered by Study of Duplicated Salmonid Fish Genomes

    PubMed Central

    Macqueen, Daniel J.; Garcia de la serrana, Daniel; Johnston, Ian A.

    2013-01-01

    Whole-genome duplication (WGD) was experienced twice by the vertebrate ancestor (2 rounds; 2R), again by the teleost fish ancestor (3R) and most recently in certain teleost lineages (4R). Consequently, vertebrate gene families are often expanded in 3R and 4R genomes. Arguably, many types of “functional divergence” present across 2R gene families will exceed that between 3R/4R paralogs of genes comprising 2R families. Accordingly, 4R offers a form of replication of 2R. Examining whether this concept has implications for molecular evolutionary research, we studied insulin-like growth factor (IGF) binding proteins (IGFBPs), whose six 2R family members carry IGF hormones and regulate interactions between IGFs and IGF1-receptors (IGF1Rs). Using phylogenomic approaches, we resolved the complete IGFBP repertoire of 4R-derived salmonid fishes (19 genes; 13 more than human) and established evolutionary relationships/nomenclature with respect to WGDs. Traits central to IGFBP action were determined for all genes, including atomic interactions in IGFBP–IGF1/IGF2 complexes regulating IGF–IGF1R binding. Using statistical methods, we demonstrate that attributes of these protein interfaces are overwhelming a product of 2R IGFBP family membership, explain 49–68% of variation in IGFBP mRNA concentration in several different tissues, and strongly predict the strength and direction of IGFBP transcriptional regulation under differing nutritional states. The results support a model where vertebrate IGFBP family members evolved divergent structural attributes to provide distinct competition for IGFs with IGF1Rs, predisposing different functions in the regulation of IGF signaling. Evolution of gene expression then acted to ensure the appropriate physiological production of IGFBPs according to their structural specializations, leading to optimal IGF-signaling according to nutritional-status and the endocrine/local mode of action. This study demonstrates that relatively recent

  1. ISSR-PCR DNA fingerprinting uncovers distinct banding patterns in Gonatocerus species 3(G.sp.3) individuals emerging from different host tribes: A prospective egg parasitoid candidate agent for the glassy-winged sharpshooter.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We started work to genetically characterize a prospective glassy-winged sharsphooter (GWSS), Homalodisca vitripennis (Germar) [=H. coagulata (Say)] egg parasitoid biological control candidate agent from South America known as Gonatocerus species 3 (G. sp. 3). This species is morphologically very si...

  2. A genetic predictive model for canine hip dysplasia: integration of Genome Wide Association Study (GWAS) and candidate gene approaches.

    PubMed

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors' opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds. PMID:25874693

  3. A Genetic Predictive Model for Canine Hip Dysplasia: Integration of Genome Wide Association Study (GWAS) and Candidate Gene Approaches

    PubMed Central

    Bartolomé, Nerea; Segarra, Sergi; Artieda, Marta; Francino, Olga; Sánchez, Elisenda; Szczypiorska, Magdalena; Casellas, Joaquim; Tejedor, Diego; Cerdeira, Joaquín; Martínez, Antonio; Velasco, Alfonso; Sánchez, Armand

    2015-01-01

    Canine hip dysplasia is one of the most prevalent developmental orthopedic diseases in dogs worldwide. Unfortunately, the success of eradication programs against this disease based on radiographic diagnosis is low. Adding the use of diagnostic genetic tools to the current phenotype-based approach might be beneficial. The aim of this study was to develop a genetic prognostic test for early diagnosis of hip dysplasia in Labrador Retrievers. To develop our DNA test, 775 Labrador Retrievers were recruited. For each dog, a blood sample and a ventrodorsal hip radiograph were taken. Dogs were divided into two groups according to their FCI hip score: control (A/B) and case (D/E). C dogs were not included in the sample. Genetic characterization combining a GWAS and a candidate gene strategy using SNPs allowed a case-control population association study. A mathematical model which included 7 SNPs was developed using logistic regression. The model showed a good accuracy (Area under the ROC curve = 0.85) and was validated in an independent population of 114 dogs. This prognostic genetic test represents a useful tool for choosing the most appropriate therapeutic approach once genetic predisposition to hip dysplasia is known. Therefore, it allows a more individualized management of the disease. It is also applicable during genetic selection processes, since breeders can benefit from the information given by this test as soon as a blood sample can be collected, and act accordingly. In the authors’ opinion, a shift towards genomic screening might importantly contribute to reducing canine hip dysplasia in the future. In conclusion, based on genetic and radiographic information from Labrador Retrievers with hip dysplasia, we developed an accurate predictive genetic test for early diagnosis of hip dysplasia in Labrador Retrievers. However, further research is warranted in order to evaluate the validity of this genetic test in other dog breeds. PMID:25874693

  4. Genome-wide analysis uncovers high frequency, strong differential chromosomal interactions and their associated epigenetic patterns in E2-mediated gene regulation

    PubMed Central

    2013-01-01

    Background An emerging Hi-C protocol has the ability to probe three-dimensional (3D) architecture and capture chromatin interactions in a genome-wide scale. It provides informative results to address how chromatin organization changes contribute to disease/tumor occurrence and progression in response to stimulation of environmental chemicals or hormones. Results In this study, using MCF7 cells as a model system, we found estrogen stimulation significantly impact chromatin interactions, leading to alteration of gene regulation and the associated histone modification states. Many chromosomal interaction regions at different levels of interaction frequency were identified. In particular, the top 10 hot regions with the highest interaction frequency are enriched with breast cancer specific genes. Furthermore, four types of E2-mediated strong differential (gain- or loss-) chromosomal (intra- or inter-) interactions were classified, in which the number of gain-chromosomal interactions is less than the number of loss-chromosomal interactions upon E2 stimulation. Finally, by integrating with eight histone modification marks, DNA methylation, regulatory elements regions, ERα and Pol-II binding activities, associations between epigenetic patterns and high chromosomal interaction frequency were revealed in E2-mediated gene regulation. Conclusions The work provides insight into the effect of chromatin interaction on E2/ERα regulated downstream genes in breast cancer cells. PMID:23368971

  5. Genome-Resolved Metagenomic Analysis Reveals Roles for Candidate Phyla and Other Microbial Community Members in Biogeochemical Transformations in Oil Reservoirs

    PubMed Central

    Hu, Ping; Tom, Lauren; Singh, Andrea; Thomas, Brian C.; Baker, Brett J.; Piceno, Yvette M.; Andersen, Gary L.

    2016-01-01

    ABSTRACT Oil reservoirs are major sites of methane production and carbon turnover, processes with significant impacts on energy resources and global biogeochemical cycles. We applied a cultivation-independent genomic approach to define microbial community membership and predict roles for specific organisms in biogeochemical transformations in Alaska North Slope oil fields. Produced water samples were collected from six locations between 1,128 m (24 to 27°C) and 2,743 m (80 to 83°C) below the surface. Microbial community complexity decreased with increasing temperature, and the potential to degrade hydrocarbon compounds was most prevalent in the lower-temperature reservoirs. Sulfate availability, rather than sulfate reduction potential, seems to be the limiting factor for sulfide production in some of the reservoirs under investigation. Most microorganisms in the intermediate- and higher-temperature samples were related to previously studied methanogenic and nonmethanogenic archaea and thermophilic bacteria, but one candidate phylum bacterium, a member of the Acetothermia (OP1), was present in Kuparuk sample K3. The greatest numbers of candidate phyla were recovered from the mesothermic reservoir samples SB1 and SB2. We reconstructed a nearly complete genome for an organism from the candidate phylum Parcubacteria (OD1) that was abundant in sample SB1. Consistent with prior findings for members of this lineage, the OD1 genome is small, and metabolic predictions support an obligately anaerobic, fermentation-based lifestyle. At moderate abundance in samples SB1 and SB2 were members of bacteria from other candidate phyla, including Microgenomates (OP11), Atribacteria (OP9), candidate phyla TA06 and WS6, and Marinimicrobia (SAR406). The results presented here elucidate potential roles of organisms in oil reservoir biological processes. PMID:26787827

  6. Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of Their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy.

    PubMed

    Mohamed, Junaith S; Hajira, Ameena; Lopez, Michael A; Boriek, Aladin M

    2015-10-01

    Muscular dystrophies (MDs) are a heterogeneous group of genetic and neuromuscular disorders, which result in severe loss of motor ability and skeletal muscle mass and function. Aberrant mechanotransduction and dysregulated-microRNA pathways are often associated with the progression of MD. Here, we hypothesized that dysregulation of mechanosensitive microRNAs (mechanomiRs) in dystrophic skeletal muscle plays a major role in the progression of MD. To test our hypothesis, we performed a genome-wide expression profile of anisotropically regulated mechanomiRs and bioinformatically analyzed their target gene networks. We assessed their functional roles in the advancement of MD using diaphragm muscles from mdm (MD with myositis) mice, an animal model of human tibial MD (titinopathy), and their wild-type littermates. We were able to show that ex vivo anisotropic mechanical stretch significantly alters the miRNA expression profile in diaphragm muscles from WT and mdm mice; as a result, some of the genes associated with MDs are dysregulated in mdm mice due to differential regulation of a distinct set of mechanomiRs. Interestingly, we found a contrasting expression pattern of the highly expressed let-7 family mechanomiRs, let-7e-5p and miR-98-5p, and their target genes associated with the extracellular matrix and TGF-β pathways, respectively, between WT and mdm mice. Gain- and loss-of-function analysis of let-7e-5p in myocytes isolated from the diaphragms of WT and mdm mice confirmed Col1a1, Col1a2, Col3a1, Col24a1, Col27a1, Itga1, Itga4, Scd1, and Thbs1 as target genes of let-7e-5p. Furthermore, we found that miR-98 negatively regulates myoblast differentiation. Our study therefore introduces additional biological players in the regulation of skeletal muscle structure and myogenesis that may contribute to unexplained disorders of MD. PMID:26272747

  7. Blood-based gene expression signatures of medication-free outpatients with major depressive disorder: integrative genome-wide and candidate gene analyses

    PubMed Central

    Hori, Hiroaki; Sasayama, Daimei; Teraishi, Toshiya; Yamamoto, Noriko; Nakamura, Seiji; Ota, Miho; Hattori, Kotaro; Kim, Yoshiharu; Higuchi, Teruhiko; Kunugi, Hiroshi

    2016-01-01

    Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the “synaptic transmission” pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research. PMID:26728011

  8. Genome-Resolved Metagenomic Analysis Reveals Roles for Candidate Phyla and Other Microbial Community Members in Biogeochemical Transformations in Oil Reservoirs

    DOE PAGESBeta

    Hu, Ping; Tom, Lauren; Singh, Andrea; Thomas, Brian C.; Baker, Brett J.; Piceno, Yvette M.; Andersen, Gary L.; Banfield, Jillian F.

    2016-01-19

    Oil reservoirs are major sites of methane production and carbon turnover, processes with significant impacts on energy resources and global biogeochemical cycles. We applied a cultivation-independent genomic approach to define microbial community membership and predict roles for specific organisms in biogeochemical transformations in Alaska North Slope oil fields. Produced water samples were collected from six locations between 1,128 m (24 to 27°C) and 2,743 m (80 to 83°C) below the surface. Microbial community complexity decreased with increasing temperature, and the potential to degrade hydrocarbon compounds was most prevalent in the lower-temperature reservoirs. Sulfate availability, rather than sulfate reduction potential, seems to bemore » the limiting factor for sulfide production in some of the reservoirs under investigation. Most microorganisms in the intermediate- and higher-temperature samples were related to previously studied methanogenic and nonmethanogenic archaea and thermophilic bacteria, but one candidate phylum bacterium, a member of theAcetothermia(OP1), was present in Kuparuk sample K3. The greatest numbers of candidate phyla were recovered from the mesothermic reservoir samples SB1 and SB2. We reconstructed a nearly complete genome for an organism from the candidate phylumParcubacteria(OD1) that was abundant in sample SB1. Consistent with prior findings for members of this lineage, the OD1 genome is small, and metabolic predictions support an obligately anaerobic, fermentation-based lifestyle. At moderate abundance in samples SB1 and SB2 were members of bacteria from other candidate phyla, includingMicrogenomates(OP11),Atribacteria(OP9), candidate phyla TA06 and WS6, andMarinimicrobia(SAR406). The results presented here elucidate potential roles of organisms in oil reservoir biological processes. The activities of microorganisms in oil reservoirs impact petroleum resource quality and the global carbon cycle. In conclusion, we show that

  9. Genome-wide association mapping and identification of candidate genes for the rumpless and ear-tufted traits of the Araucana chicken.

    PubMed

    Noorai, Rooksana E; Freese, Nowlan H; Wright, Lindsay M; Chapman, Susan C; Clark, Leigh Anne

    2012-01-01

    Araucana chickens are known for their rounded, tailless rumps and tufted ears. Inheritance studies have shown that the rumpless (Rp) and ear-tufted (Et) loci each act in an autosomal dominant fashion, segregate independently, and are associated with an increased rate of embryonic mortality. To find genomic regions associated with Rp and Et, we generated genome-wide SNP profiles for a diverse population of 60 Araucana chickens using the 60 K chicken SNP BeadChip. Genome-wide association studies using 40 rumpless and 11 tailed birds showed a strong association with rumpless on Gga 2 (P(raw) = 2.45×10(-10), P(genome) = 0.00575), and analysis of genotypes revealed a 2.14 Mb haplotype shared by all rumpless birds. Within this haplotype, a 0.74 Mb critical interval containing two Iroquois homeobox genes, Irx1 and Irx2, was unique to rumpless Araucana chickens. Irx1 and Irx2 are central for developmental prepatterning, but neither gene is known to have a role in mechanisms leading to caudal development. A second genome-wide association analysis using 30 ear-tufted and 28 non-tufted birds revealed an association with tufted on Gga 15 (P(raw) = 6.61×10(-7), P(genome) = 0.0981). We identified a 0.58 Mb haplotype common to tufted birds and harboring 7 genes. Because homozygosity for Et is nearly 100% lethal, we employed a heterozygosity mapping approach to prioritize candidate gene selection. A 60 kb region heterozygous in all Araucana chickens contains the complete coding sequence for TBX1 and partial sequence for GNB1L. TBX1 is an important transcriptional regulator of embryonic development and a key genetic determinant of human DiGeorge syndrome. Herein, we describe localization of Rp and Et and identification of positional candidate genes. PMID:22844420

  10. Integrative Genomic and Transcriptomic Analysis Identified Candidate Genes Implicated in the Pathogenesis of Hepatosplenic T-Cell Lymphoma

    PubMed Central

    Finalet Ferreiro, Julio; Rouhigharabaei, Leila; Urbankova, Helena; van der Krogt, Jo-Anne; Michaux, Lucienne; Shetty, Shashirekha; Krenacs, Laszlo; Tousseyn, Thomas; De Paepe, Pascale; Uyttebroeck, Anne; Verhoef, Gregor; Taghon, Tom; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona

    2014-01-01

    Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620–99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes

  11. Physiology and phylogeny of the candidate phylum "Atribacteria" (formerly OP9/JS1) inferred from single-cell genomics and metagenomics

    NASA Astrophysics Data System (ADS)

    Dodsworth, J. A.; Murugapiran, S.; Blainey, P. C.; Nobu, M.; Rinke, C.; Schwientek, P.; Gies, E.; Webster, G.; Kille, P.; Weightman, A.; Liu, W. T.; Hallam, S.; Tsiamis, G.; Swingley, W.; Ross, C.; Tringe, S. G.; Chain, P. S.; Scholz, M. B.; Lo, C. C.; Raymond, J.; Quake, S. R.; Woyke, T.; Hedlund, B. P.

    2014-12-01

    Single-cell sequencing and metagenomics have extended the genomics revolution to yet-uncultivated microorganisms and provided insights into the coding potential of this so-called "microbial dark matter", including microbes belonging candidate phyla with no cultivated representatives. As more datasets emerge, comparison of individual genomes from different lineages and habitats can provide insight into the phylogeny, conserved features, and potential metabolic diversity of candidate phyla. The candidate bacterial phylum OP9 was originally found in Obsidian Pool, Yellowstone National Park, and it has since been detected in geothermal springs, petroleum reservoirs, and engineered thermal environments worldwide. JS1, another uncultivated bacterial lineage affiliated with OP9, is often abundant in marine sediments associated with methane hydrates, hydrocarbon seeps, and on continental margins and shelves, and is found in other non-thermal marine and subsurface environments. The phylogenetic relationship between OP9, JS1, and other Bacteria has not been fully resolved, and to date no axenic cultures from these lineages have been reported. Recently, 31 single amplified genomes (SAGs) from six distinct OP9 and JS1 lineages have been obtained using flow cytometric and microfluidic techniques. These SAGs were used to inform metagenome binning techniques that identified OP9/JS1 sequences in several metagenomes, extending genomic coverage in three of the OP9 and JS1 lineages. Phylogenomic analyses of these SAG and metagenome bin datasets suggest that OP9 and JS1 constitute a single, deeply branching phylum, for which the name "Atribacteria" has recently been proposed. Overall, members of the "Atribacteria" are predicted to be heterotrophic anaerobes without the capacity for respiration, with some lineages potentially specializing in secondary fermentation of organic acids. A set of signature "Atribacteria" genes was tentatively identified, including components of a bacterial

  12. Uncovering Sexual Problems

    PubMed Central

    Cohen, May

    1977-01-01

    While patients frequently make it difficult for us to uncover their sexual concerns, a much greater difficulty is due to physicians' unwillingness to deal with this subject. Physicians need to acquire basic knowledge about human sexuality as well as skills in making patients feel comfortable and open. A non-judgmental attitude is essential. The physician will also be able to anticipate and prevent sexual distress by education. Expertise must be developed in differentiating those problems requiring referral for specialized sexual counselling from those which the family physician can handle. PMID:21304865

  13. Whole-genome sequence analyses of Western Central African Pygmy hunter-gatherers reveal a complex demographic history and identify candidate genes under positive natural selection

    PubMed Central

    Hsieh, PingHsun; Veeramah, Krishna R.; Lachance, Joseph; Tishkoff, Sarah A.; Wall, Jeffrey D.; Hammer, Michael F.; Gutenkunst, Ryan N.

    2016-01-01

    African Pygmies practicing a mobile hunter-gatherer lifestyle are phenotypically and genetically diverged from other anatomically modern humans, and they likely experienced strong selective pressures due to their unique lifestyle in the Central African rainforest. To identify genomic targets of adaptation, we sequenced the genomes of four Biaka Pygmies from the Central African Republic and jointly analyzed these data with the genome sequences of three Baka Pygmies from Cameroon and nine Yoruba famers. To account for the complex demographic history of these populations that includes both isolation and gene flow, we fit models using the joint allele frequency spectrum and validated them using independent approaches. Our two best-fit models both suggest ancient divergence between the ancestors of the farmers and Pygmies, 90,000 or 150,000 yr ago. We also find that bidirectional asymmetric gene flow is statistically better supported than a single pulse of unidirectional gene flow from farmers to Pygmies, as previously suggested. We then applied complementary statistics to scan the genome for evidence of selective sweeps and polygenic selection. We found that conventional statistical outlier approaches were biased toward identifying candidates in regions of high mutation or low recombination rate. To avoid this bias, we assigned P-values for candidates using whole-genome simulations incorporating demography and variation in both recombination and mutation rates. We found that genes and gene sets involved in muscle development, bone synthesis, immunity, reproduction, cell signaling and development, and energy metabolism are likely to be targets of positive natural selection in Western African Pygmies or their recent ancestors. PMID:26888263

  14. Whole-genome sequence analyses of Western Central African Pygmy hunter-gatherers reveal a complex demographic history and identify candidate genes under positive natural selection.

    PubMed

    Hsieh, PingHsun; Veeramah, Krishna R; Lachance, Joseph; Tishkoff, Sarah A; Wall, Jeffrey D; Hammer, Michael F; Gutenkunst, Ryan N

    2016-03-01

    African Pygmies practicing a mobile hunter-gatherer lifestyle are phenotypically and genetically diverged from other anatomically modern humans, and they likely experienced strong selective pressures due to their unique lifestyle in the Central African rainforest. To identify genomic targets of adaptation, we sequenced the genomes of four Biaka Pygmies from the Central African Republic and jointly analyzed these data with the genome sequences of three Baka Pygmies from Cameroon and nine Yoruba famers. To account for the complex demographic history of these populations that includes both isolation and gene flow, we fit models using the joint allele frequency spectrum and validated them using independent approaches. Our two best-fit models both suggest ancient divergence between the ancestors of the farmers and Pygmies, 90,000 or 150,000 yr ago. We also find that bidirectional asymmetric gene flow is statistically better supported than a single pulse of unidirectional gene flow from farmers to Pygmies, as previously suggested. We then applied complementary statistics to scan the genome for evidence of selective sweeps and polygenic selection. We found that conventional statistical outlier approaches were biased toward identifying candidates in regions of high mutation or low recombination rate. To avoid this bias, we assigned P-values for candidates using whole-genome simulations incorporating demography and variation in both recombination and mutation rates. We found that genes and gene sets involved in muscle development, bone synthesis, immunity, reproduction, cell signaling and development, and energy metabolism are likely to be targets of positive natural selection in Western African Pygmies or their recent ancestors. PMID:26888263

  15. A candidate packaging signal of human rotavirus differentiating Wa-like and DS-1-like genomic constellations.

    PubMed

    Suzuki, Yoshiyuki

    2015-09-01

    Rotavirus A (RVA) possesses a genome of 11 segmented RNAs. In human RVA, two major genomic constellations are represented by prototype strains Wa and DS-1. Here packaging signals differentiating Wa-like and DS-1-like genomic constellations were searched for by analyzing genomic sequences of Wa-like and DS-1-like strains. One pair of 11 nucleotide sites in the coding regions of viral structural protein (VP) 2 and VP6 was found to be complementary specifically among Wa-like strains. These sites tended to be free from base-pairing in secondary structures of genomic segments, suggesting that they may serve as a packaging signal in Wa-like strains. PMID:26224654

  16. Genome scans reveal candidate domestication and improvement genes in cultivated sunflower, as well as post-domestication introgression with wild relatives.

    PubMed

    Baute, Gregory J; Kane, Nolan C; Grassa, Christopher J; Lai, Zhao; Rieseberg, Loren H

    2015-04-01

    The development of modern crops typically involves both selection and hybridization, but to date most studies have focused on the former. In the present study, we explore how both processes, and their interactions, have molded the genome of the cultivated sunflower (Helianthus annuus), a globally important oilseed. To identify genes targeted by selection during the domestication and improvement of sunflower, and to detect post-domestication hybridization with wild species, we analyzed transcriptome sequences of 80 genotypes, including wild, landrace, and modern lines of H. annuus, as well as two cross-compatible wild relatives, Helianthus argophyllus and Helianthus petiolaris. Outlier analyses identified 122 and 15 candidate genes associated with domestication and improvement, respectively. As in several previous studies, genes putatively involved in oil biosynthesis were the most extreme outliers. Additionally, several promising associations were observed with previously mapped quantitative trait loci (QTLs), such as branching. Admixture analyses revealed that all the modern cultivar genomes we examined contained one or more introgressions from wild populations, with every chromosome having evidence of introgression in at least one modern line. Cumulatively, introgressions cover c. 10% of the cultivated sunflower genome. Surprisingly, introgressions do not avoid candidate domestication genes, probably because of the reintroduction of branching. PMID:25641359

  17. Huvariome: a web server resource of whole genome next-generation sequencing allelic frequencies to aid in pathological candidate gene selection

    PubMed Central

    2012-01-01

    Background Next generation sequencing provides clinical research scientists with direct read out of innumerable variants, including personal, pathological and common benign variants. The aim of resequencing studies is to determine the candidate pathogenic variants from individual genomes, or from family-based or tumor/normal genome comparisons. Whilst the use of appropriate controls within the experimental design will minimize the number of false positive variations selected, this number can be reduced further with the use of high quality whole genome reference data to minimize false positives variants prior to candidate gene selection. In addition the use of platform related sequencing error models can help in the recovery of ambiguous genotypes from lower coverage data. Description We have developed a whole genome database of human genetic variations, Huvariome, determined by whole genome deep sequencing data with high coverage and low error rates. The database was designed to be sequencing technology independent but is currently populated with 165 individual whole genomes consisting of small pedigrees and matched tumor/normal samples sequenced with the Complete Genomics sequencing platform. Common variants have been determined for a Benelux population cohort and represented as genotypes alongside the results of two sets of control data (73 of the 165 genomes), Huvariome Core which comprises 31 healthy individuals from the Benelux region, and Diversity Panel consisting of 46 healthy individuals representing 10 different populations and 21 samples in three Pedigrees. Users can query the database by gene or position via a web interface and the results are displayed as the frequency of the variations as detected in the datasets. We demonstrate that Huvariome can provide accurate reference allele frequencies to disambiguate sequencing inconsistencies produced in resequencing experiments. Huvariome has been used to support the selection of candidate cardiomyopathy

  18. Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin

    PubMed Central

    XU, Min-Juan; WANG, Jia-Hua; BU, Xu-Liang; YU, He-Lin; LI, Peng; OU, Hong-Yu; HE, Ying; XU, Fang-Di; HU, Xiao-Yan; Zhu, Xiao-Mei; AO, Ping; Xu, Jun

    2016-01-01

    Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites. PMID:26744183

  19. Deciphering the streamlined genome of Streptomyces xiamenensis 318 as the producer of the anti-fibrotic drug candidate xiamenmycin.

    PubMed

    Xu, Min-Juan; Wang, Jia-Hua; Bu, Xu-Liang; Yu, He-Lin; Li, Peng; Ou, Hong-Yu; He, Ying; Xu, Fang-Di; Hu, Xiao-Yan; Zhu, Xiao-Mei; Ao, Ping; Xu, Jun

    2016-01-01

    Streptomyces xiamenensis 318, a moderate halophile isolated from a mangrove sediment, produces the anti-fibrotic compound xiamenmycin. The whole genome sequence of strain 318 was obtained through long-read single-molecule real-time (SMRT) sequencing, high-throughput Illumina HiSeq and 454 pyrosequencing technologies. The assembled genome comprises a linear chromosome as a single contig of 5,961,401-bp, which is considerably smaller than other reported complete genomes of the genus Streptomyces. Based on the antiSMASH pipeline, a total of 21 gene clusters were predicted to be involved in secondary metabolism. The gene cluster responsible for the biosynthesis of xiamenmycin resides in a strain-specific 61,387-bp genomic island belonging to the left-arm region. A core metabolic network consisting of 104 reactions that supports xiamenmycin biosynthesis was constructed to illustrate the necessary precursors derived from the central metabolic pathway. In accordance with the finding of a putative ikarugamycin gene cluster in the genome, the targeted chemical profiling of polycyclic tetramate macrolactams (PTMs) resulted in the identification of ikarugamycin. A successful genome mining for bioactive molecules with different skeletons suggests that the naturally minimized genome of S. xiamenensis 318 could be used as a blueprint for constructing a chassis cell with versatile biosynthetic capabilities for the production of secondary metabolites. PMID:26744183

  20. Report from the Maryland epidemiology schizophrenia linkage study: No evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model

    SciTech Connect

    Karayiorgou, M.; Hwang, J.; Elango, R.

    1994-12-15

    Our collaborative group has undertaken a linkage study of schizophrenia, using a systematic sample of patients admitted to Maryland hospitals. An initial sample of 39 families, each having two or more affecteds, was available for genotyping candidate genes, candidate regions, and highly polymorphic markers randomly distributed throughout the genome. We used a single complex dominant model (with a disease gene frequency of 0.005 and age-dependent penetrance for affected phenotype: for under 35, penetrance = .45; for 35 and older, penetrance = .85). We report here 130 markers which met the exclusion criteria of LOD score < -2.00 at theta > 0.01 in at least 10 informative families, and no evidence for heterogeneity. We also report here markers that were tested as candidates for linkage to the schizophrenic phenotype. They were selected based on the following criteria: (a) proximity to reported chromosomal rearrangements (both 5q and 11q), (b) suggestions of linkage from other families (5q), or (c) presence of a candidate gene (5q, 11q, 3q: dopamine receptors 1, 2, and 3, respectively). We also tested for mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene and were unable to detect the C to T substitution in our schizophrenic group. 48 refs., 2 tabs.

  1. Genome-Wide Association Study Identifies Loci and Candidate Genes for Body Composition and Meat Quality Traits in Beijing-You Chickens

    PubMed Central

    Zhao, Guiping; Wang, Fangjie; Wu, Dan; Zheng, Maiqing; Chen, Jilan; Zhang, Lei; Hu, Yaodong; Wen, Jie

    2013-01-01

    Body composition and meat quality traits are important economic traits of chickens. The development of high-throughput genotyping platforms and relevant statistical methods have enabled genome-wide association studies in chickens. In order to identify molecular markers and candidate genes associated with body composition and meat quality traits, genome-wide association studies were conducted using the Illumina 60 K SNP Beadchip to genotype 724 Beijing-You chickens. For each bird, a total of 16 traits were measured, including carcass weight (CW), eviscerated weight (EW), dressing percentage, breast muscle weight (BrW) and percentage (BrP), thigh muscle weight and percentage, abdominal fat weight and percentage, dry matter and intramuscular fat contents of breast and thigh muscle, ultimate pH, and shear force of the pectoralis major muscle at 100 d of age. The SNPs that were significantly associated with the phenotypic traits were identified using both simple (GLM) and compressed mixed linear (MLM) models. For nine of ten body composition traits studied, SNPs showing genome wide significance (P<2.59E−6) have been identified. A consistent region on chicken (Gallus gallus) chromosome 4 (GGA4), including seven significant SNPs and four candidate genes (LCORL, LAP3, LDB2, TAPT1), were found to be associated with CW and EW. Another 0.65 Mb region on GGA3 for BrW and BrP was identified. After measuring the mRNA content in beast muscle for five genes located in this region, the changes in GJA1 expression were found to be consistent with that of breast muscle weight across development. It is highly possible that GJA1 is a functional gene for breast muscle development in chickens. For meat quality traits, several SNPs reaching suggestive association were identified and possible candidate genes with their functions were discussed. PMID:23637794

  2. Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses.

    PubMed

    Karube, Kennosuke; Nakagawa, Masao; Tsuzuki, Shinobu; Takeuchi, Ichiro; Honma, Keiichiro; Nakashima, Yasuhiro; Shimizu, Norio; Ko, Young-Hyeh; Morishima, Yasuo; Ohshima, Koichi; Nakamura, Shigeo; Seto, Masao

    2011-09-22

    Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK)-cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligo-array CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms. PMID:21690554

  3. Comparative genomics of Australian isolates of the wheat stem rust pathogen Puccinia graminis f. sp. tritici reveals extensive polymorphism in candidate effector genes.

    PubMed

    Upadhyaya, Narayana M; Garnica, Diana P; Karaoglu, Haydar; Sperschneider, Jana; Nemri, Adnane; Xu, Bo; Mago, Rohit; Cuomo, Christina A; Rathjen, John P; Park, Robert F; Ellis, Jeffrey G; Dodds, Peter N

    2014-01-01

    The wheat stem rust fungus Puccinia graminis f. sp. tritici (Pgt) is one of the most destructive pathogens of wheat. In this study, a draft genome was built for a founder Australian Pgt isolate of pathotype (pt.) 21-0 (collected in 1954) by next generation DNA sequencing. A combination of reference-based assembly using the genome of the previously sequenced American Pgt isolate CDL 75-36-700-3 (p7a) and de novo assembly were performed resulting in a 92 Mbp reference genome for Pgt isolate 21-0. Approximately 13 Mbp of de novo assembled sequence in this genome is not present in the p7a reference assembly. This novel sequence is not specific to 21-0 as it is also present in three other Pgt rust isolates of independent origin. The new reference genome was subsequently used to build a pan-genome based on five Australian Pgt isolates. Transcriptomes from germinated urediniospores and haustoria were separately assembled for pt. 21-0 and comparison of gene expression profiles showed differential expression in ∼10% of the genes each in germinated spores and haustoria. A total of 1,924 secreted proteins were predicted from the 21-0 transcriptome, of which 520 were classified as haustorial secreted proteins (HSPs). Comparison of 21-0 with two presumed clonal field derivatives of this lineage (collected in 1982 and 1984) that had evolved virulence on four additional resistance genes (Sr5, Sr11, Sr27, SrSatu) identified mutations in 25 HSP effector candidates. Some of these mutations could explain their novel virulence phenotypes. PMID:25620970

  4. Comparative genomics of Australian isolates of the wheat stem rust pathogen Puccinia graminis f. sp. tritici reveals extensive polymorphism in candidate effector genes

    PubMed Central

    Upadhyaya, Narayana M.; Garnica, Diana P.; Karaoglu, Haydar; Sperschneider, Jana; Nemri, Adnane; Xu, Bo; Mago, Rohit; Cuomo, Christina A.; Rathjen, John P.; Park, Robert F.; Ellis, Jeffrey G.; Dodds, Peter N.

    2015-01-01

    The wheat stem rust fungus Puccinia graminis f. sp. tritici (Pgt) is one of the most destructive pathogens of wheat. In this study, a draft genome was built for a founder Australian Pgt isolate of pathotype (pt.) 21-0 (collected in 1954) by next generation DNA sequencing. A combination of reference-based assembly using the genome of the previously sequenced American Pgt isolate CDL 75-36-700-3 (p7a) and de novo assembly were performed resulting in a 92 Mbp reference genome for Pgt isolate 21-0. Approximately 13 Mbp of de novo assembled sequence in this genome is not present in the p7a reference assembly. This novel sequence is not specific to 21-0 as it is also present in three other Pgt rust isolates of independent origin. The new reference genome was subsequently used to build a pan-genome based on five Australian Pgt isolates. Transcriptomes from germinated urediniospores and haustoria were separately assembled for pt. 21-0 and comparison of gene expression profiles showed differential expression in ∼10% of the genes each in germinated spores and haustoria. A total of 1,924 secreted proteins were predicted from the 21-0 transcriptome, of which 520 were classified as haustorial secreted proteins (HSPs). Comparison of 21-0 with two presumed clonal field derivatives of this lineage (collected in 1982 and 1984) that had evolved virulence on four additional resistance genes (Sr5, Sr11, Sr27, SrSatu) identified mutations in 25 HSP effector candidates. Some of these mutations could explain their novel virulence phenotypes. PMID:25620970

  5. AFLP Genome Scan to Detect Genetic Structure and Candidate Loci under Selection for Local Adaptation of the Invasive Weed Mikania micrantha

    PubMed Central

    Wang, Ting; Chen, Guopei; Zan, Qijie; Wang, Chunbo; Su, Ying-juan

    2012-01-01

    Why some species become successful invaders is an important issue in invasive biology. However, limited genomic resources make it very difficult for identifying candidate genes involved in invasiveness. Mikania micrantha H.B.K. (Asteraceae), one of the world's most invasive weeds, has adapted rapidly in response to novel environments since its introduction to southern China. In its genome, we expect to find outlier loci under selection for local adaptation, critical to dissecting the molecular mechanisms of invasiveness. An explorative amplified fragment length polymorphism (AFLP) genome scan was used to detect candidate loci under selection in 28 M. micrantha populations across its entire introduced range in southern China. We also estimated population genetic parameters, bottleneck signatures, and linkage disequilibrium. In binary characters, such as presence or absence of AFLP bands, if all four character combinations are present, it is referred to as a character incompatibility. Since character incompatibility is deemed to be rare in populations with extensive asexual reproduction, a character incompatibility analysis was also performed in order to infer the predominant mating system in the introduced M. micrantha populations. Out of 483 AFLP loci examined using stringent significance criteria, 14 highly credible outlier loci were identified by Dfdist and Bayescan. Moreover, remarkable genetic variation, multiple introductions, substantial bottlenecks and character compatibility were found to occur in M. micrantha. Thus local adaptation at the genome level indeed exists in M. micrantha, and may represent a major evolutionary mechanism of successful invasion. Interactions between genetic diversity, multiple introductions, and reproductive modes contribute to increase the capacity of adaptive evolution. PMID:22829939

  6. Genome-Wide Association Mapping and Identification of Candidate Genes for the Rumpless and Ear-tufted Traits of the Araucana Chicken

    PubMed Central

    Noorai, Rooksana E.; Freese, Nowlan H.; Wright, Lindsay M.; Chapman, Susan C.; Clark, Leigh Anne

    2012-01-01

    Araucana chickens are known for their rounded, tailless rumps and tufted ears. Inheritance studies have shown that the rumpless (Rp) and ear-tufted (Et) loci each act in an autosomal dominant fashion, segregate independently, and are associated with an increased rate of embryonic mortality. To find genomic regions associated with Rp and Et, we generated genome-wide SNP profiles for a diverse population of 60 Araucana chickens using the 60 K chicken SNP BeadChip. Genome-wide association studies using 40 rumpless and 11 tailed birds showed a strong association with rumpless on Gga 2 (Praw = 2.45×10−10, Pgenome = 0.00575), and analysis of genotypes revealed a 2.14 Mb haplotype shared by all rumpless birds. Within this haplotype, a 0.74 Mb critical interval containing two Iroquois homeobox genes, Irx1 and Irx2, was unique to rumpless Araucana chickens. Irx1 and Irx2 are central for developmental prepatterning, but neither gene is known to have a role in mechanisms leading to caudal development. A second genome-wide association analysis using 30 ear-tufted and 28 non-tufted birds revealed an association with tufted on Gga 15 (Praw = 6.61×10−7, Pgenome = 0.0981). We identified a 0.58 Mb haplotype common to tufted birds and harboring 7 genes. Because homozygosity for Et is nearly 100% lethal, we employed a heterozygosity mapping approach to prioritize candidate gene selection. A 60 kb region heterozygous in all Araucana chickens contains the complete coding sequence for TBX1 and partial sequence for GNB1L. TBX1 is an important transcriptional regulator of embryonic development and a key genetic determinant of human DiGeorge syndrome. Herein, we describe localization of Rp and Et and identification of positional candidate genes. PMID:22844420

  7. Genome Sequence of a Candidate World Health Organization Reference Strain of Zika Virus for Nucleic Acid Testing.

    PubMed

    Trösemeier, Jan-Hendrik; Musso, Didier; Blümel, Johannes; Thézé, Julien; Pybus, Oliver G; Baylis, Sally A

    2016-01-01

    We report here the sequence of a candidate reference strain of Zika virus (ZIKV) developed on behalf of the World Health Organization (WHO). The ZIKV reference strain is intended for use in nucleic acid amplification (NAT)-based assays for the detection and quantification of ZIKV RNA. PMID:27587826

  8. Genome Sequence of a Candidate World Health Organization Reference Strain of Zika Virus for Nucleic Acid Testing

    PubMed Central

    Trösemeier, Jan-Hendrik; Musso, Didier; Blümel, Johannes; Thézé, Julien; Pybus, Oliver G.

    2016-01-01

    We report here the sequence of a candidate reference strain of Zika virus (ZIKV) developed on behalf of the World Health Organization (WHO). The ZIKV reference strain is intended for use in nucleic acid amplification (NAT)-based assays for the detection and quantification of ZIKV RNA. PMID:27587826

  9. Genome and metabolic network of “Candidatus Phaeomarinobacter ectocarpi” Ec32, a new candidate genus of Alphaproteobacteria frequently associated with brown algae

    PubMed Central

    Dittami, Simon M.; Barbeyron, Tristan; Boyen, Catherine; Cambefort, Jeanne; Collet, Guillaume; Delage, Ludovic; Gobet, Angélique; Groisillier, Agnès; Leblanc, Catherine; Michel, Gurvan; Scornet, Delphine; Siegel, Anne; Tapia, Javier E.; Tonon, Thierry

    2014-01-01

    Rhizobiales and related orders of Alphaproteobacteria comprise several genera of nodule-inducing symbiotic bacteria associated with plant roots. Here we describe the genome and the metabolic network of “Candidatus Phaeomarinobacter ectocarpi” Ec32, a member of a new candidate genus closely related to Rhizobiales and found in association with cultures of the filamentous brown algal model Ectocarpus. The “Ca. P. ectocarpi” genome encodes numerous metabolic pathways that may be relevant for this bacterium to interact with algae. Notably, it possesses a large set of glycoside hydrolases and transporters, which may serve to process and assimilate algal metabolites. It also harbors several proteins likely to be involved in the synthesis of algal hormones such as auxins and cytokinins, as well as the vitamins pyridoxine, biotin, and thiamine. As of today, “Ca. P. ectocarpi” has not been successfully cultured, and identical 16S rDNA sequences have been found exclusively associated with Ectocarpus. However, related sequences (≥97% identity) have also been detected free-living and in a Fucus vesiculosus microbiome barcoding project, indicating that the candidate genus “Phaeomarinobacter” may comprise several species, which may colonize different niches. PMID:25120558

  10. Genome-Wide Analysis of Small Secreted Cysteine-Rich Proteins Identifies Candidate Effector Proteins Potentially Involved in Fusarium graminearum-Wheat Interactions.

    PubMed

    Lu, Shunwen; Edwards, Michael C

    2016-02-01

    Pathogen-derived, small secreted cysteine-rich proteins (SSCPs) are known to be a common source of fungal effectors that trigger resistance or susceptibility in specific host plants. This group of proteins has not been well studied in Fusarium graminearum, the primary cause of Fusarium head blight (FHB), a devastating disease of wheat. We report here a comprehensive analysis of SSCPs encoded in the genome of this fungus and selection of candidate effector proteins through proteomics and sequence/transcriptional analyses. A total of 190 SSCPs were identified in the genome of F. graminearum (isolate PH-1) based on the presence of N-terminal signal peptide sequences, size (≤200 amino acids), and cysteine content (≥2%) of the mature proteins. Twenty-five (approximately 13%) SSCPs were confirmed to be true extracellular proteins by nanoscale liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) analysis of a minimal medium-based in vitro secretome. Sequence analysis suggested that 17 SSCPs harbor conserved functional domains, including two homologous to Ecp2, a known effector produced by the tomato pathogen Cladosporium fulvum. Transcriptional analysis revealed that at least 34 SSCPs (including 23 detected in the in vitro secretome) are expressed in infected wheat heads; about half are up-regulated with expression patterns correlating with the development of FHB. This work provides a solid candidate list for SSCP-derived effectors that may play roles in mediating F. graminearum-wheat interactions. The in vitro secretome-based method presented here also may be applicable for identifying candidate effectors in other ascomycete pathogens of crop plants. PMID:26524547

  11. New Genome-Wide Methods for Elucidation of Candidate Copy Number Variations (CNVs) Contributing to Alzheimer's Disease Heritability.

    PubMed

    Szigeti, Kinga

    2016-01-01

    The complexity of human genetic variation has been extended by the observation of abundant and widespread variation in the copy number of submicroscopic DNA segments. The discovery of this novel level of genome organization opened new possibilities concerning the genetic variation that may confer susceptibility to or cause disease. Copy number variants (CNVs) influence gene expression, phenotypic variation and adaptation by altering gene dosage and genome organization. Concordant with the common disease common variant hypothesis these structural variants are now subject to interrogation for disease association. Alzheimer's disease (AD) is a progressive neurodegenerative disease with an estimated heritability of 60-80 %. Large scale genome-wide association studies (GWAS) using high frequency single nucleotide polymorphism (SNP) variants identified ten loci which do not account for the measured heritability. To find the missing heritability systematic assessment of all mutational mechanisms needs to be performed. Between the powerful SNP-GWAS studies and the planned Whole Genome Sequencing projects the contribution of copy number variation (CNV) to the genetic architecture of AD needs to be studied fully. PMID:26235076

  12. Genome-wide analysis and functional characterization of candidate effector proteins potentially involved in Fusarium graminearum-wheat interactions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fungal pathogens often produce certain small secreted cysteine-rich proteins (SSCPs) during pathogenesis that may function in triggering resistance or susceptibility in specific host plants. We have identified a total of 190 SSCPs encoded in the genome of the wheat scab fungus Fusarium graminearum a...

  13. A genome-wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gene variants within regulatory regions are thought to be major contributors of the variation of complex traits/diseases. Genome wide association studies (GWAS), have identified scores of genetic variants that appear to contribute to human disease risk. However, most of these variants do not appear...

  14. Chromosomal Mapping and Candidate Gene Discovery of Chicken Developmental Mutants and Genome-wide Variation Analysis of MHC-congenics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken has been widely used in experimental research given its importance to agriculture and its utility as a model for vertebrate biology and biomedical pursuits for over 100 years. Herein we used recently developed advanced technologies to investigate the genomic characteristics of specialize...

  15. The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. Results: We describe the sequencing and assembly of...

  16. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

    Cancer.gov

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

  17. Integration of genomic and proteomic data to identify candidate genes in HT-29 cells after incubation with Bifidobacterium bifidum ATCC 29521.

    PubMed

    Wang, Bao-Gui; Wu, Yaoping; Qiu, Liang; Shah, Nagendra P; Xu, Feng; Wei, Hua

    2016-09-01

    As the predominant group inhabiting the human gastrointestinal tract, bifidobacteria play a vital role in human nutrition, therapeutics, and health by shaping and maintaining the gut ecosystem, reducing blood cholesterol, and promoting the supply of nutrients. The interaction between bacterial cells and human intestinal epithelial cell lines has been studied for decades in an attempt to understand the mechanisms of action. These studies, however, have been limited by lack of genomic and proteomic database to aid in achieving comprehensive understanding of these mechanisms at molecular levels. Microarray data (GSE: 74119) coupled with isobaric tags for relative and absolute quantitation (iTRAQ) were performed to detect differentially expressed genes and proteins in HT-29 cells after incubation with Bifidobacterium bifidum. Real-time quantitative PCR, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were further conducted for mRNA validation, functional annotation, and pathway identification, respectively. According to the results of microarray, 1,717 differentially expressed genes, including 1,693 upregulated and 24 downregulated genes, were selected and classified by the gene ontology database. The iTRAQ analysis identified 43 differentially expressed proteins, where 29 proteins were upregulated and 14 proteins were downregulated. Eighty-two candidate genes showing consistent differences with microarray and iTRAQ were further validated in HT-29 and Caco-2 cells by real-time quantitative PCR. Nine of the top genes showing interesting results with high confidence were further investigated in vivo in mice intestine samples. Integration of genomic and proteomic data provides an approach to identify candidate genes that are more likely to function in ubiquitin-mediated proteolysis, positive regulation of apoptosis, membrane proteins, and transferase catalysis. These findings might contribute to our understanding of molecular mechanisms regulating the

  18. A combinatorial approach of comprehensive QTL-based comparative genome mapping and transcript profiling identified a seed weight-regulating candidate gene in chickpea.

    PubMed

    Bajaj, Deepak; Upadhyaya, Hari D; Khan, Yusuf; Das, Shouvik; Badoni, Saurabh; Shree, Tanima; Kumar, Vinod; Tripathi, Shailesh; Gowda, C L L; Singh, Sube; Sharma, Shivali; Tyagi, Akhilesh K; Chattopdhyay, Debasis; Parida, Swarup K

    2015-01-01

    High experimental validation/genotyping success rate (94-96%) and intra-specific polymorphic potential (82-96%) of 1536 SNP and 472 SSR markers showing in silico polymorphism between desi ICC 4958 and kabuli ICC 12968 chickpea was obtained in a 190 mapping population (ICC 4958 × ICC 12968) and 92 diverse desi and kabuli genotypes. A high-density 2001 marker-based intra-specific genetic linkage map comprising of eight LGs constructed is comparatively much saturated (mean map-density: 0.94 cM) in contrast to existing intra-specific genetic maps in chickpea. Fifteen robust QTLs (PVE: 8.8-25.8% with LOD: 7.0-13.8) associated with pod and seed number/plant (PN and SN) and 100 seed weight (SW) were identified and mapped on 10 major genomic regions of eight LGs. One of 126.8 kb major genomic region harbouring a strong SW-associated robust QTL (Caq'SW1.1: 169.1-171.3 cM) has been delineated by integrating high-resolution QTL mapping with comprehensive marker-based comparative genome mapping and differential expression profiling. This identified one potential regulatory SNP (G/A) in the cis-acting element of candidate ERF (ethylene responsive factor) TF (transcription factor) gene governing seed weight in chickpea. The functionally relevant molecular tags identified have potential to be utilized for marker-assisted genetic improvement of chickpea. PMID:25786576

  19. Genetic region characterization (Gene RECQuest) - software to assist in identification and selection of candidate genes from genomic regions

    PubMed Central

    Sadasivam, Rajani S; Sundar, Gayathri; Vaughan, Laura K; Tanik, Murat M; Arnett, Donna K

    2009-01-01

    Background The availability of research platforms like the web tools of the National Center for Biotechnology Information (NCBI) has transformed the time-consuming task of identifying candidate genes from genetic studies to an interactive process where data from a variety of sources are obtained to select likely genes for follow-up. This process presents its own set of challenges, as the genetic researcher has to interact with several tools in a time-intensive, manual, and cumbersome manner. We developed a method and implemented an effective software system to address these challenges by multidisciplinary efforts of professional software developers with domain experts. The method presented in this paper, Gene RECQuest, simplifies the interaction with existing research platforms through the use of advanced integration technologies. Findings Gene RECQuest is a web-based application that assists in the identification of candidate genes from linkage and association studies using information from Online Mendelian Inheritance in Man (OMIM) and PubMed. To illustrate the utility of Gene RECQuest we used it to identify genes physically located within a linkage region as potential candidate genes for a quantitative trait locus (QTL) for very low density lipoprotein (VLDL) response on chromosome 18. Conclusion Gene RECQuest provides a tool which enables researchers to easily identify and organize literature supporting their own expertise and make informed decisions. It is important to note that Gene RECQuest is a data acquisition and organization software, and not a data analysis method. PMID:19793396

  20. Xq27 FRAXA locus is a strong candidate for dyslexia: evidence from a genome-wide scan in French families.

    PubMed

    Huc-Chabrolle, M; Charon, C; Guilmatre, A; Vourc'h, P; Tripi, G; Barthez, M A; Sizaret, E; Thepault, R A; Le Gallic, S; Hager, J; Toutain, A; Raynaud, M; Andres, C; Campion, D; Laumonnier, F; Bonnet-Brilhault, F

    2013-03-01

    Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 5'UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227-DXS8091) to 4 Mb also disclosing a higher LOD score. PMID:23307483

  1. Recent genome reduction of Wolbachia in Drosophila recens targets phage WO and narrows candidates for reproductive parasitism

    PubMed Central

    Metcalf, Jason A.; Jo, Minhee; Bordenstein, Sarah R.; Jaenike, John

    2014-01-01

    Wolbachia are maternally transmitted endosymbionts that often alter their arthropod hosts’ biology to favor the success of infected females, and they may also serve as a speciation microbe driving reproductive isolation. Two of these host manipulations include killing males outright and reducing offspring survival when infected males mate with uninfected females, a phenomenon known as cytoplasmic incompatibility. Little is known about the mechanisms behind these phenotypes, but interestingly either effect can be caused by the same Wolbachia strain when infecting different hosts. For instance, wRec causes cytoplasmic incompatibility in its native host Drosophila recens and male killing in D. subquinaria. The discovery of prophage WO elements in most arthropod Wolbachia has generated the hypothesis that WO may encode genes involved in these reproductive manipulations. However, PCR screens for the WO minor capsid gene indicated that wRec lacks phage WO. Thus, wRec seemed to provide an example where phage WO is not needed for Wolbachia-induced reproductive manipulation. To enable investigation of the mechanism of phenotype switching in different host backgrounds, and to examine the unexpected absence of phage WO, we sequenced the genome of wRec. Analyses reveal that wRec diverged from wMel approximately 350,000 years ago, mainly by genome reduction in the phage regions. While it lost the minor capsid gene used in standard PCR screens for phage WO, it retained two regions encompassing 33 genes, several of which have previously been associated with reproductive parasitism. Thus, WO gene involvement in reproductive manipulation cannot be excluded and reliance on single gene PCR should not be used to rule out the presence of phage WO in Wolbachia. Additionally, the genome sequence for wRec will enable transcriptomic and proteomic studies that may help elucidate the Wolbachia mechanisms of altered reproductive manipulations associated with host switching, perhaps among

  2. Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus.

    PubMed

    Truvé, Katarina; Dickinson, Peter; Xiong, Anqi; York, Daniel; Jayashankar, Kartika; Pielberg, Gerli; Koltookian, Michele; Murén, Eva; Fuxelius, Hans-Henrik; Weishaupt, Holger; Swartling, Fredrik J; Andersson, Göran; Hedhammar, Åke; Bongcam-Rudloff, Erik; Forsberg-Nilsson, Karin; Bannasch, Danika; Lindblad-Toh, Kerstin

    2016-05-01

    Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10-8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility. PMID:27171399

  3. Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development—Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus

    PubMed Central

    Dickinson, Peter; Xiong, Anqi; York, Daniel; Jayashankar, Kartika; Pielberg, Gerli; Koltookian, Michele; Murén, Eva; Fuxelius, Hans-Henrik; Weishaupt, Holger; Andersson, Göran; Hedhammar, Åke; Bongcam-Rudloff, Erik; Forsberg-Nilsson, Karin

    2016-01-01

    Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10−8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility. PMID:27171399

  4. Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer’s disease

    PubMed Central

    Caberlotto, Laura; Marchetti, Luca; Lauria, Mario; Scotti, Marco; Parolo, Silvia

    2016-01-01

    Among the genetic factors known to increase the risk of late onset Alzheimer’s diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer’s disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer’s disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer’s disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer’s disease. PMID:27585646

  5. Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer's disease.

    PubMed

    Caberlotto, Laura; Marchetti, Luca; Lauria, Mario; Scotti, Marco; Parolo, Silvia

    2016-01-01

    Among the genetic factors known to increase the risk of late onset Alzheimer's diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer's disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer's disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer's disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer's disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer's disease. PMID:27585646

  6. The nucleotide sequence and genomic organization of Citrus leaf blotch virus: candidate type species for a new virus genus.

    PubMed

    Vives, M C; Galipienso, L; Navarro, L; Moreno, P; Guerri, J

    2001-08-15

    The complete nucleotide sequence of Citrus leaf blotch virus (CLBV) was determined. CLBV genomic RNA (gRNA) has 8747 nt, excluding the 3'-terminal poly(A) tail, and contains three open reading frames (ORFs) and untranslated regions (UTR) of 73 and 541 nucleotides at the 5' and 3' termini, respectively. ORF1 potentially encodes a 227.4-kDa polypeptide, which has methyltransferase, papain-like protease, helicase, and RNA-dependent RNA polymerase motifs. ORF2 encodes a 40.2-kDa polypeptide containing a motif characteristic of cell-to-cell movement proteins. The 40.7-kDa polypeptide encoded by ORF3 was identified as the coat protein. The genome organization of CLBV resembles that of viruses in the genus Trichovirus, but they differ in various aspects: (i) in trichoviruses ORF2 overlaps ORFs 1 and 3, whereas in CLBV, ORFs 2 and 3 are separated and ORFs 1 and 2 overlap in one nucleotide; (ii) CLBV gRNA and CP are larger than those of trichoviruses; and (iii) the CLBV 3' UTR is larger than that of trichoviruses. Phylogenetic comparisons based on CP amino acid signatures clearly separates CLBV from trichoviruses. Also contrasting with trichoviruses, CLBV could not be transmitted to Chenopodium quinoa Willd. Considering these singularities, we propose that CLBV should be included in a new virus genus. PMID:11504557

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

    PubMed Central

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

    2012-01-01

    Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the ‘missing heritability problem’. Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complimentary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility as well as novel candidate genes enriched for functions related to T cell receptor signaling and adenosine triphosphate synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility. PMID:22286170

  8. Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.

    PubMed

    Liang, Han; Cheung, Lydia W T; Li, Jie; Ju, Zhenlin; Yu, Shuangxing; Stemke-Hale, Katherine; Dogruluk, Turgut; Lu, Yiling; Liu, Xiuping; Gu, Chao; Guo, Wei; Scherer, Steven E; Carter, Hannah; Westin, Shannon N; Dyer, Mary D; Verhaak, Roeland G W; Zhang, Fan; Karchin, Rachel; Liu, Chang-Gong; Lu, Karen H; Broaddus, Russell R; Scott, Kenneth L; Hennessy, Bryan T; Mills, Gordon B

    2012-11-01

    Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the "sensor" cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. PMID:23028188

  9. A Genome-Wide Association Study Identifies Two Novel Promising Candidate Genes Affecting Escherichia coli F4ab/F4ac Susceptibility in Swine

    PubMed Central

    Lu, Xin; Niu, Xiao-Yan; Ding, Xiang-Dong; Liu, Jian-Feng; Zhang, Qin

    2012-01-01

    Enterotoxigenic Escherichia coli (ETEC) expressing F4 fimbria is the major pathogenic bacteria causing diarrhoea in neonatal and post-weaning piglets. Previous studies have revealed that the susceptibility to ETEC F4ab/F4ac is an autosomal Mendelian dominant trait and the loci controlling the F4ab/F4ac receptor are located on SSC13q41, between markers SW207 and S0283. To pinpoint these loci and further validate previous findings, we performed a genome-wide association study (GWAS) using a two generation family-based population, consisting of 301 piglets with phenotypes of susceptibility to ETEC F4ab/F4ac by the vitro adhesion test. The DNA of all piglets and their parents was genotyped using the Illumina PorcineSNP60 BeadChip, and 50,972 and 50,483 SNPs were available for F4ab and F4ac susceptibility, respectively, in the association analysis after quality control. In summary, 28 and 18 significant SNPs (p<0.05) were detected associated with F4ab and F4ac susceptibility respectively at genome-wide significance level. From these significant findings, two novel candidate genes, HEG1 and ITGB5, were firstly identified as the most promising genes underlying F4ab/F4ac susceptibility in swine according to their functions and positions. Our findings herein provide a novel evidence for unravelling genetic mechanism of diarrhoea risk in piglets. PMID:22457712

  10. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

    PubMed Central

    Schumann, Gunter; Coin, Lachlan J.; Lourdusamy, Anbarasu; Charoen, Pimphen; Berger, Karen H.; Stacey, David; Desrivières, Sylvane; Aliev, Fazil A.; Khan, Anokhi A.; Amin, Najaf; Aulchenko, Yurii S.; Bakalkin, Georgy; Bakker, Stephan J.; Balkau, Beverley; Beulens, Joline W.; Bilbao, Ainhoa; de Boer, Rudolf A.; Beury, Delphine; Bots, Michiel L.; Breetvelt, Elemi J.; Cauchi, Stéphane; Cavalcanti-Proença, Christine; Chambers, John C.; Clarke, Toni-Kim; Dahmen, Norbert; de Geus, Eco J.; Dick, Danielle; Ducci, Francesca; Easton, Alanna; Edenberg, Howard J.; Esko, Tõnu; Fernández-Medarde, Alberto; Foroud, Tatiana; Freimer, Nelson B.; Girault, Jean-Antoine; Grobbee, Diederick E.; Guarrera, Simonetta; Gudbjartsson, Daniel F.; Hartikainen, Anna-Liisa; Heath, Andrew C.; Hesselbrock, Victor; Hofman, Albert; Hottenga, Jouke-Jan; Isohanni, Matti K.; Kaprio, Jaakko; Khaw, Kay-Tee; Kuehnel, Brigitte; Laitinen, Jaana; Lobbens, Stéphane; Luan, Jian'an; Mangino, Massimo; Maroteaux, Matthieu; Matullo, Giuseppe; McCarthy, Mark I.; Mueller, Christian; Navis, Gerjan; Numans, Mattijs E.; Núñez, Alejandro; Nyholt, Dale R.; Onland-Moret, Charlotte N.; Oostra, Ben A.; O'Reilly, Paul F.; Palkovits, Miklos; Penninx, Brenda W.; Polidoro, Silvia; Pouta, Anneli; Prokopenko, Inga; Ricceri, Fulvio; Santos, Eugenio; Smit, Johannes H.; Soranzo, Nicole; Song, Kijoung; Sovio, Ulla; Stumvoll, Michael; Surakk, Ida; Thorgeirsson, Thorgeir E.; Thorsteinsdottir, Unnur; Troakes, Claire; Tyrfingsson, Thorarinn; Tönjes, Anke; Uiterwaal, Cuno S.; Uitterlinden, Andre G.; van der Harst, Pim; van der Schouw, Yvonne T.; Staehlin, Oliver; Vogelzangs, Nicole; Vollenweider, Peter; Waeber, Gerard; Wareham, Nicholas J.; Waterworth, Dawn M.; Whitfield, John B.; Wichmann, Erich H.; Willemsen, Gonneke; Witteman, Jacqueline C.; Yuan, Xin; Zhai, Guangju; Zhao, Jing H.; Zhang, Weihua; Martin, Nicholas G.; Metspalu, Andres; Doering, Angela; Scott, James; Spector, Tim D.; Loos, Ruth J.; Boomsma, Dorret I.; Mooser, Vincent; Peltonen, Leena; Stefansson, Kari; van Duijn, Cornelia M.; Vineis, Paolo; Sommer, Wolfgang H.; Kooner, Jaspal S.; Spanagel, Rainer; Heberlein, Ulrike A.; Jarvelin, Marjo-Riitta; Elliott, Paul

    2011-01-01

    Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 × 10−8 to P = 4 × 10−9). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior. PMID:21471458