Genome-Wide Search Identifies 1.9 Mb from the Polar Bear Y Chromosome for Evolutionary Analyses

PubMed Central

Bidon, Tobias; Schreck, Nancy; Hailer, Frank; Nilsson, Maria A.; Janke, Axel

2015-01-01

The male-inherited Y chromosome is the major haploid fraction of the mammalian genome, rendering Y-linked sequences an indispensable resource for evolutionary research. However, despite recent large-scale genome sequencing approaches, only a handful of Y chromosome sequences have been characterized to date, mainly in model organisms. Using polar bear (Ursus maritimus) genomes, we compare two different in silico approaches to identify Y-linked sequences: 1) Similarity to known Y-linked genes and 2) difference in the average read depth of autosomal versus sex chromosomal scaffolds. Specifically, we mapped available genomic sequencing short reads from a male and a female polar bear against the reference genome and identify 112 Y-chromosomal scaffolds with a combined length of 1.9 Mb. We verified the in silico findings for the longer polar bear scaffolds by male-specific in vitro amplification, demonstrating the reliability of the average read depth approach. The obtained Y chromosome sequences contain protein-coding sequences, single nucleotide polymorphisms, microsatellites, and transposable elements that are useful for evolutionary studies. A high-resolution phylogeny of the polar bear patriline shows two highly divergent Y chromosome lineages, obtained from analysis of the identified Y scaffolds in 12 previously published male polar bear genomes. Moreover, we find evidence of gene conversion among ZFX and ZFY sequences in the giant panda lineage and in the ancestor of ursine and tremarctine bears. Thus, the identification of Y-linked scaffold sequences from unordered genome sequences yields valuable data to infer phylogenomic and population-genomic patterns in bears. PMID:26019166

Using Maximum Entropy to Find Patterns in Genomes

NASA Astrophysics Data System (ADS)

Liu, Sophia; Hockenberry, Adam; Lancichinetti, Andrea; Jewett, Michael; Amaral, Luis

The existence of over- and under-represented sequence motifs in genomes provides evidence of selective evolutionary pressures on biological mechanisms such as transcription, translation, ligand-substrate binding, and host immunity. To accurately identify motifs and other genome-scale patterns of interest, it is essential to be able to generate accurate null models that are appropriate for the sequences under study. There are currently no tools available that allow users to create random coding sequences with specified amino acid composition and GC content. Using the principle of maximum entropy, we developed a method that generates unbiased random sequences with pre-specified amino acid and GC content. Our method is the simplest way to obtain maximally unbiased random sequences that are subject to GC usage and primary amino acid sequence constraints. This approach can also be easily be expanded to create unbiased random sequences that incorporate more complicated constraints such as individual nucleotide usage or even di-nucleotide frequencies. The ability to generate correctly specified null models will allow researchers to accurately identify sequence motifs which will lead to a better understanding of biological processes. National Institute of General Medical Science, Northwestern University Presidential Fellowship, National Science Foundation, David and Lucile Packard Foundation, Camille Dreyfus Teacher Scholar Award.

TCGA study identifies genomic features of cervical cancer

Cancer.gov

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified novel genomic and molecular characteristics of cervical cancer that will aid in subclassification of the disease and may help target therapies that are most appropriate for each patient.

Pattern Analysis and Decision Support for Cancer through Clinico-Genomic Profiles

NASA Astrophysics Data System (ADS)

Exarchos, Themis P.; Giannakeas, Nikolaos; Goletsis, Yorgos; Papaloukas, Costas; Fotiadis, Dimitrios I.

Advances in genome technology are playing a growing role in medicine and healthcare. With the development of new technologies and opportunities for large-scale analysis of the genome, genomic data have a clear impact on medicine. Cancer prognostics and therapeutics are among the first major test cases for genomic medicine, given that all types of cancer are related with genomic instability. In this paper we present a novel system for pattern analysis and decision support in cancer. The system integrates clinical data from electronic health records and genomic data. Pattern analysis and data mining methods are applied to these integrated data and the discovered knowledge is used for cancer decision support. Through this integration, conclusions can be drawn for early diagnosis, staging and cancer treatment.

Whole-Genome Sequencing of Sordaria macrospora Mutants Identifies Developmental Genes.

PubMed

Nowrousian, Minou; Teichert, Ines; Masloff, Sandra; Kück, Ulrich

2012-02-01

The study of mutants to elucidate gene functions has a long and successful history; however, to discover causative mutations in mutants that were generated by random mutagenesis often takes years of laboratory work and requires previously generated genetic and/or physical markers, or resources like DNA libraries for complementation. Here, we present an alternative method to identify defective genes in developmental mutants of the filamentous fungus Sordaria macrospora through Illumina/Solexa whole-genome sequencing. We sequenced pooled DNA from progeny of crosses of three mutants and the wild type and were able to pinpoint the causative mutations in the mutant strains through bioinformatics analysis. One mutant is a spore color mutant, and the mutated gene encodes a melanin biosynthesis enzyme. The causative mutation is a G to A change in the first base of an intron, leading to a splice defect. The second mutant carries an allelic mutation in the pro41 gene encoding a protein essential for sexual development. In the mutant, we detected a complex pattern of deletion/rearrangements at the pro41 locus. In the third mutant, a point mutation in the stop codon of a transcription factor-encoding gene leads to the production of immature fruiting bodies. For all mutants, transformation with a wild type-copy of the affected gene restored the wild-type phenotype. Our data demonstrate that whole-genome sequencing of mutant strains is a rapid method to identify developmental genes in an organism that can be genetically crossed and where a reference genome sequence is available, even without prior mapping information.

Whole-Genome Sequencing of Sordaria macrospora Mutants Identifies Developmental Genes

PubMed Central

Nowrousian, Minou; Teichert, Ines; Masloff, Sandra; Kück, Ulrich

2012-01-01

The study of mutants to elucidate gene functions has a long and successful history; however, to discover causative mutations in mutants that were generated by random mutagenesis often takes years of laboratory work and requires previously generated genetic and/or physical markers, or resources like DNA libraries for complementation. Here, we present an alternative method to identify defective genes in developmental mutants of the filamentous fungus Sordaria macrospora through Illumina/Solexa whole-genome sequencing. We sequenced pooled DNA from progeny of crosses of three mutants and the wild type and were able to pinpoint the causative mutations in the mutant strains through bioinformatics analysis. One mutant is a spore color mutant, and the mutated gene encodes a melanin biosynthesis enzyme. The causative mutation is a G to A change in the first base of an intron, leading to a splice defect. The second mutant carries an allelic mutation in the pro41 gene encoding a protein essential for sexual development. In the mutant, we detected a complex pattern of deletion/rearrangements at the pro41 locus. In the third mutant, a point mutation in the stop codon of a transcription factor-encoding gene leads to the production of immature fruiting bodies. For all mutants, transformation with a wild type-copy of the affected gene restored the wild-type phenotype. Our data demonstrate that whole-genome sequencing of mutant strains is a rapid method to identify developmental genes in an organism that can be genetically crossed and where a reference genome sequence is available, even without prior mapping information. PMID:22384404

Novel genomes and genome constitutions identified by GISH and 5S rDNA and knotted1 genomic sequences in the genus Setaria.

PubMed

Zhao, Meicheng; Zhi, Hui; Doust, Andrew N; Li, Wei; Wang, Yongfang; Li, Haiquan; Jia, Guanqing; Wang, Yongqiang; Zhang, Ning; Diao, Xianmin

2013-04-11

The Setaria genus is increasingly of interest to researchers, as its two species, S. viridis and S. italica, are being developed as models for understanding C4 photosynthesis and plant functional genomics. The genome constitution of Setaria species has been studied in the diploid species S. viridis, S. adhaerans and S. grisebachii, where three genomes A, B and C were identified respectively. Two allotetraploid species, S. verticillata and S. faberi, were found to have AABB genomes, and one autotetraploid species, S. queenslandica, with an AAAA genome, has also been identified. The genomes and genome constitutions of most other species remain unknown, even though it was thought there are approximately 125 species in the genus distributed world-wide. GISH was performed to detect the genome constitutions of Eurasia species of S. glauca, S. plicata, and S. arenaria, with the known A, B and C genomes as probes. No or very poor hybridization signal was detected indicating that their genomes are different from those already described. GISH was also performed reciprocally between S. glauca, S. plicata, and S. arenaria genomes, but no hybridization signals between each other were found. The two sets of chromosomes of S. lachnea both hybridized strong signals with only the known C genome of S. grisebachii. Chromosomes of Qing 9, an accession formerly considered as S. viridis, hybridized strong signal only to B genome of S. adherans. Phylogenetic trees constructed with 5S rDNA and knotted1 markers, clearly classify the samples in this study into six clusters, matching the GISH results, and suggesting that the F genome of S. arenaria is basal in the genus. Three novel genomes in the Setaria genus were identified and designated as genome D (S. glauca), E (S. plicata) and F (S. arenaria) respectively. The genome constitution of tetraploid S. lachnea is putatively CCC'C'. Qing 9 is a B genome species indigenous to China and is hypothesized to be a newly identified species. The

Novel genomes and genome constitutions identified by GISH and 5S rDNA and knotted1 genomic sequences in the genus Setaria

PubMed Central

2013-01-01

Background The Setaria genus is increasingly of interest to researchers, as its two species, S. viridis and S. italica, are being developed as models for understanding C4 photosynthesis and plant functional genomics. The genome constitution of Setaria species has been studied in the diploid species S. viridis, S. adhaerans and S. grisebachii, where three genomes A, B and C were identified respectively. Two allotetraploid species, S. verticillata and S. faberi, were found to have AABB genomes, and one autotetraploid species, S. queenslandica, with an AAAA genome, has also been identified. The genomes and genome constitutions of most other species remain unknown, even though it was thought there are approximately 125 species in the genus distributed world-wide. Results GISH was performed to detect the genome constitutions of Eurasia species of S. glauca, S. plicata, and S. arenaria, with the known A, B and C genomes as probes. No or very poor hybridization signal was detected indicating that their genomes are different from those already described. GISH was also performed reciprocally between S. glauca, S. plicata, and S. arenaria genomes, but no hybridization signals between each other were found. The two sets of chromosomes of S. lachnea both hybridized strong signals with only the known C genome of S. grisebachii. Chromosomes of Qing 9, an accession formerly considered as S. viridis, hybridized strong signal only to B genome of S. adherans. Phylogenetic trees constructed with 5S rDNA and knotted1 markers, clearly classify the samples in this study into six clusters, matching the GISH results, and suggesting that the F genome of S. arenaria is basal in the genus. Conclusions Three novel genomes in the Setaria genus were identified and designated as genome D (S. glauca), E (S. plicata) and F (S. arenaria) respectively. The genome constitution of tetraploid S. lachnea is putatively CCC’C’. Qing 9 is a B genome species indigenous to China and is hypothesized to be

Genomic suppression subtractive hybridization as a tool to identify differences in mycorrhizal fungal genomes.

PubMed

Murat, Claude; Zampieri, Elisa; Vallino, Marta; Daghino, Stefania; Perotto, Silvia; Bonfante, Paola

2011-05-01

Characterization of genomic variation among different microbial species, or different strains of the same species, is a field of significant interest with a wide range of potential applications. We have investigated the genomic variation in mycorrhizal fungal genomes through genomic suppressive subtractive hybridization. The comparison was between phylogenetically distant and close truffle species (Tuber spp.), and between isolates of the ericoid mycorrhizal fungus Oidiodendron maius featuring different degrees of metal tolerance. In the interspecies experiment, almost all the sequences that were identified in the Tuber melanosporum genome and absent in Tuber borchii and Tuber indicum corresponded to transposable elements. In the intraspecies comparison, some specific sequences corresponded to regions coding for enzymes, among them a glutathione synthetase known to be involved in metal tolerance. This approach is a quick and rather inexpensive tool to develop molecular markers for mycorrhizal fungi tracking and barcoding, to identify functional genes and to investigate the genome plasticity, adaptation and evolution. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Genome-Wide Search Identifies 1.9 Mb from the Polar Bear Y Chromosome for Evolutionary Analyses.

PubMed

Bidon, Tobias; Schreck, Nancy; Hailer, Frank; Nilsson, Maria A; Janke, Axel

2015-05-27

The male-inherited Y chromosome is the major haploid fraction of the mammalian genome, rendering Y-linked sequences an indispensable resource for evolutionary research. However, despite recent large-scale genome sequencing approaches, only a handful of Y chromosome sequences have been characterized to date, mainly in model organisms. Using polar bear (Ursus maritimus) genomes, we compare two different in silico approaches to identify Y-linked sequences: 1) Similarity to known Y-linked genes and 2) difference in the average read depth of autosomal versus sex chromosomal scaffolds. Specifically, we mapped available genomic sequencing short reads from a male and a female polar bear against the reference genome and identify 112 Y-chromosomal scaffolds with a combined length of 1.9 Mb. We verified the in silico findings for the longer polar bear scaffolds by male-specific in vitro amplification, demonstrating the reliability of the average read depth approach. The obtained Y chromosome sequences contain protein-coding sequences, single nucleotide polymorphisms, microsatellites, and transposable elements that are useful for evolutionary studies. A high-resolution phylogeny of the polar bear patriline shows two highly divergent Y chromosome lineages, obtained from analysis of the identified Y scaffolds in 12 previously published male polar bear genomes. Moreover, we find evidence of gene conversion among ZFX and ZFY sequences in the giant panda lineage and in the ancestor of ursine and tremarctine bears. Thus, the identification of Y-linked scaffold sequences from unordered genome sequences yields valuable data to infer phylogenomic and population-genomic patterns in bears. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Identifiability, genomics and U.K. data protection law.

PubMed

Curren, Liam; Boddington, Paula; Gowans, Heather; Hawkins, Naomi; Kanellopoulou, Nadja; Kaye, Jane; Melham, Karen

2010-09-01

Analyses of individuals' genomes--their entire DNA sequence--have increased knowledge about the links between genetics and disease. Anticipated advances in 'next generation' DNA-sequencing techniques will see the routine research use of whole genomes, rather than distinct parts, within the next few years. The scientific benefits of genomic research are, however, accompanied by legal and ethical concerns. Despite the assumption that genetic research data can and will be rendered anonymous, participants' identities can sometimes be elucidated, which could cause data protection legislation to apply. We undertake a timely reappraisal of these laws--particularly new penalties--and identifiability in genomic research.

The high-quality draft genome of peach (Prunus persica) identifies unique patterns of genetic diversity, domestication and genome evolution.

PubMed

Verde, Ignazio; Abbott, Albert G; Scalabrin, Simone; Jung, Sook; Shu, Shengqiang; Marroni, Fabio; Zhebentyayeva, Tatyana; Dettori, Maria Teresa; Grimwood, Jane; Cattonaro, Federica; Zuccolo, Andrea; Rossini, Laura; Jenkins, Jerry; Vendramin, Elisa; Meisel, Lee A; Decroocq, Veronique; Sosinski, Bryon; Prochnik, Simon; Mitros, Therese; Policriti, Alberto; Cipriani, Guido; Dondini, Luca; Ficklin, Stephen; Goodstein, David M; Xuan, Pengfei; Del Fabbro, Cristian; Aramini, Valeria; Copetti, Dario; Gonzalez, Susana; Horner, David S; Falchi, Rachele; Lucas, Susan; Mica, Erica; Maldonado, Jonathan; Lazzari, Barbara; Bielenberg, Douglas; Pirona, Raul; Miculan, Mara; Barakat, Abdelali; Testolin, Raffaele; Stella, Alessandra; Tartarini, Stefano; Tonutti, Pietro; Arús, Pere; Orellana, Ariel; Wells, Christina; Main, Dorrie; Vizzotto, Giannina; Silva, Herman; Salamini, Francesco; Schmutz, Jeremy; Morgante, Michele; Rokhsar, Daniel S

2013-05-01

Rosaceae is the most important fruit-producing clade, and its key commercially relevant genera (Fragaria, Rosa, Rubus and Prunus) show broadly diverse growth habits, fruit types and compact diploid genomes. Peach, a diploid Prunus species, is one of the best genetically characterized deciduous trees. Here we describe the high-quality genome sequence of peach obtained from a completely homozygous genotype. We obtained a complete chromosome-scale assembly using Sanger whole-genome shotgun methods. We predicted 27,852 protein-coding genes, as well as noncoding RNAs. We investigated the path of peach domestication through whole-genome resequencing of 14 Prunus accessions. The analyses suggest major genetic bottlenecks that have substantially shaped peach genome diversity. Furthermore, comparative analyses showed that peach has not undergone recent whole-genome duplication, and even though the ancestral triplicated blocks in peach are fragmentary compared to those in grape, all seven paleosets of paralogs from the putative paleoancestor are detectable.

The complete mitochondrial genome of Arctic Calanus hyperboreus (Copepoda, Calanoida) reveals characteristic patterns in calanoid mitochondrial genome.

PubMed

Kim, Sanghee; Lim, Byung-Jin; Min, Gi-Sik; Choi, Han-Gu

2013-05-10

Copepoda is the most diverse and abundant group of crustaceans, but its phylogenetic relationships are ambiguous. Mitochondrial (mt) genomes are useful for studying evolutionary history, but only six complete Copepoda mt genomes have been made available and these have extremely rearranged genome structures. This study determined the mt genome of Calanus hyperboreus, making it the first reported Arctic copepod mt genome and the first complete mt genome of a calanoid copepod. The mt genome of C. hyperboreus is 17,910 bp in length and it contains the entire set of 37 mt genes, including 13 protein-coding genes, 2 rRNAs, and 22 tRNAs. It has a very unusual gene structure, including the longest control region reported for a crustacean, a large tRNA gene cluster, and reversed GC skews in 11 out of 13 protein-coding genes (84.6%). Despite the unusual features, comparing this genome to published copepod genomes revealed retained pan-crustacean features, as well as a conserved calanoid-specific pattern. Our data provide a foundation for exploring the calanoid pattern and the mechanisms of mt gene rearrangement in the evolutionary history of the copepod mt genome. Copyright © 2012 Elsevier B.V. All rights reserved.

A periodic pattern of SNPs in the human genome

PubMed Central

Madsen, Bo Eskerod; Villesen, Palle; Wiuf, Carsten

2007-01-01

By surveying a filtered, high-quality set of SNPs in the human genome, we have found that SNPs positioned 1, 2, 4, 6, or 8 bp apart are more frequent than SNPs positioned 3, 5, 7, or 9 bp apart. The observed pattern is not restricted to genomic regions that are known to cause sequencing or alignment errors, for example, transposable elements (SINE, LINE, and LTR), tandem repeats, and large duplicated regions. However, we found that the pattern is almost entirely confined to what we define as “periodic DNA.” Periodic DNA is a genomic region with a high degree of periodicity in nucleotide usage. It turned out that periodic DNA is mainly small regions (average length 16.9 bp), widely distributed in the genome. Furthermore, periodic DNA has a 1.8 times higher SNP density than the rest of the genome and SNPs inside periodic DNA have a significantly higher genotyping error rate than SNPs outside periodic DNA. Our results suggest that not all SNPs in the human genome are created by independent single nucleotide mutations, and that care should be taken in analysis of SNPs from periodic DNA. The latter may have important consequences for SNP and association studies. PMID:17673700

Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome

PubMed Central

Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing; O’Connor, Timothy D.; Abecasis, Gonçalo R.; Wojcik, Genevieve L; Gignoux, Christopher R.; Gourraud, Pierre-Antoine; Lizee, Antoine; Hansen, Mark; Genuario, Rob; Bullis, Dave; Lawley, Cindy; Kenny, Eimear E.; Bustamante, Carlos; Beaty, Terri H.; Mathias, Rasika A.; Barnes, Kathleen C.; Qin, Zhaohui S.; Preethi Boorgula, Meher; Campbell, Monica; Chavan, Sameer; Ford, Jean G.; Foster, Cassandra; Gao, Li; Hansel, Nadia N.; Horowitz, Edward; Huang, Lili; Ortiz, Romina; Potee, Joseph; Rafaels, Nicholas; Ruczinski, Ingo; Scott, Alan F.; Taub, Margaret A.; Vergara, Candelaria; Levin, Albert M.; Padhukasahasram, Badri; Williams, L. Keoki; Dunston, Georgia M.; Faruque, Mezbah U.; Gietzen, Kimberly; Deshpande, Aniket; Grus, Wendy E.; Locke, Devin P.; Foreman, Marilyn G.; Avila, Pedro C.; Grammer, Leslie; Kim, Kwang-Youn A.; Kumar, Rajesh; Schleimer, Robert; De La Vega, Francisco M.; Shringarpure, Suyash S.; Musharoff, Shaila; Burchard, Esteban G.; Eng, Celeste; Hernandez, Ryan D.; Pino-Yanes, Maria; Torgerson, Dara G.; Szpiech, Zachary A.; Torres, Raul; Nicolae, Dan L.; Ober, Carole; Olopade, Christopher O; Olopade, Olufunmilayo; Oluwole, Oluwafemi; Arinola, Ganiyu; Song, Wei; Correa, Adolfo; Musani, Solomon; Wilson, James G.; Lange, Leslie A.; Akey, Joshua; Bamshad, Michael; Chong, Jessica; Fu, Wenqing; Nickerson, Deborah; Reiner, Alexander; Hartert, Tina; Ware, Lorraine B.; Bleecker, Eugene; Meyers, Deborah; Ortega, Victor E.; Maul, Pissamai; Maul, Trevor; Watson, Harold; Ilma Araujo, Maria; Riccio Oliveira, Ricardo; Caraballo, Luis; Marrugo, Javier; Martinez, Beatriz; Meza, Catherine; Ayestas, Gerardo; Francisco Herrera-Paz, Edwin; Landaverde-Torres, Pamela; Erazo, Said Omar Leiva; Martinez, Rosella; Mayorga, Alvaro; Mayorga, Luis F.; Mejia-Mejia, Delmy-Aracely; Ramos, Hector; Saenz, Allan; Varela, Gloria; Marina Vasquez, Olga; Ferguson, Trevor; Knight-Madden, Jennifer; Samms-Vaughan, Maureen; Wilks, Rainford J.; Adegnika, Akim; Ateba-Ngoa, Ulysse; Yazdanbakhsh, Maria

2017-01-01

A primary goal of The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to develop an ‘African Diaspora Power Chip’ (ADPC), a genotyping array consisting of tagging SNPs, useful in comprehensively identifying African specific genetic variation. This array is designed based on the novel variation identified in 642 CAAPA samples of African ancestry with high coverage whole genome sequence data (~30× depth). This novel variation extends the pattern of variation catalogued in the 1000 Genomes and Exome Sequencing Projects to a spectrum of populations representing the wide range of West African genomic diversity. These individuals from CAAPA also comprise a large swath of the African Diaspora population and incorporate historical genetic diversity covering nearly the entire Atlantic coast of the Americas. Here we show the results of designing and producing such a microchip array. This novel array covers African specific variation far better than other commercially available arrays, and will enable better GWAS analyses for researchers with individuals of African descent in their study populations. A recent study cataloging variation in continental African populations suggests this type of African-specific genotyping array is both necessary and valuable for facilitating large-scale GWAS in populations of African ancestry. PMID:28429804

Genome-wide DNA methylation measurements in prostate tissues uncovers novel prostate cancer diagnostic biomarkers and transcription factor binding patterns.

PubMed

Kirby, Marie K; Ramaker, Ryne C; Roberts, Brian S; Lasseigne, Brittany N; Gunther, David S; Burwell, Todd C; Davis, Nicholas S; Gulzar, Zulfiqar G; Absher, Devin M; Cooper, Sara J; Brooks, James D; Myers, Richard M

2017-04-17

Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer. We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models. We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues. DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development.

Profiling of gene duplication patterns of sequenced teleost genomes: evidence for rapid lineage-specific genome expansion mediated by recent tandem duplications.

PubMed

Lu, Jianguo; Peatman, Eric; Tang, Haibao; Lewis, Joshua; Liu, Zhanjiang

2012-06-15

Gene duplication has had a major impact on genome evolution. Localized (or tandem) duplication resulting from unequal crossing over and whole genome duplication are believed to be the two dominant mechanisms contributing to vertebrate genome evolution. While much scrutiny has been directed toward discerning patterns indicative of whole-genome duplication events in teleost species, less attention has been paid to the continuous nature of gene duplications and their impact on the size, gene content, functional diversity, and overall architecture of teleost genomes. Here, using a Markov clustering algorithm directed approach we catalogue and analyze patterns of gene duplication in the four model teleost species with chromosomal coordinates: zebrafish, medaka, stickleback, and Tetraodon. Our analyses based on set size, duplication type, synonymous substitution rate (Ks), and gene ontology emphasize shared and lineage-specific patterns of genome evolution via gene duplication. Most strikingly, our analyses highlight the extraordinary duplication and retention rate of recent duplicates in zebrafish and their likely role in the structural and functional expansion of the zebrafish genome. We find that the zebrafish genome is remarkable in its large number of duplicated genes, small duplicate set size, biased Ks distribution toward minimal mutational divergence, and proportion of tandem and intra-chromosomal duplicates when compared with the other teleost model genomes. The observed gene duplication patterns have played significant roles in shaping the architecture of teleost genomes and appear to have contributed to the recent functional diversification and divergence of important physiological processes in zebrafish. We have analyzed gene duplication patterns and duplication types among the available teleost genomes and found that a large number of genes were tandemly and intrachromosomally duplicated, suggesting their origin of independent and continuous duplication

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations.

PubMed

Wardell, Christopher P; Fujita, Masashi; Yamada, Toru; Simbolo, Michele; Fassan, Matteo; Karlic, Rosa; Polak, Paz; Kim, Jaegil; Hatanaka, Yutaka; Maejima, Kazuhiro; Lawlor, Rita T; Nakanishi, Yoshitsugu; Mitsuhashi, Tomoko; Fujimoto, Akihiro; Furuta, Mayuko; Ruzzenente, Andrea; Conci, Simone; Oosawa, Ayako; Sasaki-Oku, Aya; Nakano, Kaoru; Tanaka, Hiroko; Yamamoto, Yujiro; Michiaki, Kubo; Kawakami, Yoshiiku; Aikata, Hiroshi; Ueno, Masaki; Hayami, Shinya; Gotoh, Kunihito; Ariizumi, Shun-Ichi; Yamamoto, Masakazu; Yamaue, Hiroki; Chayama, Kazuaki; Miyano, Satoru; Getz, Gad; Scarpa, Aldo; Hirano, Satoshi; Nakamura, Toru; Nakagawa, Hidewaki

2018-05-01

Biliary tract cancers (BTCs) are clinically and pathologically heterogeneous and respond poorly to treatment. Genomic profiling can offer a clearer understanding of their carcinogenesis, classification and treatment strategy. We performed large-scale genome sequencing analyses on BTCs to investigate their somatic and germline driver events and characterize their genomic landscape. We analyzed 412 BTC samples from Japanese and Italian populations, 107 by whole-exome sequencing (WES), 39 by whole-genome sequencing (WGS), and a further 266 samples by targeted sequencing. The subtypes were 136 intrahepatic cholangiocarcinomas (ICCs), 101 distal cholangiocarcinomas (DCCs), 109 peri-hilar type cholangiocarcinomas (PHCs), and 66 gallbladder or cystic duct cancers (GBCs/CDCs). We identified somatic alterations and searched for driver genes in BTCs, finding pathogenic germline variants of cancer-predisposing genes. We predicted cell-of-origin for BTCs by combining somatic mutation patterns and epigenetic features. We identified 32 significantly and commonly mutated genes including TP53, KRAS, SMAD4, NF1, ARID1A, PBRM1, and ATR, some of which negatively affected patient prognosis. A novel deletion of MUC17 at 7q22.1 affected patient prognosis. Cell-of-origin predictions using WGS and epigenetic features suggest hepatocyte-origin of hepatitis-related ICCs. Deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, or MSH2 were detected in 11% (16/146) of BTC patients. BTCs have distinct genetic features including somatic events and germline predisposition. These findings could be useful to establish treatment and diagnostic strategies for BTCs based on genetic information. We here analyzed genomic features of 412 BTC samples from Japanese and Italian populations. A total of 32 significantly and commonly mutated genes were identified, some of which negatively affected patient prognosis, including a novel deletion of MUC17 at 7q22.1. Cell

Genome-wide high-throughput SNP discovery and genotyping for understanding natural (functional) allelic diversity and domestication patterns in wild chickpea

PubMed Central

Bajaj, Deepak; Das, Shouvik; Badoni, Saurabh; Kumar, Vinod; Singh, Mohar; Bansal, Kailash C.; Tyagi, Akhilesh K.; Parida, Swarup K.

2015-01-01

We identified 82489 high-quality genome-wide SNPs from 93 wild and cultivated Cicer accessions through integrated reference genome- and de novo-based GBS assays. High intra- and inter-specific polymorphic potential (66–85%) and broader natural allelic diversity (6–64%) detected by genome-wide SNPs among accessions signify their efficacy for monitoring introgression and transferring target trait-regulating genomic (gene) regions/allelic variants from wild to cultivated Cicer gene pools for genetic improvement. The population-specific assignment of wild Cicer accessions pertaining to the primary gene pool are more influenced by geographical origin/phenotypic characteristics than species/gene-pools of origination. The functional significance of allelic variants (non-synonymous and regulatory SNPs) scanned from transcription factors and stress-responsive genes in differentiating wild accessions (with potential known sources of yield-contributing and stress tolerance traits) from cultivated desi and kabuli accessions, fine-mapping/map-based cloning of QTLs and determination of LD patterns across wild and cultivated gene-pools are suitably elucidated. The correlation between phenotypic (agromorphological traits) and molecular diversity-based admixed domestication patterns within six structured populations of wild and cultivated accessions via genome-wide SNPs was apparent. This suggests utility of whole genome SNPs as a potential resource for identifying naturally selected trait-regulating genomic targets/functional allelic variants adaptive to diverse agroclimatic regions for genetic enhancement of cultivated gene-pools. PMID:26208313

Augmenting Chinese hamster genome assembly by identifying regions of high confidence.

PubMed

Vishwanathan, Nandita; Bandyopadhyay, Arpan A; Fu, Hsu-Yuan; Sharma, Mohit; Johnson, Kathryn C; Mudge, Joann; Ramaraj, Thiruvarangan; Onsongo, Getiria; Silverstein, Kevin A T; Jacob, Nitya M; Le, Huong; Karypis, George; Hu, Wei-Shou

2016-09-01

Chinese hamster Ovary (CHO) cell lines are the dominant industrial workhorses for therapeutic recombinant protein production. The availability of genome sequence of Chinese hamster and CHO cells will spur further genome and RNA sequencing of producing cell lines. However, the mammalian genomes assembled using shot-gun sequencing data still contain regions of uncertain quality due to assembly errors. Identifying high confidence regions in the assembled genome will facilitate its use for cell engineering and genome engineering. We assembled two independent drafts of Chinese hamster genome by de novo assembly from shotgun sequencing reads and by re-scaffolding and gap-filling the draft genome from NCBI for improved scaffold lengths and gap fractions. We then used the two independent assemblies to identify high confidence regions using two different approaches. First, the two independent assemblies were compared at the sequence level to identify their consensus regions as "high confidence regions" which accounts for at least 78 % of the assembled genome. Further, a genome wide comparison of the Chinese hamster scaffolds with mouse chromosomes revealed scaffolds with large blocks of collinearity, which were also compiled as high-quality scaffolds. Genome scale collinearity was complemented with EST based synteny which also revealed conserved gene order compared to mouse. As cell line sequencing becomes more commonly practiced, the approaches reported here are useful for assessing the quality of assembly and potentially facilitate the engineering of cell lines. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Employing genome-wide SNP discovery and genotyping strategy to extrapolate the natural allelic diversity and domestication patterns in chickpea

PubMed Central

Kujur, Alice; Bajaj, Deepak; Upadhyaya, Hari D.; Das, Shouvik; Ranjan, Rajeev; Shree, Tanima; Saxena, Maneesha S.; Badoni, Saurabh; Kumar, Vinod; Tripathi, Shailesh; Gowda, C. L. L.; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K.; Parida, Swarup K.

2015-01-01

The genome-wide discovery and high-throughput genotyping of SNPs in chickpea natural germplasm lines is indispensable to extrapolate their natural allelic diversity, domestication, and linkage disequilibrium (LD) patterns leading to the genetic enhancement of this vital legume crop. We discovered 44,844 high-quality SNPs by sequencing of 93 diverse cultivated desi, kabuli, and wild chickpea accessions using reference genome- and de novo-based GBS (genotyping-by-sequencing) assays that were physically mapped across eight chromosomes of desi and kabuli. Of these, 22,542 SNPs were structurally annotated in different coding and non-coding sequence components of genes. Genes with 3296 non-synonymous and 269 regulatory SNPs could functionally differentiate accessions based on their contrasting agronomic traits. A high experimental validation success rate (92%) and reproducibility (100%) along with strong sensitivity (93–96%) and specificity (99%) of GBS-based SNPs was observed. This infers the robustness of GBS as a high-throughput assay for rapid large-scale mining and genotyping of genome-wide SNPs in chickpea with sub-optimal use of resources. With 23,798 genome-wide SNPs, a relatively high intra-specific polymorphic potential (49.5%) and broader molecular diversity (13–89%)/functional allelic diversity (18–77%) was apparent among 93 chickpea accessions, suggesting their tremendous applicability in rapid selection of desirable diverse accessions/inter-specific hybrids in chickpea crossbred varietal improvement program. The genome-wide SNPs revealed complex admixed domestication pattern, extensive LD estimates (0.54–0.68) and extended LD decay (400–500 kb) in a structured population inclusive of 93 accessions. These findings reflect the utility of our identified SNPs for subsequent genome-wide association study (GWAS) and selective sweep-based domestication trait dissection analysis to identify potential genomic loci (gene-associated targets) specifically

Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

PubMed Central

Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

2012-01-01

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

Genomic and environmental selection patterns in two distinct lettuce crop–wild hybrid crosses

PubMed Central

Hartman, Yorike; Uwimana, Brigitte; Hooftman, Danny A P; Schranz, Michael E; van de Wiel, Clemens C M; Smulders, Marinus J M; Visser, Richard G F; van Tienderen, Peter H

2013-01-01

Genomic selection patterns and hybrid performance influence the chance that crop (trans)genes can spread to wild relatives. We measured fitness(-related) traits in two different field environments employing two different crop–wild crosses of lettuce. We performed quantitative trait loci (QTL) analyses and estimated the fitness distribution of early- and late-generation hybrids. We detected consistent results across field sites and crosses for a fitness QTL at linkage group 7, where a selective advantage was conferred by the wild allele. Two fitness QTL were detected on linkage group 5 and 6, which were unique to one of the crop–wild crosses. Average hybrid fitness was lower than the fitness of the wild parent, but several hybrid lineages outperformed the wild parent, especially in a novel habitat for the wild type. In early-generation hybrids, this may partly be due to heterosis effects, whereas in late-generation hybrids transgressive segregation played a major role. The study of genomic selection patterns can identify crop genomic regions under negative selection across multiple environments and cultivar–wild crosses that might be applicable in transgene mitigation strategies. At the same time, results were cultivar-specific, so that a case-by-case environmental risk assessment is still necessary, decreasing its general applicability. PMID:23789025

Genomic and environmental selection patterns in two distinct lettuce crop-wild hybrid crosses.

PubMed

Hartman, Yorike; Uwimana, Brigitte; Hooftman, Danny A P; Schranz, Michael E; van de Wiel, Clemens C M; Smulders, Marinus J M; Visser, Richard G F; van Tienderen, Peter H

2013-06-01

Genomic selection patterns and hybrid performance influence the chance that crop (trans)genes can spread to wild relatives. We measured fitness(-related) traits in two different field environments employing two different crop-wild crosses of lettuce. We performed quantitative trait loci (QTL) analyses and estimated the fitness distribution of early- and late-generation hybrids. We detected consistent results across field sites and crosses for a fitness QTL at linkage group 7, where a selective advantage was conferred by the wild allele. Two fitness QTL were detected on linkage group 5 and 6, which were unique to one of the crop-wild crosses. Average hybrid fitness was lower than the fitness of the wild parent, but several hybrid lineages outperformed the wild parent, especially in a novel habitat for the wild type. In early-generation hybrids, this may partly be due to heterosis effects, whereas in late-generation hybrids transgressive segregation played a major role. The study of genomic selection patterns can identify crop genomic regions under negative selection across multiple environments and cultivar-wild crosses that might be applicable in transgene mitigation strategies. At the same time, results were cultivar-specific, so that a case-by-case environmental risk assessment is still necessary, decreasing its general applicability.

ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements.

PubMed

Taylor, James; Tyekucheva, Svitlana; King, David C; Hardison, Ross C; Miller, Webb; Chiaromonte, Francesca

2006-12-01

Genomic sequence signals - such as base composition, presence of particular motifs, or evolutionary constraint - have been used effectively to identify functional elements. However, approaches based only on specific signals known to correlate with function can be quite limiting. When training data are available, application of computational learning algorithms to multispecies alignments has the potential to capture broader and more informative sequence and evolutionary patterns that better characterize a class of elements. However, effective exploitation of patterns in multispecies alignments is impeded by the vast number of possible alignment columns and by a limited understanding of which particular strings of columns may characterize a given class. We have developed a computational method, called ESPERR (evolutionary and sequence pattern extraction through reduced representations), which uses training examples to learn encodings of multispecies alignments into reduced forms tailored for the prediction of chosen classes of functional elements. ESPERR produces a greatly improved Regulatory Potential score, which can discriminate regulatory regions from neutral sites with excellent accuracy ( approximately 94%). This score captures strong signals (GC content and conservation), as well as subtler signals (with small contributions from many different alignment patterns) that characterize the regulatory elements in our training set. ESPERR is also effective for predicting other classes of functional elements, as we show for DNaseI hypersensitive sites and highly conserved regions with developmental enhancer activity. Our software, training data, and genome-wide predictions are available from our Web site (http://www.bx.psu.edu/projects/esperr).

An integrated genomics analysis of epigenetic subtypes in human breast tumors links DNA methylation patterns to chromatin states in normal mammary cells.

PubMed

Holm, Karolina; Staaf, Johan; Lauss, Martin; Aine, Mattias; Lindgren, David; Bendahl, Pär-Ola; Vallon-Christersson, Johan; Barkardottir, Rosa Bjork; Höglund, Mattias; Borg, Åke; Jönsson, Göran; Ringnér, Markus

2016-02-29

Aberrant DNA methylation is frequently observed in breast cancer. However, the relationship between methylation patterns and the heterogeneity of breast cancer has not been comprehensively characterized. Whole-genome DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChip arrays was performed on 188 human breast tumors. Unsupervised bootstrap consensus clustering was performed to identify DNA methylation epigenetic subgroups (epitypes). The Cancer Genome Atlas data, including methylation profiles of 669 human breast tumors, was used for validation. The identified epitypes were characterized by integration with publicly available genome-wide data, including gene expression levels, DNA copy numbers, whole-exome sequencing data, and chromatin states. We identified seven breast cancer epitypes. One epitype was distinctly associated with basal-like tumors and with BRCA1 mutations, one epitype contained a subset of ERBB2-amplified tumors characterized by multiple additional amplifications and the most complex genomes, and one epitype displayed a methylation profile similar to normal epithelial cells. Luminal tumors were stratified into the remaining four epitypes, with differences in promoter hypermethylation, global hypomethylation, proliferative rates, and genomic instability. Specific hyper- and hypomethylation across the basal-like epitype was rare. However, we observed that the candidate genomic instability drivers BRCA1 and HORMAD1 displayed aberrant methylation linked to gene expression levels in some basal-like tumors. Hypomethylation in luminal tumors was associated with DNA repeats and subtelomeric regions. We observed two dominant patterns of aberrant methylation in breast cancer. One pattern, constitutively methylated in both basal-like and luminal breast cancer, was linked to genes with promoters in a Polycomb-repressed state in normal epithelial cells and displayed no correlation with gene expression levels. The second pattern

Complex Patterns of Genomic Admixture within Southern Africa

PubMed Central

Petersen, Desiree C.; Libiger, Ondrej; Tindall, Elizabeth A.; Hardie, Rae-Anne; Hannick, Linda I.; Glashoff, Richard H.; Mukerji, Mitali; Fernandez, Pedro; Haacke, Wilfrid; Schork, Nicholas J.; Hayes, Vanessa M.

2013-01-01

Within-population genetic diversity is greatest within Africa, while between-population genetic diversity is directly proportional to geographic distance. The most divergent contemporary human populations include the click-speaking forager peoples of southern Africa, broadly defined as Khoesan. Both intra- (Bantu expansion) and inter-continental migration (European-driven colonization) have resulted in complex patterns of admixture between ancient geographically isolated Khoesan and more recently diverged populations. Using gender-specific analysis and almost 1 million autosomal markers, we determine the significance of estimated ancestral contributions that have shaped five contemporary southern African populations in a cohort of 103 individuals. Limited by lack of available data for homogenous Khoesan representation, we identify the Ju/'hoan (n = 19) as a distinct early diverging human lineage with little to no significant non-Khoesan contribution. In contrast to the Ju/'hoan, we identify ancient signatures of Khoesan and Bantu unions resulting in significant Khoesan- and Bantu-derived contributions to the Southern Bantu amaXhosa (n = 15) and Khoesan !Xun (n = 14), respectively. Our data further suggests that contemporary !Xun represent distinct Khoesan prehistories. Khoesan assimilation with European settlement at the most southern tip of Africa resulted in significant ancestral Khoesan contributions to the Coloured (n = 25) and Baster (n = 30) populations. The latter populations were further impacted by 170 years of East Indian slave trade and intra-continental migrations resulting in a complex pattern of genetic variation (admixture). The populations of southern Africa provide a unique opportunity to investigate the genomic variability from some of the oldest human lineages to the implications of complex admixture patterns including ancient and recently diverged human lineages. PMID:23516368

Patterns of genomic and phenomic diversity in wine and table grapes

PubMed Central

Migicovsky, Zoë; Sawler, Jason; Gardner, Kyle M; Aradhya, Mallikarjuna K; Prins, Bernard H; Schwaninger, Heidi R; Bustamante, Carlos D; Buckler, Edward S; Zhong, Gan-Yuan; Brown, Patrick J; Myles, Sean

2017-01-01

Grapes are one of the most economically and culturally important crops worldwide, and they have been bred for both winemaking and fresh consumption. Here we evaluate patterns of diversity across 33 phenotypes collected over a 17-year period from 580 table and wine grape accessions that belong to one of the world’s largest grape gene banks, the grape germplasm collection of the United States Department of Agriculture. We find that phenological events throughout the growing season are correlated, and quantify the marked difference in size between table and wine grapes. By pairing publicly available historical phenotype data with genome-wide polymorphism data, we identify large effect loci controlling traits that have been targeted during domestication and breeding, including hermaphroditism, lighter skin pigmentation and muscat aroma. Breeding for larger berries in table grapes was traditionally concentrated in geographic regions where Islam predominates and alcohol was prohibited, whereas wine grapes retained the ancestral smaller size that is more desirable for winemaking in predominantly Christian regions. We uncover a novel locus with a suggestive association with berry size that harbors a signature of positive selection for larger berries. Our results suggest that religious rules concerning alcohol consumption have had a marked impact on patterns of phenomic and genomic diversity in grapes. PMID:28791127

Patterns of genomic and phenomic diversity in wine and table grapes.

PubMed

Migicovsky, Zoë; Sawler, Jason; Gardner, Kyle M; Aradhya, Mallikarjuna K; Prins, Bernard H; Schwaninger, Heidi R; Bustamante, Carlos D; Buckler, Edward S; Zhong, Gan-Yuan; Brown, Patrick J; Myles, Sean

2017-01-01

Grapes are one of the most economically and culturally important crops worldwide, and they have been bred for both winemaking and fresh consumption. Here we evaluate patterns of diversity across 33 phenotypes collected over a 17-year period from 580 table and wine grape accessions that belong to one of the world's largest grape gene banks, the grape germplasm collection of the United States Department of Agriculture. We find that phenological events throughout the growing season are correlated, and quantify the marked difference in size between table and wine grapes. By pairing publicly available historical phenotype data with genome-wide polymorphism data, we identify large effect loci controlling traits that have been targeted during domestication and breeding, including hermaphroditism, lighter skin pigmentation and muscat aroma. Breeding for larger berries in table grapes was traditionally concentrated in geographic regions where Islam predominates and alcohol was prohibited, whereas wine grapes retained the ancestral smaller size that is more desirable for winemaking in predominantly Christian regions. We uncover a novel locus with a suggestive association with berry size that harbors a signature of positive selection for larger berries. Our results suggest that religious rules concerning alcohol consumption have had a marked impact on patterns of phenomic and genomic diversity in grapes.

Genome-wide Association Study Identifies African-Specific Susceptibility Loci in African Americans with Inflammatory Bowel Disease

PubMed Central

Brant, Steven R.; Okou, David T.; Simpson, Claire L.; Cutler, David J.; Haritunians, Talin; Bradfield, Jonathan P.; Chopra, Pankaj; Prince, Jarod; Begum, Ferdouse; Kumar, Archana; Huang, Chengrui; Venkateswaran, Suresh; Datta, Lisa W.; Wei, Zhi; Thomas, Kelly; Herrinton, Lisa J.; Klapproth, Jan-Micheal A.; Quiros, Antonio J.; Seminerio, Jenifer; Liu, Zhenqiu; Alexander, Jonathan S.; Baldassano, Robert N.; Dudley-Brown, Sharon; Cross, Raymond K.; Dassopoulos, Themistocles; Denson, Lee A.; Dhere, Tanvi A.; Dryden, Gerald W.; Hanson, John S.; Hou, Jason K.; Hussain, Sunny Z.; Hyams, Jeffrey S.; Isaacs, Kim L.; Kader, Howard; Kappelman, Michael D.; Katz, Jeffry; Kellermayer, Richard; Kirschner, Barbara S.; Kuemmerle, John F.; Kwon, John H.; Lazarev, Mark; Li, Ellen; Mack, David; Mannon, Peter; Moulton, Dedrick E.; Newberry, Rodney D.; Osuntokun, Bankole O.; Patel, Ashish S.; Saeed, Shehzad A.; Targan, Stephan R.; Valentine, John F.; Wang, Ming-Hsi; Zonca, Martin; Rioux, John D.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H.; Hakonarson, Hakon; Zwick, Michael E.; McGovern, Dermot P.B.; Kugathasan, Subra

2016-01-01

Background & Aims The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. Methods We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified [IBD-U]) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P<5.0×10−8 in meta-analysis with a nominal evidence (P<.05) in each scan were considered to have genome-wide significance. Results We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance associations for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P<1.6×10−6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B, PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. Conclusions We performed a genome-wide association study of African Americans with IBD and identified loci associated with CD and UC in only this population; we also replicated loci identified in European populations. The detection of variants associated with IBD risk in only

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

PubMed

Brant, Steven R; Okou, David T; Simpson, Claire L; Cutler, David J; Haritunians, Talin; Bradfield, Jonathan P; Chopra, Pankaj; Prince, Jarod; Begum, Ferdouse; Kumar, Archana; Huang, Chengrui; Venkateswaran, Suresh; Datta, Lisa W; Wei, Zhi; Thomas, Kelly; Herrinton, Lisa J; Klapproth, Jan-Micheal A; Quiros, Antonio J; Seminerio, Jenifer; Liu, Zhenqiu; Alexander, Jonathan S; Baldassano, Robert N; Dudley-Brown, Sharon; Cross, Raymond K; Dassopoulos, Themistocles; Denson, Lee A; Dhere, Tanvi A; Dryden, Gerald W; Hanson, John S; Hou, Jason K; Hussain, Sunny Z; Hyams, Jeffrey S; Isaacs, Kim L; Kader, Howard; Kappelman, Michael D; Katz, Jeffry; Kellermayer, Richard; Kirschner, Barbara S; Kuemmerle, John F; Kwon, John H; Lazarev, Mark; Li, Ellen; Mack, David; Mannon, Peter; Moulton, Dedrick E; Newberry, Rodney D; Osuntokun, Bankole O; Patel, Ashish S; Saeed, Shehzad A; Targan, Stephan R; Valentine, John F; Wang, Ming-Hsi; Zonca, Martin; Rioux, John D; Duerr, Richard H; Silverberg, Mark S; Cho, Judy H; Hakonarson, Hakon; Zwick, Michael E; McGovern, Dermot P B; Kugathasan, Subra

2017-01-01

The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10 -8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10 -6 ): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the

Reduced representation genome sequencing reveals patterns of genetic diversity and selection in apple.

PubMed

Ma, Baiquan; Liao, Liao; Peng, Qian; Fang, Ting; Zhou, Hui; Korban, Schuyler S; Han, Yuepeng

2017-03-01

Identifying DNA sequence variations is a fundamental step towards deciphering the genetic basis of traits of interest. Here, a total of 20 cultivated and 10 wild apples were genotyped using specific-locus amplified fragment sequencing, and 39,635 single nucleotide polymorphisms with no missing genotypes and evenly distributed along the genome were selected to investigate patterns of genome-wide genetic variations between cultivated and wild apples. Overall, wild apples displayed higher levels of genetic diversity than cultivated apples. Linkage disequilibrium (LD) decays were observed quite rapidly in cultivated and wild apples, with an r 2 -value below 0.2 at 440 and 280 bp, respectively. Moreover, bidirectional gene flow and different distribution patterns of LD blocks were detected between domesticated and wild apples. Most LD blocks unique to cultivated apples were located within QTL regions controlling fruit quality, thus suggesting that fruit quality had probably undergone selection during apple domestication. The genome of the earliest cultivated apple in China, Nai, was highly similar to that of Malus sieversii, and contained a small portion of genetic material from other wild apple species. This suggested that introgression could have been an important driving force during initial domestication of apple. These findings will facilitate future breeding and genetic dissection of complex traits in apple. © 2017 Institute of Botany, Chinese Academy of Sciences.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

PubMed

Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse; Barber, Robert; Beecham, Gary W; Bennett, David A; Buxbaum, Joseph D; Byrd, Goldie S; Carrasquillo, Minerva M; Crane, Paul K; Cruchaga, Carlos; De Jager, Philip; Ertekin-Taner, Nilufer; Evans, Denis; Fallin, M Danielle; Foroud, Tatiana M; Friedland, Robert P; Goate, Alison M; Graff-Radford, Neill R; Hendrie, Hugh; Hall, Kathleen S; Hamilton-Nelson, Kara L; Inzelberg, Rivka; Kamboh, M Ilyas; Kauwe, John S K; Kukull, Walter A; Kunkle, Brian W; Kuwano, Ryozo; Larson, Eric B; Logue, Mark W; Manly, Jennifer J; Martin, Eden R; Montine, Thomas J; Mukherjee, Shubhabrata; Naj, Adam; Reiman, Eric M; Reitz, Christiane; Sherva, Richard; St George-Hyslop, Peter H; Thornton, Timothy; Younkin, Steven G; Vardarajan, Badri N; Wang, Li-San; Wendlund, Jens R; Winslow, Ashley R; Haines, Jonathan; Mayeux, Richard; Pericak-Vance, Margaret A; Schellenberg, Gerard; Lunetta, Kathryn L; Farrer, Lindsay A

2017-07-01

Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10 -8 ) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10 -6 ) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10 -6 ). Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

High-density marker profiling confirms ancestral genomes of Avena species and identifies D-genome chromosomes of hexaploid oat.

PubMed

Yan, Honghai; Bekele, Wubishet A; Wight, Charlene P; Peng, Yuanying; Langdon, Tim; Latta, Robert G; Fu, Yong-Bi; Diederichsen, Axel; Howarth, Catherine J; Jellen, Eric N; Boyle, Brian; Wei, Yuming; Tinker, Nicholas A

2016-11-01

Genome analysis of 27 oat species identifies ancestral groups, delineates the D genome, and identifies ancestral origin of 21 mapped chromosomes in hexaploid oat. We investigated genomic relationships among 27 species of the genus Avena using high-density genetic markers revealed by genotyping-by-sequencing (GBS). Two methods of GBS analysis were used: one based on tag-level haplotypes that were previously mapped in cultivated hexaploid oat (A. sativa), and one intended to sample and enumerate tag-level haplotypes originating from all species under investigation. Qualitatively, both methods gave similar predictions regarding the clustering of species and shared ancestral genomes. Furthermore, results were consistent with previous phylogenies of the genus obtained with conventional approaches, supporting the robustness of whole genome GBS analysis. Evidence is presented to justify the final and definitive classification of the tetraploids A. insularis, A. maroccana (=A. magna), and A. murphyi as containing D-plus-C genomes, and not A-plus-C genomes, as is most often specified in past literature. Through electronic painting of the 21 chromosome representations in the hexaploid oat consensus map, we show how the relative frequency of matches between mapped hexaploid-derived haplotypes and AC (DC)-genome tetraploids vs. A- and C-genome diploids can accurately reveal the genome origin of all hexaploid chromosomes, including the approximate positions of inter-genome translocations. Evidence is provided that supports the continued classification of a diverged B genome in AB tetraploids, and it is confirmed that no extant A-genome diploids, including A. canariensis, are similar enough to the D genome of tetraploid and hexaploid oat to warrant consideration as a D-genome diploid.

Distinguishing noise from signal in patterns of genomic divergence in a highly polymorphic avian radiation.

PubMed

Campagna, Leonardo; Gronau, Ilan; Silveira, Luís Fábio; Siepel, Adam; Lovette, Irby J

2015-08-01

Recently diverged taxa provide the opportunity to search for the genetic basis of the phenotypes that distinguish them. Genomic scans aim to identify loci that are diverged with respect to an otherwise weakly differentiated genetic background. These loci are candidates for being past targets of selection because they behave differently from the rest of the genome that has either not yet differentiated or that may cross species barriers through introgressive hybridization. Here we use a reduced-representation genomic approach to explore divergence among six species of southern capuchino seedeaters, a group of recently radiated sympatric passerine birds in the genus Sporophila. For the first time in these taxa, we discovered a small proportion of markers that appeared differentiated among species. However, when assessing the significance of these signatures of divergence, we found that similar patterns can also be recovered from random grouping of individuals representing different species. A detailed demographic inference indicates that genetic differences among Sporophila species could be the consequence of neutral processes, which include a very large ancestral effective population size that accentuates the effects of incomplete lineage sorting. As these neutral phenomena can generate genomic scan patterns that mimic those of markers involved in speciation and phenotypic differentiation, they highlight the need for caution when ascertaining and interpreting differentiated markers between species, especially when large numbers of markers are surveyed. Our study provides new insights into the demography of the southern capuchino radiation and proposes controls to distinguish signal from noise in similar genomic scans. © 2015 John Wiley & Sons Ltd.

A hidden two-locus disease association pattern in genome-wide association studies

PubMed Central

2011-01-01

Background Recent association analyses in genome-wide association studies (GWAS) mainly focus on single-locus association tests (marginal tests) and two-locus interaction detections. These analysis methods have provided strong evidence of associations between genetics variances and complex diseases. However, there exists a type of association pattern, which often occurs within local regions in the genome and is unlikely to be detected by either marginal tests or interaction tests. This association pattern involves a group of correlated single-nucleotide polymorphisms (SNPs). The correlation among SNPs can lead to weak marginal effects and the interaction does not play a role in this association pattern. This phenomenon is due to the existence of unfaithfulness: the marginal effects of correlated SNPs do not express their significant joint effects faithfully due to the correlation cancelation. Results In this paper, we develop a computational method to detect this association pattern masked by unfaithfulness. We have applied our method to analyze seven data sets from the Wellcome Trust Case Control Consortium (WTCCC). The analysis for each data set takes about one week to finish the examination of all pairs of SNPs. Based on the empirical result of these real data, we show that this type of association masked by unfaithfulness widely exists in GWAS. Conclusions These newly identified associations enrich the discoveries of GWAS, which may provide new insights both in the analysis of tagSNPs and in the experiment design of GWAS. Since these associations may be easily missed by existing analysis tools, we can only connect some of them to publicly available findings from other association studies. As independent data set is limited at this moment, we also have difficulties to replicate these findings. More biological implications need further investigation. Availability The software is freely available at http://bioinformatics.ust.hk/hidden_pattern_finder.zip. PMID

rep-PCR-Mediated Genomic Fingerprinting: A Rapid and Effective Method to Identify Clavibacter michiganensis.

PubMed

Louws, F J; Bell, J; Medina-Mora, C M; Smart, C D; Opgenorth, D; Ishimaru, C A; Hausbeck, M K; de Bruijn, F J; Fulbright, D W

1998-08-01

ABSTRACT The genomic DNA fingerprinting technique known as repetitive-sequence-based polymerase chain reaction (rep-PCR) was evaluated as a tool to differentiate subspecies of Clavibacter michiganensis, with special emphasis on C. michiganensis subsp. michiganensis, the pathogen responsible for bacterial canker of tomato. DNA primers (REP, ERIC, and BOX), corresponding to conserved repetitive element motifs in the genomes of diverse bacterial species, were used to generate genomic fingerprints of C. michiganensis subsp. michiganensis, C. michiganensis subsp. sepedonicus, C. michiganensis subsp. nebraskensis, C. michiganensis subsp. tessellarius, and C. michiganensis subsp. insidiosum. The rep-PCR-generated patterns of DNA fragments observed after agarose gel electrophoresis support the current division of C. michiganensis into five subspecies. In addition, the rep-PCR fingerprints identified at least four types (A, B, C, and D) within C. michiganensis subsp. michiganensis based on limited DNA polymorphisms; the ability to differentiate individual strains may be of potential use in studies on the epidemiology and host-pathogen interactions of this organism. In addition, we have recovered from diseased tomato plants a relatively large number of naturally occurring avirulent C. michiganensis subsp. michiganensis strains with rep-PCR fingerprints identical to those of virulent C. michiganensis subsp. michiganensis strains.

Computational approaches to identify functional genetic variants in cancer genomes

PubMed Central

Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris; Ritchie, Graham R.S.; Creixell, Pau; Karchin, Rachel; Vazquez, Miguel; Fink, J. Lynn; Kassahn, Karin S.; Pearson, John V.; Bader, Gary; Boutros, Paul C.; Muthuswamy, Lakshmi; Ouellette, B.F. Francis; Reimand, Jüri; Linding, Rune; Shibata, Tatsuhiro; Valencia, Alfonso; Butler, Adam; Dronov, Serge; Flicek, Paul; Shannon, Nick B.; Carter, Hannah; Ding, Li; Sander, Chris; Stuart, Josh M.; Stein, Lincoln D.; Lopez-Bigas, Nuria

2014-01-01

The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor, but only a minority drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype. PMID:23900255

Genome-wide DNA methylation patterns of bovine blastocysts derived from in vivo embryos subjected to in vitro culture before, during or after embryonic genome activation.

PubMed

Salilew-Wondim, Dessie; Saeed-Zidane, Mohammed; Hoelker, Michael; Gebremedhn, Samuel; Poirier, Mikhaël; Pandey, Hari Om; Tholen, Ernst; Neuhoff, Christiane; Held, Eva; Besenfelder, Urban; Havlicek, Vita; Rings, Franca; Fournier, Eric; Gagné, Dominic; Sirard, Marc-André; Robert, Claude; Gad, Ahmed; Schellander, Karl; Tesfaye, Dawit

2018-06-01

Aberrant DNA methylation patterns of genes required for development are common in in vitro produced embryos. In this regard, we previously identified altered DNA methylation patterns of in vivo developed blastocysts from embryos which spent different stages of development in vitro, indicating carryover effects of suboptimal culture conditions on epigenetic signatures of preimplantation embryos. However, epigenetic responses of in vivo originated embryos to suboptimal culture conditions are not fully understood. Therefore, here we investigated DNA methylation patterns of in vivo derived bovine embryos subjected to in vitro culture condition before, during or after major embryonic genome activation (EGA). For this, in vivo produced 2-, 8- and 16-cell stage embryos were cultured in vitro until the blastocyst stage and blastocysts were used for genome-wide DNA methylation analysis. The 2- and 8-cell flushed embryo groups showed lower blastocyst rates compared to the 16-cell flush group. This was further accompanied by increased numbers of differentially methylated genomic regions (DMRs) in blastocysts of the 2- and 8-cell flush groups compared to the complete in vivo control ones. Moreover, 1623 genomic loci including imprinted genes were hypermethylated in blastocyst of 2-, 8- and 16-cell flushed groups, indicating the presence of genomic regions which are sensitive to the in vitro culture at any stage of embryonic development. Furthermore, hypermethylated genomic loci outnumbered hypomethylated ones in blastocysts of 2- and 16-cell flushed embryo groups, but the opposite occurred in the 8-cell group. Moreover, DMRs which were unique to blastocysts of the 2-cell flushed group and inversely correlated with corresponding mRNA expression levels were involved in plasma membrane lactate transport, amino acid transport and phosphorus metabolic processes, whereas DMRs which were specific to the 8-cell group and inversely correlated with corresponding mRNA expression levels

Codon usage bias: causative factors, quantification methods and genome-wide patterns: with emphasis on insect genomes.

PubMed

Behura, Susanta K; Severson, David W

2013-02-01

Codon usage bias refers to the phenomenon where specific codons are used more often than other synonymous codons during translation of genes, the extent of which varies within and among species. Molecular evolutionary investigations suggest that codon bias is manifested as a result of balance between mutational and translational selection of such genes and that this phenomenon is widespread across species and may contribute to genome evolution in a significant manner. With the advent of whole-genome sequencing of numerous species, both prokaryotes and eukaryotes, genome-wide patterns of codon bias are emerging in different organisms. Various factors such as expression level, GC content, recombination rates, RNA stability, codon position, gene length and others (including environmental stress and population size) can influence codon usage bias within and among species. Moreover, there has been a continuous quest towards developing new concepts and tools to measure the extent of codon usage bias of genes. In this review, we outline the fundamental concepts of evolution of the genetic code, discuss various factors that may influence biased usage of synonymous codons and then outline different principles and methods of measurement of codon usage bias. Finally, we discuss selected studies performed using whole-genome sequences of different insect species to show how codon bias patterns vary within and among genomes. We conclude with generalized remarks on specific emerging aspects of codon bias studies and highlight the recent explosion of genome-sequencing efforts on arthropods (such as twelve Drosophila species, species of ants, honeybee, Nasonia and Anopheles mosquitoes as well as the recent launch of a genome-sequencing project involving 5000 insects and other arthropods) that may help us to understand better the evolution of codon bias and its biological significance. © 2012 The Authors. Biological Reviews © 2012 Cambridge Philosophical Society.

Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution

PubMed Central

Basu, Swaraj; Larsson, Erik

2016-01-01

Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies. PMID:28027311

Complete genome sequence of a novel extrachromosomal virus-like element identified in planarian Girardia tigrina

PubMed Central

Rebrikov, Denis V; Bulina, Maria E; Bogdanova, Ekaterina A; Vagner, Loura L; Lukyanov, Sergey A

2002-01-01

Background Freshwater planarians are widely used as models for investigation of pattern formation and studies on genetic variation in populations. Despite extensive information on the biology and genetics of planaria, the occurrence and distribution of viruses in these animals remains an unexplored area of research. Results Using a combination of Suppression Subtractive Hybridization (SSH) and Mirror Orientation Selection (MOS), we compared the genomes of two strains of freshwater planarian, Girardia tigrina. The novel extrachromosomal DNA-containing virus-like element denoted PEVE (Planarian Extrachromosomal Virus-like Element) was identified in one planarian strain. The PEVE genome (about 7.5 kb) consists of two unique regions (Ul and Us) flanked by inverted repeats. Sequence analyses reveal that PEVE comprises two helicase-like sequences in the genome, of which the first is a homolog of a circoviral replication initiator protein (Rep), and the second is similar to the papillomavirus E1 helicase domain. PEVE genome exists in at least two variant forms with different arrangements of single-stranded and double-stranded DNA stretches that correspond to the Us and Ul regions. Using PCR analysis and whole-mount in situ hybridization, we characterized PEVE distribution and expression in the planarian body. Conclusions PEVE is the first viral element identified in free-living flatworms. This element differs from all known viruses and viral elements, and comprises two potential helicases that are homologous to proteins from distant viral phyla. PEVE is unevenly distributed in the worm body, and is detected in specific parenchyma cells. PMID:12065025

A functional genomics screen identifies an Importin-α homolog as a regulator of stem cell function and tissue patterning during planarian regeneration.

PubMed

Hubert, Amy; Henderson, Jordana M; Cowles, Martis W; Ross, Kelly G; Hagen, Matthew; Anderson, Christa; Szeterlak, Claudia J; Zayas, Ricardo M

2015-10-12

Planarians are renowned for their regenerative capacity and are an attractive model for the study of adult stem cells and tissue regeneration. In an effort to better understand the molecular mechanisms underlying planarian regeneration, we performed a functional genomics screen aimed at identifying genes involved in this process in Schmidtea mediterranea. We used microarrays to detect changes in gene expression in regenerating and non-regenerating tissues in planarians regenerating one side of the head and followed this with high-throughput screening by in situ hybridization and RNAi to characterize the expression patterns and function of the differentially expressed genes. Along with five previously characterized genes (Smed-cycD, Smed-morf41/mrg-1, Smed-pdss2/dlp1, Smed-slbp, and Smed-tph), we identified 20 additional genes necessary for stem cell maintenance (Smed-sart3, Smed-smarcc-1, Smed-espl1, Smed-rrm2b-1, Smed-rrm2b-2, Smed-dkc1, Smed-emg1, Smed-lig1, Smed-prim2, Smed-mcm7, and a novel sequence) or general regenerative capability (Smed-rbap46/48-2, Smed-mcm2, Smed-ptbp1, and Smed-fen-1) or that caused tissue-specific defects upon knockdown (Smed-ddc, Smed-gas8, Smed-pgbd4, and Smed-b9d2). We also found that a homolog of the nuclear transport factor Importin-α plays a role in stem cell function and tissue patterning, suggesting that controlled nuclear import of proteins is important for regeneration. Through this work, we described the roles of several previously uncharacterized genes in planarian regeneration and implicated nuclear import in this process. We have additionally created an online database to house our in situ and RNAi data to make it accessible to the planarian research community.

Genome wide approaches to identify protein-DNA interactions.

PubMed

Ma, Tao; Ye, Zhenqing; Wang, Liguo

2018-05-29

Transcription factors are DNA-binding proteins that play key roles in many fundamental biological processes. Unraveling their interactions with DNA is essential to identify their target genes and understand the regulatory network. Genome-wide identification of their binding sites became feasible thanks to recent progress in experimental and computational approaches. ChIP-chip, ChIP-seq, and ChIP-exo are three widely used techniques to demarcate genome-wide transcription factor binding sites. This review aims to provide an overview of these three techniques including their experiment procedures, computational approaches, and popular analytic tools. ChIP-chip, ChIP-seq, and ChIP-exo have been the major techniques to study genome-wide in vivo protein-DNA interaction. Due to the rapid development of next-generation sequencing technology, array-based ChIP-chip is deprecated and ChIP-seq has become the most widely used technique to identify transcription factor binding sites in genome-wide. The newly developed ChIP-exo further improves the spatial resolution to single nucleotide. Numerous tools have been developed to analyze ChIP-chip, ChIP-seq and ChIP-exo data. However, different programs may employ different mechanisms or underlying algorithms thus each will inherently include its own set of statistical assumption and bias. So choosing the most appropriate analytic program for a given experiment needs careful considerations. Moreover, most programs only have command line interface so their installation and usage will require basic computation expertise in Unix/Linux. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Genome-wide DNA methylation patterns in wild samples of two morphotypes of threespine stickleback (Gasterosteus aculeatus).

PubMed

Smith, Gilbert; Smith, Carl; Kenny, John G; Chaudhuri, Roy R; Ritchie, Michael G

2015-04-01

Epigenetic marks such as DNA methylation play important biological roles in gene expression regulation and cellular differentiation during development. To examine whether DNA methylation patterns are potentially associated with naturally occurring phenotypic differences, we examined genome-wide DNA methylation within Gasterosteus aculeatus, using reduced representation bisulfite sequencing. First, we identified highly methylated regions of the stickleback genome, finding such regions to be located predominantly within genes, and associated with genes functioning in metabolism and biosynthetic processes, cell adhesion, signaling pathways, and blood vessel development. Next, we identified putative differentially methylated regions (DMRs) of the genome between complete and low lateral plate morphs of G. aculeatus. We detected 77 DMRs that were mainly located in intergenic regions. Annotations of genes associated with these DMRs revealed potential functions in a number of known divergent adaptive phenotypes between G. aculeatus ecotypes, including cardiovascular development, growth, and neuromuscular development. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Illumina whole-genome complementary DNA-mediated annealing, selection, extension and ligation platform: assessing its performance in formalin-fixed, paraffin-embedded samples and identifying invasion pattern-related genes in oral squamous cell carcinoma.

PubMed

Loudig, Olivier; Brandwein-Gensler, Margaret; Kim, Ryung S; Lin, Juan; Isayeva, Tatyana; Liu, Christina; Segall, Jeffrey E; Kenny, Paraic A; Prystowsky, Michael B

2011-12-01

High-throughput gene expression profiling from formalin-fixed, paraffin-embedded tissues has become a reality, and several methods are now commercially available. The Illumina whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay (Illumina, Inc) is a full-transcriptome version of the original 512-gene complementary DNA-mediated annealing, selection, extension and ligation assay, allowing high-throughput profiling of 24,526 annotated genes from degraded and formalin-fixed, paraffin-embedded RNA. This assay has the potential to allow identification of novel gene signatures associated with clinical outcome using banked archival pathology specimen resources. We tested the reproducibility of the whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay and its sensitivity for detecting differentially expressed genes in RNA extracted from matched fresh and formalin-fixed, paraffin-embedded cells, after 1 and 13 months of storage, using the human breast cell lines MCF7 and MCF10A. Then, using tumor worst pattern of invasion as a classifier, 1 component of the "risk model," we selected 12 formalin-fixed, paraffin-embedded oral squamous cell carcinomas for whole-genome complementary DNA-mediated annealing, selection, extension and ligation assay analysis. We profiled 5 tumors with nonaggressive, nondispersed pattern of invasion, and 7 tumors with aggressive dispersed pattern of invasion and satellites scattered at least 1 mm apart. To minimize variability, the formalin-fixed, paraffin-embedded specimens were prepared from snap-frozen tissues, and RNA was obtained within 24 hours of fixation. One hundred four down-regulated genes and 72 up-regulated genes in tumors with aggressive dispersed pattern of invasion were identified. We performed quantitative reverse transcriptase polymerase chain reaction validation of 4 genes using Taqman assays and in situ protein detection of 1 gene by immunohistochemistry

The Cancer Genome Atlas Clinical Explorer: a web and mobile interface for identifying clinical-genomic driver associations.

PubMed

Lee, HoJoon; Palm, Jennifer; Grimes, Susan M; Ji, Hanlee P

2015-10-27

The Cancer Genome Atlas (TCGA) project has generated genomic data sets covering over 20 malignancies. These data provide valuable insights into the underlying genetic and genomic basis of cancer. However, exploring the relationship among TCGA genomic results and clinical phenotype remains a challenge, particularly for individuals lacking formal bioinformatics training. Overcoming this hurdle is an important step toward the wider clinical translation of cancer genomic/proteomic data and implementation of precision cancer medicine. Several websites such as the cBio portal or University of California Santa Cruz genome browser make TCGA data accessible but lack interactive features for querying clinically relevant phenotypic associations with cancer drivers. To enable exploration of the clinical-genomic driver associations from TCGA data, we developed the Cancer Genome Atlas Clinical Explorer. The Cancer Genome Atlas Clinical Explorer interface provides a straightforward platform to query TCGA data using one of the following methods: (1) searching for clinically relevant genes, micro RNAs, and proteins by name, cancer types, or clinical parameters; (2) searching for genomic/proteomic profile changes by clinical parameters in a cancer type; or (3) testing two-hit hypotheses. SQL queries run in the background and results are displayed on our portal in an easy-to-navigate interface according to user's input. To derive these associations, we relied on elastic-net estimates of optimal multiple linear regularized regression and clinical parameters in the space of multiple genomic/proteomic features provided by TCGA data. Moreover, we identified and ranked gene/micro RNA/protein predictors of each clinical parameter for each cancer. The robustness of the results was estimated by bootstrapping. Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that

Identifying and mitigating batch effects in whole genome sequencing data.

PubMed

Tom, Jennifer A; Reeder, Jens; Forrest, William F; Graham, Robert R; Hunkapiller, Julie; Behrens, Timothy W; Bhangale, Tushar R

2017-07-24

Large sample sets of whole genome sequencing with deep coverage are being generated, however assembling datasets from different sources inevitably introduces batch effects. These batch effects are not well understood and can be due to changes in the sequencing protocol or bioinformatics tools used to process the data. No systematic algorithms or heuristics exist to detect and filter batch effects or remove associations impacted by batch effects in whole genome sequencing data. We describe key quality metrics, provide a freely available software package to compute them, and demonstrate that identification of batch effects is aided by principal components analysis of these metrics. To mitigate batch effects, we developed new site-specific filters that identified and removed variants that falsely associated with the phenotype due to batch effect. These include filtering based on: a haplotype based genotype correction, a differential genotype quality test, and removing sites with missing genotype rate greater than 30% after setting genotypes with quality scores less than 20 to missing. This method removed 96.1% of unconfirmed genome-wide significant SNP associations and 97.6% of unconfirmed genome-wide significant indel associations. We performed analyses to demonstrate that: 1) These filters impacted variants known to be disease associated as 2 out of 16 confirmed associations in an AMD candidate SNP analysis were filtered, representing a reduction in power of 12.5%, 2) In the absence of batch effects, these filters removed only a small proportion of variants across the genome (type I error rate of 3%), and 3) in an independent dataset, the method removed 90.2% of unconfirmed genome-wide SNP associations and 89.8% of unconfirmed genome-wide indel associations. Researchers currently do not have effective tools to identify and mitigate batch effects in whole genome sequencing data. We developed and validated methods and filters to address this deficiency.

Patterns and architecture of genomic islands in marine bacteria

PubMed Central

2012-01-01

Background Genomic Islands (GIs) have key roles since they modulate the structure and size of bacterial genomes displaying a diverse set of laterally transferred genes. Despite their importance, GIs in marine bacterial genomes have not been explored systematically to uncover possible trends and to analyze their putative ecological significance. Results We carried out a comprehensive analysis of GIs in 70 selected marine bacterial genomes detected with IslandViewer to explore the distribution, patterns and functional gene content in these genomic regions. We detected 438 GIs containing a total of 8152 genes. GI number per genome was strongly and positively correlated with the total GI size. In 50% of the genomes analyzed the GIs accounted for approximately 3% of the genome length, with a maximum of 12%. Interestingly, we found transposases particularly enriched within Alphaproteobacteria GIs, and site-specific recombinases in Gammaproteobacteria GIs. We described specific Homologous Recombination GIs (HR-GIs) in several genera of marine Bacteroidetes and in Shewanella strains among others. In these HR-GIs, we recurrently found conserved genes such as the β-subunit of DNA-directed RNA polymerase, regulatory sigma factors, the elongation factor Tu and ribosomal protein genes typically associated with the core genome. Conclusions Our results indicate that horizontal gene transfer mediated by phages, plasmids and other mobile genetic elements, and HR by site-specific recombinases play important roles in the mobility of clusters of genes between taxa and within closely related genomes, modulating the flexible pool of the genome. Our findings suggest that GIs may increase bacterial fitness under environmental changing conditions by acquiring novel foreign genes and/or modifying gene transcription and/or transduction. PMID:22839777

In Silico Pattern-Based Analysis of the Human Cytomegalovirus Genome

PubMed Central

Rigoutsos, Isidore; Novotny, Jiri; Huynh, Tien; Chin-Bow, Stephen T.; Parida, Laxmi; Platt, Daniel; Coleman, David; Shenk, Thomas

2003-01-01

More than 200 open reading frames (ORFs) from the human cytomegalovirus genome have been reported as potentially coding for proteins. We have used two pattern-based in silico approaches to analyze this set of putative viral genes. With the help of an objective annotation method that is based on the Bio-Dictionary, a comprehensive collection of amino acid patterns that describes the currently known natural sequence space of proteins, we have reannotated all of the previously reported putative genes of the human cytomegalovirus. Also, with the help of MUSCA, a pattern-based multiple sequence alignment algorithm, we have reexamined the original human cytomegalovirus gene family definitions. Our analysis of the genome shows that many of the coded proteins comprise amino acid combinations that are unique to either the human cytomegalovirus or the larger group of herpesviruses. We have confirmed that a surprisingly large portion of the analyzed ORFs encode membrane proteins, and we have discovered a significant number of previously uncharacterized proteins that are predicted to be G-protein-coupled receptor homologues. The analysis also indicates that many of the encoded proteins undergo posttranslational modifications such as hydroxylation, phosphorylation, and glycosylation. ORFs encoding proteins with similar functional behavior appear in neighboring regions of the human cytomegalovirus genome. All of the results of the present study can be found and interactively explored online (http://cbcsrv.watson.ibm.com/virus/). PMID:12634390

In silico pattern-based analysis of the human cytomegalovirus genome.

PubMed

Rigoutsos, Isidore; Novotny, Jiri; Huynh, Tien; Chin-Bow, Stephen T; Parida, Laxmi; Platt, Daniel; Coleman, David; Shenk, Thomas

2003-04-01

More than 200 open reading frames (ORFs) from the human cytomegalovirus genome have been reported as potentially coding for proteins. We have used two pattern-based in silico approaches to analyze this set of putative viral genes. With the help of an objective annotation method that is based on the Bio-Dictionary, a comprehensive collection of amino acid patterns that describes the currently known natural sequence space of proteins, we have reannotated all of the previously reported putative genes of the human cytomegalovirus. Also, with the help of MUSCA, a pattern-based multiple sequence alignment algorithm, we have reexamined the original human cytomegalovirus gene family definitions. Our analysis of the genome shows that many of the coded proteins comprise amino acid combinations that are unique to either the human cytomegalovirus or the larger group of herpesviruses. We have confirmed that a surprisingly large portion of the analyzed ORFs encode membrane proteins, and we have discovered a significant number of previously uncharacterized proteins that are predicted to be G-protein-coupled receptor homologues. The analysis also indicates that many of the encoded proteins undergo posttranslational modifications such as hydroxylation, phosphorylation, and glycosylation. ORFs encoding proteins with similar functional behavior appear in neighboring regions of the human cytomegalovirus genome. All of the results of the present study can be found and interactively explored online (http://cbcsrv.watson.ibm.com/virus/).

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

PubMed Central

Gorski, Mathias; van der Most, Peter J.; Teumer, Alexander; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Nolte, Ilja M.; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F.; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P.; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C.; Curhan, Gary C.; d’Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H.; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J.; Harris, Tamara B.; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G.; Homuth, Georg; Hu, Frank B.; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K.; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J.; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J. F.; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A.; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J.; Olden, Matthias; WJH Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P.; Probst-Hensch, Nicole; Raitakari, Olli T.; Rettig, Rainer; Ridker, Paul M.; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E.; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J.; Sedaghat, Sanaz; Smith, Albert V.; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G.; Ulivi, Sheila; Viikari, Jorma S.; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I.; Tromp, Gerard; Snieder, Harold; Heid, Iris M.; Fox, Caroline S.; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A.; Fuchsberger, Christian

2017-01-01

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. PMID:28452372

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

PubMed

Gorski, Mathias; van der Most, Peter J; Teumer, Alexander; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Nolte, Ilja M; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C; Curhan, Gary C; d'Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J; Harris, Tamara B; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G; Homuth, Georg; Hu, Frank B; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J F; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J; Olden, Matthias; Wjh Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P; Probst-Hensch, Nicole; Raitakari, Olli T; Rettig, Rainer; Ridker, Paul M; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J; Sedaghat, Sanaz; Smith, Albert V; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G; Ulivi, Sheila; Viikari, Jorma S; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I; Tromp, Gerard; Snieder, Harold; Heid, Iris M; Fox, Caroline S; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A; Fuchsberger, Christian

2017-04-28

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 -8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

Genome-wide patterns of copy number variation in the Chinese yak genome.

PubMed

Zhang, Xiao; Wang, Kun; Wang, Lizhong; Yang, Yongzhi; Ni, Zhengqiang; Xie, Xiuyue; Shao, Xuemin; Han, Jin; Wan, Dongshi; Qiu, Qiang

2016-05-20

Copy number variation (CNV) represents an important source of genetic divergence that can produce drastic phenotypic differences and may therefore be subject to selection during domestication and environmental adaptation. To investigate the evolutionary dynamics of CNV in the yak genome, we used a read depth approach to detect CNV based on genome resequencing data from 14 wild and 65 domestic yaks and determined CNV regions related to domestication and adaptations to high-altitude. We identified 2,634 CNV regions (CNVRs) comprising a total of 153 megabases (5.7 % of the yak genome) and 3,879 overlapping annotated genes. Comparison between domestic and wild yak populations identified 121 potentially selected CNVRs, harboring genes related to neuronal development, reproduction, nutrition and energy metabolism. In addition, we found 85 CNVRs that are significantly different between domestic yak living in high- and low-altitude areas, including three genes related to hypoxia response and six related to immune defense. This analysis shows that genic CNVs may play an important role in phenotypic changes during yak domestication and adaptation to life at high-altitude. We present the first refined CNV map for yak along with comprehensive genomic analysis of yak CNV. Our results provide new insights into the genetic basis of yak domestication and adaptation to living in a high-altitude environment, as well as a valuable genetic resource that will facilitate future CNV association studies of important traits in yak and other bovid species.

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing.

PubMed

Ryland, Georgina L; Jones, Kate; Chin, Melody; Markham, John; Aydogan, Elle; Kankanige, Yamuna; Caruso, Marisa; Guinto, Jerick; Dickinson, Michael; Prince, H Miles; Yong, Kwee; Blombery, Piers

2018-05-14

Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline. At least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed. Our results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data.

PubMed

Bigham, Abigail; Bauchet, Marc; Pinto, Dalila; Mao, Xianyun; Akey, Joshua M; Mei, Rui; Scherer, Stephen W; Julian, Colleen G; Wilson, Megan J; López Herráez, David; Brutsaert, Tom; Parra, Esteban J; Moore, Lorna G; Shriver, Mark D

2010-09-09

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary

Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data

PubMed Central

Bigham, Abigail; Bauchet, Marc; Pinto, Dalila; Mao, Xianyun; Akey, Joshua M.; Mei, Rui; Scherer, Stephen W.; Julian, Colleen G.; Wilson, Megan J.; López Herráez, David; Brutsaert, Tom; Parra, Esteban J.; Moore, Lorna G.; Shriver, Mark D.

2010-01-01

High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary

The patterns of genomic variances and covariances across genome for milk production traits between Chinese and Nordic Holstein populations.

PubMed

Li, Xiujin; Lund, Mogens Sandø; Janss, Luc; Wang, Chonglong; Ding, Xiangdong; Zhang, Qin; Su, Guosheng

2017-03-15

With the development of SNP chips, SNP information provides an efficient approach to further disentangle different patterns of genomic variances and covariances across the genome for traits of interest. Due to the interaction between genotype and environment as well as possible differences in genetic background, it is reasonable to treat the performances of a biological trait in different populations as different but genetic correlated traits. In the present study, we performed an investigation on the patterns of region-specific genomic variances, covariances and correlations between Chinese and Nordic Holstein populations for three milk production traits. Variances and covariances between Chinese and Nordic Holstein populations were estimated for genomic regions at three different levels of genome region (all SNP as one region, each chromosome as one region and every 100 SNP as one region) using a novel multi-trait random regression model which uses latent variables to model heterogeneous variance and covariance. In the scenario of the whole genome as one region, the genomic variances, covariances and correlations obtained from the new multi-trait Bayesian method were comparable to those obtained from a multi-trait GBLUP for all the three milk production traits. In the scenario of each chromosome as one region, BTA 14 and BTA 5 accounted for very large genomic variance, covariance and correlation for milk yield and fat yield, whereas no specific chromosome showed very large genomic variance, covariance and correlation for protein yield. In the scenario of every 100 SNP as one region, most regions explained <0.50% of genomic variance and covariance for milk yield and fat yield, and explained <0.30% for protein yield, while some regions could present large variance and covariance. Although overall correlations between two populations for the three traits were positive and high, a few regions still showed weakly positive or highly negative genomic correlations for

Population genomic analysis reveals differential evolutionary histories and patterns of diversity across subgenomes and subpopulations of Brassica napus L.

DOE PAGES

Gazave, Elodie; Tassone, Erica E.; Ilut, Daniel C.; ...

2016-04-21

Here, the allotetraploid species Brassica napus L. is a global crop of major economic importance, providing canola oil (seed) and vegetables for human consumption and fodder and meal for livestock feed. Characterizing the genetic diversity present in the extant germplasm pool of B. napus is fundamental to better conserve, manage and utilize the genetic resources of this species. We used sequence-based genotyping to identify and genotype 30,881 SNPs in a diversity panel of 782 B. napus accessions, representing samples of winter and spring growth habits originating from 33 countries across Europe, Asia, and America. We detected strong population structure broadlymore » concordant with growth habit and geography, and identified three major genetic groups: spring (SP), winter Europe (WE), and winter Asia (WA). Subpopulation-specific polymorphism patterns suggest enriched genetic diversity within the WA group and a smaller effective breeding population for the SP group compared to WE. Interestingly, the two subgenomes of B. napus appear to have different geographic origins, with phylogenetic analysis placing WE and WA as basal clades for the other subpopulations in the C and A subgenomes, respectively. Finally, we identified 16 genomic regions where the patterns of diversity differed markedly from the genome-wide average, several of which are suggestive of genomic inversions. The results obtained in this study constitute a valuable resource for worldwide breeding efforts and the genetic dissection and prediction of complex B. napus traits.« less

Population genomic analysis reveals differential evolutionary histories and patterns of diversity across subgenomes and subpopulations of Brassica napus L.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gazave, Elodie; Tassone, Erica E.; Ilut, Daniel C.

Here, the allotetraploid species Brassica napus L. is a global crop of major economic importance, providing canola oil (seed) and vegetables for human consumption and fodder and meal for livestock feed. Characterizing the genetic diversity present in the extant germplasm pool of B. napus is fundamental to better conserve, manage and utilize the genetic resources of this species. We used sequence-based genotyping to identify and genotype 30,881 SNPs in a diversity panel of 782 B. napus accessions, representing samples of winter and spring growth habits originating from 33 countries across Europe, Asia, and America. We detected strong population structure broadlymore » concordant with growth habit and geography, and identified three major genetic groups: spring (SP), winter Europe (WE), and winter Asia (WA). Subpopulation-specific polymorphism patterns suggest enriched genetic diversity within the WA group and a smaller effective breeding population for the SP group compared to WE. Interestingly, the two subgenomes of B. napus appear to have different geographic origins, with phylogenetic analysis placing WE and WA as basal clades for the other subpopulations in the C and A subgenomes, respectively. Finally, we identified 16 genomic regions where the patterns of diversity differed markedly from the genome-wide average, several of which are suggestive of genomic inversions. The results obtained in this study constitute a valuable resource for worldwide breeding efforts and the genetic dissection and prediction of complex B. napus traits.« less

Synonymous codon usage patterns in different parasitic platyhelminth mitochondrial genomes.

PubMed

Chen, L; Yang, D Y; Liu, T F; Nong, X; Huang, X; Xie, Y; Fu, Y; Zheng, W P; Zhang, R H; Wu, X H; Gu, X B; Wang, S X; Peng, X R; Yang, G Y

2013-02-27

We analyzed synonymous codon usage patterns of the mitochondrial genomes of 43 parasitic platyhelminth species. The relative synonymous codon usage, the effective number of codons (NC) and the frequency of G+C at the third synonymously variable coding position were calculated. Correspondence analysis was used to determine the major variation trends shaping the codon usage patterns. Among the mitochondrial genomes of 19 trematode species, the GC content of third codon positions varied from 0.151 to 0.592, with a mean of 0.295 ± 0.116. In cestodes, the mean GC content of third codon positions was 0.254 ± 0.044. A comparison of the nucleotide composition at 4-fold synonymous sites revealed that, on average, there was a greater abundance of codons ending on U (51.9%) or A (22.7%) than on C (6.3%) or G (19.14%). Twenty-two codons, including UUU, UUA and UUG, were frequently used. In the NC-plot, most of points were distributed well below or around the expected NC curve. In addition to compositional constraints, the degree of hydrophobicity and the aromatic amino acids also influenced codon usage in the mitochondrial genomes of these 43 parasitic platyhelminth species.

Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles

PubMed Central

Nandi, Tannistha; Holden, Matthew T.G.; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A.; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J.; Titball, Richard; Chen, Swaine L.; Parkhill, Julian

2015-01-01

Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity. PMID:25236617

Identifying novel biomarkers in sarcoidosis using genome-based approaches

PubMed Central

Knox, Kenneth S.; Garcia, Joe G.N.

2015-01-01

Synopsis We briefly review conventional biomarkers used clinically to 1) support a diagnosis and 2) monitor disease progression in patients with sarcoidosis. We describe potential new biomarkers identified by genome-wide screening and the approaches to discover these biomarkers. PMID:26593137

Comparison of 17 genome types of adenovirus type 3 identified among strains recovered from six continents.

PubMed Central

Li, Q G; Wadell, G

1988-01-01

Restriction endonucleases BamHI, BclI, BglI, BglII, BstEII, EcoRI, HindIII, HpaI, SalI, SmalI, XbalI, and XholI were used to analyze 61 selected strains of adenovirus type 3 (Ad3) isolated from Africa, Asia, Australia, Europe, North America, and South America. It was noted that the use of BamHI, BclI, BglII, HpaI, SalI, and SmaI was sufficient to distinguish 17 genome types; 13 of them were newly identified. All 17 Ad3 genome types could be divided into three genomic clusters. Genome types of Ad3 cluster 1 occurred in Africa, Europe, South America, and North America. Genomic cluster 2 was identified in Africa; genomic cluster 3 was identified in Africa, Asia, Australia, Europe (a few), and North America. This was of interest because 15 identified genome types of Ad7 could also be divided into three genomic clusters. The degree of genetic relatedness between the 17 Ad3 and the 15 Ad7 genome types was analyzed and was expressed in a three-dimensional model. Images PMID:2838500

Whole-genome resequencing of 292 pigeonpea accessions identifies genomic regions associated with domestication and agronomic traits.

PubMed

Varshney, Rajeev K; Saxena, Rachit K; Upadhyaya, Hari D; Khan, Aamir W; Yu, Yue; Kim, Changhoon; Rathore, Abhishek; Kim, Dongseon; Kim, Jihun; An, Shaun; Kumar, Vinay; Anuradha, Ghanta; Yamini, Kalinati Narasimhan; Zhang, Wei; Muniswamy, Sonnappa; Kim, Jong-So; Penmetsa, R Varma; von Wettberg, Eric; Datta, Swapan K

2017-07-01

Pigeonpea (Cajanus cajan), a tropical grain legume with low input requirements, is expected to continue to have an important role in supplying food and nutritional security in developing countries in Asia, Africa and the tropical Americas. From whole-genome resequencing of 292 Cajanus accessions encompassing breeding lines, landraces and wild species, we characterize genome-wide variation. On the basis of a scan for selective sweeps, we find several genomic regions that were likely targets of domestication and breeding. Using genome-wide association analysis, we identify associations between several candidate genes and agronomically important traits. Candidate genes for these traits in pigeonpea have sequence similarity to genes functionally characterized in other plants for flowering time control, seed development and pod dehiscence. Our findings will allow acceleration of genetic gains for key traits to improve yield and sustainability in pigeonpea.

Genome and transcriptome sequencing identifies breeding targets in the orphan crop tef (Eragrostis tef).

PubMed

Cannarozzi, Gina; Plaza-Wüthrich, Sonia; Esfeld, Korinna; Larti, Stéphanie; Wilson, Yi Song; Girma, Dejene; de Castro, Edouard; Chanyalew, Solomon; Blösch, Regula; Farinelli, Laurent; Lyons, Eric; Schneider, Michel; Falquet, Laurent; Kuhlemeier, Cris; Assefa, Kebebew; Tadele, Zerihun

2014-07-09

Tef (Eragrostis tef), an indigenous cereal critical to food security in the Horn of Africa, is rich in minerals and protein, resistant to many biotic and abiotic stresses and safe for diabetics as well as sufferers of immune reactions to wheat gluten. We present the genome of tef, the first species in the grass subfamily Chloridoideae and the first allotetraploid assembled de novo. We sequenced the tef genome for marker-assisted breeding, to shed light on the molecular mechanisms conferring tef's desirable nutritional and agronomic properties, and to make its genome publicly available as a community resource. The draft genome contains 672 Mbp representing 87% of the genome size estimated from flow cytometry. We also sequenced two transcriptomes, one from a normalized RNA library and another from unnormalized RNASeq data. The normalized RNA library revealed around 38000 transcripts that were then annotated by the SwissProt group. The CoGe comparative genomics platform was used to compare the tef genome to other genomes, notably sorghum. Scaffolds comprising approximately half of the genome size were ordered by syntenic alignment to sorghum producing tef pseudo-chromosomes, which were sorted into A and B genomes as well as compared to the genetic map of tef. The draft genome was used to identify novel SSR markers, investigate target genes for abiotic stress resistance studies, and understand the evolution of the prolamin family of proteins that are responsible for the immune response to gluten. It is highly plausible that breeding targets previously identified in other cereal crops will also be valuable breeding targets in tef. The draft genome and transcriptome will be of great use for identifying these targets for genetic improvement of this orphan crop that is vital for feeding 50 million people in the Horn of Africa.

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

PubMed Central

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

2015-01-01

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

Genome-wide classification, evolutionary analysis and gene expression patterns of the kinome in Gossypium

PubMed Central

Yan, Jun; Li, Guilin; Guo, Xingqi; Li, Yang; Cao, Xuecheng

2018-01-01

The protein kinase (PK, kinome) family is one of the largest families in plants and regulates almost all aspects of plant processes, including plant development and stress responses. Despite their important functions, comprehensive functional classification, evolutionary analysis and expression patterns of the cotton PK gene family has yet to be performed on PK genes. In this study, we identified the cotton kinomes in the Gossypium raimondii, Gossypium arboretum, Gossypium hirsutum and Gossypium barbadense genomes and classified them into 7 groups and 122–24 subfamilies using software HMMER v3.0 scanning and neighbor-joining (NJ) phylogenetic analysis. Some conserved exon-intron structures were identified not only in cotton species but also in primitive plants, ferns and moss, suggesting the significant function and ancient origination of these PK genes. Collinearity analysis revealed that 16.6 million years ago (Mya) cotton-specific whole genome duplication (WGD) events may have played a partial role in the expansion of the cotton kinomes, whereas tandem duplication (TD) events mainly contributed to the expansion of the cotton RLK group. Synteny analysis revealed that tetraploidization of G. hirsutum and G. barbadense contributed to the expansion of G. hirsutum and G. barbadense PKs. Global expression analysis of cotton PKs revealed stress-specific and fiber development-related expression patterns, suggesting that many cotton PKs might be involved in the regulation of the stress response and fiber development processes. This study provides foundational information for further studies on the evolution and molecular function of cotton PKs. PMID:29768506

Machine-learning approach identifies a pattern of gene expression in peripheral blood that can accurately detect ischaemic stroke

PubMed Central

O’Connell, Grant C; Petrone, Ashley B; Treadway, Madison B; Tennant, Connie S; Lucke-Wold, Noelle; Chantler, Paul D; Barr, Taura L

2016-01-01

Early and accurate diagnosis of stroke improves the probability of positive outcome. The objective of this study was to identify a pattern of gene expression in peripheral blood that could potentially be optimised to expedite the diagnosis of acute ischaemic stroke (AIS). A discovery cohort was recruited consisting of 39 AIS patients and 24 neurologically asymptomatic controls. Peripheral blood was sampled at emergency department admission, and genome-wide expression profiling was performed via microarray. A machine-learning technique known as genetic algorithm k-nearest neighbours (GA/kNN) was then used to identify a pattern of gene expression that could optimally discriminate between groups. This pattern of expression was then assessed via qRT-PCR in an independent validation cohort, where it was evaluated for its ability to discriminate between an additional 39 AIS patients and 30 neurologically asymptomatic controls, as well as 20 acute stroke mimics. GA/kNN identified 10 genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B and PLXDC2) whose coordinate pattern of expression was able to identify 98.4% of discovery cohort subjects correctly (97.4% sensitive, 100% specific). In the validation cohort, the expression levels of the same 10 genes were able to identify 95.6% of subjects correctly when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 94.9% of subjects correctly when comparing AIS patients with stroke mimics (97.4% sensitive, 90.0% specific). The transcriptional pattern identified in this study shows strong diagnostic potential, and warrants further evaluation to determine its true clinical efficacy. PMID:29263821

Efficiently Identifying Significant Associations in Genome-wide Association Studies

PubMed Central

Eskin, Eleazar

2013-01-01

Abstract Over the past several years, genome-wide association studies (GWAS) have implicated hundreds of genes in common disease. More recently, the GWAS approach has been utilized to identify regions of the genome that harbor variation affecting gene expression or expression quantitative trait loci (eQTLs). Unlike GWAS applied to clinical traits, where only a handful of phenotypes are analyzed per study, in eQTL studies, tens of thousands of gene expression levels are measured, and the GWAS approach is applied to each gene expression level. This leads to computing billions of statistical tests and requires substantial computational resources, particularly when applying novel statistical methods such as mixed models. We introduce a novel two-stage testing procedure that identifies all of the significant associations more efficiently than testing all the single nucleotide polymorphisms (SNPs). In the first stage, a small number of informative SNPs, or proxies, across the genome are tested. Based on their observed associations, our approach locates the regions that may contain significant SNPs and only tests additional SNPs from those regions. We show through simulations and analysis of real GWAS datasets that the proposed two-stage procedure increases the computational speed by a factor of 10. Additionally, efficient implementation of our software increases the computational speed relative to the state-of-the-art testing approaches by a factor of 75. PMID:24033261

Genome-wide association analysis identifies 30 new susceptibility loci for schizophrenia.

PubMed

Li, Zhiqiang; Chen, Jianhua; Yu, Hao; He, Lin; Xu, Yifeng; Zhang, Dai; Yi, Qizhong; Li, Changgui; Li, Xingwang; Shen, Jiawei; Song, Zhijian; Ji, Weidong; Wang, Meng; Zhou, Juan; Chen, Boyu; Liu, Yahui; Wang, Jiqiang; Wang, Peng; Yang, Ping; Wang, Qingzhong; Feng, Guoyin; Liu, Benxiu; Sun, Wensheng; Li, Baojie; He, Guang; Li, Weidong; Wan, Chunling; Xu, Qi; Li, Wenjin; Wen, Zujia; Liu, Ke; Huang, Fang; Ji, Jue; Ripke, Stephan; Yue, Weihua; Sullivan, Patrick F; O'Donovan, Michael C; Shi, Yongyong

2017-11-01

We conducted a genome-wide association study (GWAS) with replication in 36,180 Chinese individuals and performed further transancestry meta-analyses with data from the Psychiatry Genomics Consortium (PGC2). Approximately 95% of the genome-wide significant (GWS) index alleles (or their proxies) from the PGC2 study were overrepresented in Chinese schizophrenia cases, including ∼50% that achieved nominal significance and ∼75% that continued to be GWS in the transancestry analysis. The Chinese-only analysis identified seven GWS loci; three of these also were GWS in the transancestry analyses, which identified 109 GWS loci, thus yielding a total of 113 GWS loci (30 novel) in at least one of these analyses. We observed improvements in the fine-mapping resolution at many susceptibility loci. Our results provide several lines of evidence supporting candidate genes at many loci and highlight some pathways for further research. Together, our findings provide novel insight into the genetic architecture and biological etiology of schizophrenia.

Determining coding CpG islands by identifying regions significant for pattern statistics on Markov chains.

PubMed

Singer, Meromit; Engström, Alexander; Schönhuth, Alexander; Pachter, Lior

2011-09-23

Recent experimental and computational work confirms that CpGs can be unmethylated inside coding exons, thereby showing that codons may be subjected to both genomic and epigenomic constraint. It is therefore of interest to identify coding CpG islands (CCGIs) that are regions inside exons enriched for CpGs. The difficulty in identifying such islands is that coding exons exhibit sequence biases determined by codon usage and constraints that must be taken into account. We present a method for finding CCGIs that showcases a novel approach we have developed for identifying regions of interest that are significant (with respect to a Markov chain) for the counts of any pattern. Our method begins with the exact computation of tail probabilities for the number of CpGs in all regions contained in coding exons, and then applies a greedy algorithm for selecting islands from among the regions. We show that the greedy algorithm provably optimizes a biologically motivated criterion for selecting islands while controlling the false discovery rate. We applied this approach to the human genome (hg18) and annotated CpG islands in coding exons. The statistical criterion we apply to evaluating islands reduces the number of false positives in existing annotations, while our approach to defining islands reveals significant numbers of undiscovered CCGIs in coding exons. Many of these appear to be examples of functional epigenetic specialization in coding exons.

Pooled-DNA sequencing identifies genomic regions of selection in Nigerian isolates of Plasmodium falciparum.

PubMed

Oyebola, Kolapo M; Idowu, Emmanuel T; Olukosi, Yetunde A; Awolola, Taiwo S; Amambua-Ngwa, Alfred

2017-06-29

The burden of falciparum malaria is especially high in sub-Saharan Africa. Differences in pressure from host immunity and antimalarial drugs lead to adaptive changes responsible for high level of genetic variations within and between the parasite populations. Population-specific genetic studies to survey for genes under positive or balancing selection resulting from drug pressure or host immunity will allow for refinement of interventions. We performed a pooled sequencing (pool-seq) of the genomes of 100 Plasmodium falciparum isolates from Nigeria. We explored allele-frequency based neutrality test (Tajima's D) and integrated haplotype score (iHS) to identify genes under selection. Fourteen shared iHS regions that had at least 2 SNPs with a score > 2.5 were identified. These regions code for genes that were likely to have been under strong directional selection. Two of these genes were the chloroquine resistance transporter (CRT) on chromosome 7 and the multidrug resistance 1 (MDR1) on chromosome 5. There was a weak signature of selection in the dihydrofolate reductase (DHFR) gene on chromosome 4 and MDR5 genes on chromosome 13, with only 2 and 3 SNPs respectively identified within the iHS window. We observed strong selection pressure attributable to continued chloroquine and sulfadoxine-pyrimethamine use despite their official proscription for the treatment of uncomplicated malaria. There was also a major selective sweep on chromosome 6 which had 32 SNPs within the shared iHS region. Tajima's D of circumsporozoite protein (CSP), erythrocyte-binding antigen (EBA-175), merozoite surface proteins - MSP3 and MSP7, merozoite surface protein duffy binding-like (MSPDBL2) and serine repeat antigen (SERA-5) were 1.38, 1.29, 0.73, 0.84 and 0.21, respectively. We have demonstrated the use of pool-seq to understand genomic patterns of selection and variability in P. falciparum from Nigeria, which bears the highest burden of infections. This investigation identified known

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster.

PubMed

Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F; Arthur, Robert K; Kheradpour, Pouya; Kundaje, Anshul; Nègre, Nicolas; Crofts, Alex; Ptashkin, Ryan; Zieba, Jennifer; Ostapenko, Alexander; Suchy, Sarah; Victorsen, Alec; Jameel, Nader; Grundstad, A Jason; Gao, Wenxuan; Moran, Jennifer R; Rehm, E Jay; Grossman, Robert L; Kellis, Manolis; White, Kevin P

2014-07-01

Annotation of regulatory elements and identification of the transcription-related factors (TRFs) targeting these elements are key steps in understanding how cells interpret their genetic blueprint and their environment during development, and how that process goes awry in the case of disease. One goal of the modENCODE (model organism ENCyclopedia of DNA Elements) Project is to survey a diverse sampling of TRFs, both DNA-binding and non-DNA-binding factors, to provide a framework for the subsequent study of the mechanisms by which transcriptional regulators target the genome. Here we provide an updated map of the Drosophila melanogaster regulatory genome based on the location of 84 TRFs at various stages of development. This regulatory map reveals a variety of genomic targeting patterns, including factors with strong preferences toward proximal promoter binding, factors that target intergenic and intronic DNA, and factors with distinct chromatin state preferences. The data also highlight the stringency of the Polycomb regulatory network, and show association of the Trithorax-like (Trl) protein with hotspots of DNA binding throughout development. Furthermore, the data identify more than 5800 instances in which TRFs target DNA regions with demonstrated enhancer activity. Regions of high TRF co-occupancy are more likely to be associated with open enhancers used across cell types, while lower TRF occupancy regions are associated with complex enhancers that are also regulated at the epigenetic level. Together these data serve as a resource for the research community in the continued effort to dissect transcriptional regulatory mechanisms directing Drosophila development. © 2014 Slattery et al.; Published by Cold Spring Harbor Laboratory Press.

Identifying elemental genomic track types and representing them uniformly

PubMed Central

2011-01-01

Background With the recent advances and availability of various high-throughput sequencing technologies, data on many molecular aspects, such as gene regulation, chromatin dynamics, and the three-dimensional organization of DNA, are rapidly being generated in an increasing number of laboratories. The variation in biological context, and the increasingly dispersed mode of data generation, imply a need for precise, interoperable and flexible representations of genomic features through formats that are easy to parse. A host of alternative formats are currently available and in use, complicating analysis and tool development. The issue of whether and how the multitude of formats reflects varying underlying characteristics of data has to our knowledge not previously been systematically treated. Results We here identify intrinsic distinctions between genomic features, and argue that the distinctions imply that a certain variation in the representation of features as genomic tracks is warranted. Four core informational properties of tracks are discussed: gaps, lengths, values and interconnections. From this we delineate fifteen generic track types. Based on the track type distinctions, we characterize major existing representational formats and find that the track types are not adequately supported by any single format. We also find, in contrast to the XML formats, that none of the existing tabular formats are conveniently extendable to support all track types. We thus propose two unified formats for track data, an improved XML format, BioXSD 1.1, and a new tabular format, GTrack 1.0. Conclusions The defined track types are shown to capture relevant distinctions between genomic annotation tracks, resulting in varying representational needs and analysis possibilities. The proposed formats, GTrack 1.0 and BioXSD 1.1, cater to the identified track distinctions and emphasize preciseness, flexibility and parsing convenience. PMID:22208806

Determining Epigenetic Targets: A Beginner's Guide to Identifying Genome Functionality Through Database Analysis.

PubMed

Hay, Elizabeth A; Cowie, Philip; MacKenzie, Alasdair

2017-01-01

There can now be little doubt that the cis-regulatory genome represents the largest information source within the human genome essential for health. In addition to containing up to five times more information than the coding genome, the cis-regulatory genome also acts as a major reservoir of disease-associated polymorphic variation. The cis-regulatory genome, which is comprised of enhancers, silencers, promoters, and insulators, also acts as a major functional target for epigenetic modification including DNA methylation and chromatin modifications. These epigenetic modifications impact the ability of cis-regulatory sequences to maintain tissue-specific and inducible expression of genes that preserve health. There has been limited ability to identify and characterize the functional components of this huge and largely misunderstood part of the human genome that, for decades, was ignored as "Junk" DNA. In an attempt to address this deficit, the current chapter will first describe methods of identifying and characterizing functional elements of the cis-regulatory genome at a genome-wide level using databases such as ENCODE, the UCSC browser, and NCBI. We will then explore the databases on the UCSC genome browser, which provides access to DNA methylation and chromatin modification datasets. Finally, we will describe how we can superimpose the huge volume of study data contained in the NCBI archives onto that contained within the UCSC browser in order to glean relevant in vivo study data for any locus within the genome. An ability to access and utilize these information sources will become essential to informing the future design of experiments and subsequent determination of the role of epigenetics in health and disease and will form a critical step in our development of personalized medicine.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

PubMed

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J; Tropf, Felix C; Shen, Xia; Wilson, James F; Chasman, Daniel I; Nolte, Ilja M; Tragante, Vinicius; van der Laan, Sander W; Perry, John R B; Kong, Augustine; Ahluwalia, Tarunveer S; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J; Gieger, Christian; Gunderson, Erica P; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F; McMahon, George; Meddens, S Fleur W; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A; Monnereau, Claire; van der Most, Peter J; Myhre, Ronny; Nalls, Mike A; Nutile, Teresa; Kalafati, Ioanna Panagiota; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B; Rich-Edwards, Janet; Rietveld, Cornelius A; Robino, Antonietta; Rose, Lynda M; Rueedi, Rico; Ryan, Kathleen A; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A; Stolk, Lisette; Streeten, Elizabeth; Tönjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I; Buring, Julie E; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R; Cucca, Francesco; Toniolo, Daniela; Davey-Smith, George; Deary, Ian J; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M; de Geus, Eco J C; Eriksson, Johan G; Evans, Denis A; Faul, Jessica D; Sala, Cinzia Felicita; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J F; de Haan, Hugoline G; Haerting, Johannes; Harris, Tamara B; Heath, Andrew C; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hyppönen, Elina; Jacobsson, Bo; Jaddoe, Vincent W V; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L R; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William G; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia M; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McQuillan, Ruth; Medland, Sarah E; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Traglia, Michela; Milani, Lili; Mitchell, Paul; Montgomery, Grant W; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W J H; Perola, Markus; Peyser, Patricia A; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M; Ring, Susan M; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D; Starr, John M; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tung, Joyce Y; Uitterlinden, André G; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G; Wang, Jie Jin; Wareham, Nicholas J; Weir, David R; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F; Zondervan, Krina T; Stefansson, Kari; Krueger, Robert F; Lee, James J; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C

2016-12-01

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

Identifying artificial selection signals in the chicken genome.

PubMed

Ma, Yunlong; Gu, Lantao; Yang, Liubin; Sun, Chenghao; Xie, Shengsong; Fang, Chengchi; Gong, Yangzhang; Li, Shijun

2018-01-01

Identifying the signals of artificial selection can contribute to further shaping economically important traits. Here, a chicken 600k SNP-array was employed to detect the signals of artificial selection using 331 individuals from 9 breeds, including Jingfen (JF), Jinghong (JH), Araucanas (AR), White Leghorn (WL), Pekin-Bantam (PB), Shamo (SH), Gallus-Gallus-Spadiceus (GA), Rheinlander (RH) and Vorwerkhuhn (VO). Per the population genetic structure, 9 breeds were combined into 5 breed-pools, and a 'two-step' strategy was used to reveal the signals of artificial selection. GA, which has little artificial selection, was defined as the reference population, and a total of 204, 155, 305 and 323 potential artificial selection signals were identified in AR_VO, PB, RH_WL and JH_JF, respectively. We also found signals derived from standing and de-novo genetic variations have contributed to adaptive evolution during artificial selection. Further enrichment analysis suggests that the genomic regions of artificial selection signals harbour genes, including THSR, PTHLH and PMCH, responsible for economic traits, such as fertility, growth and immunization. Overall, this study found a series of genes that contribute to the improvement of chicken breeds and revealed the genetic mechanisms of adaptive evolution, which can be used as fundamental information in future chicken functional genomics study.

Comparative primate genomics: emerging patterns of genome content and dynamics

PubMed Central

Rogers, Jeffrey; Gibbs, Richard A.

2014-01-01

Preface Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for several primates, with analyses of several others underway. Whole genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other nonhuman primates provide valuable insight into genetic similarities and differences among species used as models for disease-related research. This review summarizes current knowledge regarding primate genome content and dynamics and offers a series of goals for the near future. PMID:24709753

Comparative primate genomics: emerging patterns of genome content and dynamics.

PubMed

Rogers, Jeffrey; Gibbs, Richard A

2014-05-01

Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for various primate species, and analyses of several others are underway. Whole-genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other non-human primates offer valuable insights into genetic similarities and differences among species that are used as models for disease-related research. This Review summarizes current knowledge regarding primate genome content and dynamics, and proposes a series of goals for the near future.

Comparative Genomics of 12 Strains of Erwinia amylovora Identifies a Pan-Genome with a Large Conserved Core

PubMed Central

Mann, Rachel A.; Smits, Theo H. M.; Bühlmann, Andreas; Blom, Jochen; Goesmann, Alexander; Frey, Jürg E.; Plummer, Kim M.; Beer, Steven V.; Luck, Joanne; Duffy, Brion; Rodoni, Brendan

2013-01-01

The plant pathogen Erwinia amylovora can be divided into two host-specific groupings; strains infecting a broad range of hosts within the Rosaceae subfamily Spiraeoideae (e.g., Malus, Pyrus, Crataegus, Sorbus) and strains infecting Rubus (raspberries and blackberries). Comparative genomic analysis of 12 strains representing distinct populations (e.g., geographic, temporal, host origin) of E. amylovora was used to describe the pan-genome of this major pathogen. The pan-genome contains 5751 coding sequences and is highly conserved relative to other phytopathogenic bacteria comprising on average 89% conserved, core genes. The chromosomes of Spiraeoideae-infecting strains were highly homogeneous, while greater genetic diversity was observed between Spiraeoideae- and Rubus-infecting strains (and among individual Rubus-infecting strains), the majority of which was attributed to variable genomic islands. Based on genomic distance scores and phylogenetic analysis, the Rubus-infecting strain ATCC BAA-2158 was genetically more closely related to the Spiraeoideae-infecting strains of E. amylovora than it was to the other Rubus-infecting strains. Analysis of the accessory genomes of Spiraeoideae- and Rubus-infecting strains has identified putative host-specific determinants including variation in the effector protein HopX1Ea and a putative secondary metabolite pathway only present in Rubus-infecting strains. PMID:23409014

Comparative genomics of 12 strains of Erwinia amylovora identifies a pan-genome with a large conserved core.

PubMed

Mann, Rachel A; Smits, Theo H M; Bühlmann, Andreas; Blom, Jochen; Goesmann, Alexander; Frey, Jürg E; Plummer, Kim M; Beer, Steven V; Luck, Joanne; Duffy, Brion; Rodoni, Brendan

2013-01-01

The plant pathogen Erwinia amylovora can be divided into two host-specific groupings; strains infecting a broad range of hosts within the Rosaceae subfamily Spiraeoideae (e.g., Malus, Pyrus, Crataegus, Sorbus) and strains infecting Rubus (raspberries and blackberries). Comparative genomic analysis of 12 strains representing distinct populations (e.g., geographic, temporal, host origin) of E. amylovora was used to describe the pan-genome of this major pathogen. The pan-genome contains 5751 coding sequences and is highly conserved relative to other phytopathogenic bacteria comprising on average 89% conserved, core genes. The chromosomes of Spiraeoideae-infecting strains were highly homogeneous, while greater genetic diversity was observed between Spiraeoideae- and Rubus-infecting strains (and among individual Rubus-infecting strains), the majority of which was attributed to variable genomic islands. Based on genomic distance scores and phylogenetic analysis, the Rubus-infecting strain ATCC BAA-2158 was genetically more closely related to the Spiraeoideae-infecting strains of E. amylovora than it was to the other Rubus-infecting strains. Analysis of the accessory genomes of Spiraeoideae- and Rubus-infecting strains has identified putative host-specific determinants including variation in the effector protein HopX1(Ea) and a putative secondary metabolite pathway only present in Rubus-infecting strains.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

PubMed Central

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

2017-01-01

The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

Functional genomics identifies specific vulnerabilities in PTEN-deficient breast cancer.

PubMed

Tang, Yew Chung; Ho, Szu-Chi; Tan, Elisabeth; Ng, Alvin Wei Tian; McPherson, John R; Goh, Germaine Yen Lin; Teh, Bin Tean; Bard, Frederic; Rozen, Steven G

2018-03-22

Phosphatase and tensin homolog (PTEN) is one of the most frequently inactivated tumor suppressors in breast cancer. While PTEN itself is not considered a druggable target, PTEN synthetic-sick or synthetic-lethal (PTEN-SSL) genes are potential drug targets in PTEN-deficient breast cancers. Therefore, with the aim of identifying potential targets for precision breast cancer therapy, we sought to discover PTEN-SSL genes present in a broad spectrum of breast cancers. To discover broad-spectrum PTEN-SSL genes in breast cancer, we used a multi-step approach that started with (1) a genome-wide short interfering RNA (siRNA) screen of ~ 21,000 genes in a pair of isogenic human mammary epithelial cell lines, followed by (2) a short hairpin RNA (shRNA) screen of ~ 1200 genes focused on hits from the first screen in a panel of 11 breast cancer cell lines; we then determined reproducibility of hits by (3) identification of overlaps between our results and reanalyzed data from 3 independent gene-essentiality screens, and finally, for selected candidate PTEN-SSL genes we (4) confirmed PTEN-SSL activity using either drug sensitivity experiments in a panel of 19 cell lines or mutual exclusivity analysis of publicly available pan-cancer somatic mutation data. The screens (steps 1 and 2) and the reproducibility analysis (step 3) identified six candidate broad-spectrum PTEN-SSL genes (PIK3CB, ADAMTS20, AP1M2, HMMR, STK11, and NUAK1). PIK3CB was previously identified as PTEN-SSL, while the other five genes represent novel PTEN-SSL candidates. Confirmation studies (step 4) provided additional evidence that NUAK1 and STK11 have PTEN-SSL patterns of activity. Consistent with PTEN-SSL status, inhibition of the NUAK1 protein kinase by the small molecule drug HTH-01-015 selectively impaired viability in multiple PTEN-deficient breast cancer cell lines, while mutations affecting STK11 and PTEN were largely mutually exclusive across large pan-cancer data sets. Six genes showed PTEN

Combining Genome-Scale Experimental and Computational Methods To Identify Essential Genes in Rhodobacter sphaeroides

DOE PAGES

Burger, Brian T.; Imam, Saheed; Scarborough, Matthew J.; ...

2017-06-06

Rhodobacter sphaeroides is one of the best-studied alphaproteobacteria from biochemical, genetic, and genomic perspectives. To gain a better systems-level understanding of this organism, we generated a large transposon mutant library and used transposon sequencing (Tn-seq) to identify genes that are essential under several growth conditions. Using newly developed Tn-seq analysis software (TSAS), we identified 493 genes as essential for aerobic growth on a rich medium. We then used the mutant library to identify conditionally essential genes under two laboratory growth conditions, identifying 85 additional genes required for aerobic growth in a minimal medium and 31 additional genes required for photosyntheticmore » growth. In all instances, our analyses confirmed essentiality for many known genes and identified genes not previously considered to be essential. We used the resulting Tn-seq data to refine and improve a genome-scale metabolic network model (GEM) for R. sphaeroides. Together, we demonstrate how genetic, genomic, and computational approaches can be combined to obtain a systems-level understanding of the genetic framework underlying metabolic diversity in bacterial species.« less

Genome-wide association study identifies 74 loci associated with educational attainment

PubMed Central

Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

2016-01-01

Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

Genome-wide association study identifies 74 loci associated with educational attainment.

PubMed

Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

2016-05-26

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Genome-wide study of resistant hypertension identified from electronic health records.

PubMed

Dumitrescu, Logan; Ritchie, Marylyn D; Denny, Joshua C; El Rouby, Nihal M; McDonough, Caitrin W; Bradford, Yuki; Ramirez, Andrea H; Bielinski, Suzette J; Basford, Melissa A; Chai, High Seng; Peissig, Peggy; Carrell, David; Pathak, Jyotishman; Rasmussen, Luke V; Wang, Xiaoming; Pacheco, Jennifer A; Kho, Abel N; Hayes, M Geoffrey; Matsumoto, Martha; Smith, Maureen E; Li, Rongling; Cooper-DeHoff, Rhonda M; Kullo, Iftikhar J; Chute, Christopher G; Chisholm, Rex L; Jarvik, Gail P; Larson, Eric B; Carey, David; McCarty, Catherine A; Williams, Marc S; Roden, Dan M; Bottinger, Erwin; Johnson, Julie A; de Andrade, Mariza; Crawford, Dana C

2017-01-01

Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10-6 (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.

Inferring patterns of folktale diffusion using genomic data

PubMed Central

Bortolini, Eugenio; Pagani, Luca; Sarno, Stefania; Boattini, Alessio; Sazzini, Marco; da Silva, Sara Graça; Martini, Gessica; Metspalu, Mait; Pettener, Davide; Luiselli, Donata; Tehrani, Jamshid J.

2017-01-01

Observable patterns of cultural variation are consistently intertwined with demic movements, cultural diffusion, and adaptation to different ecological contexts [Cavalli-Sforza and Feldman (1981) Cultural Transmission and Evolution: A Quantitative Approach; Boyd and Richerson (1985) Culture and the Evolutionary Process]. The quantitative study of gene–culture coevolution has focused in particular on the mechanisms responsible for change in frequency and attributes of cultural traits, the spread of cultural information through demic and cultural diffusion, and detecting relationships between genetic and cultural lineages. Here, we make use of worldwide whole-genome sequences [Pagani et al. (2016) Nature 538:238–242] to assess the impact of processes involving population movement and replacement on cultural diversity, focusing on the variability observed in folktale traditions (n = 596) [Uther (2004) The Types of International Folktales: A Classification and Bibliography. Based on the System of Antti Aarne and Stith Thompson] in Eurasia. We find that a model of cultural diffusion predicted by isolation-by-distance alone is not sufficient to explain the observed patterns, especially at small spatial scales (up to ∼4,000 km). We also provide an empirical approach to infer presence and impact of ethnolinguistic barriers preventing the unbiased transmission of both genetic and cultural information. After correcting for the effect of ethnolinguistic boundaries, we show that, of the alternative models that we propose, the one entailing cultural diffusion biased by linguistic differences is the most plausible. Additionally, we identify 15 tales that are more likely to be predominantly transmitted through population movement and replacement and locate putative focal areas for a set of tales that are spread worldwide. PMID:28784786

Inferring patterns of folktale diffusion using genomic data.

PubMed

Bortolini, Eugenio; Pagani, Luca; Crema, Enrico R; Sarno, Stefania; Barbieri, Chiara; Boattini, Alessio; Sazzini, Marco; da Silva, Sara Graça; Martini, Gessica; Metspalu, Mait; Pettener, Davide; Luiselli, Donata; Tehrani, Jamshid J

2017-08-22

Observable patterns of cultural variation are consistently intertwined with demic movements, cultural diffusion, and adaptation to different ecological contexts [Cavalli-Sforza and Feldman (1981) Cultural Transmission and Evolution: A Quantitative Approach ; Boyd and Richerson (1985) Culture and the Evolutionary Process ]. The quantitative study of gene-culture coevolution has focused in particular on the mechanisms responsible for change in frequency and attributes of cultural traits, the spread of cultural information through demic and cultural diffusion, and detecting relationships between genetic and cultural lineages. Here, we make use of worldwide whole-genome sequences [Pagani et al. (2016) Nature 538:238-242] to assess the impact of processes involving population movement and replacement on cultural diversity, focusing on the variability observed in folktale traditions ( n  = 596) [Uther (2004) The Types of International Folktales: A Classification and Bibliography. Based on the System of Antti Aarne and Stith Thompson ] in Eurasia. We find that a model of cultural diffusion predicted by isolation-by-distance alone is not sufficient to explain the observed patterns, especially at small spatial scales (up to [Formula: see text]4,000 km). We also provide an empirical approach to infer presence and impact of ethnolinguistic barriers preventing the unbiased transmission of both genetic and cultural information. After correcting for the effect of ethnolinguistic boundaries, we show that, of the alternative models that we propose, the one entailing cultural diffusion biased by linguistic differences is the most plausible. Additionally, we identify 15 tales that are more likely to be predominantly transmitted through population movement and replacement and locate putative focal areas for a set of tales that are spread worldwide.

Survey of protein–DNA interactions in Aspergillus oryzae on a genomic scale

PubMed Central

Wang, Chao; Lv, Yangyong; Wang, Bin; Yin, Chao; Lin, Ying; Pan, Li

2015-01-01

The genome-scale delineation of in vivo protein–DNA interactions is key to understanding genome function. Only ∼5% of transcription factors (TFs) in the Aspergillus genus have been identified using traditional methods. Although the Aspergillus oryzae genome contains >600 TFs, knowledge of the in vivo genome-wide TF-binding sites (TFBSs) in aspergilli remains limited because of the lack of high-quality antibodies. We investigated the landscape of in vivo protein–DNA interactions across the A. oryzae genome through coupling the DNase I digestion of intact nuclei with massively parallel sequencing and the analysis of cleavage patterns in protein–DNA interactions at single-nucleotide resolution. The resulting map identified overrepresented de novo TF-binding motifs from genomic footprints, and provided the detailed chromatin remodeling patterns and the distribution of digital footprints near transcription start sites. The TFBSs of 19 known Aspergillus TFs were also identified based on DNase I digestion data surrounding potential binding sites in conjunction with TF binding specificity information. We observed that the cleavage patterns of TFBSs were dependent on the orientation of TF motifs and independent of strand orientation, consistent with the DNA shape features of binding motifs with flanking sequences. PMID:25883143

Whole genome co-expression analysis of soybean cytochrome P450 genes identifies nodulation-specific P450 monooxygenases

PubMed Central

2010-01-01

Background Cytochrome P450 monooxygenases (P450s) catalyze oxidation of various substrates using oxygen and NAD(P)H. Plant P450s are involved in the biosynthesis of primary and secondary metabolites performing diverse biological functions. The recent availability of the soybean genome sequence allows us to identify and analyze soybean putative P450s at a genome scale. Co-expression analysis using an available soybean microarray and Illumina sequencing data provides clues for functional annotation of these enzymes. This approach is based on the assumption that genes that have similar expression patterns across a set of conditions may have a functional relationship. Results We have identified a total number of 332 full-length P450 genes and 378 pseudogenes from the soybean genome. From the full-length sequences, 195 genes belong to A-type, which could be further divided into 20 families. The remaining 137 genes belong to non-A type P450s and are classified into 28 families. A total of 178 probe sets were found to correspond to P450 genes on the Affymetrix soybean array. Out of these probe sets, 108 represented single genes. Using the 28 publicly available microarray libraries that contain organ-specific information, some tissue-specific P450s were identified. Similarly, stress responsive soybean P450s were retrieved from 99 microarray soybean libraries. We also utilized Illumina transcriptome sequencing technology to analyze the expressions of all 332 soybean P450 genes. This dataset contains total RNAs isolated from nodules, roots, root tips, leaves, flowers, green pods, apical meristem, mock-inoculated and Bradyrhizobium japonicum-infected root hair cells. The tissue-specific expression patterns of these P450 genes were analyzed and the expression of a representative set of genes were confirmed by qRT-PCR. We performed the co-expression analysis on many of the 108 P450 genes on the Affymetrix arrays. First we confirmed that CYP93C5 (an isoflavone synthase gene) is

Phylogenetic Conflict in Bears Identified by Automated Discovery of Transposable Element Insertions in Low-Coverage Genomes

PubMed Central

Gallus, Susanne; Janke, Axel

2017-01-01

Abstract Phylogenetic reconstruction from transposable elements (TEs) offers an additional perspective to study evolutionary processes. However, detecting phylogenetically informative TE insertions requires tedious experimental work, limiting the power of phylogenetic inference. Here, we analyzed the genomes of seven bear species using high-throughput sequencing data to detect thousands of TE insertions. The newly developed pipeline for TE detection called TeddyPi (TE detection and discovery for Phylogenetic Inference) identified 150,513 high-quality TE insertions in the genomes of ursine and tremarctine bears. By integrating different TE insertion callers and using a stringent filtering approach, the TeddyPi pipeline produced highly reliable TE insertion calls, which were confirmed by extensive in vitro validation experiments. Analysis of single nucleotide substitutions in the flanking regions of the TEs shows that these substitutions correlate with the phylogenetic signal from the TE insertions. Our phylogenomic analyses show that TEs are a major driver of genomic variation in bears and enabled phylogenetic reconstruction of a well-resolved species tree, despite strong signals for incomplete lineage sorting and introgression. The analyses show that the Asiatic black, sun, and sloth bear form a monophyletic clade, in which phylogenetic incongruence originates from incomplete lineage sorting. TeddyPi is open source and can be adapted to various TE and structural variation callers. The pipeline makes it possible to confidently extract thousands of TE insertions even from low-coverage genomes (∼10×) of nonmodel organisms. This opens new possibilities for biologists to study phylogenies and evolutionary processes as well as rates and patterns of (retro-)transposition and structural variation. PMID:28985298

A robust clustering algorithm for identifying problematic samples in genome-wide association studies.

PubMed

Bellenguez, Céline; Strange, Amy; Freeman, Colin; Donnelly, Peter; Spencer, Chris C A

2012-01-01

High-throughput genotyping arrays provide an efficient way to survey single nucleotide polymorphisms (SNPs) across the genome in large numbers of individuals. Downstream analysis of the data, for example in genome-wide association studies (GWAS), often involves statistical models of genotype frequencies across individuals. The complexities of the sample collection process and the potential for errors in the experimental assay can lead to biases and artefacts in an individual's inferred genotypes. Rather than attempting to model these complications, it has become a standard practice to remove individuals whose genome-wide data differ from the sample at large. Here we describe a simple, but robust, statistical algorithm to identify samples with atypical summaries of genome-wide variation. Its use as a semi-automated quality control tool is demonstrated using several summary statistics, selected to identify different potential problems, and it is applied to two different genotyping platforms and sample collections. The algorithm is written in R and is freely available at www.well.ox.ac.uk/chris-spencer chris.spencer@well.ox.ac.uk Supplementary data are available at Bioinformatics online.

Using comparative genome analysis to identify problems in annotated microbial genomes.

PubMed

Poptsova, Maria S; Gogarten, J Peter

2010-07-01

Genome annotation is a tedious task that is mostly done by automated methods; however, the accuracy of these approaches has been questioned since the beginning of the sequencing era. Genome annotation is a multilevel process, and errors can emerge at different stages: during sequencing, as a result of gene-calling procedures, and in the process of assigning gene functions. Missed or wrongly annotated genes differentially impact different types of analyses. Here we discuss and demonstrate how the methods of comparative genome analysis can refine annotations by locating missing orthologues. We also discuss possible reasons for errors and show that the second-generation annotation systems, which combine multiple gene-calling programs with similarity-based methods, perform much better than the first annotation tools. Since old errors may propagate to the newly sequenced genomes, we emphasize that the problem of continuously updating popular public databases is an urgent and unresolved one. Due to the progress in genome-sequencing technologies, automated annotation techniques will remain the main approach in the future. Researchers need to be aware of the existing errors in the annotation of even well-studied genomes, such as Escherichia coli, and consider additional quality control for their results.

An Early Mathematical Patterning Assessment: identifying young Australian Indigenous children's patterning skills

NASA Astrophysics Data System (ADS)

Papic, Marina

2015-12-01

This paper presents an Early Mathematical Patterning Assessment (EMPA) tool that provides early childhood educators with a valuable opportunity to identify young children's mathematical thinking and patterning skills through a series of hands-on and drawing tasks. EMPA was administered through one-to-one assessment interviews to children aged 4 to 5 years in the year prior to formal school. Two hundred and seventeen assessments indicated that the young low socioeconomic and predominantly Australian Indigenous children in the study group had varied patterning and counting skills. Three percent of the study group was able to consistently copy and draw an ABABAB pattern made with coloured blocks. Fifty percent could count to six by ones and count out six items with 4 % of the total group able to identify six items presented in regular formations without counting. The integration of patterning into early mathematics learning is critical to the abstraction of mathematical ideas and relationships and to the development of mathematical reasoning in young children. By using the insights into the children's thinking that the EMPA tool provides, early childhood educators can better inform mathematics teaching and learning and so help close the persistent gap in numeracy between Indigenous and non-Indigenous children.

Genome-wide association study identifies three novel loci for type 2 diabetes.

PubMed

Hara, Kazuo; Fujita, Hayato; Johnson, Todd A; Yamauchi, Toshimasa; Yasuda, Kazuki; Horikoshi, Momoko; Peng, Chen; Hu, Cheng; Ma, Ronald C W; Imamura, Minako; Iwata, Minoru; Tsunoda, Tatsuhiko; Morizono, Takashi; Shojima, Nobuhiro; So, Wing Yee; Leung, Ting Fan; Kwan, Patrick; Zhang, Rong; Wang, Jie; Yu, Weihui; Maegawa, Hiroshi; Hirose, Hiroshi; Kaku, Kohei; Ito, Chikako; Watada, Hirotaka; Tanaka, Yasushi; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Jia, Weiping; Chan, Juliana C N; Teo, Yik Ying; Shyong, Tai E; Kamatani, Naoyuki; Kubo, Michiaki; Maeda, Shiro; Kadowaki, Takashi

2014-01-01

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci.

PubMed

Amaral, Paulo P; Leonardi, Tommaso; Han, Namshik; Viré, Emmanuelle; Gascoigne, Dennis K; Arias-Carrasco, Raúl; Büscher, Magdalena; Pandolfini, Luca; Zhang, Anda; Pluchino, Stefano; Maracaja-Coutinho, Vinicius; Nakaya, Helder I; Hemberg, Martin; Shiekhattar, Ramin; Enright, Anton J; Kouzarides, Tony

2018-03-15

The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality. We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other's expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers. This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

PubMed

Ruth, Katherine S; Campbell, Purdey J; Chew, Shelby; Lim, Ee Mun; Hadlow, Narelle; Stuckey, Bronwyn G A; Brown, Suzanne J; Feenstra, Bjarke; Joseph, John; Surdulescu, Gabriela L; Zheng, Hou Feng; Richards, J Brent; Murray, Anna; Spector, Tim D; Wilson, Scott G; Perry, John R B

2016-02-01

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

PubMed Central

Yang, Fan; Wang, Jiebiao; Pierce, Brandon L.; Chen, Lin S.

2017-01-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is “mediation” by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are “cis-mediators” of trans-eQTLs, including those “cis-hubs” involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types. PMID:29021290

Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis.

PubMed

Yang, Fan; Wang, Jiebiao; Pierce, Brandon L; Chen, Lin S

2017-11-01

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes ( cis -eQTLs). More research is needed to identify effects of genetic variation on distant genes ( trans -eQTLs) and understand their biological mechanisms. One common trans -eQTLs mechanism is "mediation" by a local ( cis ) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are " cis -mediators" of trans -eQTLs, including those " cis -hubs" involved in regulation of many trans -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis -hubs and trans -eQTL regulation across tissue types. © 2017 Yang et al.; Published by Cold Spring Harbor Laboratory Press.

kmer-SVM: a web server for identifying predictive regulatory sequence features in genomic data sets.

PubMed

Fletez-Brant, Christopher; Lee, Dongwon; McCallion, Andrew S; Beer, Michael A

2013-07-01

Massively parallel sequencing technologies have made the generation of genomic data sets a routine component of many biological investigations. For example, Chromatin immunoprecipitation followed by sequence assays detect genomic regions bound (directly or indirectly) by specific factors, and DNase-seq identifies regions of open chromatin. A major bottleneck in the interpretation of these data is the identification of the underlying DNA sequence code that defines, and ultimately facilitates prediction of, these transcription factor (TF) bound or open chromatin regions. We have recently developed a novel computational methodology, which uses a support vector machine (SVM) with kmer sequence features (kmer-SVM) to identify predictive combinations of short transcription factor-binding sites, which determine the tissue specificity of these genomic assays (Lee, Karchin and Beer, Discriminative prediction of mammalian enhancers from DNA sequence. Genome Res. 2011; 21:2167-80). This regulatory information can (i) give confidence in genomic experiments by recovering previously known binding sites, and (ii) reveal novel sequence features for subsequent experimental testing of cooperative mechanisms. Here, we describe the development and implementation of a web server to allow the broader research community to independently apply our kmer-SVM to analyze and interpret their genomic datasets. We analyze five recently published data sets and demonstrate how this tool identifies accessory factors and repressive sequence elements. kmer-SVM is available at http://kmersvm.beerlab.org.

kmer-SVM: a web server for identifying predictive regulatory sequence features in genomic data sets

PubMed Central

Fletez-Brant, Christopher; Lee, Dongwon; McCallion, Andrew S.; Beer, Michael A.

2013-01-01

Massively parallel sequencing technologies have made the generation of genomic data sets a routine component of many biological investigations. For example, Chromatin immunoprecipitation followed by sequence assays detect genomic regions bound (directly or indirectly) by specific factors, and DNase-seq identifies regions of open chromatin. A major bottleneck in the interpretation of these data is the identification of the underlying DNA sequence code that defines, and ultimately facilitates prediction of, these transcription factor (TF) bound or open chromatin regions. We have recently developed a novel computational methodology, which uses a support vector machine (SVM) with kmer sequence features (kmer-SVM) to identify predictive combinations of short transcription factor-binding sites, which determine the tissue specificity of these genomic assays (Lee, Karchin and Beer, Discriminative prediction of mammalian enhancers from DNA sequence. Genome Res. 2011; 21:2167–80). This regulatory information can (i) give confidence in genomic experiments by recovering previously known binding sites, and (ii) reveal novel sequence features for subsequent experimental testing of cooperative mechanisms. Here, we describe the development and implementation of a web server to allow the broader research community to independently apply our kmer-SVM to analyze and interpret their genomic datasets. We analyze five recently published data sets and demonstrate how this tool identifies accessory factors and repressive sequence elements. kmer-SVM is available at http://kmersvm.beerlab.org. PMID:23771147

Genome-wide association study identifies multiple loci associated with bladder cancer risk

PubMed Central

Figueroa, Jonine D.; Ye, Yuanqing; Siddiq, Afshan; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P.; Malats, Núria; Baris, Dalsu; Purdue, Mark; Jacobs, Eric J.; Albanes, Demetrius; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Tang, Wei; Bas Bueno-de-Mesquita, H.; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M.; Lerner, Seth P.; Barton Grossman, H.; Lin, Jie; Gu, Jian; Pu, Xia; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schwenn, Molly; Karagas, Margaret R.; Johnson, Alison; Schned, Alan; Armenti, Karla R.; Hosain, G.M.; Andriole, Gerald; Grubb, Robert; Black, Amanda; Ryan Diver, W.; Gapstur, Susan M.; Weinstein, Stephanie J.; Virtamo, Jarmo; Haiman, Chris A.; Landi, Maria T.; Caporaso, Neil; Fraumeni, Joseph F.; Vineis, Paolo; Wu, Xifeng; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel

2014-01-01

Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. PMID:24163127

Navigating the currents of seascape genomics: how spatial analyses can augment population genomic studies

PubMed Central

Crandall, Eric D.; Liggins, Libby; Bongaerts, Pim; Treml, Eric A.

2016-01-01

Population genomic approaches are making rapid inroads in the study of non-model organisms, including marine taxa. To date, these marine studies have predominantly focused on rudimentary metrics describing the spatial and environmental context of their study region (e.g., geographical distance, average sea surface temperature, average salinity). We contend that a more nuanced and considered approach to quantifying seascape dynamics and patterns can strengthen population genomic investigations and help identify spatial, temporal, and environmental factors associated with differing selective regimes or demographic histories. Nevertheless, approaches for quantifying marine landscapes are complicated. Characteristic features of the marine environment, including pelagic living in flowing water (experienced by most marine taxa at some point in their life cycle), require a well-designed spatial-temporal sampling strategy and analysis. Many genetic summary statistics used to describe populations may be inappropriate for marine species with large population sizes, large species ranges, stochastic recruitment, and asymmetrical gene flow. Finally, statistical approaches for testing associations between seascapes and population genomic patterns are still maturing with no single approach able to capture all relevant considerations. None of these issues are completely unique to marine systems and therefore similar issues and solutions will be shared for many organisms regardless of habitat. Here, we outline goals and spatial approaches for landscape genomics with an emphasis on marine systems and review the growing empirical literature on seascape genomics. We review established tools and approaches and highlight promising new strategies to overcome select issues including a strategy to spatially optimize sampling. Despite the many challenges, we argue that marine systems may be especially well suited for identifying candidate genomic regions under environmentally mediated

Navigating the currents of seascape genomics: how spatial analyses can augment population genomic studies.

PubMed

Riginos, Cynthia; Crandall, Eric D; Liggins, Libby; Bongaerts, Pim; Treml, Eric A

2016-12-01

Population genomic approaches are making rapid inroads in the study of non-model organisms, including marine taxa. To date, these marine studies have predominantly focused on rudimentary metrics describing the spatial and environmental context of their study region (e.g., geographical distance, average sea surface temperature, average salinity). We contend that a more nuanced and considered approach to quantifying seascape dynamics and patterns can strengthen population genomic investigations and help identify spatial, temporal, and environmental factors associated with differing selective regimes or demographic histories. Nevertheless, approaches for quantifying marine landscapes are complicated. Characteristic features of the marine environment, including pelagic living in flowing water (experienced by most marine taxa at some point in their life cycle), require a well-designed spatial-temporal sampling strategy and analysis. Many genetic summary statistics used to describe populations may be inappropriate for marine species with large population sizes, large species ranges, stochastic recruitment, and asymmetrical gene flow. Finally, statistical approaches for testing associations between seascapes and population genomic patterns are still maturing with no single approach able to capture all relevant considerations. None of these issues are completely unique to marine systems and therefore similar issues and solutions will be shared for many organisms regardless of habitat. Here, we outline goals and spatial approaches for landscape genomics with an emphasis on marine systems and review the growing empirical literature on seascape genomics. We review established tools and approaches and highlight promising new strategies to overcome select issues including a strategy to spatially optimize sampling. Despite the many challenges, we argue that marine systems may be especially well suited for identifying candidate genomic regions under environmentally mediated

Phylogenomic analysis of UDP glycosyltransferase 1 multigene family in Linum usitatissimum identified genes with varied expression patterns.

PubMed

Barvkar, Vitthal T; Pardeshi, Varsha C; Kale, Sandip M; Kadoo, Narendra Y; Gupta, Vidya S

2012-05-08

The glycosylation process, catalyzed by ubiquitous glycosyltransferase (GT) family enzymes, is a prevalent modification of plant secondary metabolites that regulates various functions such as hormone homeostasis, detoxification of xenobiotics and biosynthesis and storage of secondary metabolites. Flax (Linum usitatissimum L.) is a commercially grown oilseed crop, important because of its essential fatty acids and health promoting lignans. Identification and characterization of UDP glycosyltransferase (UGT) genes from flax could provide valuable basic information about this important gene family and help to explain the seed specific glycosylated metabolite accumulation and other processes in plants. Plant genome sequencing projects are useful to discover complexity within this gene family and also pave way for the development of functional genomics approaches. Taking advantage of the newly assembled draft genome sequence of flax, we identified 137 UDP glycosyltransferase (UGT) genes from flax using a conserved signature motif. Phylogenetic analysis of these protein sequences clustered them into 14 major groups (A-N). Expression patterns of these genes were investigated using publicly available expressed sequence tag (EST), microarray data and reverse transcription quantitative real time PCR (RT-qPCR). Seventy-three per cent of these genes (100 out of 137) showed expression evidence in 15 tissues examined and indicated varied expression profiles. The RT-qPCR results of 10 selected genes were also coherent with the digital expression analysis. Interestingly, five duplicated UGT genes were identified, which showed differential expression in various tissues. Of the seven intron loss/gain positions detected, two intron positions were conserved among most of the UGTs, although a clear relationship about the evolution of these genes could not be established. Comparison of the flax UGTs with orthologs from four other sequenced dicot genomes indicated that seven UGTs were

The FUN of identifying gene function in bacterial pathogens; insights from Salmonella functional genomics.

PubMed

Hammarlöf, Disa L; Canals, Rocío; Hinton, Jay C D

2013-10-01

The availability of thousands of genome sequences of bacterial pathogens poses a particular challenge because each genome contains hundreds of genes of unknown function (FUN). How can we easily discover which FUN genes encode important virulence factors? One solution is to combine two different functional genomic approaches. First, transcriptomics identifies bacterial FUN genes that show differential expression during the process of mammalian infection. Second, global mutagenesis identifies individual FUN genes that the pathogen requires to cause disease. The intersection of these datasets can reveal a small set of candidate genes most likely to encode novel virulence attributes. We demonstrate this approach with the Salmonella infection model, and propose that a similar strategy could be used for other bacterial pathogens. Copyright © 2013 Elsevier Ltd. All rights reserved.

Complete mitochondrial genome sequences of three bats species and whole genome mitochondrial analyses reveal patterns of codon bias and lend support to a basal split in Chiroptera.

PubMed

Meganathan, P R; Pagan, Heidi J T; McCulloch, Eve S; Stevens, Richard D; Ray, David A

2012-01-15

Order Chiroptera is a unique group of mammals whose members have attained self-powered flight as their main mode of locomotion. Much speculation persists regarding bat evolution; however, lack of sufficient molecular data hampers evolutionary and conservation studies. Of ~1200 species, complete mitochondrial genome sequences are available for only eleven. Additional sequences should be generated if we are to resolve many questions concerning these fascinating mammals. Herein, we describe the complete mitochondrial genomes of three bats: Corynorhinus rafinesquii, Lasiurus borealis and Artibeus lituratus. We also compare the currently available mitochondrial genomes and analyze codon usage in Chiroptera. C. rafinesquii, L. borealis and A. lituratus mitochondrial genomes are 16438 bp, 17048 bp and 16709 bp, respectively. Genome organization and gene arrangements are similar to other bats. Phylogenetic analyses using complete mitochondrial genome sequences support previously established phylogenetic relationships and suggest utility in future studies focusing on the evolutionary aspects of these species. Comprehensive analyses of available bat mitochondrial genomes reveal distinct nucleotide patterns and synonymous codon preferences corresponding to different chiropteran families. These patterns suggest that mutational and selection forces are acting to different extents within Chiroptera and shape their mitochondrial genomes. Copyright © 2011 Elsevier B.V. All rights reserved.

A survey of single nucleotide polymorphisms identified from whole-genome sequencing and their functional effect in the porcine genome.

PubMed

Keel, B N; Nonneman, D J; Rohrer, G A

2017-08-01

Genetic variants detected from sequence have been used to successfully identify causal variants and map complex traits in several organisms. High and moderate impact variants, those expected to alter or disrupt the protein coded by a gene and those that regulate protein production, likely have a more significant effect on phenotypic variation than do other types of genetic variants. Hence, a comprehensive list of these functional variants would be of considerable interest in swine genomic studies, particularly those targeting fertility and production traits. Whole-genome sequence was obtained from 72 of the founders of an intensely phenotyped experimental swine herd at the U.S. Meat Animal Research Center (USMARC). These animals included all 24 of the founding boars (12 Duroc and 12 Landrace) and 48 Yorkshire-Landrace composite sows. Sequence reads were mapped to the Sscrofa10.2 genome build, resulting in a mean of 6.1 fold (×) coverage per genome. A total of 22 342 915 high confidence SNPs were identified from the sequenced genomes. These included 21 million previously reported SNPs and 79% of the 62 163 SNPs on the PorcineSNP60 BeadChip assay. Variation was detected in the coding sequence or untranslated regions (UTRs) of 87.8% of the genes in the porcine genome: loss-of-function variants were predicted in 504 genes, 10 202 genes contained nonsynonymous variants, 10 773 had variation in UTRs and 13 010 genes contained synonymous variants. Approximately 139 000 SNPs were classified as loss-of-function, nonsynonymous or regulatory, which suggests that over 99% of the variation detected in our pigs could potentially be ignored, allowing us to focus on a much smaller number of functional SNPs during future analyses. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

A Genome-Wide Association Study to Identify Genomic Modulators of Rate Control Therapy in Patients with Atrial Fibrillation

PubMed Central

Kolek, Matthew J.; Edwards, Todd L.; Muhammad, Raafia; Balouch, Adnan; Shoemaker, M. Benjamin; Blair, Marcia A.; Kor, Kaylen C.; Takahashi, Atsushi; Kubo, Michiaki; Roden, Dan M.; Tanaka, Toshihiro; Darbar, Dawood

2014-01-01

For many patients with atrial fibrillation (AF), ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, though response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (N=190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. 554,041 single nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of P<5 × 10−8. Sixty-three SNPs with P<10−5 at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, P=9.36 × 10−8), 4q12 (IGFBP7, P=1.75 × 10−7), 6q22.33 (C6orf174, P=4.86 × 10−7), 3p21.31 (CDCP1, P=1.18 × 10−6), 12p12.1 (SOX5, P=1.62 × 10−6), and 7p11 (LANCL2, P=6.51 × 10−6). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in AF, particularly SOX5, which was previously associated with resting heart rate and PR interval. However these failed to reach genome-wide significance. PMID:25015694

A genome-wide association study to identify genomic modulators of rate control therapy in patients with atrial fibrillation.

PubMed

Kolek, Matthew J; Edwards, Todd L; Muhammad, Raafia; Balouch, Adnan; Shoemaker, M Benjamin; Blair, Marcia A; Kor, Kaylen C; Takahashi, Atsushi; Kubo, Michiaki; Roden, Dan M; Tanaka, Toshihiro; Darbar, Dawood

2014-08-15

For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 × 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 × 10(-8)), 4q12 (IGFBP7, p = 1.75 × 10(-7)), 6q22.33 (C6orf174, p = 4.86 × 10(-7)), 3p21.31 (CDCP1, p = 1.18 × 10(-6)), 12p12.1 (SOX5, p = 1.62 × 10(-6)), and 7p11 (LANCL2, p = 6.51 × 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance. Copyright © 2014 Elsevier Inc. All rights reserved.

Big Data Analytics for Genomic Medicine.

PubMed

He, Karen Y; Ge, Dongliang; He, Max M

2017-02-15

Genomic medicine attempts to build individualized strategies for diagnostic or therapeutic decision-making by utilizing patients' genomic information. Big Data analytics uncovers hidden patterns, unknown correlations, and other insights through examining large-scale various data sets. While integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a Big Data infrastructure exhibit challenges, they also provide a feasible opportunity to develop an efficient and effective approach to identify clinically actionable genetic variants for individualized diagnosis and therapy. In this paper, we review the challenges of manipulating large-scale next-generation sequencing (NGS) data and diverse clinical data derived from the EHRs for genomic medicine. We introduce possible solutions for different challenges in manipulating, managing, and analyzing genomic and clinical data to implement genomic medicine. Additionally, we also present a practical Big Data toolset for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs.

Phylogenetic Conflict in Bears Identified by Automated Discovery of Transposable Element Insertions in Low-Coverage Genomes.

PubMed

Lammers, Fritjof; Gallus, Susanne; Janke, Axel; Nilsson, Maria A

2017-10-01

Phylogenetic reconstruction from transposable elements (TEs) offers an additional perspective to study evolutionary processes. However, detecting phylogenetically informative TE insertions requires tedious experimental work, limiting the power of phylogenetic inference. Here, we analyzed the genomes of seven bear species using high-throughput sequencing data to detect thousands of TE insertions. The newly developed pipeline for TE detection called TeddyPi (TE detection and discovery for Phylogenetic Inference) identified 150,513 high-quality TE insertions in the genomes of ursine and tremarctine bears. By integrating different TE insertion callers and using a stringent filtering approach, the TeddyPi pipeline produced highly reliable TE insertion calls, which were confirmed by extensive in vitro validation experiments. Analysis of single nucleotide substitutions in the flanking regions of the TEs shows that these substitutions correlate with the phylogenetic signal from the TE insertions. Our phylogenomic analyses show that TEs are a major driver of genomic variation in bears and enabled phylogenetic reconstruction of a well-resolved species tree, despite strong signals for incomplete lineage sorting and introgression. The analyses show that the Asiatic black, sun, and sloth bear form a monophyletic clade, in which phylogenetic incongruence originates from incomplete lineage sorting. TeddyPi is open source and can be adapted to various TE and structural variation callers. The pipeline makes it possible to confidently extract thousands of TE insertions even from low-coverage genomes (∼10×) of nonmodel organisms. This opens new possibilities for biologists to study phylogenies and evolutionary processes as well as rates and patterns of (retro-)transposition and structural variation. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma

PubMed Central

Yates, Katherine P.; Zhou, Xiaobo; Guo, Feng; Sternberg, Alice L.; Van Natta, Mark L.; Wise, Robert A.; Szefler, Stanley J.; Sharma, Sunita; Kho, Alvin T.; Cho, Michael H.; Croteau-Chonka, Damien C.; Castaldi, Peter J.; Jain, Gaurav; Sanyal, Amartya; Zhan, Ye; Lajoie, Bryan R.; Dekker, Job; Stamatoyannopoulos, John; Covar, Ronina A.; Zeiger, Robert S.; Adkinson, N. Franklin; Williams, Paul V.; Kelly, H. William; Grasemann, Hartmut; Vonk, Judith M.; Koppelman, Gerard H.; Postma, Dirkje S.; Raby, Benjamin A.; Houston, Isaac; Lu, Quan; Fuhlbrigge, Anne L.; Tantisira, Kelan G.; Silverman, Edwin K.; Tonascia, James; Strunk, Robert C.; Weiss, Scott T.

2016-01-01

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. Measurements and Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10−9; odds ratio, 2.8; 95% confidence interval, 2.0–4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575). PMID:27367781

Genomic Analyses Yield Markers for Identifying Agronomically Important Genes in Potato

USDA-ARS?s Scientific Manuscript database

This study explores the genetic architecture underling the potato evolution through a comprehensive assessment of wild and cultivated potato species based on the re-sequencing of 201 accessions of Solanum section Petota with >12 × genome coverage. We identified 450 domesticated genes, which showed e...

Genome-wide oxidative bisulfite sequencing identifies sex-specific methylation differences in the human placenta

PubMed Central

Johnson, Michelle D; Dopierala, Justyna

2018-01-01

ABSTRACT DNA methylation is an important regulator of gene function. Fetal sex is associated with the risk of several specific pregnancy complications related to placental function. However, the association between fetal sex and placental DNA methylation remains poorly understood. We carried out whole-genome oxidative bisulfite sequencing in the placentas of two healthy female and two healthy male pregnancies generating an average genome depth of coverage of 25x. Most highly ranked differentially methylated regions (DMRs) were located on the X chromosome but we identified a 225 kb sex-specific DMR in the body of the CUB and Sushi Multiple Domains 1 (CSMD1) gene on chromosome 8. The sex-specific differential methylation pattern observed in this region was validated in additional placentas using in-solution target capture. In a new RNA-seq data set from 64 female and 67 male placentas, CSMD1 mRNA was 1.8-fold higher in male than in female placentas (P value = 8.5 × 10−7, Mann-Whitney test). Exon-level quantification of CSMD1 mRNA from these 131 placentas suggested a likely placenta-specific CSMD1 isoform not detected in the 21 somatic tissues analyzed. We show that the gene body of an autosomal gene, CSMD1, is differentially methylated in a sex- and placental-specific manner, displaying sex-specific differences in placental transcript abundance. PMID:29376485

Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines

PubMed Central

Noor, Dzul Azri Mohamed; Jeyapalan, Jennie N; Alhazmi, Safiah; Carr, Matthew; Squibb, Benjamin; Wallace, Claire; Tan, Christopher; Cusack, Martin; Hughes, Jaime; Reader, Tom; Shipley, Janet; Sheer, Denise; Scotting, Paul J

2016-01-01

Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours’ biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription–quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes. PMID:29263807

Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines.

PubMed

Noor, Dzul Azri Mohamed; Jeyapalan, Jennie N; Alhazmi, Safiah; Carr, Matthew; Squibb, Benjamin; Wallace, Claire; Tan, Christopher; Cusack, Martin; Hughes, Jaime; Reader, Tom; Shipley, Janet; Sheer, Denise; Scotting, Paul J

2016-01-01

Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours' biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription-quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes.

Current and Emerging Technologies for the Analysis of the Genome-Wide and Locus-Specific DNA Methylation Patterns.

PubMed

Tost, Jörg

2016-01-01

DNA methylation is the most studied epigenetic modification, and altered DNA methylation patterns have been identified in cancer and more recently also in many other complex diseases. Furthermore, DNA methylation is influenced by a variety of environmental factors, and the analysis of DNA methylation patterns might allow deciphering previous exposure. Although a large number of techniques to study DNA methylation either genome-wide or at specific loci have been devised, they all are based on a limited number of principles for differentiating the methylation state, viz., methylation-specific/methylation-dependent restriction enzymes, antibodies or methyl-binding proteins, chemical-based enrichment, or bisulfite conversion. Second-generation sequencing has largely replaced microarrays as readout platform and is also becoming more popular for locus-specific DNA methylation analysis. In this chapter, the currently used methods for both genome-wide and locus-specific analysis of 5-methylcytosine and as its oxidative derivatives, such as 5-hydroxymethylcytosine, are reviewed in detail, and the advantages and limitations of each approach are discussed. Furthermore, emerging technologies avoiding PCR amplification and allowing a direct readout of DNA methylation are summarized, together with novel applications, such as the detection of DNA methylation in single cells or in circulating cell-free DNA.

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile▿†

PubMed Central

Forgetta, Vincenzo; Oughton, Matthew T.; Marquis, Pascale; Brukner, Ivan; Blanchette, Ruth; Haub, Kevin; Magrini, Vince; Mardis, Elaine R.; Gerding, Dale N.; Loo, Vivian G.; Miller, Mark A.; Mulvey, Michael R.; Rupnik, Maja; Dascal, Andre; Dewar, Ken

2011-01-01

Clostridium difficile is a common cause of infectious diarrhea in hospitalized patients. A severe and increased incidence of C. difficile infection (CDI) is associated predominantly with the NAP1 strain; however, the existence of other severe-disease-associated (SDA) strains and the extensive genetic diversity across C. difficile complicate reliable detection and diagnosis. Comparative genome analysis of 14 sequenced genomes, including those of a subset of NAP1 isolates, allowed the assessment of genetic diversity within and between strain types to identify DNA markers that are associated with severe disease. Comparative genome analysis of 14 isolates, including five publicly available strains, revealed that C. difficile has a core genome of 3.4 Mb, comprising ∼3,000 genes. Analysis of the core genome identified candidate DNA markers that were subsequently evaluated using a multistrain panel of 177 isolates, representing more than 50 pulsovars and 8 toxinotypes. A subset of 117 isolates from the panel had associated patient data that allowed assessment of an association between the DNA markers and severe CDI. We identified 20 candidate DNA markers for species-wide detection and 10,683 single nucleotide polymorphisms (SNPs) associated with the predominant SDA strain (NAP1). A species-wide detection candidate marker, the sspA gene, was found to be the same across 177 sequenced isolates and lacked significant similarity to those of other species. Candidate SNPs in genes CD1269 and CD1265 were found to associate more closely with disease severity than currently used diagnostic markers, as they were also present in the toxin A-negative and B-positive (A-B+) strain types. The genetic markers identified illustrate the potential of comparative genomics for the discovery of diagnostic DNA-based targets that are species specific or associated with multiple SDA strains. PMID:21508155

Sparse whole genome sequencing identifies two loci for major depressive disorder

PubMed Central

2015-01-01

Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date no robustly replicated genetic loci have been identified 2, despite analysis of more than 9,000 cases3. Using low coverage genome sequence of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified and replicated two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P-value = 2.53×10−10) the other in an intron of the LHPP gene (P = 6.45×10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness. PMID:26176920

Dynamics of Genome Rearrangement in Bacterial Populations

PubMed Central

Darling, Aaron E.; Miklós, István; Ragan, Mark A.

2008-01-01

Genome structure variation has profound impacts on phenotype in organisms ranging from microbes to humans, yet little is known about how natural selection acts on genome arrangement. Pathogenic bacteria such as Yersinia pestis, which causes bubonic and pneumonic plague, often exhibit a high degree of genomic rearrangement. The recent availability of several Yersinia genomes offers an unprecedented opportunity to study the evolution of genome structure and arrangement. We introduce a set of statistical methods to study patterns of rearrangement in circular chromosomes and apply them to the Yersinia. We constructed a multiple alignment of eight Yersinia genomes using Mauve software to identify 78 conserved segments that are internally free from genome rearrangement. Based on the alignment, we applied Bayesian statistical methods to infer the phylogenetic inversion history of Yersinia. The sampling of genome arrangement reconstructions contains seven parsimonious tree topologies, each having different histories of 79 inversions. Topologies with a greater number of inversions also exist, but were sampled less frequently. The inversion phylogenies agree with results suggested by SNP patterns. We then analyzed reconstructed inversion histories to identify patterns of rearrangement. We confirm an over-representation of “symmetric inversions”—inversions with endpoints that are equally distant from the origin of chromosomal replication. Ancestral genome arrangements demonstrate moderate preference for replichore balance in Yersinia. We found that all inversions are shorter than expected under a neutral model, whereas inversions acting within a single replichore are much shorter than expected. We also found evidence for a canonical configuration of the origin and terminus of replication. Finally, breakpoint reuse analysis reveals that inversions with endpoints proximal to the origin of DNA replication are nearly three times more frequent. Our findings represent the

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

PubMed Central

Toomey, David; Hoppe, Heinrich C.; Brennan, Marian P.; Nolan, Kevin B.; Chubb, Anthony J.

2009-01-01

Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents. PMID:19593435

Markov models of genome segmentation

NASA Astrophysics Data System (ADS)

Thakur, Vivek; Azad, Rajeev K.; Ramaswamy, Ram

2007-01-01

We introduce Markov models for segmentation of symbolic sequences, extending a segmentation procedure based on the Jensen-Shannon divergence that has been introduced earlier. Higher-order Markov models are more sensitive to the details of local patterns and in application to genome analysis, this makes it possible to segment a sequence at positions that are biologically meaningful. We show the advantage of higher-order Markov-model-based segmentation procedures in detecting compositional inhomogeneity in chimeric DNA sequences constructed from genomes of diverse species, and in application to the E. coli K12 genome, boundaries of genomic islands, cryptic prophages, and horizontally acquired regions are accurately identified.

Big Data Analytics for Genomic Medicine

PubMed Central

He, Karen Y.; Ge, Dongliang; He, Max M.

2017-01-01

Genomic medicine attempts to build individualized strategies for diagnostic or therapeutic decision-making by utilizing patients’ genomic information. Big Data analytics uncovers hidden patterns, unknown correlations, and other insights through examining large-scale various data sets. While integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a Big Data infrastructure exhibit challenges, they also provide a feasible opportunity to develop an efficient and effective approach to identify clinically actionable genetic variants for individualized diagnosis and therapy. In this paper, we review the challenges of manipulating large-scale next-generation sequencing (NGS) data and diverse clinical data derived from the EHRs for genomic medicine. We introduce possible solutions for different challenges in manipulating, managing, and analyzing genomic and clinical data to implement genomic medicine. Additionally, we also present a practical Big Data toolset for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs. PMID:28212287

Structural Genomics: Correlation Blocks, Population Structure, and Genome Architecture

PubMed Central

Hu, Xin-Sheng; Yeh, Francis C.; Wang, Zhiquan

2011-01-01

An integration of the pattern of genome-wide inter-site associations with evolutionary forces is important for gaining insights into the genomic evolution in natural or artificial populations. Here, we assess the inter-site correlation blocks and their distributions along chromosomes. A correlation block is broadly termed as the DNA segment within which strong correlations exist between genetic diversities at any two sites. We bring together the population genetic structure and the genomic diversity structure that have been independently built on different scales and synthesize the existing theories and methods for characterizing genomic structure at the population level. We discuss how population structure could shape correlation blocks and their patterns within and between populations. Effects of evolutionary forces (selection, migration, genetic drift, and mutation) on the pattern of genome-wide correlation blocks are discussed. In eukaryote organisms, we briefly discuss the associations between the pattern of correlation blocks and genome assembly features in eukaryote organisms, including the impacts of multigene family, the perturbation of transposable elements, and the repetitive nongenic sequences and GC-rich isochores. Our reviews suggest that the observable pattern of correlation blocks can refine our understanding of the ecological and evolutionary processes underlying the genomic evolution at the population level. PMID:21886455

Newly discovered young CORE-SINEs in marsupial genomes.

PubMed

Munemasa, Maruo; Nikaido, Masato; Nishihara, Hidenori; Donnellan, Stephen; Austin, Christopher C; Okada, Norihiro

2008-01-15

Although recent mammalian genome projects have uncovered a large part of genomic component of various groups, several repetitive sequences still remain to be characterized and classified for particular groups. The short interspersed repetitive elements (SINEs) distributed among marsupial genomes are one example. We have identified and characterized two new SINEs from marsupial genomes that belong to the CORE-SINE family, characterized by a highly conserved "CORE" domain. PCR and genomic dot blot analyses revealed that the distribution of each SINE shows distinct patterns among the marsupial genomes, implying different timing of their retroposition during the evolution of marsupials. The members of Mar3 (Marsupialia 3) SINE are distributed throughout the genomes of all marsupials, whereas the Mac1 (Macropodoidea 1) SINE is distributed specifically in the genomes of kangaroos. Sequence alignment of the Mar3 SINEs revealed that they can be further divided into four subgroups, each of which has diagnostic nucleotides. The insertion patterns of each SINE at particular genomic loci, together with the distribution patterns of each SINE, suggest that the Mar3 SINEs have intensively amplified after the radiation of diprotodontians, whereas the Mac1 SINE has amplified only slightly after the divergence of hypsiprimnodons from other macropods. By compiling the information of CORE-SINEs characterized to date, we propose a comprehensive picture of how SINE evolution occurred in the genomes of marsupials.

Combining functional genomics and chemical biology to identify targets of bioactive compounds.

PubMed

Ho, Cheuk Hei; Piotrowski, Jeff; Dixon, Scott J; Baryshnikova, Anastasia; Costanzo, Michael; Boone, Charles

2011-02-01

Genome sequencing projects have revealed thousands of suspected genes, challenging researchers to develop efficient large-scale functional analysis methodologies. Determining the function of a gene product generally requires a means to alter its function. Genetically tractable model organisms have been widely exploited for the isolation and characterization of activating and inactivating mutations in genes encoding proteins of interest. Chemical genetics represents a complementary approach involving the use of small molecules capable of either inactivating or activating their targets. Saccharomyces cerevisiae has been an important test bed for the development and application of chemical genomic assays aimed at identifying targets and modes of action of known and uncharacterized compounds. Here we review yeast chemical genomic assays strategies for drug target identification. Copyright © 2010 Elsevier Ltd. All rights reserved.

Reprogramming the Maternal Zebrafish Genome after Fertilization to Match the Paternal Methylation Pattern

PubMed Central

Potok, Magdalena E.; Nix, David A.; Parnell, Timothy J.; Cairns, Bradley R.

2014-01-01

SUMMARY Early vertebrate embryos must achieve totipotency and prepare for zygotic genome activation (ZGA). To understand this process, we determined the DNA methylation (DNAme) profiles of zebrafish gametes, embryos at different stages, and somatic muscle and compared them to gene activity and histone modifications. Sperm chromatin patterns are virtually identical to those at ZGA. Unexpectedly, the DNA of many oocyte genes important for germ-line functions (i.e., piwil1) or early development (i.e., hox genes) is methylated, but the loci are demethylated during zygotic cleavage stages to precisely the state observed in sperm, even in parthenogenetic embryos lacking a replicating paternal genome. Furthermore, this cohort constitutes the genes and loci that acquire DNAme during development (i.e., ZGA to muscle). Finally, DNA methyltransferase inhibition experiments suggest that DNAme silences particular gene and chromatin cohorts at ZGA, preventing their precocious expression. Thus, zebrafish achieve a totipotent chromatin state at ZGA through paternal genome competency and maternal genome DNAme reprogramming. PMID:23663776

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

PubMed

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

2015-04-23

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

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

PubMed Central

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

2015-01-01

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

New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes.

PubMed

Parker, Brian J; Moltke, Ida; Roth, Adam; Washietl, Stefan; Wen, Jiayu; Kellis, Manolis; Breaker, Ronald; Pedersen, Jakob Skou

2011-11-01

Regulatory RNA structures are often members of families with multiple paralogous instances across the genome. Family members share functional and structural properties, which allow them to be studied as a whole, facilitating both bioinformatic and experimental characterization. We have developed a comparative method, EvoFam, for genome-wide identification of families of regulatory RNA structures, based on primary sequence and secondary structure similarity. We apply EvoFam to a 41-way genomic vertebrate alignment. Genome-wide, we identify 220 human, high-confidence families outside protein-coding regions comprising 725 individual structures, including 48 families with known structural RNA elements. Known families identified include both noncoding RNAs, e.g., miRNAs and the recently identified MALAT1/MEN β lincRNA family; and cis-regulatory structures, e.g., iron-responsive elements. We also identify tens of new families supported by strong evolutionary evidence and other statistical evidence, such as GO term enrichments. For some of these, detailed analysis has led to the formulation of specific functional hypotheses. Examples include two hypothesized auto-regulatory feedback mechanisms: one involving six long hairpins in the 3'-UTR of MAT2A, a key metabolic gene that produces the primary human methyl donor S-adenosylmethionine; the other involving a tRNA-like structure in the intron of the tRNA maturation gene POP1. We experimentally validate the predicted MAT2A structures. Finally, we identify potential new regulatory networks, including large families of short hairpins enriched in immunity-related genes, e.g., TNF, FOS, and CTLA4, which include known transcript destabilizing elements. Our findings exemplify the diversity of post-transcriptional regulation and provide a resource for further characterization of new regulatory mechanisms and families of noncoding RNAs.

Can we use genetic and genomic approaches to identify candidate animals for targeted selective treatment.

PubMed

Laurenson, Yan C S M; Kyriazakis, Ilias; Bishop, Stephen C

2013-10-18

Estimated breeding values (EBV) for faecal egg count (FEC) and genetic markers for host resistance to nematodes may be used to identify resistant animals for selective breeding programmes. Similarly, targeted selective treatment (TST) requires the ability to identify the animals that will benefit most from anthelmintic treatment. A mathematical model was used to combine the concepts and evaluate the potential of using genetic-based methods to identify animals for a TST regime. EBVs obtained by genomic prediction were predicted to be the best determinant criterion for TST in terms of the impact on average empty body weight and average FEC, whereas pedigree-based EBVs for FEC were predicted to be marginally worse than using phenotypic FEC as a determinant criterion. Whilst each method has financial implications, if the identification of host resistance is incorporated into a wider genomic selection indices or selective breeding programmes, then genetic or genomic information may be plausibly included in TST regimes. Copyright © 2013 Elsevier B.V. All rights reserved.

Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

PubMed Central

Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.

2011-01-01

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

PubMed

Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Carr, J Jeffrey; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Kao, W H Linda; Hirschhorn, Joel N; Borecki, Ingrid B

2011-03-01

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

An integrative strategy to identify the entire protein coding potential of prokaryotic genomes by proteogenomics.

PubMed

Omasits, Ulrich; Varadarajan, Adithi R; Schmid, Michael; Goetze, Sandra; Melidis, Damianos; Bourqui, Marc; Nikolayeva, Olga; Québatte, Maxime; Patrignani, Andrea; Dehio, Christoph; Frey, Juerg E; Robinson, Mark D; Wollscheid, Bernd; Ahrens, Christian H

2017-12-01

Accurate annotation of all protein-coding sequences (CDSs) is an essential prerequisite to fully exploit the rapidly growing repertoire of completely sequenced prokaryotic genomes. However, large discrepancies among the number of CDSs annotated by different resources, missed functional short open reading frames (sORFs), and overprediction of spurious ORFs represent serious limitations. Our strategy toward accurate and complete genome annotation consolidates CDSs from multiple reference annotation resources, ab initio gene prediction algorithms and in silico ORFs (a modified six-frame translation considering alternative start codons) in an integrated proteogenomics database (iPtgxDB) that covers the entire protein-coding potential of a prokaryotic genome. By extending the PeptideClassifier concept of unambiguous peptides for prokaryotes, close to 95% of the identifiable peptides imply one distinct protein, largely simplifying downstream analysis. Searching a comprehensive Bartonella henselae proteomics data set against such an iPtgxDB allowed us to unambiguously identify novel ORFs uniquely predicted by each resource, including lipoproteins, differentially expressed and membrane-localized proteins, novel start sites and wrongly annotated pseudogenes. Most novelties were confirmed by targeted, parallel reaction monitoring mass spectrometry, including unique ORFs and single amino acid variations (SAAVs) identified in a re-sequenced laboratory strain that are not present in its reference genome. We demonstrate the general applicability of our strategy for genomes with varying GC content and distinct taxonomic origin. We release iPtgxDBs for B. henselae , Bradyrhizobium diazoefficiens and Escherichia coli and the software to generate both proteogenomics search databases and integrated annotation files that can be viewed in a genome browser for any prokaryote. © 2017 Omasits et al.; Published by Cold Spring Harbor Laboratory Press.

Phylogenomic analysis of UDP glycosyltransferase 1 multigene family in Linum usitatissimum identified genes with varied expression patterns

PubMed Central

2012-01-01

Background The glycosylation process, catalyzed by ubiquitous glycosyltransferase (GT) family enzymes, is a prevalent modification of plant secondary metabolites that regulates various functions such as hormone homeostasis, detoxification of xenobiotics and biosynthesis and storage of secondary metabolites. Flax (Linum usitatissimum L.) is a commercially grown oilseed crop, important because of its essential fatty acids and health promoting lignans. Identification and characterization of UDP glycosyltransferase (UGT) genes from flax could provide valuable basic information about this important gene family and help to explain the seed specific glycosylated metabolite accumulation and other processes in plants. Plant genome sequencing projects are useful to discover complexity within this gene family and also pave way for the development of functional genomics approaches. Results Taking advantage of the newly assembled draft genome sequence of flax, we identified 137 UDP glycosyltransferase (UGT) genes from flax using a conserved signature motif. Phylogenetic analysis of these protein sequences clustered them into 14 major groups (A-N). Expression patterns of these genes were investigated using publicly available expressed sequence tag (EST), microarray data and reverse transcription quantitative real time PCR (RT-qPCR). Seventy-three per cent of these genes (100 out of 137) showed expression evidence in 15 tissues examined and indicated varied expression profiles. The RT-qPCR results of 10 selected genes were also coherent with the digital expression analysis. Interestingly, five duplicated UGT genes were identified, which showed differential expression in various tissues. Of the seven intron loss/gain positions detected, two intron positions were conserved among most of the UGTs, although a clear relationship about the evolution of these genes could not be established. Comparison of the flax UGTs with orthologs from four other sequenced dicot genomes indicated that

Comparative genomics of pathogenic lineages of Vibrio nigripulchritudo identifies virulence-associated traits

PubMed Central

Goudenège, David; Labreuche, Yannick; Krin, Evelyne; Ansquer, Dominique; Mangenot, Sophie; Calteau, Alexandra; Médigue, Claudine; Mazel, Didier; Polz, Martin F; Le Roux, Frédérique

2013-01-01

Vibrio nigripulchritudo is an emerging pathogen of farmed shrimp in New Caledonia and other regions in the Indo-Pacific. The molecular determinants of V. nigripulchritudo pathogenicity are unknown; however, molecular epidemiological studies have suggested that pathogenicity is linked to particular lineages. Here, we performed high-throughput sequencing-based comparative genome analysis of 16 V. nigripulchritudo strains to explore the genomic diversity and evolutionary history of pathogen-containing lineages and to identify pathogen-specific genetic elements. Our phylogenetic analysis revealed three pathogen-containing V. nigripulchritudo clades, including two clades previously identified from New Caledonia and one novel clade comprising putatively pathogenic isolates from septicemic shrimp in Madagascar. The similar genetic distance between the three clades indicates that they have diverged from an ancestral population roughly at the same time and recombination analysis indicates that these genomes have, in the past, shared a common gene pool and exchanged genes. As each contemporary lineage is comprised of nearly identical strains, comparative genomics allowed differentiation of genetic elements specific to shrimp pathogenesis of varying severity. Notably, only a large plasmid present in all highly pathogenic (HP) strains encodes a toxin. Although less/non-pathogenic strains contain related plasmids, these are differentiated by a putative toxin locus. Expression of this gene by a non-pathogenic V. nigripulchritudo strain resulted in production of toxic culture supernatant, normally an exclusive feature of HP strains. Thus, this protein, here termed ‘nigritoxin', is implicated to an extent that remains to be precisely determined in the toxicity of V. nigripulchritudo. PMID:23739050

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

Genome-wide patterns of copy number variation in the diversified chicken genomes using next-generation sequencing.

PubMed

Yi, Guoqiang; Qu, Lujiang; Liu, Jianfeng; Yan, Yiyuan; Xu, Guiyun; Yang, Ning

2014-11-07

Copy number variation (CNV) is important and widespread in the genome, and is a major cause of disease and phenotypic diversity. Herein, we performed a genome-wide CNV analysis in 12 diversified chicken genomes based on whole genome sequencing. A total of 8,840 CNV regions (CNVRs) covering 98.2 Mb and representing 9.4% of the chicken genome were identified, ranging in size from 1.1 to 268.8 kb with an average of 11.1 kb. Sequencing-based predictions were confirmed at a high validation rate by two independent approaches, including array comparative genomic hybridization (aCGH) and quantitative PCR (qPCR). The Pearson's correlation coefficients between sequencing and aCGH results ranged from 0.435 to 0.755, and qPCR experiments revealed a positive validation rate of 91.71% and a false negative rate of 22.43%. In total, 2,214 (25.0%) predicted CNVRs span 2,216 (36.4%) RefSeq genes associated with specific biological functions. Besides two previously reported copy number variable genes EDN3 and PRLR, we also found some promising genes with potential in phenotypic variation. Two genes, FZD6 and LIMS1, related to disease susceptibility/resistance are covered by CNVRs. The highly duplicated SOCS2 may lead to higher bone mineral density. Entire or partial duplication of some genes like POPDC3 may have great economic importance in poultry breeding. Our results based on extensive genetic diversity provide a more refined chicken CNV map and genome-wide gene copy number estimates, and warrant future CNV association studies for important traits in chickens.

A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries).

PubMed

Ren, Xue; Yang, Guang-Li; Peng, Wei-Feng; Zhao, Yong-Xin; Zhang, Min; Chen, Ze-Hui; Wu, Fu-An; Kantanen, Juha; Shen, Min; Li, Meng-Hua

2016-02-17

Horns are a cranial appendage found exclusively in Bovidae, and play important roles in accessing resources and mates. In sheep (Ovies aries), horns vary from polled to six-horned, and human have been selecting polled animals in farming and breeding. Here, we conducted a genome-wide association study on 24 two-horned versus 22 four-horned phenotypes in a native Chinese breed of Sishui Fur sheep. Together with linkage disequilibrium (LD) analyses and haplotype-based association tests, we identified a genomic region comprising 132.0-133.1 Mb on chromosome 2 that contained the top 10 SNPs (including 4 significant SNPs) and 5 most significant haplotypes associated with the polycerate phenotype. In humans and mice, this genomic region contains the HOXD gene cluster and adjacent functional genes EVX2 and KIAA1715, which have a close association with the formation of limbs and genital buds. Our results provide new insights into the genetic basis underlying variable numbers of horns and represent a new resource for use in sheep genetics and breeding.

Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells

PubMed Central

Bodemann, Brian; Petersen, Sean; Aruri, Jayavani; Koshy, Shiney; Richardson, Zachary; Le, Lu Q.; Krasieva, Tatiana; Roth, Michael G.; Farmer, Pat; White, Michael A.

2008-01-01

Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo), neurologic disorders (Parkinson's disease), auditory disorders (Waardenburg's syndrome), and opthalmologic disorders (age related macular degeneration). Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi) provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype and operate

Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma

PubMed Central

Yucesoy, Berran; Kaufman, Kenneth M.; Lummus, Zana L.; Weirauch, Matthew T.; Zhang, Ge; Cartier, André; Boulet, Louis-Philippe; Sastre, Joaquin; Quirce, Santiago; Tarlo, Susan M.; Cruz, Maria-Jesus; Munoz, Xavier; Harley, John B.; Bernstein, David I.

2015-01-01

Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10−14). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10−9 and rs2514805, p = 1.22 × 10−8, respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10−6). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies. PMID:25918132

Mining a database of single amplified genomes from Red Sea brine pool extremophiles—improving reliability of gene function prediction using a profile and pattern matching algorithm (PPMA)

PubMed Central

Grötzinger, Stefan W.; Alam, Intikhab; Ba Alawi, Wail; Bajic, Vladimir B.; Stingl, Ulrich; Eppinger, Jörg

2014-01-01

Reliable functional annotation of genomic data is the key-step in the discovery of novel enzymes. Intrinsic sequencing data quality problems of single amplified genomes (SAGs) and poor homology of novel extremophile's genomes pose significant challenges for the attribution of functions to the coding sequences identified. The anoxic deep-sea brine pools of the Red Sea are a promising source of novel enzymes with unique evolutionary adaptation. Sequencing data from Red Sea brine pool cultures and SAGs are annotated and stored in the Integrated Data Warehouse of Microbial Genomes (INDIGO) data warehouse. Low sequence homology of annotated genes (no similarity for 35% of these genes) may translate into false positives when searching for specific functions. The Profile and Pattern Matching (PPM) strategy described here was developed to eliminate false positive annotations of enzyme function before progressing to labor-intensive hyper-saline gene expression and characterization. It utilizes InterPro-derived Gene Ontology (GO)-terms (which represent enzyme function profiles) and annotated relevant PROSITE IDs (which are linked to an amino acid consensus pattern). The PPM algorithm was tested on 15 protein families, which were selected based on scientific and commercial potential. An initial list of 2577 enzyme commission (E.C.) numbers was translated into 171 GO-terms and 49 consensus patterns. A subset of INDIGO-sequences consisting of 58 SAGs from six different taxons of bacteria and archaea were selected from six different brine pool environments. Those SAGs code for 74,516 genes, which were independently scanned for the GO-terms (profile filter) and PROSITE IDs (pattern filter). Following stringent reliability filtering, the non-redundant hits (106 profile hits and 147 pattern hits) are classified as reliable, if at least two relevant descriptors (GO-terms and/or consensus patterns) are present. Scripts for annotation, as well as for the PPM algorithm, are available

A genome-wide analysis of long noncoding RNA profile identifies differentially expressed lncRNAs associated with Esophageal cancer.

PubMed

Liu, Wenjia; Zhang, Yiyang; Chen, Min; Shi, Liangliang; Xu, Lei; Zou, Xiaoping

2018-06-21

Esophageal cancer is one of the most common cancers and a leading cause of cancer-related death worldwide. However, the mechanism of esophageal cancer pathogenesis remains poorly understood. Long noncoding RNAs (lncRNAs) dysregulation have been reported to involve in various human cancers, which highlights the potential of lncRNAs used as novel biomarkers for cancer diagnosis. Although more efforts have been made to identify novel lncRNAs signature in esophageal cancer, the expression pattern, prognostic value, and biological function of most lncRNAs in esophageal cancer still need to be systematically investigated. In this study, we comprehensively analyzed the expression profile of lncRNAs in more than 200 esophageal cancer patients tissue samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). We identified thousands of lncRNAs are differentially expressed in esophageal cancer tissues, and many of those lncRNAs expression are associated with patients overall survival or recurrence-free survival time. Moreover, copy number variation analyses revealed that genomic loci copy number amplification or deletion might contribute to these lncRNAs dysregulation. Among these lncRNAs, DUXAP8 and LINC00460 were significantly upregulated, and GO enrichment analyses indicated that the two lncRNAs associated protein-coding genes involve with many known biological processes, such as cell cycle and cell-cell adherens junction. Further experimental validation revealed that knockdown of DUXAP8 could impair esophageal cancer cells proliferation and invasion in vitro. Taken together, our findings identified more aberrantly expressed lncRNAs in esophageal cancer that may provide a useful resource for identifying novel esophageal cancer associated lncRNAs. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Predicting human genetic interactions from cancer genome evolution.

PubMed

Lu, Xiaowen; Megchelenbrink, Wout; Notebaart, Richard A; Huynen, Martijn A

2015-01-01

Synthetic Lethal (SL) genetic interactions play a key role in various types of biological research, ranging from understanding genotype-phenotype relationships to identifying drug-targets against cancer. Despite recent advances in empirical measuring SL interactions in human cells, the human genetic interaction map is far from complete. Here, we present a novel approach to predict this map by exploiting patterns in cancer genome evolution. First, we show that empirically determined SL interactions are reflected in various gene presence, absence, and duplication patterns in hundreds of cancer genomes. The most evident pattern that we discovered is that when one member of an SL interaction gene pair is lost, the other gene tends not to be lost, i.e. the absence of co-loss. This observation is in line with expectation, because the loss of an SL interacting pair will be lethal to the cancer cell. SL interactions are also reflected in gene expression profiles, such as an under representation of cases where the genes in an SL pair are both under expressed, and an over representation of cases where one gene of an SL pair is under expressed, while the other one is over expressed. We integrated the various previously unknown cancer genome patterns and the gene expression patterns into a computational model to identify SL pairs. This simple, genome-wide model achieves a high prediction power (AUC = 0.75) for known genetic interactions. It allows us to present for the first time a comprehensive genome-wide list of SL interactions with a high estimated prediction precision, covering up to 591,000 gene pairs. This unique list can potentially be used in various application areas ranging from biotechnology to medical genetics.

High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations

PubMed Central

Stegelmann, Frank; Bullinger, Lars; Griesshammer, Martin; Holzmann, Karlheinz; Habdank, Marianne; Kuhn, Susanne; Maile, Carmen; Schauer, Stefanie; Döhner, Hartmut; Döhner, Konstanze

2010-01-01

Single-nucleotide polymorphism arrays allow for genome-wide profiling of copy-number alterations and copy-neutral runs of homozygosity at high resolution. To identify novel genetic lesions in myeloproliferative neoplasms, a large series of 151 clinically well characterized patients was analyzed in our study. Copy-number alterations were rare in essential thrombocythemia and polycythemia vera. In contrast, approximately one third of myelofibrosis patients exhibited small genomic losses (less than 5 Mb). In 2 secondary myelofibrosis cases the tumor suppressor gene NF1 in 17q11.2 was affected. Sequencing analyses revealed a mutation in the remaining NF1 allele of one patient. In terms of copy-neutral aberrations, no chromosomes other than 9p were recurrently affected. In conclusion, novel genomic aberrations were identified in our study, in particular in patients with myelofibrosis. Further analyses on single-gene level are necessary to uncover the mechanisms that are involved in the pathogenesis of myeloproliferative neoplasms. PMID:20015882

A genomic approach to identify hybrid incompatibility genes.

PubMed

Cooper, Jacob C; Phadnis, Nitin

2016-07-02

Uncovering the genetic and molecular basis of barriers to gene flow between populations is key to understanding how new species are born. Intrinsic postzygotic reproductive barriers such as hybrid sterility and hybrid inviability are caused by deleterious genetic interactions known as hybrid incompatibilities. The difficulty in identifying these hybrid incompatibility genes remains a rate-limiting step in our understanding of the molecular basis of speciation. We recently described how whole genome sequencing can be applied to identify hybrid incompatibility genes, even from genetically terminal hybrids. Using this approach, we discovered a new hybrid incompatibility gene, gfzf, between Drosophila melanogaster and Drosophila simulans, and found that it plays an essential role in cell cycle regulation. Here, we discuss the history of the hunt for incompatibility genes between these species, discuss the molecular roles of gfzf in cell cycle regulation, and explore how intragenomic conflict drives the evolution of fundamental cellular mechanisms that lead to the developmental arrest of hybrids.

A genomic approach to identify hybrid incompatibility genes

PubMed Central

Cooper, Jacob C.; Phadnis, Nitin

2016-01-01

ABSTRACT Uncovering the genetic and molecular basis of barriers to gene flow between populations is key to understanding how new species are born. Intrinsic postzygotic reproductive barriers such as hybrid sterility and hybrid inviability are caused by deleterious genetic interactions known as hybrid incompatibilities. The difficulty in identifying these hybrid incompatibility genes remains a rate-limiting step in our understanding of the molecular basis of speciation. We recently described how whole genome sequencing can be applied to identify hybrid incompatibility genes, even from genetically terminal hybrids. Using this approach, we discovered a new hybrid incompatibility gene, gfzf, between Drosophila melanogaster and Drosophila simulans, and found that it plays an essential role in cell cycle regulation. Here, we discuss the history of the hunt for incompatibility genes between these species, discuss the molecular roles of gfzf in cell cycle regulation, and explore how intragenomic conflict drives the evolution of fundamental cellular mechanisms that lead to the developmental arrest of hybrids. PMID:27230814

Understanding Historical Human Migration Patterns and Interbreeding (JGI Seventh Annual User Meeting 2012: Genomics of Energy and Environment)

ScienceCinema

Willerslev, Eske

2018-02-14

Eske Willerslev from the University of Copenhagen on Understanding Historical Human Migration Patterns and Interbreeding Using the Ancient Genomes of a Palaeo-Eskimo and an Aboriginal Australian at the 7th Annual Genomics of Energy & Environment Meeting on March 21, 2012 in Walnut Creek, California.

Genome scan of hybridizing sunflowers from Texas (Helianthus annuus and H. debilis) reveals asymmetric patterns of introgression and small islands of genomic differentiation.

PubMed

Scascitelli, M; Whitney, K D; Randell, R A; King, Matthew; Buerkle, C A; Rieseberg, L H

2010-02-01

Although the sexual transfer of genetic material between species (i.e. introgression) has been documented in many groups of plants and animals, genome-wide patterns of introgression are poorly understood. Is most of the genome permeable to interspecific gene flow, or is introgression typically restricted to a handful of genomic regions? Here, we assess the genomic extent and direction of introgression between three sunflowers from the south-central USA: the common sunflower, Helianthus annuus ssp. annuus; a near-endemic to Texas, Helianthus debilis ssp. cucumerifolius; and their putative hybrid derivative, thought to have recently colonized Texas, H. annuus ssp. texanus. Analyses of variation at 88 genetically mapped microsatellite loci revealed that long-term migration rates were high, genome-wide and asymmetric, with higher migration rates from H. annuus texanus into the two parental taxa than vice versa. These results imply a longer history of intermittent contact between H. debilis and H. annuus than previously believed, and that H. annuus texanus may serve as a bridge for the transfer of alleles between its parental taxa. They also contradict recent theory suggesting that introgression should predominantly be in the direction of the colonizing species. As in previous studies of hybridizing sunflower species, regions of genetic differentiation appear small, whether estimated in terms of FST or unidirectional migration rates. Estimates of recent immigration and admixture were inconsistent, depending on the type of analysis. At the individual locus level, one marker showed striking asymmetry in migration rates, a pattern consistent with tight linkage to a Bateson-Dobzhansky-Muller incompatibility.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

PubMed

Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L; Kähler, Anna K; Akterin, Susanne; Bergen, Sarah E; Collins, Ann L; Crowley, James J; Fromer, Menachem; Kim, Yunjung; Lee, Sang Hong; Magnusson, Patrik K E; Sanchez, Nick; Stahl, Eli A; Williams, Stephanie; Wray, Naomi R; Xia, Kai; Bettella, Francesco; Borglum, Anders D; Bulik-Sullivan, Brendan K; Cormican, Paul; Craddock, Nick; de Leeuw, Christiaan; Durmishi, Naser; Gill, Michael; Golimbet, Vera; Hamshere, Marian L; Holmans, Peter; Hougaard, David M; Kendler, Kenneth S; Lin, Kuang; Morris, Derek W; Mors, Ole; Mortensen, Preben B; Neale, Benjamin M; O'Neill, Francis A; Owen, Michael J; Milovancevic, Milica Pejovic; Posthuma, Danielle; Powell, John; Richards, Alexander L; Riley, Brien P; Ruderfer, Douglas; Rujescu, Dan; Sigurdsson, Engilbert; Silagadze, Teimuraz; Smit, August B; Stefansson, Hreinn; Steinberg, Stacy; Suvisaari, Jaana; Tosato, Sarah; Verhage, Matthijs; Walters, James T; Levinson, Douglas F; Gejman, Pablo V; Kendler, Kenneth S; Laurent, Claudine; Mowry, Bryan J; O'Donovan, Michael C; Owen, Michael J; Pulver, Ann E; Riley, Brien P; Schwab, Sibylle G; Wildenauer, Dieter B; Dudbridge, Frank; Holmans, Peter; Shi, Jianxin; Albus, Margot; Alexander, Madeline; Campion, Dominique; Cohen, David; Dikeos, Dimitris; Duan, Jubao; Eichhammer, Peter; Godard, Stephanie; Hansen, Mark; Lerer, F Bernard; Liang, Kung-Yee; Maier, Wolfgang; Mallet, Jacques; Nertney, Deborah A; Nestadt, Gerald; Norton, Nadine; O'Neill, Francis A; Papadimitriou, George N; Ribble, Robert; Sanders, Alan R; Silverman, Jeremy M; Walsh, Dermot; Williams, Nigel M; Wormley, Brandon; Arranz, Maria J; Bakker, Steven; Bender, Stephan; Bramon, Elvira; Collier, David; Crespo-Facorro, Benedicto; Hall, Jeremy; Iyegbe, Conrad; Jablensky, Assen; Kahn, Rene S; Kalaydjieva, Luba; Lawrie, Stephen; Lewis, Cathryn M; Lin, Kuang; Linszen, Don H; Mata, Ignacio; McIntosh, Andrew; Murray, Robin M; Ophoff, Roel A; Powell, John; Rujescu, Dan; Van Os, Jim; Walshe, Muriel; Weisbrod, Matthias; Wiersma, Durk; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden P; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin N A; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas W; Spencer, Chris C A; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard D; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T; Liddle, Jennifer; Potter, Simon C; Ravindrarajah, Radhi; Ricketts, Michelle; Tashakkori-Ghanbaria, Avazeh; Waller, Matthew J; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G; Blackwell, Jenefer M; Brown, Matthew A; Corvin, Aiden P; McCarthy, Mark I; Spencer, Chris C A; Bramon, Elvira; Corvin, Aiden P; O'Donovan, Michael C; Stefansson, Kari; Scolnick, Edward; Purcell, Shaun; McCarroll, Steven A; Sklar, Pamela; Hultman, Christina M; Sullivan, Patrick F

2013-10-01

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Genome-wide association studies to identify rice salt-tolerance markers.

PubMed

Patishtan, Juan; Hartley, Tom N; Fonseca de Carvalho, Raquel; Maathuis, Frans J M

2018-05-01

Salinity is an ever increasing menace that affects agriculture worldwide. Crops such as rice are salt sensitive, but its degree of susceptibility varies widely between cultivars pointing to extensive genetic diversity that can be exploited to identify genes and proteins that are relevant in the response of rice to salt stress. We used a diversity panel of 306 rice accessions and collected phenotypic data after short (6 h), medium (7 d) and long (30 d) salinity treatment (50 mm NaCl). A genome-wide association study (GWAS) was subsequently performed, which identified around 1200 candidate genes from many functional categories, but this was treatment period dependent. Further analysis showed the presence of cation transporters and transcription factors with a known role in salinity tolerance and those that hitherto were not known to be involved in salt stress. Localization analysis of single nucleotide polymorphisms (SNPs) showed the presence of several hundred non-synonymous SNPs (nsSNPs) in coding regions and earmarked specific genomic regions with increased numbers of nsSNPs. It points to components of the ubiquitination pathway as important sources of genetic diversity that could underpin phenotypic variation in stress tolerance. © 2017 John Wiley & Sons Ltd.

Whole Genome Sequencing Demonstrates Limited Transmission within Identified Mycobacterium tuberculosis Clusters in New South Wales, Australia

PubMed Central

Gurjav, Ulziijargal; Outhred, Alexander C.; Jelfs, Peter; McCallum, Nadine; Wang, Qinning; Hill-Cawthorne, Grant A.; Marais, Ben J.; Sintchenko, Vitali

2016-01-01

Australia has a low tuberculosis incidence rate with most cases occurring among recent immigrants. Given suboptimal cluster resolution achieved with 24-locus mycobacterium interspersed repetitive unit (MIRU-24) genotyping, the added value of whole genome sequencing was explored. MIRU-24 profiles of all Mycobacterium tuberculosis culture-confirmed tuberculosis cases diagnosed between 2009 and 2013 in New South Wales (NSW), Australia, were examined and clusters identified. The relatedness of cases within the largest MIRU-24 clusters was assessed using whole genome sequencing and phylogenetic analyses. Of 1841 culture-confirmed TB cases, 91.9% (1692/1841) had complete demographic and genotyping data. East-African Indian (474; 28.0%) and Beijing (470; 27.8%) lineage strains predominated. The overall rate of MIRU-24 clustering was 20.1% (340/1692) and was highest among Beijing lineage strains (35.7%; 168/470). One Beijing and three East-African Indian (EAI) clonal complexes were responsible for the majority of observed clusters. Whole genome sequencing of the 4 largest clusters (30 isolates) demonstrated diverse single nucleotide polymorphisms (SNPs) within identified clusters. All sequenced EAI strains and 70% of Beijing lineage strains clustered by MIRU-24 typing demonstrated distinct SNP profiles. The superior resolution provided by whole genome sequencing demonstrated limited M. tuberculosis transmission within NSW, even within identified MIRU-24 clusters. Routine whole genome sequencing could provide valuable public health guidance in low burden settings. PMID:27737005

Unbiased Combinatorial Genomic Approaches to Identify Alternative Therapeutic Targets within the TSC Signaling Network

DTIC Science & Technology

2015-09-01

assessed the specificity of mutation in Drosophila S2R+ cells. We generated a quantitative mutation reporter vector in which an sgRNA target sequence ...phosphatases (563 genes) in the Drosophila genome (Figure 4). 65 samples that displayed synthetic lethality (15 genes) or synthetic increases in viability...targeting all kinases and phosphatases (563 genes) in the Drosophila genome . . Identified three hits (mRNA-Cap, Pitslre and CycT) that scored as

Whole genome association study identifies regions of the bovine genome and biological pathways involved in carcass trait performance in Holstein-Friesian cattle.

PubMed

Doran, Anthony G; Berry, Donagh P; Creevey, Christopher J

2014-10-01

Four traits related to carcass performance have been identified as economically important in beef production: carcass weight, carcass fat, carcass conformation of progeny and cull cow carcass weight. Although Holstein-Friesian cattle are primarily utilized for milk production, they are also an important source of meat for beef production and export. Because of this, there is great interest in understanding the underlying genomic structure influencing these traits. Several genome-wide association studies have identified regions of the bovine genome associated with growth or carcass traits, however, little is known about the mechanisms or underlying biological pathways involved. This study aims to detect regions of the bovine genome associated with carcass performance traits (employing a panel of 54,001 SNPs) using measures of genetic merit (as predicted transmitting abilities) for 5,705 Irish Holstein-Friesian animals. Candidate genes and biological pathways were then identified for each trait under investigation. Following adjustment for false discovery (q-value < 0.05), 479 quantitative trait loci (QTL) were associated with at least one of the four carcass traits using a single SNP regression approach. Using a Bayesian approach, 46 QTL were associated (posterior probability > 0.5) with at least one of the four traits. In total, 557 unique bovine genes, which mapped to 426 human orthologs, were within 500kbs of QTL found associated with a trait using the Bayesian approach. Using this information, 24 significantly over-represented pathways were identified across all traits. The most significantly over-represented biological pathway was the peroxisome proliferator-activated receptor (PPAR) signaling pathway. A large number of genomic regions putatively associated with bovine carcass traits were detected using two different statistical approaches. Notably, several significant associations were detected in close proximity to genes with a known role in animal growth

Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma

PubMed Central

Zhao, Ling-Hao; Liu, Xiao; Yan, He-Xin; Li, Wei-Yang; Zeng, Xi; Yang, Yuan; Zhao, Jie; Liu, Shi-Ping; Zhuang, Xue-Han; Lin, Chuan; Qin, Chen-Jie; Zhao, Yi; Pan, Ze-Ya; Huang, Gang; Liu, Hui; Zhang, Jin; Wang, Ruo-Yu; Yang, Yun; Wen, Wen; Lv, Gui-Shuai; Zhang, Hui-Lu; Wu, Han; Huang, Shuai; Wang, Ming-Da; Tang, Liang; Cao, Hong-Zhi; Wang, Ling; Lee, Tin-Lap; Jiang, Hui; Tan, Ye-Xiong; Yuan, Sheng-Xian; Hou, Guo-Jun; Tao, Qi-Fei; Xu, Qin-Guo; Zhang, Xiu-Qing; Wu, Meng-Chao; Xu, Xun; Wang, Jun; Yang, Huan-Ming; Zhou, Wei-Ping; Wang, Hong-Yang

2016-01-01

Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation. PMID:27703150

Complete sequences of organelle genomes from the medicinal plant Rhazya stricta (Apocynaceae) and contrasting patterns of mitochondrial genome evolution across asterids.

PubMed

Park, Seongjun; Ruhlman, Tracey A; Sabir, Jamal S M; Mutwakil, Mohammed H Z; Baeshen, Mohammed N; Sabir, Meshaal J; Baeshen, Nabih A; Jansen, Robert K

2014-05-28

Rhazya stricta is native to arid regions in South Asia and the Middle East and is used extensively in folk medicine to treat a wide range of diseases. In addition to generating genomic resources for this medicinally important plant, analyses of the complete plastid and mitochondrial genomes and a nuclear transcriptome from Rhazya provide insights into inter-compartmental transfers between genomes and the patterns of evolution among eight asterid mitochondrial genomes. The 154,841 bp plastid genome is highly conserved with gene content and order identical to the ancestral organization of angiosperms. The 548,608 bp mitochondrial genome exhibits a number of phenomena including the presence of recombinogenic repeats that generate a multipartite organization, transferred DNA from the plastid and nuclear genomes, and bidirectional DNA transfers between the mitochondrion and the nucleus. The mitochondrial genes sdh3 and rps14 have been transferred to the nucleus and have acquired targeting presequences. In the case of rps14, two copies are present in the nucleus; only one has a mitochondrial targeting presequence and may be functional. Phylogenetic analyses of both nuclear and mitochondrial copies of rps14 across angiosperms suggests Rhazya has experienced a single transfer of this gene to the nucleus, followed by a duplication event. Furthermore, the phylogenetic distribution of gene losses and the high level of sequence divergence in targeting presequences suggest multiple, independent transfers of both sdh3 and rps14 across asterids. Comparative analyses of mitochondrial genomes of eight sequenced asterids indicates a complicated evolutionary history in this large angiosperm clade with considerable diversity in genome organization and size, repeat, gene and intron content, and amount of foreign DNA from the plastid and nuclear genomes. Organelle genomes of Rhazya stricta provide valuable information for improving the understanding of mitochondrial genome evolution

Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity

USDA-ARS?s Scientific Manuscript database

Background: Access to sheep genome sequences significantly improves the chances of identifying genes that may influence the health, welfare, and productivity of these animals. Methods: A public, searchable DNA sequence resource for U.S. sheep was created with whole genome sequence (WGS) of 96 rams. ...

EG-13GENOME-WIDE METHYLATION ANALYSIS IDENTIFIES GENOMIC DNA DEMETHYLATION DURING MALIGNANT PROGRESSION OF GLIOMAS

PubMed Central

Saito, Kuniaki; Mukasa, Akitake; Nagae, Genta; Aihara, Koki; Otani, Ryohei; Takayanagi, Shunsaku; Omata, Mayu; Tanaka, Shota; Shibahara, Junji; Takahashi, Miwako; Momose, Toshimitsu; Shimamura, Teppei; Miyano, Satoru; Narita, Yoshitaka; Ueki, Keisuke; Nishikawa, Ryo; Nagane, Motoo; Aburatani, Hiroyuki; Saito, Nobuhito

2014-01-01

Low-grade gliomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the molecular mechanisms underlying malignant tumor progression are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the impact of epigenetic changes during malignant progression of low-grade gliomas. Specifically, we used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 120 gliomas and four normal brains. This study sample included 25 matched-pairs of initial low-grade gliomas and recurrent tumors (temporal heterogeneity) and 20 of the 25 recurring tumors recurred as malignant progressions, and one matched-pair of newly emerging malignant lesions and pre-existing lesions (spatial heterogeneity). Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (43/51; 84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 50% of secondary glioblastomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. In

Population genomics of parallel hybrid zones in the mimetic butterflies, H. melpomene and H. erato

PubMed Central

Ruiz, Mayté; Salazar, Patricio; Counterman, Brian; Medina, Jose Alejandro; Ortiz-Zuazaga, Humberto; Morrison, Anna; Papa, Riccardo

2014-01-01

Hybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies of Heliconius butterflies can be very narrow and are maintained by strong selection acting on color pattern. The comimetic species, H. erato and H. melpomene, have parallel hybrid zones in which both species undergo a change from one color pattern form to another. We use restriction-associated DNA sequencing to obtain several thousand genome-wide sequence markers and use these to analyze patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data—alignment to a reference genome and de novo assembly—and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato, ∼15% divergent) related to the reference sequence. Our results confirm that the color pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to color pattern differences. We also use association mapping to identify previously unmapped color pattern loci, in particular the Ro locus. Finally, we identify a new cryptic population of H. timareta in Ecuador, which occurs at relatively low altitude and is mimetic with H. melpomene malleti. PMID:24823669

Identifying homomorphic sex chromosomes from wild-caught adults with limited genomic resources.

PubMed

Brelsford, Alan; Lavanchy, Guillaume; Sermier, Roberto; Rausch, Anna; Perrin, Nicolas

2017-07-01

We demonstrate a genotyping-by-sequencing approach to identify homomorphic sex chromosomes and their homolog in a distantly related reference genome, based on noninvasive sampling of wild-caught individuals, in the moor frog Rana arvalis. Double-digest RADseq libraries were generated using buccal swabs from 30 males and 21 females from the same population. Search for sex-limited markers from the unfiltered data set (411 446 RAD tags) was more successful than searches from a filtered data set (33 073 RAD tags) for markers showing sex differences in heterozygosity or in allele frequencies. Altogether, we obtained 292 putatively sex-linked RAD loci, 98% of which point to male heterogamety. We could map 15 of them to the Xenopus tropicalis genome, all but one on chromosome pair 1, which seems regularly co-opted for sex determination among amphibians. The most efficient mapping strategy was a three-step hierarchical approach, where R. arvalis reads were first mapped to a low-coverage genome of Rana temporaria (17 My divergence), then the R. temporaria scaffolds to the Nanorana parkeri genome (90 My divergence), and finally the N. parkeri scaffolds to the X. tropicalis genome (210 My). We validated our conclusions with PCR primers amplifying part of Dmrt1, a candidate sex determination gene mapping to chromosome 1: a sex-diagnostic allele was present in all 30 males but in none of the 21 females. Our approach is likely to be productive in many situations where biological samples and/or genomic resources are limited. © 2016 John Wiley & Sons Ltd.

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus.

PubMed

Julià, Antonio; López-Longo, Francisco Javier; Pérez Venegas, José J; Bonàs-Guarch, Silvia; Olivé, Àlex; Andreu, José Luís; Aguirre-Zamorano, Mª Ángeles; Vela, Paloma; Nolla, Joan M; de la Fuente, José Luís Marenco; Zea, Antonio; Pego-Reigosa, José María; Freire, Mercedes; Díez, Elvira; Rodríguez-Almaraz, Esther; Carreira, Patricia; Blanco, Ricardo; Taboada, Víctor Martínez; López-Lasanta, María; Corbeto, Mireia López; Mercader, Josep M; Torrents, David; Absher, Devin; Marsal, Sara; Fernández-Nebro, Antonio

2018-05-30

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10 - 8 ): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10 - 6 ), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10 - 5 ), interleukin-4 signaling (p = 3.97 × 10 - 5 ) and cell surface interactions at the vascular wall (p = 4.63 × 10 - 5 ). Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.

Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python).

PubMed

Irizarry, Kristopher J L; Rutllant, Josep

2016-01-01

Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 gene-phenotype relationships in the python which are implicated in 10 specific sperm phenotypes. Results obtained through our systematic analysis identified subsets of python genes exhibiting associations with gene ontology annotation terms. Functional annotation data was represented in a semantic scatter plot. Together, these newly annotated Python bivittatus genome resources provide a high resolution framework from which the biology relating to reptile spermatogenesis, fertility, and reproduction can be further investigated. Applications of our research include (1) production of genetic diagnostics for assessing fertility in domestic and wild reptiles; (2) enhanced assisted reproduction technology for endangered and captive reptiles; and (3) novel molecular targets for biotechnology-based approaches aimed at reducing fertility and reproduction of invasive reptiles. Additional enhancements to reptile genomic resources will further enhance their value.

A Genome-Wide Association Study Identifies Genetic Variants Associated with Mathematics Ability

PubMed Central

Chen, Huan; Gu, Xiao-hong; Zhou, Yuxi; Ge, Zeng; Wang, Bin; Siok, Wai Ting; Wang, Guoqing; Huen, Michael; Jiang, Yuyang; Tan, Li-Hai; Sun, Yimin

2017-01-01

Mathematics ability is a complex cognitive trait with polygenic heritability. Genome-wide association study (GWAS) has been an effective approach to investigate genetic components underlying mathematic ability. Although previous studies reported several candidate genetic variants, none of them exceeded genome-wide significant threshold in general populations. Herein, we performed GWAS in Chinese elementary school students to identify potential genetic variants associated with mathematics ability. The discovery stage included 494 and 504 individuals from two independent cohorts respectively. The replication stage included another cohort of 599 individuals. In total, 28 of 81 candidate SNPs that met validation criteria were further replicated. Combined meta-analysis of three cohorts identified four SNPs (rs1012694, rs11743006, rs17778739 and rs17777541) of SPOCK1 gene showing association with mathematics ability (minimum p value 5.67 × 10−10, maximum β −2.43). The SPOCK1 gene is located on chromosome 5q31.2 and encodes a highly conserved glycoprotein testican-1 which was associated with tumor progression and prognosis as well as neurogenesis. This is the first study to report genome-wide significant association of individual SNPs with mathematics ability in general populations. Our preliminary results further supported the role of SPOCK1 during neurodevelopment. The genetic complexities underlying mathematics ability might contribute to explain the basis of human cognition and intelligence at genetic level. PMID:28155865

A Genome-Wide Association Study Identifies Genetic Variants Associated with Mathematics Ability.

PubMed

Chen, Huan; Gu, Xiao-Hong; Zhou, Yuxi; Ge, Zeng; Wang, Bin; Siok, Wai Ting; Wang, Guoqing; Huen, Michael; Jiang, Yuyang; Tan, Li-Hai; Sun, Yimin

2017-02-03

Mathematics ability is a complex cognitive trait with polygenic heritability. Genome-wide association study (GWAS) has been an effective approach to investigate genetic components underlying mathematic ability. Although previous studies reported several candidate genetic variants, none of them exceeded genome-wide significant threshold in general populations. Herein, we performed GWAS in Chinese elementary school students to identify potential genetic variants associated with mathematics ability. The discovery stage included 494 and 504 individuals from two independent cohorts respectively. The replication stage included another cohort of 599 individuals. In total, 28 of 81 candidate SNPs that met validation criteria were further replicated. Combined meta-analysis of three cohorts identified four SNPs (rs1012694, rs11743006, rs17778739 and rs17777541) of SPOCK1 gene showing association with mathematics ability (minimum p value 5.67 × 10 -10 , maximum β -2.43). The SPOCK1 gene is located on chromosome 5q31.2 and encodes a highly conserved glycoprotein testican-1 which was associated with tumor progression and prognosis as well as neurogenesis. This is the first study to report genome-wide significant association of individual SNPs with mathematics ability in general populations. Our preliminary results further supported the role of SPOCK1 during neurodevelopment. The genetic complexities underlying mathematics ability might contribute to explain the basis of human cognition and intelligence at genetic level.

Genomic determinants of epidermal appendage patterning and structure in domestic birds

PubMed Central

Boer, Elena F.; Van Hollebeke, Hannah F.; Shapiro, Michael D.

2017-01-01

Variation in regional identity, patterning, and structure of epidermal appendages contributes to skin diversity among many vertebrate groups, and is perhaps most striking in birds. In pioneering work on epidermal appendage patterning, John Saunders and his contemporaries took advantage of epidermal appendage diversity within and among domestic chicken breeds to establish the importance of mesoderm-ectoderm signaling in determining skin patterning. Diversity in chickens and other domestic birds, including pigeons, is driving a new wave of research to dissect the molecular genetic basis of epidermal appendage patterning. Domestic birds are not only outstanding models for embryonic manipulations, as Saunders recognized, but they are also ideal genetic models for discovering the specific genes that control normal development and the mutations that contribute to skin diversity. Here, we review recent genetic and genomic approaches to uncover the basis of epidermal macropatterning, micropatterning, and structural variation. We also present new results that confirm expression changes in two limb identity genes in feather-footed pigeons, a case of variation in appendage structure and identity. PMID:28347644

Genomic determinants of epidermal appendage patterning and structure in domestic birds.

PubMed

Boer, Elena F; Van Hollebeke, Hannah F; Shapiro, Michael D

2017-09-15

Variation in regional identity, patterning, and structure of epidermal appendages contributes to skin diversity among many vertebrate groups, and is perhaps most striking in birds. In pioneering work on epidermal appendage patterning, John Saunders and his contemporaries took advantage of epidermal appendage diversity within and among domestic chicken breeds to establish the importance of mesoderm-ectoderm signaling in determining skin patterning. Diversity in chickens and other domestic birds, including pigeons, is driving a new wave of research to dissect the molecular genetic basis of epidermal appendage patterning. Domestic birds are not only outstanding models for embryonic manipulations, as Saunders recognized, but they are also ideal genetic models for discovering the specific genes that control normal development and the mutations that contribute to skin diversity. Here, we review recent genetic and genomic approaches to uncover the basis of epidermal macropatterning, micropatterning, and structural variation. We also present new results that confirm expression changes in two limb identity genes in feather-footed pigeons, a case of variation in appendage structure and identity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Genome-wide Association Study Identifies New Loci for Resistance to Leptosphaeria maculans in Canola

PubMed Central

Raman, Harsh; Raman, Rosy; Coombes, Neil; Song, Jie; Diffey, Simon; Kilian, Andrzej; Lindbeck, Kurt; Barbulescu, Denise M.; Batley, Jacqueline; Edwards, David; Salisbury, Phil A.; Marcroft, Steve

2016-01-01

Key message “We identified both quantitative and quantitative resistance loci to Leptosphaeria maculans, a fungal pathogen, causing blackleg disease in canola. Several genome-wide significant associations were detected at known and new loci for blackleg resistance. We further validated statistically significant associations in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. maculans. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance in canola.” Blackleg, caused by Leptosphaeria maculans, is a significant disease which affects the sustainable production of canola (Brassica napus). This study reports a genome-wide association study based on 18,804 polymorphic SNPs to identify loci associated with qualitative and quantitative resistance to L. maculans. Genomic regions delimited with 694 significant SNP markers, that are associated with resistance evaluated using 12 single spore isolates and pathotypes from four canola stubble were identified. Several significant associations were detected at known disease resistance loci including in the vicinity of recently cloned Rlm2/LepR3 genes, and at new loci on chromosomes A01/C01, A02/C02, A03/C03, A05/C05, A06, A08, and A09. In addition, we validated statistically significant associations on A01, A07, and A10 in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. maculans. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance and mapped within 13.2 kb from Arabidopsis R gene of TIR-NBS class. We showed that resistance loci are located in the vicinity of R genes of Arabidopsis thaliana and Brassica napus on the sequenced genome of B. napus cv. Darmor-bzh. Significantly associated SNP markers provide a valuable tool to enrich germplasm for favorable alleles in order to improve the level of resistance to L. maculans in

Cell Context Dependent p53 Genome-Wide Binding Patterns and Enrichment at Repeats

DOE PAGES

Botcheva, Krassimira; McCorkle, Sean R.

2014-11-21

The p53 ability to elicit stress specific and cell type specific responses is well recognized, but how that specificity is established remains to be defined. Whether upon activation p53 binds to its genomic targets in a cell type and stress type dependent manner is still an open question. Here we show that the p53 binding to the human genome is selective and cell context-dependent. We mapped the genomic binding sites for the endogenous wild type p53 protein in the human cancer cell line HCT116 and compared them to those we previously determined in the normal cell line IMR90. We reportmore » distinct p53 genome-wide binding landscapes in two different cell lines, analyzed under the same treatment and experimental conditions, using the same ChIP-seq approach. This is evidence for cell context dependent p53 genomic binding. The observed differences affect the p53 binding sites distribution with respect to major genomic and epigenomic elements (promoter regions, CpG islands and repeats). We correlated the high-confidence p53 ChIP-seq peaks positions with the annotated human repeats (UCSC Human Genome Browser) and observed both common and cell line specific trends. In HCT116, the p53 binding was specifically enriched at LINE repeats, compared to IMR90 cells. The p53 genome-wide binding patterns in HCT116 and IMR90 likely reflect the different epigenetic landscapes in these two cell lines, resulting from cancer-associated changes (accumulated in HCT116) superimposed on tissue specific differences (HCT116 has epithelial, while IMR90 has mesenchymal origin). In conclusion, our data support the model for p53 binding to the human genome in a highly selective manner, mobilizing distinct sets of genes, contributing to distinct pathways.« less

A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast

DTIC Science & Technology

2004-05-01

AD Award Number: DAMD17-03-1-0232 TITLE: A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast PRINCIPAL INVESTIGATOR...Approach to Identify Novel Breast DAMD17-03-1-0232 Cancer Gene Targets in Yeast 6. A UTHOR(S) Craig Bennett, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S...Unlimited 13. ABSTRACT (Maximum 200 Words) We are using the yeast Saccharomyces cerevisiae to identify new cancer gene targets that interact with the

Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species.

PubMed

Adamek, Martina; Alanjary, Mohammad; Sales-Ortells, Helena; Goodfellow, Michael; Bull, Alan T; Winkler, Anika; Wibberg, Daniel; Kalinowski, Jörn; Ziemert, Nadine

2018-06-01

Genome mining tools have enabled us to predict biosynthetic gene clusters that might encode compounds with valuable functions for industrial and medical applications. With the continuously increasing number of genomes sequenced, we are confronted with an overwhelming number of predicted clusters. In order to guide the effective prioritization of biosynthetic gene clusters towards finding the most promising compounds, knowledge about diversity, phylogenetic relationships and distribution patterns of biosynthetic gene clusters is necessary. Here, we provide a comprehensive analysis of the model actinobacterial genus Amycolatopsis and its potential for the production of secondary metabolites. A phylogenetic characterization, together with a pan-genome analysis showed that within this highly diverse genus, four major lineages could be distinguished which differed in their potential to produce secondary metabolites. Furthermore, we were able to distinguish gene cluster families whose distribution correlated with phylogeny, indicating that vertical gene transfer plays a major role in the evolution of secondary metabolite gene clusters. Still, the vast majority of the diverse biosynthetic gene clusters were derived from clusters unique to the genus, and also unique in comparison to a database of known compounds. Our study on the locations of biosynthetic gene clusters in the genomes of Amycolatopsis' strains showed that clusters acquired by horizontal gene transfer tend to be incorporated into non-conserved regions of the genome thereby allowing us to distinguish core and hypervariable regions in Amycolatopsis genomes. Using a comparative genomics approach, it was possible to determine the potential of the genus Amycolatopsis to produce a huge diversity of secondary metabolites. Furthermore, the analysis demonstrates that horizontal and vertical gene transfer play an important role in the acquisition and maintenance of valuable secondary metabolites. Our results cast

Identifying candidate drivers of drug response in heterogeneous cancer by mining high throughput genomics data.

PubMed

Nabavi, Sheida

2016-08-15

With advances in technologies, huge amounts of multiple types of high-throughput genomics data are available. These data have tremendous potential to identify new and clinically valuable biomarkers to guide the diagnosis, assessment of prognosis, and treatment of complex diseases, such as cancer. Integrating, analyzing, and interpreting big and noisy genomics data to obtain biologically meaningful results, however, remains highly challenging. Mining genomics datasets by utilizing advanced computational methods can help to address these issues. To facilitate the identification of a short list of biologically meaningful genes as candidate drivers of anti-cancer drug resistance from an enormous amount of heterogeneous data, we employed statistical machine-learning techniques and integrated genomics datasets. We developed a computational method that integrates gene expression, somatic mutation, and copy number aberration data of sensitive and resistant tumors. In this method, an integrative method based on module network analysis is applied to identify potential driver genes. This is followed by cross-validation and a comparison of the results of sensitive and resistance groups to obtain the final list of candidate biomarkers. We applied this method to the ovarian cancer data from the cancer genome atlas. The final result contains biologically relevant genes, such as COL11A1, which has been reported as a cis-platinum resistant biomarker for epithelial ovarian carcinoma in several recent studies. The described method yields a short list of aberrant genes that also control the expression of their co-regulated genes. The results suggest that the unbiased data driven computational method can identify biologically relevant candidate biomarkers. It can be utilized in a wide range of applications that compare two conditions with highly heterogeneous datasets.

Admixture patterns and genetic differentiation in negrito groups from West Malaysia estimated from genome-wide SNP data.

PubMed

Jinam, Timothy A; Phipps, Maude E; Saitou, Naruya

2013-01-01

Southeast Asia houses various culturally and linguistically diverse ethnic groups. In Malaysia, where the Malay, Chinese, and Indian ethnic groups form the majority, there exist minority groups such as the "negritos" who are believed to be descendants of the earliest settlers of Southeast Asia. Here we report patterns of genetic substructure and admixture in two Malaysian negrito populations (Jehai and Kensiu), using ~50,000 genome-wide single-nucleotide polymorphism (SNP) data. We found traces of recent admixture in both the negrito populations, particularly in the Jehai, with the Malay through principal component analysis and STRUCTURE analysis software, which suggested that the admixture was as recent as one generation ago. We also identified significantly differentiated nonsynonymous SNPs and haplotype blocks related to intracellular transport, metabolic processes, and detection of stimulus. These results highlight the different levels of admixture experienced by the two Malaysian negritos. Delineating admixture and differentiated genomic regions should be of importance in designing and interpretation of molecular anthropology and disease association studies. Copyright © 2013 Wayne State University Press, Detroit, Michigan 48201-1309.

Patterns of genome size variation in snapping shrimp.

PubMed

Jeffery, Nicholas W; Hultgren, Kristin; Chak, Solomon Tin Chi; Gregory, T Ryan; Rubenstein, Dustin R

2016-06-01

Although crustaceans vary extensively in genome size, little is known about how genome size may affect the ecology and evolution of species in this diverse group, in part due to the lack of large genome size datasets. Here we investigate interspecific, intraspecific, and intracolony variation in genome size in 39 species of Synalpheus shrimps, representing one of the largest genome size datasets for a single genus within crustaceans. We find that genome size ranges approximately 4-fold across Synalpheus with little phylogenetic signal, and is not related to body size. In a subset of these species, genome size is related to chromosome size, but not to chromosome number, suggesting that despite large genomes, these species are not polyploid. Interestingly, there appears to be 35% intraspecific genome size variation in Synalpheus idios among geographic regions, and up to 30% variation in Synalpheus duffyi genome size within the same colony.

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

Genome-wide screen identifies a novel prognostic signature for breast cancer survival

DOE PAGES

Mao, Xuan Y.; Lee, Matthew J.; Zhu, Jeffrey; ...

2017-01-21

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion,more » cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.« less

MVisAGe Identifies Concordant and Discordant Genomic Alterations of Driver Genes in Squamous Tumors.

PubMed

Walter, Vonn; Du, Ying; Danilova, Ludmila; Hayward, Michele C; Hayes, D Neil

2018-06-15

Integrated analyses of multiple genomic datatypes are now common in cancer profiling studies. Such data present opportunities for numerous computational experiments, yet analytic pipelines are limited. Tools such as the cBioPortal and Regulome Explorer, although useful, are not easy to access programmatically or to implement locally. Here, we introduce the MVisAGe R package, which allows users to quantify gene-level associations between two genomic datatypes to investigate the effect of genomic alterations (e.g., DNA copy number changes on gene expression). Visualizing Pearson/Spearman correlation coefficients according to the genomic positions of the underlying genes provides a powerful yet novel tool for conducting exploratory analyses. We demonstrate its utility by analyzing three publicly available cancer datasets. Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN , genes not identified by copy number analysis in the primary reports. We demonstrate highly concordant usage of shared oncogenes on chr3q, yet strikingly diverse oncogene usage on chr11q as a function of HPV infection status. Regions of chr19 that display remarkable associations between methylation and gene expression were identified, as were previously unreported miRNA-gene expression associations that may contribute to the epithelial-to-mesenchymal transition. Significance: This study presents an important bioinformatics tool that will enable integrated analyses of multiple genomic datatypes. Cancer Res; 78(12); 3375-85. ©2018 AACR . ©2018 American Association for Cancer Research.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

PubMed Central

Lu, Xiangfeng; Wang, Laiyuan; Lin, Xu; Huang, Jianfeng; Charles Gu, C.; He, Meian; Shen, Hongbing; He, Jiang; Zhu, Jingwen; Li, Huaixing; Hixson, James E.; Wu, Tangchun; Dai, Juncheng; Lu, Ling; Shen, Chong; Chen, Shufeng; He, Lin; Mo, Zengnan; Hao, Yongchen; Mo, Xingbo; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Fan, Zhongjie; Li, Ying; Zhao, Liancheng; Li, Hongfan; Lu, Fanghong; Yao, Cailiang; Yu, Lin; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Deng, Ying; Hu, Dongsheng; Zhang, Weidong; Ji, Xu; Guo, Dongshuang; Guo, Zhirong; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Zhou, Xiaoyang; Yan, Weili; Sun, Ningling; Gao, Pingjin; Gu, Dongfeng

2015-01-01

Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10−8) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10−3 to 5.16 × 10−8. These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments. PMID:25249183

Identifying structural variation in haploid microbial genomes from short-read resequencing data using breseq.

PubMed

Barrick, Jeffrey E; Colburn, Geoffrey; Deatherage, Daniel E; Traverse, Charles C; Strand, Matthew D; Borges, Jordan J; Knoester, David B; Reba, Aaron; Meyer, Austin G

2014-11-29

Mutations that alter chromosomal structure play critical roles in evolution and disease, including in the origin of new lifestyles and pathogenic traits in microbes. Large-scale rearrangements in genomes are often mediated by recombination events involving new or existing copies of mobile genetic elements, recently duplicated genes, or other repetitive sequences. Most current software programs for predicting structural variation from short-read DNA resequencing data are intended primarily for use on human genomes. They typically disregard information in reads mapping to repeat sequences, and significant post-processing and manual examination of their output is often required to rule out false-positive predictions and precisely describe mutational events. We have implemented an algorithm for identifying structural variation from DNA resequencing data as part of the breseq computational pipeline for predicting mutations in haploid microbial genomes. Our method evaluates the support for new sequence junctions present in a clonal sample from split-read alignments to a reference genome, including matches to repeat sequences. Then, it uses a statistical model of read coverage evenness to accept or reject these predictions. Finally, breseq combines predictions of new junctions and deleted chromosomal regions to output biologically relevant descriptions of mutations and their effects on genes. We demonstrate the performance of breseq on simulated Escherichia coli genomes with deletions generating unique breakpoint sequences, new insertions of mobile genetic elements, and deletions mediated by mobile elements. Then, we reanalyze data from an E. coli K-12 mutation accumulation evolution experiment in which structural variation was not previously identified. Transposon insertions and large-scale chromosomal changes detected by breseq account for ~25% of spontaneous mutations in this strain. In all cases, we find that breseq is able to reliably predict structural variation

Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution

PubMed Central

Kumar, Narender; Mariappan, Vanitha; Baddam, Ramani; Lankapalli, Aditya K.; Shaik, Sabiha; Goh, Khean-Lee; Loke, Mun Fai; Perkins, Tim; Benghezal, Mohammed; Hasnain, Seyed E.; Vadivelu, Jamuna; Marshall, Barry J.; Ahmed, Niyaz

2015-01-01

The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host–pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. PMID:25452339

Patterns of divergence across the geographic and genomic landscape of a butterfly hybrid zone associated with a climatic gradient

USDA-ARS?s Scientific Manuscript database

The process of speciation is impacted by the interaction between the genomic architecture of diverging lineages and the environmental context they occupy. Yet, while climate can have a significant impact on this interaction, its role in determining the patterns of geographic and genomic divergence i...

Genome-Wide Variation Patterns Uncover the Origin and Selection in Cultivated Ginseng (Panax ginseng Meyer)

PubMed Central

Li, Ming-Rui; Shi, Feng-Xue; Li, Ya-Ling; Jiang, Peng; Jiao, Lili

2017-01-01

Abstract Chinese ginseng (Panax ginseng Meyer) is a medicinally important herb and plays crucial roles in traditional Chinese medicine. Pharmacological analyses identified diverse bioactive components from Chinese ginseng. However, basic biological attributes including domestication and selection of the ginseng plant remain under-investigated. Here, we presented a genome-wide view of the domestication and selection of cultivated ginseng based on the whole genome data. A total of 8,660 protein-coding genes were selected for genome-wide scanning of the 30 wild and cultivated ginseng accessions. In complement, the 45s rDNA, chloroplast and mitochondrial genomes were included to perform phylogenetic and population genetic analyses. The observed spatial genetic structure between northern cultivated ginseng (NCG) and southern cultivated ginseng (SCG) accessions suggested multiple independent origins of cultivated ginseng. Genome-wide scanning further demonstrated that NCG and SCG have undergone distinct selection pressures during the domestication process, with more genes identified in the NCG (97 genes) than in the SCG group (5 genes). Functional analyses revealed that these genes are involved in diverse pathways, including DNA methylation, lignin biosynthesis, and cell differentiation. These findings suggested that the SCG and NCG groups have distinct demographic histories. Candidate genes identified are useful for future molecular breeding of cultivated ginseng. PMID:28922794

Genomic analyses identify molecular subtypes of pancreatic cancer.

PubMed

Bailey, Peter; Chang, David K; Nones, Katia; Johns, Amber L; Patch, Ann-Marie; Gingras, Marie-Claude; Miller, David K; Christ, Angelika N; Bruxner, Tim J C; Quinn, Michael C; Nourse, Craig; Murtaugh, L Charles; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourbakhsh, Ehsan; Wani, Shivangi; Fink, Lynn; Holmes, Oliver; Chin, Venessa; Anderson, Matthew J; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Xu, Qinying; Wilson, Peter J; Cloonan, Nicole; Kassahn, Karin S; Taylor, Darrin; Quek, Kelly; Robertson, Alan; Pantano, Lorena; Mincarelli, Laura; Sanchez, Luis N; Evers, Lisa; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chantrill, Lorraine A; Mawson, Amanda; Humphris, Jeremy; Chou, Angela; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Moran-Jones, Kim; Jamieson, Nigel B; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Grützmann, Robert; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Rusev, Borislav; Capelli, Paola; Salvia, Roberto; Tortora, Giampaolo; Mukhopadhyay, Debabrata; Petersen, Gloria M; Munzy, Donna M; Fisher, William E; Karim, Saadia A; Eshleman, James R; Hruban, Ralph H; Pilarsky, Christian; Morton, Jennifer P; Sansom, Owen J; Scarpa, Aldo; Musgrove, Elizabeth A; Bailey, Ulla-Maja Hagbo; Hofmann, Oliver; Sutherland, Robert L; Wheeler, David A; Gill, Anthony J; Gibbs, Richard A; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M

2016-03-03

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python)

PubMed Central

Rutllant, Josep

2016-01-01

Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 gene-phenotype relationships in the python which are implicated in 10 specific sperm phenotypes. Results obtained through our systematic analysis identified subsets of python genes exhibiting associations with gene ontology annotation terms. Functional annotation data was represented in a semantic scatter plot. Together, these newly annotated Python bivittatus genome resources provide a high resolution framework from which the biology relating to reptile spermatogenesis, fertility, and reproduction can be further investigated. Applications of our research include (1) production of genetic diagnostics for assessing fertility in domestic and wild reptiles; (2) enhanced assisted reproduction technology for endangered and captive reptiles; and (3) novel molecular targets for biotechnology-based approaches aimed at reducing fertility and reproduction of invasive reptiles. Additional enhancements to reptile genomic resources will further enhance their value. PMID:27200191

4C-ker: A Method to Reproducibly Identify Genome-Wide Interactions Captured by 4C-Seq Experiments.

PubMed

Raviram, Ramya; Rocha, Pedro P; Müller, Christian L; Miraldi, Emily R; Badri, Sana; Fu, Yi; Swanzey, Emily; Proudhon, Charlotte; Snetkova, Valentina; Bonneau, Richard; Skok, Jane A

2016-03-01

4C-Seq has proven to be a powerful technique to identify genome-wide interactions with a single locus of interest (or "bait") that can be important for gene regulation. However, analysis of 4C-Seq data is complicated by the many biases inherent to the technique. An important consideration when dealing with 4C-Seq data is the differences in resolution of signal across the genome that result from differences in 3D distance separation from the bait. This leads to the highest signal in the region immediately surrounding the bait and increasingly lower signals in far-cis and trans. Another important aspect of 4C-Seq experiments is the resolution, which is greatly influenced by the choice of restriction enzyme and the frequency at which it can cut the genome. Thus, it is important that a 4C-Seq analysis method is flexible enough to analyze data generated using different enzymes and to identify interactions across the entire genome. Current methods for 4C-Seq analysis only identify interactions in regions near the bait or in regions located in far-cis and trans, but no method comprehensively analyzes 4C signals of different length scales. In addition, some methods also fail in experiments where chromatin fragments are generated using frequent cutter restriction enzymes. Here, we describe 4C-ker, a Hidden-Markov Model based pipeline that identifies regions throughout the genome that interact with the 4C bait locus. In addition, we incorporate methods for the identification of differential interactions in multiple 4C-seq datasets collected from different genotypes or experimental conditions. Adaptive window sizes are used to correct for differences in signal coverage in near-bait regions, far-cis and trans chromosomes. Using several datasets, we demonstrate that 4C-ker outperforms all existing 4C-Seq pipelines in its ability to reproducibly identify interaction domains at all genomic ranges with different resolution enzymes.

4C-ker: A Method to Reproducibly Identify Genome-Wide Interactions Captured by 4C-Seq Experiments

PubMed Central

Raviram, Ramya; Rocha, Pedro P.; Müller, Christian L.; Miraldi, Emily R.; Badri, Sana; Fu, Yi; Swanzey, Emily; Proudhon, Charlotte; Snetkova, Valentina

2016-01-01

4C-Seq has proven to be a powerful technique to identify genome-wide interactions with a single locus of interest (or “bait”) that can be important for gene regulation. However, analysis of 4C-Seq data is complicated by the many biases inherent to the technique. An important consideration when dealing with 4C-Seq data is the differences in resolution of signal across the genome that result from differences in 3D distance separation from the bait. This leads to the highest signal in the region immediately surrounding the bait and increasingly lower signals in far-cis and trans. Another important aspect of 4C-Seq experiments is the resolution, which is greatly influenced by the choice of restriction enzyme and the frequency at which it can cut the genome. Thus, it is important that a 4C-Seq analysis method is flexible enough to analyze data generated using different enzymes and to identify interactions across the entire genome. Current methods for 4C-Seq analysis only identify interactions in regions near the bait or in regions located in far-cis and trans, but no method comprehensively analyzes 4C signals of different length scales. In addition, some methods also fail in experiments where chromatin fragments are generated using frequent cutter restriction enzymes. Here, we describe 4C-ker, a Hidden-Markov Model based pipeline that identifies regions throughout the genome that interact with the 4C bait locus. In addition, we incorporate methods for the identification of differential interactions in multiple 4C-seq datasets collected from different genotypes or experimental conditions. Adaptive window sizes are used to correct for differences in signal coverage in near-bait regions, far-cis and trans chromosomes. Using several datasets, we demonstrate that 4C-ker outperforms all existing 4C-Seq pipelines in its ability to reproducibly identify interaction domains at all genomic ranges with different resolution enzymes. PMID:26938081

Overview Article: Identifying transcriptional cis-regulatory modules in animal genomes

PubMed Central

Suryamohan, Kushal; Halfon, Marc S.

2014-01-01

Gene expression is regulated through the activity of transcription factors and chromatin modifying proteins acting on specific DNA sequences, referred to as cis-regulatory elements. These include promoters, located at the transcription initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs), the most common of which are transcriptional enhancers. Because regulated gene expression is fundamental to cell differentiation and acquisition of new cell fates, identifying, characterizing, and understanding the mechanisms of action of CRMs is critical for understanding development. CRM discovery has historically been challenging, as CRMs can be located far from the genes they regulate, have few readily-identifiable sequence characteristics, and for many years were not amenable to high-throughput discovery methods. However, the recent availability of complete genome sequences and the development of next-generation sequencing methods has led to an explosion of both computational and empirical methods for CRM discovery in model and non-model organisms alike. Experimentally, CRMs can be identified through chromatin immunoprecipitation directed against transcription factors or histone post-translational modifications, identification of nucleosome-depleted “open” chromatin regions, or sequencing-based high-throughput functional screening. Computational methods include comparative genomics, clustering of known or predicted transcription factor binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. Experimental confirmation of predictions is essential, although shortcomings in current methods suggest that additional means of validation need to be developed. PMID:25704908

Exploiting genomic data to identify proteins involved in abalone reproduction.

PubMed

Mendoza-Porras, Omar; Botwright, Natasha A; McWilliam, Sean M; Cook, Mathew T; Harris, James O; Wijffels, Gene; Colgrave, Michelle L

2014-08-28

Aside from their critical role in reproduction, abalone gonads serve as an indicator of sexual maturity and energy balance, two key considerations for effective abalone culture. Temperate abalone farmers face issues with tank restocking with highly marketable abalone owing to inefficient spawning induction methods. The identification of key proteins in sexually mature abalone will serve as the foundation for a greater understanding of reproductive biology. Addressing this knowledge gap is the first step towards improving abalone aquaculture methods. Proteomic profiling of female and male gonads of greenlip abalone, Haliotis laevigata, was undertaken using liquid chromatography-mass spectrometry. Owing to the incomplete nature of abalone protein databases, in addition to searching against two publicly available databases, a custom database comprising genomic data was used. Overall, 162 and 110 proteins were identified in females and males respectively with 40 proteins common to both sexes. For proteins involved in sexual maturation, sperm and egg structure, motility, acrosomal reaction and fertilization, 23 were identified only in females, 18 only in males and 6 were common. Gene ontology analysis revealed clear differences between the female and male protein profiles reflecting a higher rate of protein synthesis in the ovary and higher metabolic activity in the testis. A comprehensive mass spectrometry-based analysis was performed to profile the abalone gonad proteome providing the foundation for future studies of reproduction in abalone. Key proteins involved in both reproduction and energy balance were identified. Genomic resources were utilised to build a database of molluscan proteins yielding >60% more protein identifications than in a standard workflow employing public protein databases. Copyright © 2014 Elsevier B.V. All rights reserved.

A Genome Wide Association Study Identifies Common Variants Associated with Lipid Levels in the Chinese Population

PubMed Central

Wu, Chen; Yang, Handong; Yu, Dianke; Yang, Xiaobo; Zhang, Xiaomin; Wang, Yiqin; Sun, Jielin; Gao, Yong; Tan, Aihua; He, Yunfeng; Zhang, Haiying; Qin, Xue; Zhu, Jingwen; Li, Huaixing; Lin, Xu; Zhu, Jiang; Min, Xinwen; Lang, Mingjian; Li, Dongfeng; Zhai, Kan; Chang, Jiang; Tan, Wen; Yuan, Jing; Chen, Weihong; Wang, Youjie; Wei, Sheng; Miao, Xiaoping; Wang, Feng; Fang, Weimin; Liang, Yuan; Deng, Qifei; Dai, Xiayun; Lin, Dafeng; Huang, Suli; Guo, Huan; Lilly Zheng, S.; Xu, Jianfeng; Lin, Dongxin; Hu, Frank B.; Wu, Tangchun

2013-01-01

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52×10-16, 1.38×10-6 and 5.59×10-9, respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population. PMID:24386095

Identifying genomic and developmental causes of adverse drug reactions in children

PubMed Central

Becker, Mara L; Leeder, J Steven

2011-01-01

Adverse drug reactions are a concern for all clinicians who utilize medications to treat adults and children; however, the frequency of adult and pediatric adverse drug reactions is likely to be under-reported. In this age of genomics and personalized medicine, identifying genetic variation that results in differences in drug biotransformation and response has contributed to significant advances in the utilization of several commonly used medications in adults. In order to better understand the variability of drug response in children however, we must not only consider differences in genotype, but also variation in gene expression during growth and development, namely ontogeny. In this article, recommendations for systematically approaching pharmacogenomic studies in children are discussed, and several examples of studies that investigate the genomic and developmental contribution to adverse drug reactions in children are reviewed. PMID:21121777

Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.

PubMed

Salvi, Erika; Wang, Zhiying; Rizzi, Federica; Gong, Yan; McDonough, Caitrin W; Padmanabhan, Sandosh; Hiltunen, Timo P; Lanzani, Chiara; Zaninello, Roberta; Chittani, Martina; Bailey, Kent R; Sarin, Antti-Pekka; Barcella, Matteo; Melander, Olle; Chapman, Arlene B; Manunta, Paolo; Kontula, Kimmo K; Glorioso, Nicola; Cusi, Daniele; Dominiczak, Anna F; Johnson, Julie A; Barlassina, Cristina; Boerwinkle, Eric; Cooper-DeHoff, Rhonda M; Turner, Stephen T

2017-01-01

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10 - 8 ), and the suggestive regions (P<10 -5 ) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10 - 4 ). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment. © 2016

Comparative genome-scale modelling of Staphylococcus aureus strains identifies strain-specific metabolic capabilities linked to pathogenicity

PubMed Central

Bosi, Emanuele; Monk, Jonathan M.; Aziz, Ramy K.; Fondi, Marco; Nizet, Victor; Palsson, Bernhard Ø.

2016-01-01

Staphylococcus aureus is a preeminent bacterial pathogen capable of colonizing diverse ecological niches within its human host. We describe here the pangenome of S. aureus based on analysis of genome sequences from 64 strains of S. aureus spanning a range of ecological niches, host types, and antibiotic resistance profiles. Based on this set, S. aureus is expected to have an open pangenome composed of 7,411 genes and a core genome composed of 1,441 genes. Metabolism was highly conserved in this core genome; however, differences were identified in amino acid and nucleotide biosynthesis pathways between the strains. Genome-scale models (GEMs) of metabolism were constructed for the 64 strains of S. aureus. These GEMs enabled a systems approach to characterizing the core metabolic and panmetabolic capabilities of the S. aureus species. All models were predicted to be auxotrophic for the vitamins niacin (vitamin B3) and thiamin (vitamin B1), whereas strain-specific auxotrophies were predicted for riboflavin (vitamin B2), guanosine, leucine, methionine, and cysteine, among others. GEMs were used to systematically analyze growth capabilities in more than 300 different growth-supporting environments. The results identified metabolic capabilities linked to pathogenic traits and virulence acquisitions. Such traits can be used to differentiate strains responsible for mild vs. severe infections and preference for hosts (e.g., animals vs. humans). Genome-scale analysis of multiple strains of a species can thus be used to identify metabolic determinants of virulence and increase our understanding of why certain strains of this deadly pathogen have spread rapidly throughout the world. PMID:27286824

Genome-wide association analysis identifies a meningioma risk locus at 11p15.5.

PubMed

Claus, Elizabeth B; Cornish, Alex J; Broderick, Peter; Schildkraut, Joellen M; Dobbins, Sara E; Holroyd, Amy; Calvocoressi, Lisa; Lu, Lingeng; Hansen, Helen M; Smirnov, Ivan; Walsh, Kyle M; Schramm, Johannes; Hoffmann, Per; Nöthen, Markus M; Jöckel, Karl-Heinz; Swerdlow, Anthony; Larsen, Signe Benzon; Johansen, Christoffer; Simon, Matthias; Bondy, Melissa; Wrensch, Margaret; Houlston, Richard; Wiemels, Joseph L

2018-05-12

Meningioma are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome-wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31. To identify a susceptibility locus for meningioma, we conducted a meta-analysis of two GWAS, imputed using a merged reference panel of 1,000 Genomes and UK10K data, with validation in two independent sample series totaling 2,138 cases and 12,081 controls. We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 × 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges. This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma.

Genomic approaches to identifying transcriptional regulators of osteoblast differentiation

NASA Technical Reports Server (NTRS)

Stains, Joseph P.; Civitelli, Roberto

2003-01-01

Recent microarray studies of mouse and human osteoblast differentiation in vitro have identified novel transcription factors that may be important in the establishment and maintenance of differentiation. These findings help unravel the pattern of gene-expression changes that underly the complex process of bone formation.

Genomic Signature of Kin Selection in an Ant with Obligately Sterile Workers

PubMed Central

Warner, Michael R.; Mikheyev, Alexander S.

2017-01-01

Abstract Kin selection is thought to drive the evolution of cooperation and conflict, but the specific genes and genome-wide patterns shaped by kin selection are unknown. We identified thousands of genes associated with the sterile ant worker caste, the archetype of an altruistic phenotype shaped by kin selection, and then used population and comparative genomic approaches to study patterns of molecular evolution at these genes. Consistent with population genetic theoretical predictions, worker-upregulated genes experienced reduced selection compared with genes upregulated in reproductive castes. Worker-upregulated genes included more taxonomically restricted genes, indicating that the worker caste has recruited more novel genes, yet these genes also experienced reduced selection. Our study identifies a putative genomic signature of kin selection and helps to integrate emerging sociogenomic data with longstanding social evolution theory. PMID:28419349

Coexpression network analysis identifies transcriptional modules associated with genomic alterations in neuroblastoma.

PubMed

Yang, Liulin; Li, Yun; Wei, Zhi; Chang, Xiao

2018-06-01

Neuroblastoma is a highly complex and heterogeneous cancer in children. Acquired genomic alterations including MYCN amplification, 1p deletion and 11q deletion are important risk factors and biomarkers in neuroblastoma. Here, we performed a co-expression-based gene network analysis to study the intrinsic association between specific genomic changes and transcriptome organization. We identified multiple gene coexpression modules which are recurrent in two independent datasets and associated with functional pathways including nervous system development, cell cycle, immune system process and extracellular matrix/space. Our results also indicated that modules involved in nervous system development and cell cycle are highly associated with MYCN amplification and 1p deletion, while modules responding to immune system process are associated with MYCN amplification only. In summary, this integrated analysis provides novel insights into molecular heterogeneity and pathogenesis of neuroblastoma. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. Copyright © 2017. Published by Elsevier B.V.

A novel prokaryotic promoter identified in the genome of some monopartite begomoviruses.

PubMed

Wang, Wei-Chen; Hsu, Yau-Heiu; Lin, Na-Sheng; Wu, Chia-Ying; Lai, Yi-Chin; Hu, Chung-Chi

2013-01-01

Geminiviruses are known to exhibit both prokaryotic and eukaryotic features in their genomes, with the ability to express their genes and even replicate in bacterial cells. We have demonstrated previously the existence of unit-length single-stranded circular DNAs of Ageratum yellow vein virus (AYVV, a species in the genus Begomovirus, family Geminiviridae) in Escherichia coli cells, which prompted our search for unknown prokaryotic functions in the begomovirus genomes. By using a promoter trapping strategy, we identified a novel prokaryotic promoter, designated AV3 promoter, in nts 762-831 of the AYVV genome. Activity assays revealed that the AV3 promoter is strong, unidirectional, and constitutive, with an endogenous downstream ribosome binding site and a translatable short open reading frame of eight amino acids. Sequence analyses suggested that the AV3 promoter might be a remnant of prokaryotic ancestors that could be related to certain promoters of bacteria from marine or freshwater environments. The discovery of the prokaryotic AV3 promoter provided further evidence for the prokaryotic origin in the evolutionary history of geminiviruses.

A Novel Prokaryotic Promoter Identified in the Genome of Some Monopartite Begomoviruses

PubMed Central

Wang, Wei-Chen; Hsu, Yau-Heiu; Lin, Na-Sheng; Wu, Chia-Ying; Lai, Yi-Chin; Hu, Chung-Chi

2013-01-01

Geminiviruses are known to exhibit both prokaryotic and eukaryotic features in their genomes, with the ability to express their genes and even replicate in bacterial cells. We have demonstrated previously the existence of unit-length single-stranded circular DNAs of Ageratum yellow vein virus (AYVV, a species in the genus Begomovirus, family Geminiviridae) in Escherichia coli cells, which prompted our search for unknown prokaryotic functions in the begomovirus genomes. By using a promoter trapping strategy, we identified a novel prokaryotic promoter, designated AV3 promoter, in nts 762-831 of the AYVV genome. Activity assays revealed that the AV3 promoter is strong, unidirectional, and constitutive, with an endogenous downstream ribosome binding site and a translatable short open reading frame of eight amino acids. Sequence analyses suggested that the AV3 promoter might be a remnant of prokaryotic ancestors that could be related to certain promoters of bacteria from marine or freshwater environments. The discovery of the prokaryotic AV3 promoter provided further evidence for the prokaryotic origin in the evolutionary history of geminiviruses. PMID:23936138

Genome-Wide Variation Patterns Uncover the Origin and Selection in Cultivated Ginseng (Panax ginseng Meyer).

PubMed

Li, Ming-Rui; Shi, Feng-Xue; Li, Ya-Ling; Jiang, Peng; Jiao, Lili; Liu, Bao; Li, Lin-Feng

2017-09-01

Chinese ginseng (Panax ginseng Meyer) is a medicinally important herb and plays crucial roles in traditional Chinese medicine. Pharmacological analyses identified diverse bioactive components from Chinese ginseng. However, basic biological attributes including domestication and selection of the ginseng plant remain under-investigated. Here, we presented a genome-wide view of the domestication and selection of cultivated ginseng based on the whole genome data. A total of 8,660 protein-coding genes were selected for genome-wide scanning of the 30 wild and cultivated ginseng accessions. In complement, the 45s rDNA, chloroplast and mitochondrial genomes were included to perform phylogenetic and population genetic analyses. The observed spatial genetic structure between northern cultivated ginseng (NCG) and southern cultivated ginseng (SCG) accessions suggested multiple independent origins of cultivated ginseng. Genome-wide scanning further demonstrated that NCG and SCG have undergone distinct selection pressures during the domestication process, with more genes identified in the NCG (97 genes) than in the SCG group (5 genes). Functional analyses revealed that these genes are involved in diverse pathways, including DNA methylation, lignin biosynthesis, and cell differentiation. These findings suggested that the SCG and NCG groups have distinct demographic histories. Candidate genes identified are useful for future molecular breeding of cultivated ginseng. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Comparative genomics identifies distinct lineages of S. Enteritidis from Queensland, Australia.

PubMed

Graham, Rikki M A; Hiley, Lester; Rathnayake, Irani U; Jennison, Amy V

2018-01-01

Salmonella enterica is a major cause of gastroenteritis and foodborne illness in Australia where notification rates in the state of Queensland are the highest in the country. S. Enteritidis is among the five most common serotypes reported in Queensland and it is a priority for epidemiological surveillance due to concerns regarding its emergence in Australia. Using whole genome sequencing, we have analysed the genomic epidemiology of 217 S. Enteritidis isolates from Queensland, and observed that they fall into three distinct clades, which we have differentiated as Clades A, B and C. Phage types and MLST sequence types differed between the clades and comparative genomic analysis has shown that each has a unique profile of prophage and genomic islands. Several of the phage regions present in the S. Enteritidis reference strain P125109 were absent in Clades A and C, and these clades also had difference in the presence of pathogenicity islands, containing complete SPI-6 and SPI-19 regions, while P125109 does not. Antimicrobial resistance markers were found in 39 isolates, all but one of which belonged to Clade B. Phylogenetic analysis of the Queensland isolates in the context of 170 international strains showed that Queensland Clade B isolates group together with the previously identified global clade, while the other two clades are distinct and appear largely restricted to Australia. Locally sourced environmental isolates included in this analysis all belonged to Clades A and C, which is consistent with the theory that these clades are a source of locally acquired infection, while Clade B isolates are mostly travel related.

The Jujube Genome Provides Insights into Genome Evolution and the Domestication of Sweetness/Acidity Taste in Fruit Trees.

PubMed

Huang, Jian; Zhang, Chunmei; Zhao, Xing; Fei, Zhangjun; Wan, KangKang; Zhang, Zhong; Pang, Xiaoming; Yin, Xiao; Bai, Yang; Sun, Xiaoqing; Gao, Lizhi; Li, Ruiqiang; Zhang, Jinbo; Li, Xingang

2016-12-01

Jujube (Ziziphus jujuba Mill.) belongs to the Rhamnaceae family and is a popular fruit tree species with immense economic and nutritional value. Here, we report a draft genome of the dry jujube cultivar 'Junzao' and the genome resequencing of 31 geographically diverse accessions of cultivated and wild jujubes (Ziziphus jujuba var. spinosa). Comparative analysis revealed that the genome of 'Dongzao', a fresh jujube, was ~86.5 Mb larger than that of the 'Junzao', partially due to the recent insertions of transposable elements in the 'Dongzao' genome. We constructed eight proto-chromosomes of the common ancestor of Rhamnaceae and Rosaceae, two sister families in the order Rosales, and elucidated the evolutionary processes that have shaped the genome structures of modern jujubes. Population structure analysis revealed the complex genetic background of jujubes resulting from extensive hybridizations between jujube and its wild relatives. Notably, several key genes that control fruit organic acid metabolism and sugar content were identified in the selective sweep regions. We also identified S-locus genes controlling gametophytic self-incompatibility and investigated haplotype patterns of the S locus in the jujube genomes, which would provide a guideline for parent selection for jujube crossbreeding. This study provides valuable genomic resources for jujube improvement, and offers insights into jujube genome evolution and its population structure and domestication.

Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution.

PubMed

Kumar, Narender; Mariappan, Vanitha; Baddam, Ramani; Lankapalli, Aditya K; Shaik, Sabiha; Goh, Khean-Lee; Loke, Mun Fai; Perkins, Tim; Benghezal, Mohammed; Hasnain, Seyed E; Vadivelu, Jamuna; Marshall, Barry J; Ahmed, Niyaz

2015-01-01

The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host-pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Efficient Genome-wide Association in Biobanks Using Topic Modeling Identifies Multiple Novel Disease Loci

PubMed Central

McCoy, Thomas H; Castro, Victor M; Snapper, Leslie A; Hart, Kamber L; Perlis, Roy H

2017-01-01

Biobanks and national registries represent a powerful tool for genomic discovery, but rely on diagnostic codes that can be unreliable and fail to capture relationships between related diagnoses. We developed an efficient means of conducting genome-wide association studies using combinations of diagnostic codes from electronic health records for 10,845 participants in a biobanking program at two large academic medical centers. Specifically, we applied latent Dirichilet allocation to fit 50 disease topics based on diagnostic codes, then conducted a genome-wide common-variant association for each topic. In sensitivity analysis, these results were contrasted with those obtained from traditional single-diagnosis phenome-wide association analysis, as well as those in which only a subset of diagnostic codes were included per topic. In meta-analysis across three biobank cohorts, we identified 23 disease-associated loci with p < 1e-15, including previously associated autoimmune disease loci. In all cases, observed significant associations were of greater magnitude than single phenome-wide diagnostic codes, and incorporation of less strongly loading diagnostic codes enhanced association. This strategy provides a more efficient means of identifying phenome-wide associations in biobanks with coded clinical data. PMID:28861588

A genomic survey of the fish parasite Spironucleus salmonicida indicates genomic plasticity among diplomonads and significant lateral gene transfer in eukaryote genome evolution

PubMed Central

Andersson, Jan O; Sjögren, Åsa M; Horner, David S; Murphy, Colleen A; Dyal, Patricia L; Svärd, Staffan G; Logsdon, John M; Ragan, Mark A; Hirt, Robert P; Roger, Andrew J

2007-01-01

Background Comparative genomic studies of the mitochondrion-lacking protist group Diplomonadida (diplomonads) has been lacking, although Giardia lamblia has been intensively studied. We have performed a sequence survey project resulting in 2341 expressed sequence tags (EST) corresponding to 853 unique clones, 5275 genome survey sequences (GSS), and eleven finished contigs from the diplomonad fish parasite Spironucleus salmonicida (previously described as S. barkhanus). Results The analyses revealed a compact genome with few, if any, introns and very short 3' untranslated regions. Strikingly different patterns of codon usage were observed in genes corresponding to frequently sampled ESTs versus genes poorly sampled, indicating that translational selection is influencing the codon usage of highly expressed genes. Rigorous phylogenomic analyses identified 84 genes – mostly encoding metabolic proteins – that have been acquired by diplomonads or their relatively close ancestors via lateral gene transfer (LGT). Although most acquisitions were from prokaryotes, more than a dozen represent likely transfers of genes between eukaryotic lineages. Many genes that provide novel insights into the genetic basis of the biology and pathogenicity of this parasitic protist were identified including 149 that putatively encode variant-surface cysteine-rich proteins which are candidate virulence factors. A number of genomic properties that distinguish S. salmonicida from its human parasitic relative G. lamblia were identified such as nineteen putative lineage-specific gene acquisitions, distinct mutational biases and codon usage and distinct polyadenylation signals. Conclusion Our results highlight the power of comparative genomic studies to yield insights into the biology of parasitic protists and the evolution of their genomes, and suggest that genetic exchange between distantly-related protist lineages may be occurring at an appreciable rate in eukaryote genome evolution. PMID

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

PubMed

Cheng, Timothy Ht; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica Mj; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Consortium, Chibcha; Jun Li, Mulin; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

2016-06-01

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

Integrating transcriptome and genome re-sequencing data to identify key genes and mutations affecting chicken eggshell qualities.

PubMed

Zhang, Quan; Zhu, Feng; Liu, Long; Zheng, Chuan Wei; Wang, De He; Hou, Zhuo Cheng; Ning, Zhong Hua

2015-01-01

Eggshell damages lead to economic losses in the egg production industry and are a threat to human health. We examined 49-wk-old Rhode Island White hens (Gallus gallus) that laid eggs having shells with significantly different strengths and thicknesses. We used HiSeq 2000 (Illumina) sequencing to characterize the chicken transcriptome and whole genome to identify the key genes and genetic mutations associated with eggshell calcification. We identified a total of 14,234 genes expressed in the chicken uterus, representing 89% of all annotated chicken genes. A total of 889 differentially expressed genes were identified by comparing low eggshell strength (LES) and normal eggshell strength (NES) genomes. The DEGs are enriched in calcification-related processes, including calcium ion transport and calcium signaling pathways as revealed by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Some important matrix proteins, such as OC-116, LTF and SPP1, were also expressed differentially between two groups. A total of 3,671,919 single-nucleotide polymorphisms (SNPs) and 508,035 Indels were detected in protein coding genes by whole-genome re-sequencing, including 1775 non-synonymous variations and 19 frame-shift Indels in DEGs. SNPs and Indels found in this study could be further investigated for eggshell traits. This is the first report to integrate the transcriptome and genome re-sequencing to target the genetic variations which decreased the eggshell qualities. These findings further advance our understanding of eggshell calcification in the chicken uterus.

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

PubMed Central

Lo, Min-Tzu; Hinds, David A.; Tung, Joyce Y.; Franz, Carol; Fan, Chun-Chieh; Wang, Yunpeng; Smeland, Olav B.; Schork, Andrew; Holland, Dominic; Kauppi, Karolina; Sanyal, Nilotpal; Escott-Price, Valentina; Smith, Daniel J.; O'Donovan, Michael; Stefansson, Hreinn; Bjornsdottir, Gyda; Thorgeirsson, Thorgeir E.; Stefansson, Kari; McEvoy, Linda K.; Dale, Anders M.; Andreassen, Ole A.; Chen, Chi-Hua

2017-01-01

Summary Personality is influenced by genetic and environmental factors1, and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N=123,132–260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N=5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit/hyperactivity disorder (ADHD), and between openness and schizophrenia/bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression/anxiety). PMID:27918536

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders.

PubMed

Lo, Min-Tzu; Hinds, David A; Tung, Joyce Y; Franz, Carol; Fan, Chun-Chieh; Wang, Yunpeng; Smeland, Olav B; Schork, Andrew; Holland, Dominic; Kauppi, Karolina; Sanyal, Nilotpal; Escott-Price, Valentina; Smith, Daniel J; O'Donovan, Michael; Stefansson, Hreinn; Bjornsdottir, Gyda; Thorgeirsson, Thorgeir E; Stefansson, Kari; McEvoy, Linda K; Dale, Anders M; Andreassen, Ole A; Chen, Chi-Hua

2017-01-01

Personality is influenced by genetic and environmental factors and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit-hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

PubMed

He, Meian; Xu, Min; Zhang, Ben; Liang, Jun; Chen, Peng; Lee, Jong-Young; Johnson, Todd A; Li, Huaixing; Yang, Xiaobo; Dai, Juncheng; Liang, Liming; Gui, Lixuan; Qi, Qibin; Huang, Jinyan; Li, Yanping; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Cheng, Ching-Yu; Cho, Myeong-Chan; Cho, Yoon Shin; Chu, Minjie; Cui, Bin; Gao, Yu-Tang; Go, Min Jin; Gu, Dongfeng; Gu, Weiqiong; Guo, Huan; Hao, Yongchen; Hong, Jie; Hu, Zhibin; Hu, Yanling; Huang, Jianfeng; Hwang, Joo-Yeon; Ikram, Mohammad Kamran; Jin, Guangfu; Kang, Dae-Hee; Khor, Chiea Chuen; Kim, Bong-Jo; Kim, Hung Tae; Kubo, Michiaki; Lee, Jeannette; Lee, Juyoung; Lee, Nanette R; Li, Ruoying; Li, Jun; Liu, JianJun; Longe, Jirong; Lu, Wei; Lu, Xiangfeng; Miao, Xiaoping; Okada, Yukinori; Ong, Rick Twee-Hee; Qiu, Gaokun; Seielstad, Mark; Sim, Xueling; Song, Huaidong; Takeuchi, Fumihiko; Tanaka, Toshihiro; Taylor, Phil R; Wang, Laiyuan; Wang, Weiqing; Wang, Yiqin; Wu, Chen; Wu, Ying; Xiang, Yong-Bing; Yamamoto, Ken; Yang, Handong; Liao, Ming; Yokota, Mitsuhiro; Young, Terri; Zhang, Xiaomin; Kato, Norihiro; Wang, Qing K; Zheng, Wei; Hu, Frank B; Lin, Dongxin; Shen, Hongbing; Teo, Yik Ying; Mo, Zengnan; Wong, Tien Yin; Lin, Xu; Mohlke, Karen L; Ning, Guang; Tsunoda, Tatsuhiko; Han, Bok-Ghee; Shu, Xiao-Ou; Tai, E Shyong; Wu, Tangchun; Qi, Lu

2015-03-15

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Recombinant transfer in the basic genome of E. coli

DOE PAGES

Dixit, Purushottam; Studier, F. William; Pang, Tin Yau; ...

2015-07-07

An approximation to the ~4-Mbp basic genome shared by 32 strains of E. coli representing six evolutionary groups has been derived and analyzed computationally. A multiple-alignment of the 32 complete genome sequences was filtered to remove mobile elements and identify the most reliable ~90% of the aligned length of each of the resulting 496 basic-genome pairs. Patterns of single bp mutations (SNPs) in aligned pairs distinguish clonally inherited regions from regions where either genome has acquired DNA fragments from diverged genomes by homologous recombination since their last common ancestor. Such recombinant transfer is pervasive across the basic genome, mostly betweenmore » genomes in the same evolutionary group, and generates many unique mosaic patterns. The six least-diverged genome-pairs have one or two recombinant transfers of length ~40–115 kbp (and few if any other transfers), each containing one or more gene clusters known to confer strong selective advantage in some environments. Moderately diverged genome pairs (0.4–1% SNPs) show mosaic patterns of interspersed clonal and recombinant regions of varying lengths throughout the basic genome, whereas more highly diverged pairs within an evolutionary group or pairs between evolutionary groups having >1.3% SNPs have few clonal matches longer than a few kbp. Many recombinant transfers appear to incorporate fragments of the entering DNA produced by restriction systems of the recipient cell. A simple computational model can closely fit the data. As a result, most recombinant transfers seem likely to be due to generalized transduction by co-evolving populations of phages, which could efficiently distribute variability throughout bacterial genomes.« less

Recombinant transfer in the basic genome of E. coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dixit, Purushottam; Studier, F. William; Pang, Tin Yau

An approximation to the ~4-Mbp basic genome shared by 32 strains of E. coli representing six evolutionary groups has been derived and analyzed computationally. A multiple-alignment of the 32 complete genome sequences was filtered to remove mobile elements and identify the most reliable ~90% of the aligned length of each of the resulting 496 basic-genome pairs. Patterns of single bp mutations (SNPs) in aligned pairs distinguish clonally inherited regions from regions where either genome has acquired DNA fragments from diverged genomes by homologous recombination since their last common ancestor. Such recombinant transfer is pervasive across the basic genome, mostly betweenmore » genomes in the same evolutionary group, and generates many unique mosaic patterns. The six least-diverged genome-pairs have one or two recombinant transfers of length ~40–115 kbp (and few if any other transfers), each containing one or more gene clusters known to confer strong selective advantage in some environments. Moderately diverged genome pairs (0.4–1% SNPs) show mosaic patterns of interspersed clonal and recombinant regions of varying lengths throughout the basic genome, whereas more highly diverged pairs within an evolutionary group or pairs between evolutionary groups having >1.3% SNPs have few clonal matches longer than a few kbp. Many recombinant transfers appear to incorporate fragments of the entering DNA produced by restriction systems of the recipient cell. A simple computational model can closely fit the data. As a result, most recombinant transfers seem likely to be due to generalized transduction by co-evolving populations of phages, which could efficiently distribute variability throughout bacterial genomes.« less

DNA demethylation in the Arabidopsis genome

PubMed Central

Penterman, Jon; Zilberman, Daniel; Huh, Jin Hoe; Ballinger, Tracy; Henikoff, Steven; Fischer, Robert L.

2007-01-01

Cytosine DNA methylation is considered to be a stable epigenetic mark, but active demethylation has been observed in both plants and animals. In Arabidopsis thaliana, DNA glycosylases of the DEMETER (DME) family remove methylcytosines from DNA. Demethylation by DME is necessary for genomic imprinting, and demethylation by a related protein, REPRESSOR OF SILENCING1, prevents gene silencing in a transgenic background. However, the extent and function of demethylation by DEMETER-LIKE (DML) proteins in WT plants is not known. Using genome-tiling microarrays, we mapped DNA methylation in mutant and WT plants and identified 179 loci actively demethylated by DML enzymes. Mutations in DML genes lead to locus-specific DNA hypermethylation. Reintroducing WT DML genes restores most loci to the normal pattern of methylation, although at some loci, hypermethylated epialleles persist. Of loci demethylated by DML enzymes, >80% are near or overlap genes. Genic demethylation by DML enzymes primarily occurs at the 5′ and 3′ ends, a pattern opposite to the overall distribution of WT DNA methylation. Our results show that demethylation by DML DNA glycosylases edits the patterns of DNA methylation within the Arabidopsis genome to protect genes from potentially deleterious methylation. PMID:17409185

Open Window: When Easily Identifiable Genomes and Traits Are in the Public Domain

PubMed Central

Angrist, Misha

2014-01-01

“One can't be of an enquiring and experimental nature, and still be very sensible.” - Charles Fort [1] As the costs of personal genetic testing “self-quantification” fall, publicly accessible databases housing people's genotypic and phenotypic information are gradually increasing in number and scope. The latest entrant is openSNP, which allows participants to upload their personal genetic/genomic and self-reported phenotypic data. I believe the emergence of such open repositories of human biological data is a natural reflection of inquisitive and digitally literate people's desires to make genomic and phenotypic information more easily available to a community beyond the research establishment. Such unfettered databases hold the promise of contributing mightily to science, science education and medicine. That said, in an age of increasingly widespread governmental and corporate surveillance, we would do well to be mindful that genomic DNA is uniquely identifying. Participants in open biological databases are engaged in a real-time experiment whose outcome is unknown. PMID:24647311

TSSer: an automated method to identify transcription start sites in prokaryotic genomes from differential RNA sequencing data.

PubMed

Jorjani, Hadi; Zavolan, Mihaela

2014-04-01

Accurate identification of transcription start sites (TSSs) is an essential step in the analysis of transcription regulatory networks. In higher eukaryotes, the capped analysis of gene expression technology enabled comprehensive annotation of TSSs in genomes such as those of mice and humans. In bacteria, an equivalent approach, termed differential RNA sequencing (dRNA-seq), has recently been proposed, but the application of this approach to a large number of genomes is hindered by the paucity of computational analysis methods. With few exceptions, when the method has been used, annotation of TSSs has been largely done manually. In this work, we present a computational method called 'TSSer' that enables the automatic inference of TSSs from dRNA-seq data. The method rests on a probabilistic framework for identifying both genomic positions that are preferentially enriched in the dRNA-seq data as well as preferentially captured relative to neighboring genomic regions. Evaluating our approach for TSS calling on several publicly available datasets, we find that TSSer achieves high consistency with the curated lists of annotated TSSs, but identifies many additional TSSs. Therefore, TSSer can accelerate genome-wide identification of TSSs in bacterial genomes and can aid in further characterization of bacterial transcription regulatory networks. TSSer is freely available under GPL license at http://www.clipz.unibas.ch/TSSer/index.php

A comparative physical map reveals the pattern of chromosomal evolution between the turkey (Meleagris gallopavo) and chicken (Gallus gallus) genomes

PubMed Central

2011-01-01

Background A robust bacterial artificial chromosome (BAC)-based physical map is essential for many aspects of genomics research, including an understanding of chromosome evolution, high-resolution genome mapping, marker-assisted breeding, positional cloning of genes, and quantitative trait analysis. To facilitate turkey genetics research and better understand avian genome evolution, a BAC-based integrated physical, genetic, and comparative map was developed for this important agricultural species. Results The turkey genome physical map was constructed based on 74,013 BAC fingerprints (11.9 × coverage) from two independent libraries, and it was integrated with the turkey genetic map and chicken genome sequence using over 41,400 BAC assignments identified by 3,499 overgo hybridization probes along with > 43,000 BAC end sequences. The physical-comparative map consists of 74 BAC contigs, with an average contig size of 13.6 Mb. All but four of the turkey chromosomes were spanned on this map by three or fewer contigs, with 14 chromosomes spanned by a single contig and nine chromosomes spanned by two contigs. This map predicts 20 to 27 major rearrangements distinguishing turkey and chicken chromosomes, despite up to 40 million years of separate evolution between the two species. These data elucidate the chromosomal evolutionary pattern within the Phasianidae that led to the modern turkey and chicken karyotypes. The predominant rearrangement mode involves intra-chromosomal inversions, and there is a clear bias for these to result in centromere locations at or near telomeres in turkey chromosomes, in comparison to interstitial centromeres in the orthologous chicken chromosomes. Conclusion The BAC-based turkey-chicken comparative map provides novel insights into the evolution of avian genomes, a framework for assembly of turkey whole genome shotgun sequencing data, and tools for enhanced genetic improvement of these important agricultural and model species. PMID:21906286

Primer in Genetics and Genomics, Article 4-Inheritance Patterns.

PubMed

Aiello, Lisa B; Chiatti, Beth Desaretz

2017-07-01

Since the completion of the Human Genome Project, much has been uncovered about inheritance of various illnesses and disorders. There are two main types of inheritance: Mendelian and non-Mendelian. Mendelian inheritance includes autosomal dominant, autosomal recessive, X-linked, and Y-linked inheritance. Non-Mendelian inheritance includes mitochondrial and multifactorial inheritance. Nurses must understand the types of inheritance in order to identify red flags that may indicate the possibility of a hereditary disorder in a patient or family.

Going, going, gone: predicting the fate of genomic insertions in plant RNA viruses.

PubMed

Willemsen, Anouk; Carrasco, José L; Elena, Santiago F; Zwart, Mark P

2018-05-10

Horizontal gene transfer is common among viruses, while they also have highly compact genomes and tend to lose artificial genomic insertions rapidly. Understanding the stability of genomic insertions in viral genomes is therefore relevant for explaining and predicting their evolutionary patterns. Here, we revisit a large body of experimental research on a plant RNA virus, tobacco etch potyvirus (TEV), to identify the patterns underlying the stability of a range of homologous and heterologous insertions in the viral genome. We obtained a wide range of estimates for the recombination rate-the rate at which deletions removing the insertion occur-and these appeared to be independent of the type of insertion and its location. Of the factors we considered, recombination rate was the best predictor of insertion stability, although we could not identify the specific sequence characteristics that would help predict insertion instability. We also considered experimentally the possibility that functional insertions lead to higher mutational robustness through increased redundancy. However, our observations suggest that both functional and non-functional increases in genome size decreased the mutational robustness. Our results therefore demonstrate the importance of recombination rates for predicting the long-term stability and evolution of viral RNA genomes and suggest that there are unexpected drawbacks to increases in genome size for mutational robustness.

Comparative Analysis of the Full Genome of Helicobacter pylori Isolate Sahul64 Identifies Genes of High Divergence

PubMed Central

Lu, Wei; Wise, Michael J.; Tay, Chin Yen; Windsor, Helen M.; Marshall, Barry J.; Peacock, Christopher

2014-01-01

Isolates of Helicobacter pylori can be classified phylogeographically. High genetic diversity and rapid microevolution are a hallmark of H. pylori genomes, a phenomenon that is proposed to play a functional role in persistence and colonization of diverse human populations. To provide further genomic evidence in the lineage of H. pylori and to further characterize diverse strains of this pathogen in different human populations, we report the finished genome sequence of Sahul64, an H. pylori strain isolated from an indigenous Australian. Our analysis identified genes that were highly divergent compared to the 38 publically available genomes, which include genes involved in the biosynthesis and modification of lipopolysaccharide, putative prophage genes, restriction modification components, and hypothetical genes. Furthermore, the virulence-associated vacA locus is a pseudogene and the cag pathogenicity island (cagPAI) is not present. However, the genome does contain a gene cluster associated with pathogenicity, including dupA. Our analysis found that with the addition of Sahul64 to the 38 genomes, the core genome content of H. pylori is reduced by approximately 14% (∼170 genes) and the pan-genome has expanded from 2,070 to 2,238 genes. We have identified three putative horizontally acquired regions, including one that is likely to have been acquired from the closely related Helicobacter cetorum prior to speciation. Our results suggest that Sahul64, with the absence of cagPAI, highly divergent cell envelope proteins, and a predicted nontransportable VacA protein, could be more highly adapted to ancient indigenous Australian people but with lower virulence potential compared to other sequenced and cagPAI-positive H. pylori strains. PMID:24375107

Comparative analysis of the full genome of Helicobacter pylori isolate Sahul64 identifies genes of high divergence.

PubMed

Lu, Wei; Wise, Michael J; Tay, Chin Yen; Windsor, Helen M; Marshall, Barry J; Peacock, Christopher; Perkins, Tim

2014-03-01

Isolates of Helicobacter pylori can be classified phylogeographically. High genetic diversity and rapid microevolution are a hallmark of H. pylori genomes, a phenomenon that is proposed to play a functional role in persistence and colonization of diverse human populations. To provide further genomic evidence in the lineage of H. pylori and to further characterize diverse strains of this pathogen in different human populations, we report the finished genome sequence of Sahul64, an H. pylori strain isolated from an indigenous Australian. Our analysis identified genes that were highly divergent compared to the 38 publically available genomes, which include genes involved in the biosynthesis and modification of lipopolysaccharide, putative prophage genes, restriction modification components, and hypothetical genes. Furthermore, the virulence-associated vacA locus is a pseudogene and the cag pathogenicity island (cagPAI) is not present. However, the genome does contain a gene cluster associated with pathogenicity, including dupA. Our analysis found that with the addition of Sahul64 to the 38 genomes, the core genome content of H. pylori is reduced by approximately 14% (∼170 genes) and the pan-genome has expanded from 2,070 to 2,238 genes. We have identified three putative horizontally acquired regions, including one that is likely to have been acquired from the closely related Helicobacter cetorum prior to speciation. Our results suggest that Sahul64, with the absence of cagPAI, highly divergent cell envelope proteins, and a predicted nontransportable VacA protein, could be more highly adapted to ancient indigenous Australian people but with lower virulence potential compared to other sequenced and cagPAI-positive H. pylori strains.

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

DOE PAGES

Behjati, Sam; Tarpey, Patrick S.; Haase, Kerstin; ...

2017-06-23

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation,more » we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. Lastly, it may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.« less

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Behjati, Sam; Tarpey, Patrick S.; Haase, Kerstin

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation,more » we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. Lastly, it may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.« less

Nonparametric Bayesian clustering to detect bipolar methylated genomic loci.

PubMed

Wu, Xiaowei; Sun, Ming-An; Zhu, Hongxiao; Xie, Hehuang

2015-01-16

With recent development in sequencing technology, a large number of genome-wide DNA methylation studies have generated massive amounts of bisulfite sequencing data. The analysis of DNA methylation patterns helps researchers understand epigenetic regulatory mechanisms. Highly variable methylation patterns reflect stochastic fluctuations in DNA methylation, whereas well-structured methylation patterns imply deterministic methylation events. Among these methylation patterns, bipolar patterns are important as they may originate from allele-specific methylation (ASM) or cell-specific methylation (CSM). Utilizing nonparametric Bayesian clustering followed by hypothesis testing, we have developed a novel statistical approach to identify bipolar methylated genomic regions in bisulfite sequencing data. Simulation studies demonstrate that the proposed method achieves good performance in terms of specificity and sensitivity. We used the method to analyze data from mouse brain and human blood methylomes. The bipolar methylated segments detected are found highly consistent with the differentially methylated regions identified by using purified cell subsets. Bipolar DNA methylation often indicates epigenetic heterogeneity caused by ASM or CSM. With allele-specific events filtered out or appropriately taken into account, our proposed approach sheds light on the identification of cell-specific genes/pathways under strong epigenetic control in a heterogeneous cell population.

Genome-Wide Association Analysis to Identify Loci for Milk Yield in Gyr Breed

USDA-ARS?s Scientific Manuscript database

A genome scan was conducted to identify QTL affecting milk yield in a Brazilian Gyr population of progeny test bulls (N=319). Data used in this study was derived from traditional genetic evaluation records computed by the Embrapa Dairy Cattleand released in May/2009 (http://www.cnpgl.embrapa.br/nova...

[Genomics innovative teaching pattern based upon amalgamation between modern educational technology and constructivism studying theory].

PubMed

Liang, Xu-Fang; Peng, Jing; Zhou, Tian-Hong

2007-04-01

In order to overcome various malpractices in the traditional teaching methods, and also as part of the Guangdong province molecular biology perfect course project, some reforms were carried out to the teaching pattern of genomics. The reforms include using the foreign original teaching materials, bilingual teaching, as well as taking the constructivism-directed discussion teaching method and the multimedia computer-assisted instruction. To improve the scoring way and the laboratory course of the subject, we carried on a multiplex inspection systems and a self-designing experiments. Through the teaching reform on Genomics, we have gradually consummated the construction of molecular biology curriculum system.

Microsatellites in the Genome of the Edible Mushroom, Volvariella volvacea

PubMed Central

Chen, Mingjie; Wang, Hong; Bao, Dapeng

2014-01-01

Using bioinformatics software and database, we have characterized the microsatellite pattern in the V. volvacea genome and compared it with microsatellite patterns found in the genomes of four other edible fungi: Coprinopsis cinerea, Schizophyllum commune, Agaricus bisporus, and Pleurotus ostreatus. A total of 1346 microsatellites have been identified, with mono-nucleotides being the most frequent motif. The relative abundance of microsatellites was lower in coding regions with 21 No./Mb. However, the microsatellites in the V. volvacea gene models showed a greater tendency to be located in the CDS regions. There was also a higher preponderance of trinucleotide repeats, especially in the kinase genes, which implied a possible role in phenotypic variation. Among the five fungal genomes, microsatellite abundance appeared to be unrelated to genome size. Furthermore, the short motifs (mono- to tri-nucleotides) outnumbered other categories although these differed in proportion. Data analysis indicated a possible relationship between the most frequent microsatellite types and the genetic distance between the five fungal genomes. PMID:24575404

Microsatellites in the genome of the edible mushroom, Volvariella volvacea.

PubMed

Wang, Ying; Chen, Mingjie; Wang, Hong; Wang, Jing-Fang; Bao, Dapeng

2014-01-01

Using bioinformatics software and database, we have characterized the microsatellite pattern in the V. volvacea genome and compared it with microsatellite patterns found in the genomes of four other edible fungi: Coprinopsis cinerea, Schizophyllum commune, Agaricus bisporus, and Pleurotus ostreatus. A total of 1346 microsatellites have been identified, with mono-nucleotides being the most frequent motif. The relative abundance of microsatellites was lower in coding regions with 21 No./Mb. However, the microsatellites in the V. volvacea gene models showed a greater tendency to be located in the CDS regions. There was also a higher preponderance of trinucleotide repeats, especially in the kinase genes, which implied a possible role in phenotypic variation. Among the five fungal genomes, microsatellite abundance appeared to be unrelated to genome size. Furthermore, the short motifs (mono- to tri-nucleotides) outnumbered other categories although these differed in proportion. Data analysis indicated a possible relationship between the most frequent microsatellite types and the genetic distance between the five fungal genomes.

Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

PubMed Central

Tsai, Chia-Ti; Hsieh, Chia-Shan; Chang, Sheng-Nan; Chuang, Eric Y.; Ueng, Kwo-Chang; Tsai, Chin-Feng; Lin, Tsung-Hsien; Wu, Cho-Kai; Lee, Jen-Kuang; Lin, Lian-Yu; Wang, Yi-Chih; Yu, Chih-Chieh; Lai, Ling-Ping; Tseng, Chuen-Den; Hwang, Juey-Jen; Chiang, Fu-Tien; Lin, Jiunn-Lee

2016-01-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway. PMID:26831368

A genome-wide scan study identifies a single nucleotide substitution in ASIP associated with white versus non-white coat-colour variation in sheep (Ovis aries)

PubMed Central

Li, M-H; Tiirikka, T; Kantanen, J

2014-01-01

In sheep, coat colour (and pattern) is one of the important traits of great biological, economic and social importance. However, the genetics of sheep coat colour has not yet been fully clarified. We conducted a genome-wide association study of sheep coat colours by genotyping 47 303 single-nucleotide polymorphisms (SNPs) in the Finnsheep population in Finland. We identified 35 SNPs associated with all the coat colours studied, which cover genomic regions encompassing three known pigmentation genes (TYRP1, ASIP and MITF) in sheep. Eighteen of these associations were confirmed in further tests between white versus non-white individuals, but none of the 35 associations were significant in the analysis of only non-white colours. Across the tests, the s66432.1 in ASIP showed significant association (P=4.2 × 10−11 for all the colours; P=2.3 × 10−11 for white versus non-white colours) with the variation in coat colours and strong linkage disequilibrium with other significant variants surrounding the ASIP gene. The signals detected around the ASIP gene were explained by differences in white versus non-white alleles. Further, a genome scan for selection for white coat pigmentation identified a strong and striking selection signal spanning ASIP. Our study identified the main candidate gene for the coat colour variation between white and non-white as ASIP, an autosomal gene that has been directly implicated in the pathway regulating melanogenesis. Together with ASIP, the two other newly identified genes (TYRP1 and MITF) in the Finnsheep, bordering associated SNPs, represent a new resource for enriching sheep coat-colour genetics and breeding. PMID:24022497

Integrating Transcriptome and Genome Re-Sequencing Data to Identify Key Genes and Mutations Affecting Chicken Eggshell Qualities

PubMed Central

Liu, Long; Zheng, Chuan Wei; Wang, De He; Hou, Zhuo Cheng; Ning, Zhong Hua

2015-01-01

Eggshell damages lead to economic losses in the egg production industry and are a threat to human health. We examined 49-wk-old Rhode Island White hens (Gallus gallus) that laid eggs having shells with significantly different strengths and thicknesses. We used HiSeq 2000 (Illumina) sequencing to characterize the chicken transcriptome and whole genome to identify the key genes and genetic mutations associated with eggshell calcification. We identified a total of 14,234 genes expressed in the chicken uterus, representing 89% of all annotated chicken genes. A total of 889 differentially expressed genes were identified by comparing low eggshell strength (LES) and normal eggshell strength (NES) genomes. The DEGs are enriched in calcification-related processes, including calcium ion transport and calcium signaling pathways as reveled by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Some important matrix proteins, such as OC-116, LTF and SPP1, were also expressed differentially between two groups. A total of 3,671,919 single-nucleotide polymorphisms (SNPs) and 508,035 Indels were detected in protein coding genes by whole-genome re-sequencing, including 1775 non-synonymous variations and 19 frame-shift Indels in DEGs. SNPs and Indels found in this study could be further investigated for eggshell traits. This is the first report to integrate the transcriptome and genome re-sequencing to target the genetic variations which decreased the eggshell qualities. These findings further advance our understanding of eggshell calcification in the chicken uterus. PMID:25974068

Structural RNAs of known and unknown function identified in malaria parasites by comparative genomics and RNA analysis

PubMed Central

Chakrabarti, Kausik; Pearson, Michael; Grate, Leslie; Sterne-Weiler, Timothy; Deans, Jonathan; Donohue, John Paul; Ares, Manuel

2007-01-01

As the genomes of more eukaryotic pathogens are sequenced, understanding how molecular differences between parasite and host might be exploited to provide new therapies has become a major focus. Central to cell function are RNA-containing complexes involved in gene expression, such as the ribosome, the spliceosome, snoRNAs, RNase P, and telomerase, among others. In this article we identify by comparative genomics and validate by RNA analysis numerous previously unknown structural RNAs encoded by the Plasmodium falciparum genome, including the telomerase RNA, U3, 31 snoRNAs, as well as previously predicted spliceosomal snRNAs, SRP RNA, MRP RNA, and RNAse P RNA. Furthermore, we identify six new RNA coding genes of unknown function. To investigate the relationships of the RNA coding genes to other genomic features in related parasites, we developed a genome browser for P. falciparum (http://areslab.ucsc.edu/cgi-bin/hgGateway). Additional experiments provide evidence supporting the prediction that snoRNAs guide methylation of a specific position on U4 snRNA, as well as predicting an snRNA promoter element particular to Plasmodium sp. These findings should allow detailed structural comparisons between the RNA components of the gene expression machinery of the parasite and its vertebrate hosts. PMID:17901154

Identification of a β-glucosidase from the Mucor circinelloides genome by peptide pattern recognition.

PubMed

Huang, Yuhong; Busk, Peter Kamp; Grell, Morten Nedergaard; Zhao, Hai; Lange, Lene

2014-12-01

Mucor circinelloides produces plant cell wall degrading enzymes that allow it to grow on complex polysaccharides. Although the genome of M. circinelloides has been sequenced, only few plant cell wall degrading enzymes are annotated in this species. We applied peptide pattern recognition, which is a non-alignment based method for sequence analysis to map conserved sequences in glycoside hydrolase families. The conserved sequences were used to identify similar genes in the M. circinelloides genome. We found 12 different novel genes encoding members of the GH3, GH5, GH9, GH16, GH38, GH47 and GH125 families in M. circinelloides. One of the two GH3-encoding genes was predicted to encode a β-glucosidase (EC 3.2.1.21). We expressed this gene in Pichia pastoris KM71H and found that the purified recombinant protein had relative high β-glucosidase activity (1.73U/mg) at pH5 and 50°C. The Km and Vmax with p-nitrophenyl-β-d-glucopyranoside as substrate was 0.20mM and 2.41U/mg, respectively. The enzyme was not inhibited by glucose and retained 84% activity at glucose concentrations up to 140mM. Although zygomycetes are not considered to be important degraders of lignocellulosic biomass in nature, the present finding of an active β-glucosidase in M. circinelloides demonstrates that enzymes from this group of fungi have a potential for cellulose degradation. Copyright © 2014 Elsevier Inc. All rights reserved.

The Jujube Genome Provides Insights into Genome Evolution and the Domestication of Sweetness/Acidity Taste in Fruit Trees

PubMed Central

Wan, KangKang; Zhang, Zhong; Pang, Xiaoming; Yin, Xiao; Bai, Yang; Sun, Xiaoqing; Gao, Lizhi; Li, Ruiqiang; Zhang, Jinbo

2016-01-01

Jujube (Ziziphus jujuba Mill.) belongs to the Rhamnaceae family and is a popular fruit tree species with immense economic and nutritional value. Here, we report a draft genome of the dry jujube cultivar ‘Junzao’ and the genome resequencing of 31 geographically diverse accessions of cultivated and wild jujubes (Ziziphus jujuba var. spinosa). Comparative analysis revealed that the genome of ‘Dongzao’, a fresh jujube, was ~86.5 Mb larger than that of the ‘Junzao’, partially due to the recent insertions of transposable elements in the ‘Dongzao’ genome. We constructed eight proto-chromosomes of the common ancestor of Rhamnaceae and Rosaceae, two sister families in the order Rosales, and elucidated the evolutionary processes that have shaped the genome structures of modern jujubes. Population structure analysis revealed the complex genetic background of jujubes resulting from extensive hybridizations between jujube and its wild relatives. Notably, several key genes that control fruit organic acid metabolism and sugar content were identified in the selective sweep regions. We also identified S-locus genes controlling gametophytic self-incompatibility and investigated haplotype patterns of the S locus in the jujube genomes, which would provide a guideline for parent selection for jujube crossbreeding. This study provides valuable genomic resources for jujube improvement, and offers insights into jujube genome evolution and its population structure and domestication. PMID:28005948

Genomic Imprinting Was Evolutionarily Conserved during Wheat Polyploidization.

PubMed

Yang, Guanghui; Liu, Zhenshan; Gao, Lulu; Yu, Kuohai; Feng, Man; Yao, Yingyin; Peng, Huiru; Hu, Zhaorong; Sun, Qixin; Ni, Zhongfu; Xin, Mingming

2018-01-01

Genomic imprinting is an epigenetic phenomenon that causes genes to be differentially expressed depending on their parent of origin. To evaluate the evolutionary conservation of genomic imprinting and the effects of ploidy on this process, we investigated parent-of-origin-specific gene expression patterns in the endosperm of diploid ( Aegilops spp), tetraploid, and hexaploid wheat ( Triticum spp) at various stages of development via high-throughput transcriptome sequencing. We identified 91, 135, and 146 maternally or paternally expressed genes (MEGs or PEGs, respectively) in diploid, tetraploid, and hexaploid wheat, respectively, 52.7% of which exhibited dynamic expression patterns at different developmental stages. Gene Ontology enrichment analysis suggested that MEGs and PEGs were involved in metabolic processes and DNA-dependent transcription, respectively. Nearly half of the imprinted genes exhibited conserved expression patterns during wheat hexaploidization. In addition, 40% of the homoeolog pairs originating from whole-genome duplication were consistently maternally or paternally biased in the different subgenomes of hexaploid wheat. Furthermore, imprinted expression was found for 41.2% and 50.0% of homolog pairs that evolved by tandem duplication after genome duplication in tetraploid and hexaploid wheat, respectively. These results suggest that genomic imprinting was evolutionarily conserved between closely related Triticum and Aegilops species and in the face of polyploid hybridization between species in these genera. © 2018 American Society of Plant Biologists. All rights reserved.

Comparative genome analysis of a large Dutch Legionella pneumophila strain collection identifies five markers highly correlated with clinical strains

PubMed Central

2010-01-01

Background Discrimination between clinical and environmental strains within many bacterial species is currently underexplored. Genomic analyses have clearly shown the enormous variability in genome composition between different strains of a bacterial species. In this study we have used Legionella pneumophila, the causative agent of Legionnaire's disease, to search for genomic markers related to pathogenicity. During a large surveillance study in The Netherlands well-characterized patient-derived strains and environmental strains were collected. We have used a mixed-genome microarray to perform comparative-genome analysis of 257 strains from this collection. Results Microarray analysis indicated that 480 DNA markers (out of in total 3360 markers) showed clear variation in presence between individual strains and these were therefore selected for further analysis. Unsupervised statistical analysis of these markers showed the enormous genomic variation within the species but did not show any correlation with a pathogenic phenotype. We therefore used supervised statistical analysis to identify discriminating markers. Genetic programming was used both to identify predictive markers and to define their interrelationships. A model consisting of five markers was developed that together correctly predicted 100% of the clinical strains and 69% of the environmental strains. Conclusions A novel approach for identifying predictive markers enabling discrimination between clinical and environmental isolates of L. pneumophila is presented. Out of over 3000 possible markers, five were selected that together enabled correct prediction of all the clinical strains included in this study. This novel approach for identifying predictive markers can be applied to all bacterial species, allowing for better discrimination between strains well equipped to cause human disease and relatively harmless strains. PMID:20630115

Identifying Driver Genomic Alterations in Cancers by Searching Minimum-Weight, Mutually Exclusive Sets

PubMed Central

Lu, Songjian; Lu, Kevin N.; Cheng, Shi-Yuan; Hu, Bo; Ma, Xiaojun; Nystrom, Nicholas; Lu, Xinghua

2015-01-01

An important goal of cancer genomic research is to identify the driving pathways underlying disease mechanisms and the heterogeneity of cancers. It is well known that somatic genome alterations (SGAs) affecting the genes that encode the proteins within a common signaling pathway exhibit mutual exclusivity, in which these SGAs usually do not co-occur in a tumor. With some success, this characteristic has been utilized as an objective function to guide the search for driver mutations within a pathway. However, mutual exclusivity alone is not sufficient to indicate that genes affected by such SGAs are in common pathways. Here, we propose a novel, signal-oriented framework for identifying driver SGAs. First, we identify the perturbed cellular signals by mining the gene expression data. Next, we search for a set of SGA events that carries strong information with respect to such perturbed signals while exhibiting mutual exclusivity. Finally, we design and implement an efficient exact algorithm to solve an NP-hard problem encountered in our approach. We apply this framework to the ovarian and glioblastoma tumor data available at the TCGA database, and perform systematic evaluations. Our results indicate that the signal-oriented approach enhances the ability to find informative sets of driver SGAs that likely constitute signaling pathways. PMID:26317392

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

PubMed Central

Chambers, John C; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Van der Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E; Coin, Lachlan J; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Kühnel, Brigitte; Kumar, Vinod; Lagou, Vasiliki; Liang, Liming; Luan, Jian’an; Vidal, Pedro Marques; Leach, Irene Mateo; O’Reilly, Paul F; Peden, John F; Rahmioglu, Nilufer; Soininen, Pasi; Speliotes, Elizabeth K; Yuan, Xin; Thorleifsson, Gudmar; Alizadeh, Behrooz Z; Atwood, Larry D; Borecki, Ingrid B; Brown, Morris J; Charoen, Pimphen; Cucca, Francesco; Das, Debashish; de Geus, Eco J C; Dixon, Anna L; Döring, Angela; Ehret, Georg; Eyjolfsson, Gudmundur I; Farrall, Martin; Forouhi, Nita G; Friedrich, Nele; Goessling, Wolfram; Gudbjartsson, Daniel F; Harris, Tamara B; Hartikainen, Anna-Liisa; Heath, Simon; Hirschfield, Gideon M; Hofman, Albert; Homuth, Georg; Hyppönen, Elina; Janssen, Harry L A; Johnson, Toby; Kangas, Antti J; Kema, Ido P; Kühn, Jens P; Lai, Sandra; Lathrop, Mark; Lerch, Markus M; Li, Yun; Liang, T Jake; Lin, Jing-Ping; Loos, Ruth J F; Martin, Nicholas G; Moffatt, Miriam F; Montgomery, Grant W; Munroe, Patricia B; Musunuru, Kiran; Nakamura, Yusuke; O’Donnell, Christopher J; Olafsson, Isleifur; Penninx, Brenda W; Pouta, Anneli; Prins, Bram P; Prokopenko, Inga; Puls, Ralf; Ruokonen, Aimo; Savolainen, Markku J; Schlessinger, David; Schouten, Jeoffrey N L; Seedorf, Udo; Sen-Chowdhry, Srijita; Siminovitch, Katherine A; Smit, Johannes H; Spector, Timothy D; Tan, Wenting; Teslovich, Tanya M; Tukiainen, Taru; Uitterlinden, Andre G; Van der Klauw, Melanie M; Vasan, Ramachandran S; Wallace, Chris; Wallaschofski, Henri; Wichmann, H-Erich; Willemsen, Gonneke; Würtz, Peter; Xu, Chun; Yerges-Armstrong, Laura M; Abecasis, Goncalo R; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark; Cookson, William O; van Duijn, Cornelia M; Froguel, Philippe; Matsuda, Koichi; McCarthy, Mark I; Meisinger, Christa; Mooser, Vincent; Pietiläinen, Kirsi H; Schumann, Gunter; Snieder, Harold; Sternberg, Michael J E; Stolk, Ronald P; Thomas, Howard C; Thorsteinsdottir, Unnur; Uda, Manuela; Waeber, Gérard; Wareham, Nicholas J; Waterworth, Dawn M; Watkins, Hugh; Whitfield, John B; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Fox, Caroline S; Ala-Korpela, Mika; Stefansson, Kari; Vollenweider, Peter; Völzke, Henry; Schadt, Eric E; Scott, James; Järvelin, Marjo-Riitta; Elliott, Paul; Kooner, Jaspal S

2012-01-01

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10−8 to P = 10−190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. PMID:22001757

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

PubMed

Chambers, John C; Zhang, Weihua; Sehmi, Joban; Li, Xinzhong; Wass, Mark N; Van der Harst, Pim; Holm, Hilma; Sanna, Serena; Kavousi, Maryam; Baumeister, Sebastian E; Coin, Lachlan J; Deng, Guohong; Gieger, Christian; Heard-Costa, Nancy L; Hottenga, Jouke-Jan; Kühnel, Brigitte; Kumar, Vinod; Lagou, Vasiliki; Liang, Liming; Luan, Jian'an; Vidal, Pedro Marques; Mateo Leach, Irene; O'Reilly, Paul F; Peden, John F; Rahmioglu, Nilufer; Soininen, Pasi; Speliotes, Elizabeth K; Yuan, Xin; Thorleifsson, Gudmar; Alizadeh, Behrooz Z; Atwood, Larry D; Borecki, Ingrid B; Brown, Morris J; Charoen, Pimphen; Cucca, Francesco; Das, Debashish; de Geus, Eco J C; Dixon, Anna L; Döring, Angela; Ehret, Georg; Eyjolfsson, Gudmundur I; Farrall, Martin; Forouhi, Nita G; Friedrich, Nele; Goessling, Wolfram; Gudbjartsson, Daniel F; Harris, Tamara B; Hartikainen, Anna-Liisa; Heath, Simon; Hirschfield, Gideon M; Hofman, Albert; Homuth, Georg; Hyppönen, Elina; Janssen, Harry L A; Johnson, Toby; Kangas, Antti J; Kema, Ido P; Kühn, Jens P; Lai, Sandra; Lathrop, Mark; Lerch, Markus M; Li, Yun; Liang, T Jake; Lin, Jing-Ping; Loos, Ruth J F; Martin, Nicholas G; Moffatt, Miriam F; Montgomery, Grant W; Munroe, Patricia B; Musunuru, Kiran; Nakamura, Yusuke; O'Donnell, Christopher J; Olafsson, Isleifur; Penninx, Brenda W; Pouta, Anneli; Prins, Bram P; Prokopenko, Inga; Puls, Ralf; Ruokonen, Aimo; Savolainen, Markku J; Schlessinger, David; Schouten, Jeoffrey N L; Seedorf, Udo; Sen-Chowdhry, Srijita; Siminovitch, Katherine A; Smit, Johannes H; Spector, Timothy D; Tan, Wenting; Teslovich, Tanya M; Tukiainen, Taru; Uitterlinden, Andre G; Van der Klauw, Melanie M; Vasan, Ramachandran S; Wallace, Chris; Wallaschofski, Henri; Wichmann, H-Erich; Willemsen, Gonneke; Würtz, Peter; Xu, Chun; Yerges-Armstrong, Laura M; Abecasis, Goncalo R; Ahmadi, Kourosh R; Boomsma, Dorret I; Caulfield, Mark; Cookson, William O; van Duijn, Cornelia M; Froguel, Philippe; Matsuda, Koichi; McCarthy, Mark I; Meisinger, Christa; Mooser, Vincent; Pietiläinen, Kirsi H; Schumann, Gunter; Snieder, Harold; Sternberg, Michael J E; Stolk, Ronald P; Thomas, Howard C; Thorsteinsdottir, Unnur; Uda, Manuela; Waeber, Gérard; Wareham, Nicholas J; Waterworth, Dawn M; Watkins, Hugh; Whitfield, John B; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Fox, Caroline S; Ala-Korpela, Mika; Stefansson, Kari; Vollenweider, Peter; Völzke, Henry; Schadt, Eric E; Scott, James; Järvelin, Marjo-Riitta; Elliott, Paul; Kooner, Jaspal S

2011-10-16

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice

PubMed Central

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-01-01

Background In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Results Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Conclusion Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice.

PubMed

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-08-01

In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription factors. Further studies will be

Novel genes identified in a high-density genome wide association study for nicotine dependence.

PubMed

Bierut, Laura Jean; Madden, Pamela A F; Breslau, Naomi; Johnson, Eric O; Hatsukami, Dorothy; Pomerleau, Ovide F; Swan, Gary E; Rutter, Joni; Bertelsen, Sarah; Fox, Louis; Fugman, Douglas; Goate, Alison M; Hinrichs, Anthony L; Konvicka, Karel; Martin, Nicholas G; Montgomery, Grant W; Saccone, Nancy L; Saccone, Scott F; Wang, Jen C; Chase, Gary A; Rice, John P; Ballinger, Dennis G

2007-01-01

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Patterns of Metabolite Changes Identified from Large-Scale Gene Perturbations in Arabidopsis Using a Genome-Scale Metabolic Network1[OPEN

PubMed Central

Kim, Taehyong; Dreher, Kate; Nilo-Poyanco, Ricardo; Lee, Insuk; Fiehn, Oliver; Lange, Bernd Markus; Nikolau, Basil J.; Sumner, Lloyd; Welti, Ruth; Wurtele, Eve S.; Rhee, Seung Y.

2015-01-01

Metabolomics enables quantitative evaluation of metabolic changes caused by genetic or environmental perturbations. However, little is known about how perturbing a single gene changes the metabolic system as a whole and which network and functional properties are involved in this response. To answer this question, we investigated the metabolite profiles from 136 mutants with single gene perturbations of functionally diverse Arabidopsis (Arabidopsis thaliana) genes. Fewer than 10 metabolites were changed significantly relative to the wild type in most of the mutants, indicating that the metabolic network was robust to perturbations of single metabolic genes. These changed metabolites were closer to each other in a genome-scale metabolic network than expected by chance, supporting the notion that the genetic perturbations changed the network more locally than globally. Surprisingly, the changed metabolites were close to the perturbed reactions in only 30% of the mutants of the well-characterized genes. To determine the factors that contributed to the distance between the observed metabolic changes and the perturbation site in the network, we examined nine network and functional properties of the perturbed genes. Only the isozyme number affected the distance between the perturbed reactions and changed metabolites. This study revealed patterns of metabolic changes from large-scale gene perturbations and relationships between characteristics of the perturbed genes and metabolic changes. PMID:25670818

Single-virus genomics reveals hidden cosmopolitan and abundant viruses

PubMed Central

Martinez-Hernandez, Francisco; Fornas, Oscar; Lluesma Gomez, Monica; Bolduc, Benjamin; de la Cruz Peña, Maria Jose; Martínez, Joaquín Martínez; Anton, Josefa; Gasol, Josep M.; Rosselli, Riccardo; Rodriguez-Valera, Francisco; Sullivan, Matthew B.; Acinas, Silvia G.; Martinez-Garcia, Manuel

2017-01-01

Microbes drive ecosystems under constraints imposed by viruses. However, a lack of virus genome information hinders our ability to answer fundamental, biological questions concerning microbial communities. Here we apply single-virus genomics (SVGs) to assess whether portions of marine viral communities are missed by current techniques. The majority of the here-identified 44 viral single-amplified genomes (vSAGs) are more abundant in global ocean virome data sets than published metagenome-assembled viral genomes or isolates. This indicates that vSAGs likely best represent the dsDNA viral populations dominating the oceans. Species-specific recruitment patterns and virome simulation data suggest that vSAGs are highly microdiverse and that microdiversity hinders the metagenomic assembly, which could explain why their genomes have not been identified before. Altogether, SVGs enable the discovery of some of the likely most abundant and ecologically relevant marine viral species, such as vSAG 37-F6, which were overlooked by other methodologies. PMID:28643787

Single-virus genomics reveals hidden cosmopolitan and abundant viruses

DOE PAGES

Martinez-Hernandez, Francisco; Fornas, Oscar; Lluesma Gomez, Monica; ...

2017-06-23

Microbes drive ecosystems under constraints imposed by viruses. However, a lack of virus genome information hinders our ability to answer fundamental, biological questions concerning microbial communities. Here we apply single-virus genomics (SVGs) to assess whether portions of marine viral communities are missed by current techniques. The majority of the here-identified 44 viral single-amplified genomes (vSAGs) are more abundant in global ocean virome data sets than published metagenome-assembled viral genomes or isolates. This indicates that vSAGs likely best represent the dsDNA viral populations dominating the oceans. Species-specific recruitment patterns and virome simulation data suggest that vSAGs are highly microdiverse and thatmore » microdiversity hinders the metagenomic assembly, which could explain why their genomes have not been identified before. Altogether, SVGs enable the discovery of some of the likely most abundant and ecologically relevant marine viral species, such as vSAG 37-F6, which were overlooked by other methodologies.« less

Single-virus genomics reveals hidden cosmopolitan and abundant viruses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martinez-Hernandez, Francisco; Fornas, Oscar; Lluesma Gomez, Monica

Microbes drive ecosystems under constraints imposed by viruses. However, a lack of virus genome information hinders our ability to answer fundamental, biological questions concerning microbial communities. Here we apply single-virus genomics (SVGs) to assess whether portions of marine viral communities are missed by current techniques. The majority of the here-identified 44 viral single-amplified genomes (vSAGs) are more abundant in global ocean virome data sets than published metagenome-assembled viral genomes or isolates. This indicates that vSAGs likely best represent the dsDNA viral populations dominating the oceans. Species-specific recruitment patterns and virome simulation data suggest that vSAGs are highly microdiverse and thatmore » microdiversity hinders the metagenomic assembly, which could explain why their genomes have not been identified before. Altogether, SVGs enable the discovery of some of the likely most abundant and ecologically relevant marine viral species, such as vSAG 37-F6, which were overlooked by other methodologies.« less

Similar genomic proportions of copy number variation within gray wolves and modern dog breeds inferred from whole genome sequencing.

PubMed

Serres-Armero, Aitor; Povolotskaya, Inna S; Quilez, Javier; Ramirez, Oscar; Santpere, Gabriel; Kuderna, Lukas F K; Hernandez-Rodriguez, Jessica; Fernandez-Callejo, Marcos; Gomez-Sanchez, Daniel; Freedman, Adam H; Fan, Zhenxin; Novembre, John; Navarro, Arcadi; Boyko, Adam; Wayne, Robert; Vilà, Carles; Lorente-Galdos, Belen; Marques-Bonet, Tomas

2017-12-19

Whole genome re-sequencing data from dogs and wolves are now commonly used to study how natural and artificial selection have shaped the patterns of genetic diversity. Single nucleotide polymorphisms, microsatellites and variants in mitochondrial DNA have been interrogated for links to specific phenotypes or signals of domestication. However, copy number variation (CNV), despite its increasingly recognized importance as a contributor to phenotypic diversity, has not been extensively explored in canids. Here, we develop a new accurate probabilistic framework to create fine-scale genomic maps of segmental duplications (SDs), compare patterns of CNV across groups and investigate their role in the evolution of the domestic dog by using information from 34 canine genomes. Our analyses show that duplicated regions are enriched in genes and hence likely possess functional importance. We identify 86 loci with large CNV differences between dogs and wolves, enriched in genes responsible for sensory perception, immune response, metabolic processes, etc. In striking contrast to the observed loss of nucleotide diversity in domestic dogs following the population bottlenecks that occurred during domestication and breed creation, we find a similar proportion of CNV loci in dogs and wolves, suggesting that other dynamics are acting to particularly select for CNVs with potentially functional impacts. This work is the first comparison of genome wide CNV patterns in domestic and wild canids using whole-genome sequencing data and our findings contribute to study the impact of novel kinds of genetic changes on the evolution of the domestic dog.

Genetic architecture and genomic patterns of gene flow between hybridizing species of Picea

PubMed Central

De La Torre, A; Ingvarsson, P K; Aitken, S N

2015-01-01

Hybrid zones provide an opportunity to study the effects of selection and gene flow in natural settings. We employed nuclear microsatellites (single sequence repeat (SSR)) and candidate gene single-nucleotide polymorphism markers (SNPs) to characterize the genetic architecture and patterns of interspecific gene flow in the Picea glauca × P. engelmannii hybrid zone across a broad latitudinal (40–60 degrees) and elevational (350–3500 m) range in western North America. Our results revealed a wide and complex hybrid zone with broad ancestry levels and low interspecific heterozygosity, shaped by asymmetric advanced-generation introgression, and low reproductive barriers between parental species. The clinal variation based on geographic variables, lack of concordance in clines among loci and the width of the hybrid zone points towards the maintenance of species integrity through environmental selection. Congruency between geographic and genomic clines suggests that loci with narrow clines are under strong selection, favoring either one parental species (directional selection) or their hybrids (overdominance) as a result of strong associations with climatic variables such as precipitation as snow and mean annual temperature. Cline movement due to past demographic events (evidenced by allelic richness and heterozygosity shifts from the average cline center) may explain the asymmetry in introgression and predominance of P. engelmannii found in this study. These results provide insights into the genetic architecture and fine-scale patterns of admixture, and identify loci that may be involved in reproductive barriers between the species. PMID:25806545

Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth

The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefitmore » in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.« less

Genome-wide meta-analysis identifies new susceptibility loci for migraine.

PubMed

Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E; Todt, Unda; McArdle, Wendy L; Quaye, Lydia; Koiranen, Markku; Ikram, M Arfan; Lehtimäki, Terho; Stam, Anine H; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M; Palta, Priit; Hamalainen, Eija; Schürks, Markus; Rose, Lynda M; Buring, Julie E; Ridker, Paul M; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A; Evans, David M; Ring, Susan M; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari A; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R; Pelzer, Nadine; Weller, Claudia M; Zielman, Ronald; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant W; Martin, Nicholas G; Borck, Guntram; Göbel, Hartmut; Heinze, Axel; Heinze-Kuhn, Katja; Williams, Frances M K; Hartikainen, Anna-Liisa; Pouta, Anneli; van den Ende, Joyce; Uitterlinden, Andre G; Hofman, Albert; Amin, Najaf; Hottenga, Jouke-Jan; Vink, Jacqueline M; Heikkilä, Kauko; Alexander, Michael; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G; Traynor, Bryan; Trabzuni, Daniah; Rossin, Elizabeth; Lage, Kasper; Jacobs, Suzanne B R; Gibbs, J Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W; Boomsma, Dorret I; van Duijn, Cornelia; Raitakari, Olli; Jarvelin, Marjo-Riitta; Zwart, John-Anker; Cherkas, Lynn; Strachan, David P; Kubisch, Christian; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefansson, Kari; Daly, Mark J; Nyholt, Dale R; Chasman, Daniel; Palotie, Aarno

2013-08-01

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

The nucleotide composition of microbial genomes indicates differential patterns of selection on core and accessory genomes.

PubMed

Bohlin, Jon; Eldholm, Vegard; Pettersson, John H O; Brynildsrud, Ola; Snipen, Lars

2017-02-10

The core genome consists of genes shared by the vast majority of a species and is therefore assumed to have been subjected to substantially stronger purifying selection than the more mobile elements of the genome, also known as the accessory genome. Here we examine intragenic base composition differences in core genomes and corresponding accessory genomes in 36 species, represented by the genomes of 731 bacterial strains, to assess the impact of selective forces on base composition in microbes. We also explore, in turn, how these results compare with findings for whole genome intragenic regions. We found that GC content in coding regions is significantly higher in core genomes than accessory genomes and whole genomes. Likewise, GC content variation within coding regions was significantly lower in core genomes than in accessory genomes and whole genomes. Relative entropy in coding regions, measured as the difference between observed and expected trinucleotide frequencies estimated from mononucleotide frequencies, was significantly higher in the core genomes than in accessory and whole genomes. Relative entropy was positively associated with coding region GC content within the accessory genomes, but not within the corresponding coding regions of core or whole genomes. The higher intragenic GC content and relative entropy, as well as the lower GC content variation, observed in the core genomes is most likely associated with selective constraints. It is unclear whether the positive association between GC content and relative entropy in the more mobile accessory genomes constitutes signatures of selection or selective neutral processes.

GENOMIC ORGANIZATION OF THE SP22 GENE AND A UNIQUE PATTERN OF EXPRESSION IN SPERMATOGENIC CELLS

EPA Science Inventory

GENOMIC ORGANIZATION OF THE SP22 GENE AND A UNIQUE PATTERN OF EXPRESSION IN SPERMATOGENIC CELLS.
JE Welch*, RR Barbee*, JD Suarez*, NL Roberts*, and GR Klinefelter. Reproductive Toxicology Division, NHEERL, U.S. EPA, Research Triangle Park, NC, USA.
Our laboratory has rep...

Genomic analysis and selected molecular pathways in rare cancers

NASA Astrophysics Data System (ADS)

Liu, Stephen V.; Lenkiewicz, Elizabeth; Evers, Lisa; Holley, Tara; Kiefer, Jeffrey; Ruiz, Christian; Glatz, Katharina; Bubendorf, Lukas; Demeure, Michael J.; Eng, Cathy; Ramanathan, Ramesh K.; Von Hoff, Daniel D.; Barrett, Michael T.

2012-12-01

It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer.

Genomic analysis and selected molecular pathways in rare cancers.

PubMed

Liu, Stephen V; Lenkiewicz, Elizabeth; Evers, Lisa; Holley, Tara; Kiefer, Jeffrey; Ruiz, Christian; Glatz, Katharina; Bubendorf, Lukas; Demeure, Michael J; Eng, Cathy; Ramanathan, Ramesh K; Von Hoff, Daniel D; Barrett, Michael T

2012-12-01

It is widely accepted that many cancers arise as a result of an acquired genomic instability and the subsequent evolution of tumor cells with variable patterns of selected and background aberrations. The presence and behaviors of distinct neoplastic cell populations within a patient's tumor may underlie multiple clinical phenotypes in cancers. A goal of many current cancer genome studies is the identification of recurring selected driver events that can be advanced for the development of personalized therapies. Unfortunately, in the majority of rare tumors, this type of analysis can be particularly challenging. Large series of specimens for analysis are simply not available, allowing recurring patterns to remain hidden. In this paper, we highlight the use of DNA content-based flow sorting to identify and isolate DNA-diploid and DNA-aneuploid populations from tumor biopsies as a strategy to comprehensively study the genomic composition and behaviors of individual cancers in a series of rare solid tumors: intrahepatic cholangiocarcinoma, anal carcinoma, adrenal leiomyosarcoma, and pancreatic neuroendocrine tumors. We propose that the identification of highly selected genomic events in distinct tumor populations within each tumor can identify candidate driver events that can facilitate the development of novel, personalized treatment strategies for patients with cancer.

A DNA-based pattern classifier with in vitro learning and associative recall for genomic characterization and biosensing without explicit sequence knowledge.

PubMed

Lee, Ju Seok; Chen, Junghuei; Deaton, Russell; Kim, Jin-Woo

2014-01-01

Genetic material extracted from in situ microbial communities has high promise as an indicator of biological system status. However, the challenge is to access genomic information from all organisms at the population or community scale to monitor the biosystem's state. Hence, there is a need for a better diagnostic tool that provides a holistic view of a biosystem's genomic status. Here, we introduce an in vitro methodology for genomic pattern classification of biological samples that taps large amounts of genetic information from all genes present and uses that information to detect changes in genomic patterns and classify them. We developed a biosensing protocol, termed Biological Memory, that has in vitro computational capabilities to "learn" and "store" genomic sequence information directly from genomic samples without knowledge of their explicit sequences, and that discovers differences in vitro between previously unknown inputs and learned memory molecules. The Memory protocol was designed and optimized based upon (1) common in vitro recombinant DNA operations using 20-base random probes, including polymerization, nuclease digestion, and magnetic bead separation, to capture a snapshot of the genomic state of a biological sample as a DNA memory and (2) the thermal stability of DNA duplexes between new input and the memory to detect similarities and differences. For efficient read out, a microarray was used as an output method. When the microarray-based Memory protocol was implemented to test its capability and sensitivity using genomic DNA from two model bacterial strains, i.e., Escherichia coli K12 and Bacillus subtilis, results indicate that the Memory protocol can "learn" input DNA, "recall" similar DNA, differentiate between dissimilar DNA, and detect relatively small concentration differences in samples. This study demonstrated not only the in vitro information processing capabilities of DNA, but also its promise as a genomic pattern classifier that could

Identifying core gene modules in glioblastoma based on multilayer factor-mediated dysfunctional regulatory networks through integrating multi-dimensional genomic data

PubMed Central

Ping, Yanyan; Deng, Yulan; Wang, Li; Zhang, Hongyi; Zhang, Yong; Xu, Chaohan; Zhao, Hongying; Fan, Huihui; Yu, Fulong; Xiao, Yun; Li, Xia

2015-01-01

The driver genetic aberrations collectively regulate core cellular processes underlying cancer development. However, identifying the modules of driver genetic alterations and characterizing their functional mechanisms are still major challenges for cancer studies. Here, we developed an integrative multi-omics method CMDD to identify the driver modules and their affecting dysregulated genes through characterizing genetic alteration-induced dysregulated networks. Applied to glioblastoma (GBM), the CMDD identified a core gene module of 17 genes, including seven known GBM drivers, and their dysregulated genes. The module showed significant association with shorter survival of GBM. When classifying driver genes in the module into two gene sets according to their genetic alteration patterns, we found that one gene set directly participated in the glioma pathway, while the other indirectly regulated the glioma pathway, mostly, via their dysregulated genes. Both of the two gene sets were significant contributors to survival and helpful for classifying GBM subtypes, suggesting their critical roles in GBM pathogenesis. Also, by applying the CMDD to other six cancers, we identified some novel core modules associated with overall survival of patients. Together, these results demonstrate integrative multi-omics data can identify driver modules and uncover their dysregulated genes, which is useful for interpreting cancer genome. PMID:25653168

A Genome-Wide Landscape of Retrocopies in Primate Genomes.

PubMed

Navarro, Fábio C P; Galante, Pedro A F

2015-07-29

Gene duplication is a key factor contributing to phenotype diversity across and within species. Although the availability of complete genomes has led to the extensive study of genomic duplications, the dynamics and variability of gene duplications mediated by retrotransposition are not well understood. Here, we predict mRNA retrotransposition and use comparative genomics to investigate their origin and variability across primates. Analyzing seven anthropoid primate genomes, we found a similar number of mRNA retrotranspositions (∼7,500 retrocopies) in Catarrhini (Old Word Monkeys, including humans), but a surprising large number of retrocopies (∼10,000) in Platyrrhini (New World Monkeys), which may be a by-product of higher long interspersed nuclear element 1 activity in these genomes. By inferring retrocopy orthology, we dated most of the primate retrocopy origins, and estimated a decrease in the fixation rate in recent primate history, implying a smaller number of species-specific retrocopies. Moreover, using RNA-Seq data, we identified approximately 3,600 expressed retrocopies. As expected, most of these retrocopies are located near or within known genes, present tissue-specific and even species-specific expression patterns, and no expression correlation to their parental genes. Taken together, our results provide further evidence that mRNA retrotransposition is an active mechanism in primate evolution and suggest that retrocopies may not only introduce great genetic variability between lineages but also create a large reservoir of potentially functional new genomic loci in primate genomes. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Random Distribution Pattern and Non-adaptivity of Genome Size in a Highly Variable Population of Festuca pallens

PubMed Central

Šmarda, Petr; Bureš, Petr; Horová, Lucie

2007-01-01

Background and Aims The spatial and statistical distribution of genome sizes and the adaptivity of genome size to some types of habitat, vegetation or microclimatic conditions were investigated in a tetraploid population of Festuca pallens. The population was previously documented to vary highly in genome size and is assumed as a model for the study of the initial stages of genome size differentiation. Methods Using DAPI flow cytometry, samples were measured repeatedly with diploid Festuca pallens as the internal standard. Altogether 172 plants from 57 plots (2·25 m2), distributed in contrasting habitats over the whole locality in South Moravia, Czech Republic, were sampled. The differences in DNA content were confirmed by the double peaks of simultaneously measured samples. Key Results At maximum, a 1·115-fold difference in genome size was observed. The statistical distribution of genome sizes was found to be continuous and best fits the extreme (Gumbel) distribution with rare occurrences of extremely large genomes (positive-skewed), as it is similar for the log-normal distribution of the whole Angiosperms. Even plants from the same plot frequently varied considerably in genome size and the spatial distribution of genome sizes was generally random and unautocorrelated (P > 0·05). The observed spatial pattern and the overall lack of correlations of genome size with recognized vegetation types or microclimatic conditions indicate the absence of ecological adaptivity of genome size in the studied population. Conclusions These experimental data on intraspecific genome size variability in Festuca pallens argue for the absence of natural selection and the selective non-significance of genome size in the initial stages of genome size differentiation, and corroborate the current hypothetical model of genome size evolution in Angiosperms (Bennetzen et al., 2005, Annals of Botany 95: 127–132). PMID:17565968

The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

Cancer.gov

Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

Molecular Networking and Pattern-Based Genome Mining Improves Discovery of Biosynthetic Gene Clusters and their Products from Salinispora Species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duncan, Katherine R.; Crüsemann, Max; Lechner, Anna

Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. In this paper, we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains, including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated themore » identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. Finally, these efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches.« less

Molecular Networking and Pattern-Based Genome Mining Improves Discovery of Biosynthetic Gene Clusters and their Products from Salinispora Species

DOE PAGES

Duncan, Katherine R.; Crüsemann, Max; Lechner, Anna; ...

2015-04-09

Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. In this paper, we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains, including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated themore » identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. Finally, these efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches.« less

Molecular Networking and Pattern-Based Genome Mining Improves discovery of biosynthetic gene clusters and their products from Salinispora species

PubMed Central

Duncan, Katherine R.; Crüsemann, Max; Lechner, Anna; Sarkar, Anindita; Li, Jie; Ziemert, Nadine; Wang, Mingxun; Bandeira, Nuno; Moore, Bradley S.; Dorrestein, Pieter C.; Jensen, Paul R.

2015-01-01

Summary Genome sequencing has revealed that bacteria contain many more biosynthetic gene clusters than predicted based on the number of secondary metabolites discovered to date. While this biosynthetic reservoir has fostered interest in new tools for natural product discovery, there remains a gap between gene cluster detection and compound discovery. Here we apply molecular networking and the new concept of pattern-based genome mining to 35 Salinispora strains including 30 for which draft genome sequences were either available or obtained for this study. The results provide a method to simultaneously compare large numbers of complex microbial extracts, which facilitated the identification of media components, known compounds and their derivatives, and new compounds that could be prioritized for structure elucidation. These efforts revealed considerable metabolite diversity and led to several molecular family-gene cluster pairings, of which the quinomycin-type depsipeptide retimycin A was characterized and linked to gene cluster NRPS40 using pattern-based bioinformatic approaches. PMID:25865308

Initial Genomics of the Human Nucleolus

PubMed Central

Németh, Attila; Conesa, Ana; Santoyo-Lopez, Javier; Medina, Ignacio; Montaner, David; Péterfia, Bálint; Solovei, Irina; Cremer, Thomas; Dopazo, Joaquin; Längst, Gernot

2010-01-01

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD–localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD–specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture. PMID:20361057

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

PubMed Central

McCorkle, Sean R; McCombie, WR; Dunn, John J

2011-01-01

Here, we report genome-wide analysis of the tumor suppressor p53 binding sites in normal human cells. 743 high-confidence ChIP-seq peaks representing putative genomic binding sites were identified in normal IMR90 fibroblasts using a reference chromatin sample. More than 40% were located within 2 kb of a transcription start site (TSS), a distribution similar to that documented for individually studied, functional p53 binding sites and, to date, not observed by previous p53 genome-wide studies. Nearly half of the high-confidence binding sites in the IMR90 cells reside in CpG islands in marked contrast to sites reported in cancer-derived cells. The distinct genomic features of the IMR90 binding sites do not reflect a distinct preference for specific sequences, since the de novo developed p53 motif based on our study is similar to those reported by genome-wide studies of cancer cells. More likely, the different chromatin landscape in normal, compared with cancer-derived cells, influences p53 binding via modulating availability of the sites. We compared the IMR90 ChIP-seq peaks to the recently published IMR90 methylome1 and demonstrated that they are enriched at hypomethylated DNA. Our study represents the first genome-wide, de novo mapping of p53 binding sites in normal human cells and reveals that p53 binding sites reside in distinct genomic landscapes in normal and cancer-derived human cells. PMID:22127205

An enhanced genome-scale metabolic reconstruction of Streptomyces clavuligerus identifies novel strain improvement strategies.

PubMed

Toro, León; Pinilla, Laura; Avignone-Rossa, Claudio; Ríos-Estepa, Rigoberto

2018-05-01

In this work, we expanded and updated a genome-scale metabolic model of Streptomyces clavuligerus. The model includes 1021 genes and 1494 biochemical reactions; genome-reaction information was curated and new features related to clavam metabolism and to the biomass synthesis equation were incorporated. The model was validated using experimental data from the literature and simulations were performed to predict cellular growth and clavulanic acid biosynthesis. Flux balance analysis (FBA) showed that limiting concentrations of phosphate and an excess of ammonia accumulation are unfavorable for growth and clavulanic acid biosynthesis. The evaluation of different objective functions for FBA showed that maximization of ATP yields the best predictions for cellular behavior in continuous cultures, while the maximization of growth rate provides better predictions for batch cultures. Through gene essentiality analysis, 130 essential genes were found using a limited in silico media, while 100 essential genes were identified in amino acid-supplemented media. Finally, a strain design was carried out to identify candidate genes to be overexpressed or knocked out so as to maximize antibiotic biosynthesis. Interestingly, potential metabolic engineering targets, identified in this study, have not been tested experimentally.

Genome-wide divergence, haplotype distribution and population demographic histories for Gossypium hirsutum and Gossypium barbadense as revealed by genome-anchored SNPs

PubMed Central

Reddy, Umesh K.; Nimmakayala, Padma; Abburi, Venkata Lakshmi; Reddy, C. V. C. M.; Saminathan, Thangasamy; Percy, Richard G.; Yu, John Z.; Frelichowski, James; Udall, Joshua A.; Page, Justin T.; Zhang, Dong; Shehzad, Tariq; Paterson, Andrew H.

2017-01-01

Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using the SNPs distributed genome-wide, we examined genetic diversity, haplotype distribution and linkage disequilibrium patterns in the G. hirsutum and G. barbadense genomes to clarify population demographic history. Diversity and identity-by-state analyses have revealed little sharing of alleles between the two cultivated allotetraploid genomes, with a few exceptions that indicated sporadic gene flow. We found a high number of new alleles, representing increased nucleotide diversity, on chromosomes 1 and 2 in cultivated G. hirsutum as compared with low nucleotide diversity on these chromosomes in landrace G. hirsutum. In contrast, G. barbadense chromosomes showed negative Tajima’s D on several chromosomes for both cultivated and landrace types, which indicate that speciation of G. barbadense itself, might have occurred with relatively narrow genetic diversity. The presence of conserved linkage disequilibrium (LD) blocks and haplotypes between G. hirsutum and G. barbadense provides strong evidence for comparable patterns of evolution in their domestication processes. Our study illustrates the potential use of population genetic techniques to identify genomic regions for domestication. PMID:28128280

snpTree--a web-server to identify and construct SNP trees from whole genome sequence data.

PubMed

Leekitcharoenphon, Pimlapas; Kaas, Rolf S; Thomsen, Martin Christen Frølund; Friis, Carsten; Rasmussen, Simon; Aarestrup, Frank M

2012-01-01

The advances and decreasing economical cost of whole genome sequencing (WGS), will soon make this technology available for routine infectious disease epidemiology. In epidemiological studies, outbreak isolates have very little diversity and require extensive genomic analysis to differentiate and classify isolates. One of the successfully and broadly used methods is analysis of single nucletide polymorphisms (SNPs). Currently, there are different tools and methods to identify SNPs including various options and cut-off values. Furthermore, all current methods require bioinformatic skills. Thus, we lack a standard and simple automatic tool to determine SNPs and construct phylogenetic tree from WGS data. Here we introduce snpTree, a server for online-automatic SNPs analysis. This tool is composed of different SNPs analysis suites, perl and python scripts. snpTree can identify SNPs and construct phylogenetic trees from WGS as well as from assembled genomes or contigs. WGS data in fastq format are aligned to reference genomes by BWA while contigs in fasta format are processed by Nucmer. SNPs are concatenated based on position on reference genome and a tree is constructed from concatenated SNPs using FastTree and a perl script. The online server was implemented by HTML, Java and python script.The server was evaluated using four published bacterial WGS data sets (V. cholerae, S. aureus CC398, S. Typhimurium and M. tuberculosis). The evaluation results for the first three cases was consistent and concordant for both raw reads and assembled genomes. In the latter case the original publication involved extensive filtering of SNPs, which could not be repeated using snpTree. The snpTree server is an easy to use option for rapid standardised and automatic SNP analysis in epidemiological studies also for users with limited bioinformatic experience. The web server is freely accessible at http://www.cbs.dtu.dk/services/snpTree-1.0/.

APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma

PubMed Central

Leonard, Brandon; Hart, Steven N.; Burns, Michael B.; Carpenter, Michael A.; Temiz, Nuri A.; Rathore, Anurag; Vogel, Rachel Isaksson; Nikas, Jason B.; Law, Emily K.; Brown, William L.; Li, Ying; Zhang, Yuji; Maurer, Matthew J.; Oberg, Ann L.; Cunningham, Julie M.; Shridhar, Viji; Bell, Debra A.; April, Craig; Bentley, David; Bibikova, Marina; Cheetham, R. Keira; Fan, Jian-Bing; Grocock, Russell; Humphray, Sean; Kingsbury, Zoya; Peden, John; Chien, Jeremy; Swisher, Elizabeth M.; Hartmann, Lynn C.; Kalli, Kimberly R.; Goode, Ellen L.; Sicotte, Hugues; Kaufmann, Scott H.; Harris, Reuben S.

2013-01-01

Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here we report wide variation in expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in a majority of ovarian cancer cell lines (3 standard deviations above the mean of normal ovarian surface epithelial cells) and high grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′TC dinucleotide motifs in early-stage high grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA ‘repair’ enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. PMID:24154874

GFinisher: a new strategy to refine and finish bacterial genome assemblies

NASA Astrophysics Data System (ADS)

Guizelini, Dieval; Raittz, Roberto T.; Cruz, Leonardo M.; Souza, Emanuel M.; Steffens, Maria B. R.; Pedrosa, Fabio O.

2016-10-01

Despite the development in DNA sequencing technology, improving the number and the length of reads, the process of reconstruction of complete genome sequences, the so called genome assembly, is still complex. Only 13% of the prokaryotic genome sequencing projects have been completed. Draft genome sequences deposited in public databases are fragmented in contigs and may lack the full gene complement. The aim of the present work is to identify assembly errors and improve the assembly process of bacterial genomes. The biological patterns observed in genomic sequences and the application of a priori information can allow the identification of misassembled regions, and the reorganization and improvement of the overall de novo genome assembly. GFinisher starts generating a Fuzzy GC skew graphs for each contig in an assembly and follows breaking down the contigs in critical points in order to reassemble and close them using jFGap. This has been successfully applied to dataset from 96 genome assemblies, decreasing the number of contigs by up to 86%. GFinisher can easily optimize assemblies of prokaryotic draft genomes and can be used to improve the assembly programs based on nucleotide sequence patterns in the genome. The software and source code are available at http://gfinisher.sourceforge.net/.

GFinisher: a new strategy to refine and finish bacterial genome assemblies.

PubMed

Guizelini, Dieval; Raittz, Roberto T; Cruz, Leonardo M; Souza, Emanuel M; Steffens, Maria B R; Pedrosa, Fabio O

2016-10-10

Despite the development in DNA sequencing technology, improving the number and the length of reads, the process of reconstruction of complete genome sequences, the so called genome assembly, is still complex. Only 13% of the prokaryotic genome sequencing projects have been completed. Draft genome sequences deposited in public databases are fragmented in contigs and may lack the full gene complement. The aim of the present work is to identify assembly errors and improve the assembly process of bacterial genomes. The biological patterns observed in genomic sequences and the application of a priori information can allow the identification of misassembled regions, and the reorganization and improvement of the overall de novo genome assembly. GFinisher starts generating a Fuzzy GC skew graphs for each contig in an assembly and follows breaking down the contigs in critical points in order to reassemble and close them using jFGap. This has been successfully applied to dataset from 96 genome assemblies, decreasing the number of contigs by up to 86%. GFinisher can easily optimize assemblies of prokaryotic draft genomes and can be used to improve the assembly programs based on nucleotide sequence patterns in the genome. The software and source code are available at http://gfinisher.sourceforge.net/.

Genome-Wide Association Scan in HIV-1-Infected Individuals Identifying Variants Influencing Disease Course

PubMed Central

van Manen, Daniëlle; Delaneau, Olivier; Kootstra, Neeltje A.; Boeser-Nunnink, Brigitte D.; Limou, Sophie; Bol, Sebastiaan M.; Burger, Judith A.; Zwinderman, Aeilko H.; Moerland, Perry D.; van 't Slot, Ruben; Zagury, Jean-François; van 't Wout, Angélique B.; Schuitemaker, Hanneke

2011-01-01

Background AIDS develops typically after 7–11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (<2 years) and long-term non-progression (>15 years). To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. Methods The association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints. Results Multiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS-related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression. Conclusions Our study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection. PMID:21811574

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

PubMed

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

2016-09-08

Apicomplexan parasites are leading causes of human and livestock diseases such as malaria and toxoplasmosis, yet most of their genes remain uncharacterized. Here, we present the first genome-wide genetic screen of an apicomplexan. We adapted CRISPR/Cas9 to assess the contribution of each gene from the parasite Toxoplasma gondii during infection of human fibroblasts. Our analysis defines ∼200 previously uncharacterized, fitness-conferring genes unique to the phylum, from which 16 were investigated, revealing essential functions during infection of human cells. Secondary screens identify as an invasion factor the claudin-like apicomplexan microneme protein (CLAMP), which resembles mammalian tight-junction proteins and localizes to secretory organelles, making it critical to the initiation of infection. CLAMP is present throughout sequenced apicomplexan genomes and is essential during the asexual stages of the malaria parasite Plasmodium falciparum. These results provide broad-based functional information on T. gondii genes and will facilitate future approaches to expand the horizon of antiparasitic interventions. Copyright © 2016 Elsevier Inc. All rights reserved.

The Human Genome Project and Eugenics: Identifying the Impact on Individuals with Mental Retardation.

ERIC Educational Resources Information Center

Kuna, Jason

2001-01-01

This article explores the impact of the mapping work of the Human Genome Project on individuals with mental retardation and the negative effects of genetic testing. The potential to identify disabilities and the concept of eugenics are discussed, along with ethical issues surrounding potential genetic therapies. (Contains references.) (CR)

Recent genomic heritage in Scotland.

PubMed

Amador, Carmen; Huffman, Jennifer; Trochet, Holly; Campbell, Archie; Porteous, David; Wilson, James F; Hastie, Nick; Vitart, Veronique; Hayward, Caroline; Navarro, Pau; Haley, Chris S

2015-06-06

The Generation Scotland Scottish Family Health Study (GS:SFHS) includes 23,960 participants from across Scotland with records for many health-related traits and environmental covariates. Genotypes at ~700 K SNPs are currently available for 10,000 participants. The cohort was designed as a resource for genetic and health related research and the study of complex traits. In this study we developed a suite of analyses to disentangle the genomic differentiation within GS:SFHS individuals to describe and optimise the sample and methods for future analyses. We combined the genotypic information of GS:SFHS with 1092 individuals from the 1000 Genomes project and estimated their genomic relationships. Then, we performed Principal Component Analyses of the resulting relationships to investigate the genomic origin of different groups. We characterised two groups of individuals: those with a few sparse rare markers in the genome, and those with several large rare haplotypes which might represent relatively recent exogenous ancestors. We identified some individuals with likely Italian ancestry and a group with some potential African/Asian ancestry. An analysis of homozygosity in the GS:SFHS sample revealed a very similar pattern to other European populations. We also identified an individual carrying a chromosome 1 uniparental disomy. We found evidence of local geographic stratification within the population having impact on the genomic structure. These findings illuminate the history of the Scottish population and have implications for further analyses such as the study of the contributions of common and rare variants to trait heritabilities and the evaluation of genomic and phenotypic prediction of disease.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

PubMed

Saunus, Jodi M; Quinn, Michael C J; Patch, Ann-Marie; Pearson, John V; Bailey, Peter J; Nones, Katia; McCart Reed, Amy E; Miller, David; Wilson, Peter J; Al-Ejeh, Fares; Mariasegaram, Mythily; Lau, Queenie; Withers, Teresa; Jeffree, Rosalind L; Reid, Lynne E; Da Silva, Leonard; Matsika, Admire; Niland, Colleen M; Cummings, Margaret C; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Anderson, Matthew J; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Kassahn, Karin S; Narayanan, Vairavan; Taib, Nur Aishah; Teo, Soo-Hwang; Chow, Yock Ping; kConFab; Jat, Parmjit S; Brandner, Sebastian; Flanagan, Adrienne M; Khanna, Kum Kum; Chenevix-Trench, Georgia; Grimmond, Sean M; Simpson, Peter T; Waddell, Nicola; Lakhani, Sunil R

2015-11-01

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting

Virtual Genomes in Flux: An Interplay of Neutrality and Adaptability Explains Genome Expansion and Streamlining

PubMed Central

Cuypers, Thomas D.; Hogeweg, Paulien

2012-01-01

The picture that emerges from phylogenetic gene content reconstructions is that genomes evolve in a dynamic pattern of rapid expansion and gradual streamlining. Ancestral organisms have been estimated to possess remarkably rich gene complements, although gene loss is a driving force in subsequent lineage adaptation and diversification. Here, we study genome dynamics in a model of virtual cells evolving to maintain homeostasis. We observe a pattern of an initial rapid expansion of the genome and a prolonged phase of mutational load reduction. Generally, load reduction is achieved by the deletion of redundant genes, generating a streamlining pattern. Load reduction can also occur as a result of the generation of highly neutral genomic regions. These regions can expand and contract in a neutral fashion. Our study suggests that genome expansion and streamlining are generic patterns of evolving systems. We propose that the complex genotype to phenotype mapping in virtual cells as well as in their biological counterparts drives genome size dynamics, due to an emerging interplay between adaptation, neutrality, and evolvability. PMID:22234601

Genomic signatures of positive selection in humans and the limits of outlier approaches.

PubMed

Kelley, Joanna L; Madeoy, Jennifer; Calhoun, John C; Swanson, Willie; Akey, Joshua M

2006-08-01

Identifying regions of the human genome that have been targets of positive selection will provide important insights into recent human evolutionary history and may facilitate the search for complex disease genes. However, the confounding effects of population demographic history and selection on patterns of genetic variation complicate inferences of selection when a small number of loci are studied. To this end, identifying outlier loci from empirical genome-wide distributions of genetic variation is a promising strategy to detect targets of selection. Here, we evaluate the power and efficiency of a simple outlier approach and describe a genome-wide scan for positive selection using a dense catalog of 1.58 million SNPs that were genotyped in three human populations. In total, we analyzed 14,589 genes, 385 of which possess patterns of genetic variation consistent with the hypothesis of positive selection. Furthermore, several extended genomic regions were found, spanning >500 kb, that contained multiple contiguous candidate selection genes. More generally, these data provide important practical insights into the limits of outlier approaches in genome-wide scans for selection, provide strong candidate selection genes to study in greater detail, and may have important implications for disease related research.

Genomic Imprinting Was Evolutionarily Conserved during Wheat Polyploidization[OPEN

PubMed Central

Yang, Guanghui; Liu, Zhenshan; Gao, Lulu; Yu, Kuohai; Feng, Man; Peng, Huiru; Sun, Qixin; Ni, Zhongfu

2018-01-01

Genomic imprinting is an epigenetic phenomenon that causes genes to be differentially expressed depending on their parent of origin. To evaluate the evolutionary conservation of genomic imprinting and the effects of ploidy on this process, we investigated parent-of-origin-specific gene expression patterns in the endosperm of diploid (Aegilops spp), tetraploid, and hexaploid wheat (Triticum spp) at various stages of development via high-throughput transcriptome sequencing. We identified 91, 135, and 146 maternally or paternally expressed genes (MEGs or PEGs, respectively) in diploid, tetraploid, and hexaploid wheat, respectively, 52.7% of which exhibited dynamic expression patterns at different developmental stages. Gene Ontology enrichment analysis suggested that MEGs and PEGs were involved in metabolic processes and DNA-dependent transcription, respectively. Nearly half of the imprinted genes exhibited conserved expression patterns during wheat hexaploidization. In addition, 40% of the homoeolog pairs originating from whole-genome duplication were consistently maternally or paternally biased in the different subgenomes of hexaploid wheat. Furthermore, imprinted expression was found for 41.2% and 50.0% of homolog pairs that evolved by tandem duplication after genome duplication in tetraploid and hexaploid wheat, respectively. These results suggest that genomic imprinting was evolutionarily conserved between closely related Triticum and Aegilops species and in the face of polyploid hybridization between species in these genera. PMID:29298834

Motif mismatches in microsatellites: insights from genome-wide investigation among 20 insect species.

PubMed

Behura, Susanta K; Severson, David W

2015-02-01

We present a detailed genome-wide comparative study of motif mismatches of microsatellites among 20 insect species representing five taxonomic orders. The results show that varying proportions (∼15-46%) of microsatellites identified in these species are imperfect in motif structure, and that they also vary in chromosomal distribution within genomes. It was observed that the genomic abundance of imperfect repeats is significantly associated with the length and number of motif mismatches of microsatellites. Furthermore, microsatellites with a higher number of mismatches tend to have lower abundance in the genome, suggesting that sequence heterogeneity of repeat motifs is a key determinant of genomic abundance of microsatellites. This relationship seems to be a general feature of microsatellites even in unrelated species such as yeast, roundworm, mouse and human. We provide a mechanistic explanation of the evolutionary link between motif heterogeneity and genomic abundance of microsatellites by examining the patterns of motif mismatches and allele sequences of single-nucleotide polymorphisms identified within microsatellite loci. Using Drosophila Reference Genetic Panel data, we further show that pattern of allelic variation modulates motif heterogeneity of microsatellites, and provide estimates of allele age of specific imperfect microsatellites found within protein-coding genes. © The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Resequencing a core collection of upland cotton identifies genomic variation and loci influencing fiber quality and yield.

PubMed

Ma, Zhiying; He, Shoupu; Wang, Xingfen; Sun, Junling; Zhang, Yan; Zhang, Guiyin; Wu, Liqiang; Li, Zhikun; Liu, Zhihao; Sun, Gaofei; Yan, Yuanyuan; Jia, Yinhua; Yang, Jun; Pan, Zhaoe; Gu, Qishen; Li, Xueyuan; Sun, Zhengwen; Dai, Panhong; Liu, Zhengwen; Gong, Wenfang; Wu, Jinhua; Wang, Mi; Liu, Hengwei; Feng, Keyun; Ke, Huifeng; Wang, Junduo; Lan, Hongyu; Wang, Guoning; Peng, Jun; Wang, Nan; Wang, Liru; Pang, Baoyin; Peng, Zhen; Li, Ruiqiang; Tian, Shilin; Du, Xiongming

2018-05-07

Upland cotton is the most important natural-fiber crop. The genomic variation of diverse germplasms and alleles underpinning fiber quality and yield should be extensively explored. Here, we resequenced a core collection comprising 419 accessions with 6.55-fold coverage depth and identified approximately 3.66 million SNPs for evaluating the genomic variation. We performed phenotyping across 12 environments and conducted genome-wide association study of 13 fiber-related traits. 7,383 unique SNPs were significantly associated with these traits and were located within or near 4,820 genes; more associated loci were detected for fiber quality than fiber yield, and more fiber genes were detected in the D than the A subgenome. Several previously undescribed causal genes for days to flowering, fiber length, and fiber strength were identified. Phenotypic selection for these traits increased the frequency of elite alleles during domestication and breeding. These results provide targets for molecular selection and genetic manipulation in cotton improvement.

Genomic analysis of adult B-ALL identifies potential markers of shorter survival.

PubMed

Patel, Shiven; Mason, Clinton C; Glenn, Martha J; Paxton, Christian N; South, Sara T; Cessna, Melissa H; Asch, Julie; Cobain, Erin F; Bixby, Dale L; Smith, Lauren B; Reshmi, Shalini; Gastier-Foster, Julie M; Schiffman, Joshua D; Miles, Rodney R

2017-05-01

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pan-genome analysis of human gastric pathogen H. pylori: comparative genomics and pathogenomics approaches to identify regions associated with pathogenicity and prediction of potential core therapeutic targets.

PubMed

Ali, Amjad; Naz, Anam; Soares, Siomar C; Bakhtiar, Marriam; Tiwari, Sandeep; Hassan, Syed S; Hanan, Fazal; Ramos, Rommel; Pereira, Ulisses; Barh, Debmalya; Figueiredo, Henrique César Pereira; Ussery, David W; Miyoshi, Anderson; Silva, Artur; Azevedo, Vasco

2015-01-01

Helicobacter pylori is a human gastric pathogen implicated as the major cause of peptic ulcer and second leading cause of gastric cancer (~70%) around the world. Conversely, an increased resistance to antibiotics and hindrances in the development of vaccines against H. pylori are observed. Pan-genome analyses of the global representative H. pylori isolates consisting of 39 complete genomes are presented in this paper. Phylogenetic analyses have revealed close relationships among geographically diverse strains of H. pylori. The conservation among these genomes was further analyzed by pan-genome approach; the predicted conserved gene families (1,193) constitute ~77% of the average H. pylori genome and 45% of the global gene repertoire of the species. Reverse vaccinology strategies have been adopted to identify and narrow down the potential core-immunogenic candidates. Total of 28 nonhost homolog proteins were characterized as universal therapeutic targets against H. pylori based on their functional annotation and protein-protein interaction. Finally, pathogenomics and genome plasticity analysis revealed 3 highly conserved and 2 highly variable putative pathogenicity islands in all of the H. pylori genomes been analyzed.

RNA-Seq identifies SPGs as a ventral skeletal patterning cue in sea urchins.

PubMed

Piacentino, Michael L; Zuch, Daniel T; Fishman, Julie; Rose, Sviatlana; Speranza, Emily E; Li, Christy; Yu, Jia; Chung, Oliver; Ramachandran, Janani; Ferrell, Patrick; Patel, Vijeta; Reyna, Arlene; Hameeduddin, Hajerah; Chaves, James; Hewitt, Finnegan B; Bardot, Evan; Lee, David; Core, Amanda B; Hogan, John D; Keenan, Jessica L; Luo, Lingqi; Coulombe-Huntington, Jasmin; Blute, Todd A; Oleinik, Ekaterina; Ibn-Salem, Jonas; Poustka, Albert J; Bradham, Cynthia A

2016-02-15

The sea urchin larval skeleton offers a simple model for formation of developmental patterns. The calcium carbonate skeleton is secreted by primary mesenchyme cells (PMCs) in response to largely unknown patterning cues expressed by the ectoderm. To discover novel ectodermal cues, we performed an unbiased RNA-Seq-based screen and functionally tested candidates; we thereby identified several novel skeletal patterning cues. Among these, we show that SLC26a2/7 is a ventrally expressed sulfate transporter that promotes a ventral accumulation of sulfated proteoglycans, which is required for ventral PMC positioning and skeletal patterning. We show that the effects of SLC perturbation are mimicked by manipulation of either external sulfate levels or proteoglycan sulfation. These results identify novel skeletal patterning genes and demonstrate that ventral proteoglycan sulfation serves as a positional cue for sea urchin skeletal patterning. © 2016. Published by The Company of Biologists Ltd.

Complete genome sequence of southern tomato virus identified from China using next generation sequencing

USDA-ARS?s Scientific Manuscript database

Complete genome sequence of a double-stranded RNA (dsRNA) virus, southern tomato virus (STV), on tomatoes in China, was elucidated using small RNAs deep sequencing. The identified STV_CN12 shares 99% sequence identity to other isolates from Mexico, France, Spain, and U.S. This is the first report ...

Shotgun Bisulfite Sequencing of the Betula platyphylla Genome Reveals the Tree’s DNA Methylation Patterning

PubMed Central

Su, Chang; Wang, Chao; He, Lin; Yang, Chuanping; Wang, Yucheng

2014-01-01

DNA methylation plays a critical role in the regulation of gene expression. Most studies of DNA methylation have been performed in herbaceous plants, and little is known about the methylation patterns in tree genomes. In the present study, we generated a map of methylated cytosines at single base pair resolution for Betula platyphylla (white birch) by bisulfite sequencing combined with transcriptomics to analyze DNA methylation and its effects on gene expression. We obtained a detailed view of the function of DNA methylation sequence composition and distribution in the genome of B. platyphylla. There are 34,460 genes in the whole genome of birch, and 31,297 genes are methylated. Conservatively, we estimated that 14.29% of genomic cytosines are methylcytosines in birch. Among the methylation sites, the CHH context accounts for 48.86%, and is the largest proportion. Combined transcriptome and methylation analysis showed that the genes with moderate methylation levels had higher expression levels than genes with high and low methylation. In addition, methylated genes are highly enriched for the GO subcategories of binding activities, catalytic activities, cellular processes, response to stimulus and cell death, suggesting that methylation mediates these pathways in birch trees. PMID:25514241

Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

PubMed

Rotival, Maxime; Zeller, Tanja; Wild, Philipp S; Maouche, Seraya; Szymczak, Silke; Schillert, Arne; Castagné, Raphaele; Deiseroth, Arne; Proust, Carole; Brocheton, Jessy; Godefroy, Tiphaine; Perret, Claire; Germain, Marine; Eleftheriadis, Medea; Sinning, Christoph R; Schnabel, Renate B; Lubos, Edith; Lackner, Karl J; Rossmann, Heidi; Münzel, Thomas; Rendon, Augusto; Erdmann, Jeanette; Deloukas, Panos; Hengstenberg, Christian; Diemert, Patrick; Montalescot, Gilles; Ouwehand, Willem H; Samani, Nilesh J; Schunkert, Heribert; Tregouet, David-Alexandre; Ziegler, Andreas; Goodall, Alison H; Cambien, François; Tiret, Laurence; Blankenberg, Stefan

2011-12-01

One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking

The variable genomic architecture of isolation between hybridizing species of house mice.

PubMed

Teeter, Katherine C; Thibodeau, Lisa M; Gompert, Zachariah; Buerkle, C Alex; Nachman, Michael W; Tucker, Priscilla K

2010-02-01

Studies of the genetics of hybrid zones can provide insight into the genomic architecture of species boundaries. By examining patterns of introgression of multiple loci across a hybrid zone, it may be possible to identify regions of the genome that have experienced selection. Here, we present a comparison of introgression in two replicate transects through the house mouse hybrid zone through central Europe, using data from 41 single nucleotide markers. Using both genomic and geographic clines, we found many differences in patterns of introgression between the two transects, as well as some similarities. We found that many loci may have experienced the effects of selection at linked sites, including selection against hybrid genotypes, as well as positive selection in the form of genotypes introgressed into a foreign genetic background. We also found many positive associations of conspecific alleles among unlinked markers, which could be caused by epistatic interactions. Different patterns of introgression in the two transects highlight the challenge of using hybrid zones to identify genes underlying isolation and raise the possibility that the genetic basis of isolation between these species may be dependent on the local population genetic make-up or the local ecological setting.

Fluorescence Reporter-Based Genome-Wide RNA Interference Screening to Identify Alternative Splicing Regulators.

PubMed

Misra, Ashish; Green, Michael R

2017-01-01

Alternative splicing is a regulated process that leads to inclusion or exclusion of particular exons in a pre-mRNA transcript, resulting in multiple protein isoforms being encoded by a single gene. With more than 90 % of human genes known to undergo alternative splicing, it represents a major source for biological diversity inside cells. Although in vitro splicing assays have revealed insights into the mechanisms regulating individual alternative splicing events, our global understanding of alternative splicing regulation is still evolving. In recent years, genome-wide RNA interference (RNAi) screening has transformed biological research by enabling genome-scale loss-of-function screens in cultured cells and model organisms. In addition to resulting in the identification of new cellular pathways and potential drug targets, these screens have also uncovered many previously unknown mechanisms regulating alternative splicing. Here, we describe a method for the identification of alternative splicing regulators using genome-wide RNAi screening, as well as assays for further validation of the identified candidates. With modifications, this method can also be adapted to study the splicing regulation of pre-mRNAs that contain two or more splice isoforms.

Whole genome sequencing of Oryza sativa L. cv. Seeragasamba identifies a new fragrance allele in rice

PubMed Central

Bindusree, Ganigara; Natarajan, Purushothaman; Kalva, Sukesh

2017-01-01

Fragrance of rice is an important trait that confers a large economic benefit to the farmers who cultivate aromatic rice varieties. Several aromatic rice varieties have limited geographic distribution, and are endowed with variety-specific unique fragrances. BADH2 was identified as a fragrance gene in 2005, and it is essential to identify the fragrance alleles from diverse geographical locations and genetic backgrounds. Seeragasamba is a short-grain aromatic rice variety of the indica type, which is cultivated in a limited area in India. Whole genome sequencing of this variety identified a new badh2 allele (badh2-p) with an 8 bp insertion in the promoter region of the BADH2 gene. When the whole genome sequences of 76 aromatic varieties in the 3000 rice genome project were analyzed, the badh2-p allele was present in 13 varieties (approximately 17%) of both indica and japonica types. In addition, the badh2-p allele was present in 17 varieties that already had the loss-of-function allele, badh2-E7. Taken together, the frequency of badh2-p allele (approximately 40%) was found to be greater than that of the badh2-E7 allele (approximately 34%) among the aromatic rice varieties. Therefore, it is suggested to include badh2-p as a predominant allele when screening for fragrance alleles in aromatic rice varieties. PMID:29190814

Sampling the genomic pool of protein tyrosine kinase genes using the polymerase chain reaction with genomic DNA.

PubMed

Oates, A C; Wollberg, P; Achen, M G; Wilks, A F

1998-08-28

The polymerase chain reaction (PCR), with cDNA as template, has been widely used to identify members of protein families from many species. A major limitation of using cDNA in PCR is that detection of a family member is dependent on temporal and spatial patterns of gene expression. To circumvent this restriction, and in order to develop a technique that is broadly applicable we have tested the use of genomic DNA as PCR template to identify members of protein families in an expression-independent manner. This test involved amplification of DNA encoding protein tyrosine kinase (PTK) genes from the genomes of three animal species that are well known development models; namely, the mouse Mus musculus, the fruit fly Drosophila melanogaster, and the nematode worm Caenorhabditis elegans. Ten PTK genes were identified from the mouse, 13 from the fruit fly, and 13 from the nematode worm. Among these kinases were 13 members of the PTK family that had not been reported previously. Selected PTKs from this screen were shown to be expressed during development, demonstrating that the amplified fragments did not arise from pseudogenes. This approach will be useful for the identification of many novel members of gene families in organisms of agricultural, medical, developmental and evolutionary significance and for analysis of gene families from any species, or biological sample whose habitat precludes the isolation of mRNA. Furthermore, as a tool to hasten the discovery of members of gene families that are of particular interest, this method offers an opportunity to sample the genome for new members irrespective of their expression pattern.

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

PubMed Central

van Rheenen, Wouter; Shatunov, Aleksey; Dekker, Annelot M; McLaughlin, Russell L; Diekstra, Frank P; Pulit, Sara L; van der Spek, Rick A A; Võsa, Urmo; de Jong, Simone; Robinson, Matthew R; Yang, Jian; Fogh, Isabella; van Doormaal, Perry TC; Tazelaar, Gijs H P; Koppers, Max; Blokhuis, Anna M; Sproviero, William; Jones, Ashley R; Kenna, Kevin P; van Eijk, Kristel R; Harschnitz, Oliver; Schellevis, Raymond D; Brands, William J; Medic, Jelena; Menelaou, Androniki; Vajda, Alice; Ticozzi, Nicola; Lin, Kuang; Rogelj, Boris; Vrabec, Katarina; Ravnik-Glavač, Metka; Koritnik, Blaž; Zidar, Janez; Leonardis, Lea; Grošelj, Leja Dolenc; Millecamps, Stéphanie; Salachas, François; Meininger, Vincent; de Carvalho, Mamede; Pinto, Susana; Mora, Jesus S; Rojas-García, Ricardo; Polak, Meraida; Chandran, Siddharthan; Colville, Shuna; Swingler, Robert; Morrison, Karen E; Shaw, Pamela J; Hardy, John; Orrell, Richard W; Pittman, Alan; Sidle, Katie; Fratta, Pietro; Malaspina, Andrea; Topp, Simon; Petri, Susanne; Abdulla, Susanne; Drepper, Carsten; Sendtner, Michael; Meyer, Thomas; Ophoff, Roel A; Staats, Kim A; Wiedau-Pazos, Martina; Lomen-Hoerth, Catherine; Van Deerlin, Vivianna M; Trojanowski, John Q; Elman, Lauren; McCluskey, Leo; Basak, A Nazli; Tunca, Ceren; Hamzeiy, Hamid; Parman, Yesim; Meitinger, Thomas; Lichtner, Peter; Radivojkov-Blagojevic, Milena; Andres, Christian R; Maurel, Cindy; Bensimon, Gilbert; Landwehrmeyer, Bernhard; Brice, Alexis; Payan, Christine A M; Saker-Delye, Safaa; Dürr, Alexandra; Wood, Nicholas W; Tittmann, Lukas; Lieb, Wolfgang; Franke, Andre; Rietschel, Marcella; Cichon, Sven; Nöthen, Markus M; Amouyel, Philippe; Tzourio, Christophe; Dartigues, Jean-François; Uitterlinden, Andre G; Rivadeneira, Fernando; Estrada, Karol; Hofman, Albert; Curtis, Charles; Blauw, Hylke M; van der Kooi, Anneke J; de Visser, Marianne; Goris, An; Weber, Markus; Shaw, Christopher E; Smith, Bradley N; Pansarasa, Orietta; Cereda, Cristina; Bo, Roberto Del; Comi, Giacomo P; D’Alfonso, Sandra; Bertolin, Cinzia; Sorarù, Gianni; Mazzini, Letizia; Pensato, Viviana; Gellera, Cinzia; Tiloca, Cinzia; Ratti, Antonia; Calvo, Andrea; Moglia, Cristina; Brunetti, Maura; Arcuti, Simona; Capozzo, Rosa; Zecca, Chiara; Lunetta, Christian; Penco, Silvana; Riva, Nilo; Padovani, Alessandro; Filosto, Massimiliano; Muller, Bernard; Stuit, Robbert Jan; Blair, Ian; Zhang, Katharine; McCann, Emily P; Fifita, Jennifer A; Nicholson, Garth A; Rowe, Dominic B; Pamphlett, Roger; Kiernan, Matthew C; Grosskreutz, Julian; Witte, Otto W; Ringer, Thomas; Prell, Tino; Stubendorff, Beatrice; Kurth, Ingo; Hübner, Christian A; Leigh, P Nigel; Casale, Federico; Chio, Adriano; Beghi, Ettore; Pupillo, Elisabetta; Tortelli, Rosanna; Logroscino, Giancarlo; Powell, John; Ludolph, Albert C; Weishaupt, Jochen H; Robberecht, Wim; Van Damme, Philip; Franke, Lude; Pers, Tune H; Brown, Robert H; Glass, Jonathan D; Landers, John E; Hardiman, Orla; Andersen, Peter M; Corcia, Philippe; Vourc’h, Patrick; Silani, Vincenzo; Wray, Naomi R; Visscher, Peter M; de Bakker, Paul I W; van Es, Michael A; Pasterkamp, R Jeroen; Lewis, Cathryn M; Breen, Gerome; Al-Chalabi, Ammar; van den Berg, Leonard H; Veldink, Jan H

2017-01-01

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk. PMID:27455348

Epigenetics, chromatin and genome organization: recent advances from the ENCODE project.

PubMed

Siggens, L; Ekwall, K

2014-09-01

The organization of the genome into functional units, such as enhancers and active or repressed promoters, is associated with distinct patterns of DNA and histone modifications. The Encyclopedia of DNA Elements (ENCODE) project has advanced our understanding of the principles of genome, epigenome and chromatin organization, identifying hundreds of thousands of potential regulatory regions and transcription factor binding sites. Part of the ENCODE consortium, GENCODE, has annotated the human genome with novel transcripts including new noncoding RNAs and pseudogenes, highlighting transcriptional complexity. Many disease variants identified in genome-wide association studies are located within putative enhancer regions defined by the ENCODE project. Understanding the principles of chromatin and epigenome organization will help to identify new disease mechanisms, biomarkers and drug targets, particularly as ongoing epigenome mapping projects generate data for primary human cell types that play important roles in disease. © 2014 The Association for the Publication of the Journal of Internal Medicine.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

PubMed

Sung, Yun J; Winkler, Thomas W; de Las Fuentes, Lisa; Bentley, Amy R; Brown, Michael R; Kraja, Aldi T; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Kilpeläinen, Tuomas O; Richard, Melissa A; Noordam, Raymond; Aslibekyan, Stella; Aschard, Hugues; Bartz, Traci M; Dorajoo, Rajkumar; Liu, Yongmei; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M; Tayo, Bamidele O; Warren, Helen R; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E; Hartwig, Fernando Pires; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Kühnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; 'an Luan, Jian; McKenzie, Colin A; Meian, He; Nelson, Christopher P; Rauramaa, Rainer; Schupf, Nicole; Scott, Robert A; Sheu, Wayne H H; Stančáková, Alena; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Wang, Heming; Wang, Yajuan; Ware, Erin B; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Alfred, Tamuno; Amin, Najaf; Arking, Dan; Aung, Tin; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Braund, Peter S; Brody, Jennifer A; Broeckel, Ulrich; Cabrera, Claudia P; Cade, Brian; Caizheng, Yu; Campbell, Archie; Canouil, Mickaël; Chakravarti, Aravinda; Chauhan, Ganesh; Christensen, Kaare; Cocca, Massimiliano; Collins, Francis S; Connell, John M; de Mutsert, Renée; de Silva, H Janaka; Debette, Stephanie; Dörr, Marcus; Duan, Qing; Eaton, Charles B; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D; Fisher, Virginia A; Forouhi, Nita G; Franco, Oscar H; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Graff, Misa; Gu, C Charles; Gu, Dongfeng; Gupta, Preeti; Hagenaars, Saskia P; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hofman, Albert; Howard, Barbara V; Hunt, Steven; Irvin, Marguerite R; Jia, Yucheng; Joehanes, Roby; Justice, Anne E; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A; Komulainen, Pirjo; Kooperberg, Charles; Krieger, Jose E; Kubo, Michiaki; Kuusisto, Johanna; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lim, Sing Hui; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Kiang; Liu, Yeheng; Loh, Marie; Lohman, Kurt K; Long, Jirong; Louie, Tin; Mägi, Reedik; Mahajan, Anubha; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Morris, Andrew P; Mosley, Thomas H; Munson, Peter; Murray, Alison D; Nalls, Mike A; Nasri, Ubaydah; Norris, Jill M; North, Kari; Ogunniyi, Adesola; Padmanabhan, Sandosh; Palmas, Walter R; Palmer, Nicholette D; Pankow, James S; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Raitakari, Olli T; Renström, Frida; Rice, Treva K; Ridker, Paul M; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Sabanayagam, Charumathi; Salako, Babatunde L; Sandow, Kevin; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Seshadri, Sudha; Sever, Peter; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; Waldenberger, Melanie; Wang, Lihua; Wang, Ya X; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Chen, Yii-Der Ida; de Faire, Ulf; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Forrester, Terrence; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost B; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Lehtimäki, Terho; Liang, Kae-Woei; Magnusson, Patrik K E; Newman, Anne B; Oldehinkel, Albertine J; Pereira, Alexandre C; Redline, Susan; Rettig, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Kamatani, Yoichiro; Laurie, Cathy C; Bouchard, Claude; Cooper, Richard S; Evans, Michele K; Gudnason, Vilmundur; Kardia, Sharon L R; Kritchevsky, Stephen B; Levy, Daniel; O'Connell, Jeff R; Psaty, Bruce M; van Dam, Rob M; Sims, Mario; Arnett, Donna K; Mook-Kanamori, Dennis O; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; Fornage, Myriam; Rotimi, Charles N; Province, Michael A; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Reiner, Alex P; Rotter, Jerome I; Zhu, Xiaofeng; Bierut, Laura J; Gauderman, W James; Caulfield, Mark J; Elliott, Paul; Rice, Kenneth; Munroe, Patricia B; Morrison, Alanna C; Cupples, L Adrienne; Rao, Dabeeru C; Chasman, Daniel I

2018-03-01

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10 -8 ) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10 -8 ). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2). Copyright © 2018 American Society of Human Genetics. All rights reserved.

A smart way to identify and extract repeated patterns of a layout

NASA Astrophysics Data System (ADS)

Wei, Fang; Gu, Tingting; Chu, Zhihao; Zhang, Chenming; Chen, Han; Zhu, Jun; Hu, Xinyi; Du, Chunshan; Wan, Qijian; Liu, Zhengfang

2018-03-01

As integrated circuits (IC) technology moves forward, manufacturing process is facing more and more challenges. Optical proximity correction (OPC) has been playing an important role in the whole manufacturing process. In the deep sub-micron technology, OPC engineers not only need to guarantee the layout designs to be manufacturable but also take a more precise control of the critical patterns to ensure a high performance circuit. One of the tasks that would like to be performed is the consistency checking as the identical patterns under identical context should have identical OPC results in theory, like SRAM regions. Consistency checking is essentially a technique of repeated patterns identification, extraction and derived patterns (i.e. OPC results) comparison. The layout passing to the OPC team may not have enough design hierarchical information either because the original designs may have undergone several layout processing steps or some other unknown reasons. This paper presents a generic way to identify and extract repeated layout structures in SRAM regions purely based on layout pattern analysis through Calibre Pattern Matching and Calibre equation-based DRC (eqDRC). Without Pattern Matching and eqDRC, it will take lots of effort to manually get it done by trial and error, it is almost impossible to automate the pattern analysis process. Combining Pattern Matching and eqDRC opens a new way to implement this flow. The repeated patterns must have some fundamental features for measurement of pitches in the horizontal and vertical direction separately by Calibre eqDRC and meanwhile can be a helper to generate some anchor points which will be the starting points for Pattern Matching to capture patterns. The informative statistical report from the pattern search tells the match counts individually for each patterns captured. Experiment shows that this is a smart way of identifying and extracting repeated structures effectively. The OPC results are the derived

Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.

PubMed

Mendrzyk, Frank; Radlwimmer, Bernhard; Joos, Stefan; Kokocinski, Felix; Benner, Axel; Stange, Daniel E; Neben, Kai; Fiegler, Heike; Carter, Nigel P; Reifenberger, Guido; Korshunov, Andrey; Lichter, Peter

2005-12-01

Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms. We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival. Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02). We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms.

PubMed

Tashjian, Robert Z; Granger, Erin K; Farnham, James M; Cannon-Albright, Lisa A; Teerlink, Craig C

2016-02-01

The precise etiology of rotator cuff disease is unknown, but prior evidence suggests a role for genetic factors. Limited data exist identifying specific genes associated with rotator cuff tearing. The purpose of this study was to identify specific genes or genetic variants associated with rotator cuff tearing by a genome-wide association study with an independent set of rotator cuff tear cases. A set of 311 full-thickness rotator cuff tear cases genotyped on the Illumina 5M single-nucleotide polymorphism (SNP) platform were used in a genome-wide association study with 2641 genetically matched white population controls available from the Illumina iControls database. Tests of association were performed with GEMMA software at 257,558 SNPs that compose the intersection of Illumina SNP platforms and that passed general quality control metrics. SNPs were considered significant if P < 1.94 × 10(-7) (Bonferroni correction: 0.05/257,558). Tests of association revealed 2 significantly associated SNPs, one occurring in SAP30BP (rs820218; P = 3.8E-9) on chromosome 17q25 and another occurring in SASH1 (rs12527089; P = 1.9E-7) on chromosome 6q24. This study represents the first attempt to identify genetic factors influencing rotator cuff tearing by a genome-wide association study using a dense/complete set of SNPs. Two SNPs were significantly associated with rotator cuff tearing, residing in SAP30BP on chromosome 17 and SASH1 on chromosome 6. Both genes are associated with the cellular process of apoptosis. Identification of potential genes or genetic variants associated with rotator cuff tearing may help in identifying individuals at risk for the development of rotator cuff tearing. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Analysis of evolutionary conservation patterns and their influence on identifying protein functional sites.

PubMed

Fang, Chun; Noguchi, Tamotsu; Yamana, Hayato

2014-10-01

Evolutionary conservation information included in position-specific scoring matrix (PSSM) has been widely adopted by sequence-based methods for identifying protein functional sites, because all functional sites, whether in ordered or disordered proteins, are found to be conserved at some extent. However, different functional sites have different conservation patterns, some of them are linear contextual, some of them are mingled with highly variable residues, and some others seem to be conserved independently. Every value in PSSMs is calculated independently of each other, without carrying the contextual information of residues in the sequence. Therefore, adopting the direct output of PSSM for prediction fails to consider the relationship between conservation patterns of residues and the distribution of conservation scores in PSSMs. In order to demonstrate the importance of combining PSSMs with the specific conservation patterns of functional sites for prediction, three different PSSM-based methods for identifying three kinds of functional sites have been analyzed. Results suggest that, different PSSM-based methods differ in their capability to identify different patterns of functional sites, and better combining PSSMs with the specific conservation patterns of residues would largely facilitate the prediction.

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

PubMed

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

2011-11-01

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

Genome Patterns of Selection and Introgression of Haplotypes in Natural Populations of the House Mouse (Mus musculus)

PubMed Central

Staubach, Fabian; Lorenc, Anna; Messer, Philipp W.; Tang, Kun; Petrov, Dmitri A.; Tautz, Diethard

2012-01-01

General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus) is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP) typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1), homologues of human genes involved in adaptations (e.g. alpha-amylase genes) or in genetic diseases (e.g. Huntingtin and Parkin). Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice may also have

Lessons for livestock genomics from genome and transcriptome sequencing in cattle and other mammals.

PubMed

Taylor, Jeremy F; Whitacre, Lynsey K; Hoff, Jesse L; Tizioto, Polyana C; Kim, JaeWoo; Decker, Jared E; Schnabel, Robert D

2016-08-17

Decreasing sequencing costs and development of new protocols for characterizing global methylation, gene expression patterns and regulatory regions have stimulated the generation of large livestock datasets. Here, we discuss experiences in the analysis of whole-genome and transcriptome sequence data. We analyzed whole-genome sequence (WGS) data from 132 individuals from five canid species (Canis familiaris, C. latrans, C. dingo, C. aureus and C. lupus) and 61 breeds, three bison (Bison bison), 64 water buffalo (Bubalus bubalis) and 297 bovines from 17 breeds. By individual, data vary in extent of reference genome depth of coverage from 4.9X to 64.0X. We have also analyzed RNA-seq data for 580 samples representing 159 Bos taurus and Rattus norvegicus animals and 98 tissues. By aligning reads to a reference assembly and calling variants, we assessed effects of average depth of coverage on the actual coverage and on the number of called variants. We examined the identity of unmapped reads by assembling them and querying produced contigs against the non-redundant nucleic acids database. By imputing high-density single nucleotide polymorphism data on 4010 US registered Angus animals to WGS using Run4 of the 1000 Bull Genomes Project and assessing the accuracy of imputation, we identified misassembled reference sequence regions. We estimate that a 24X depth of coverage is required to achieve 99.5 % coverage of the reference assembly and identify 95 % of the variants within an individual's genome. Genomes sequenced to low average coverage (e.g., <10X) may fail to cover 10 % of the reference genome and identify <75 % of variants. About 10 % of genomic DNA or transcriptome sequence reads fail to align to the reference assembly. These reads include loci missing from the reference assembly and misassembled genes and interesting symbionts, commensal and pathogenic organisms. Assembly errors and a lack of annotation of functional elements significantly limit the utility of

Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer

PubMed Central

Morrison, Carl D.; Liu, Pengyuan; Woloszynska-Read, Anna; Zhang, Jianmin; Luo, Wei; Qin, Maochun; Bshara, Wiam; Conroy, Jeffrey M.; Sabatini, Linda; Vedell, Peter; Xiong, Donghai; Liu, Song; Wang, Jianmin; Shen, He; Li, Yinwei; Omilian, Angela R.; Hill, Annette; Head, Karen; Guru, Khurshid; Kunnev, Dimiter; Leach, Robert; Eng, Kevin H.; Darlak, Christopher; Hoeflich, Christopher; Veeranki, Srividya; Glenn, Sean; You, Ming; Pruitt, Steven C.; Johnson, Candace S.; Trump, Donald L.

2014-01-01

Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as “stitchers,” to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication–licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer. PMID:24469795

Identifying typical patterns of vulnerability: A 5-step approach based on cluster analysis

NASA Astrophysics Data System (ADS)

Sietz, Diana; Lüdeke, Matthias; Kok, Marcel; Lucas, Paul; Carsten, Walther; Janssen, Peter

2013-04-01

Specific processes that shape the vulnerability of socio-ecological systems to climate, market and other stresses derive from diverse background conditions. Within the multitude of vulnerability-creating mechanisms, distinct processes recur in various regions inspiring research on typical patterns of vulnerability. The vulnerability patterns display typical combinations of the natural and socio-economic properties that shape a systems' vulnerability to particular stresses. Based on the identification of a limited number of vulnerability patterns, pattern analysis provides an efficient approach to improving our understanding of vulnerability and decision-making for vulnerability reduction. However, current pattern analyses often miss explicit descriptions of their methods and pay insufficient attention to the validity of their groupings. Therefore, the question arises as to how do we identify typical vulnerability patterns in order to enhance our understanding of a systems' vulnerability to stresses? A cluster-based pattern recognition applied at global and local levels is scrutinised with a focus on an applicable methodology and practicable insights. Taking the example of drylands, this presentation demonstrates the conditions necessary to identify typical vulnerability patterns. They are summarised in five methodological steps comprising the elicitation of relevant cause-effect hypotheses and the quantitative indication of mechanisms as well as an evaluation of robustness, a validation and a ranking of the identified patterns. Reflecting scale-dependent opportunities, a global study is able to support decision-making with insights into the up-scaling of interventions when available funds are limited. In contrast, local investigations encourage an outcome-based validation. This constitutes a crucial step in establishing the credibility of the patterns and hence their suitability for informing extension services and individual decisions. In this respect, working at

Finding functional features in Saccharomyces genomes by phylogenetic footprinting.

PubMed

Cliften, Paul; Sudarsanam, Priya; Desikan, Ashwin; Fulton, Lucinda; Fulton, Bob; Majors, John; Waterston, Robert; Cohen, Barak A; Johnston, Mark

2003-07-04

The sifting and winnowing of DNA sequence that occur during evolution cause nonfunctional sequences to diverge, leaving phylogenetic footprints of functional sequence elements in comparisons of genome sequences. We searched for such footprints among the genome sequences of six Saccharomyces species and identified potentially functional sequences. Comparison of these sequences allowed us to revise the catalog of yeast genes and identify sequence motifs that may be targets of transcriptional regulatory proteins. Some of these conserved sequence motifs reside upstream of genes with similar functional annotations or similar expression patterns or those bound by the same transcription factor and are thus good candidates for functional regulatory sequences.

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation

PubMed Central

Artigas, María Soler; Wain, Louise V.; Miller, Suzanne; Kheirallah, Abdul Kader; Huffman, Jennifer E.; Ntalla, Ioanna; Shrine, Nick; Obeidat, Ma'en; Trochet, Holly; McArdle, Wendy L.; Alves, Alexessander Couto; Hui, Jennie; Zhao, Jing Hua; Joshi, Peter K.; Teumer, Alexander; Albrecht, Eva; Imboden, Medea; Rawal, Rajesh; Lopez, Lorna M.; Marten, Jonathan; Enroth, Stefan; Surakka, Ida; Polasek, Ozren; Lyytikäinen, Leo-Pekka; Granell, Raquel; Hysi, Pirro G.; Flexeder, Claudia; Mahajan, Anubha; Beilby, John; Bossé, Yohan; Brandsma, Corry-Anke; Campbell, Harry; Gieger, Christian; Gläser, Sven; González, Juan R.; Grallert, Harald; Hammond, Chris J.; Harris, Sarah E.; Hartikainen, Anna-Liisa; Heliövaara, Markku; Henderson, John; Hocking, Lynne; Horikoshi, Momoko; Hutri-Kähönen, Nina; Ingelsson, Erik; Johansson, Åsa; Kemp, John P.; Kolcic, Ivana; Kumar, Ashish; Lind, Lars; Melén, Erik; Musk, Arthur W.; Navarro, Pau; Nickle, David C.; Padmanabhan, Sandosh; Raitakari, Olli T.; Ried, Janina S.; Ripatti, Samuli; Schulz, Holger; Scott, Robert A.; Sin, Don D.; Starr, John M.; Deloukas, Panos; Hansell, Anna L.; Hubbard, Richard; Jackson, Victoria E.; Marchini, Jonathan; Pavord, Ian; Thomson, Neil C.; Zeggini, Eleftheria; Viñuela, Ana; Völzke, Henry; Wild, Sarah H.; Wright, Alan F.; Zemunik, Tatijana; Jarvis, Deborah L.; Spector, Tim D.; Evans, David M.; Lehtimäki, Terho; Vitart, Veronique; Kähönen, Mika; Gyllensten, Ulf; Rudan, Igor; Deary, Ian J.; Karrasch, Stefan; Probst-Hensch, Nicole M.; Heinrich, Joachim; Stubbe, Beate; Wilson, James F.; Wareham, Nicholas J.; James, Alan L.; Morris, Andrew P.; Jarvelin, Marjo-Riitta; Hayward, Caroline; Sayers, Ian; Strachan, David P.; Hall, Ian P.; Tobin, Martin D.

2015-01-01

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered. PMID:26635082

Cytoplasmic male sterility-associated chimeric open reading frames identified by mitochondrial genome sequencing of four Cajanus genotypes.

PubMed

Tuteja, Reetu; Saxena, Rachit K; Davila, Jaime; Shah, Trushar; Chen, Wenbin; Xiao, Yong-Li; Fan, Guangyi; Saxena, K B; Alverson, Andrew J; Spillane, Charles; Town, Christopher; Varshney, Rajeev K

2013-10-01

The hybrid pigeonpea (Cajanus cajan) breeding technology based on cytoplasmic male sterility (CMS) is currently unique among legumes and displays major potential for yield increase. CMS is defined as a condition in which a plant is unable to produce functional pollen grains. The novel chimeric open reading frames (ORFs) produced as a results of mitochondrial genome rearrangements are considered to be the main cause of CMS. To identify these CMS-related ORFs in pigeonpea, we sequenced the mitochondrial genomes of three C. cajan lines (the male-sterile line ICPA 2039, the maintainer line ICPB 2039, and the hybrid line ICPH 2433) and of the wild relative (Cajanus cajanifolius ICPW 29). A single, circular-mapping molecule of length 545.7 kb was assembled and annotated for the ICPA 2039 line. Sequence annotation predicted 51 genes, including 34 protein-coding and 17 RNA genes. Comparison of the mitochondrial genomes from different Cajanus genotypes identified 31 ORFs, which differ between lines within which CMS is present or absent. Among these chimeric ORFs, 13 were identified by comparison of the related male-sterile and maintainer lines. These ORFs display features that are known to trigger CMS in other plant species and to represent the most promising candidates for CMS-related mitochondrial rearrangements in pigeonpea.

Cytoplasmic Male Sterility-Associated Chimeric Open Reading Frames Identified by Mitochondrial Genome Sequencing of Four Cajanus Genotypes

PubMed Central

Tuteja, Reetu; Saxena, Rachit K.; Davila, Jaime; Shah, Trushar; Chen, Wenbin; Xiao, Yong-Li; Fan, Guangyi; Saxena, K. B.; Alverson, Andrew J.; Spillane, Charles; Town, Christopher; Varshney, Rajeev K.

2013-01-01

The hybrid pigeonpea (Cajanus cajan) breeding technology based on cytoplasmic male sterility (CMS) is currently unique among legumes and displays major potential for yield increase. CMS is defined as a condition in which a plant is unable to produce functional pollen grains. The novel chimeric open reading frames (ORFs) produced as a results of mitochondrial genome rearrangements are considered to be the main cause of CMS. To identify these CMS-related ORFs in pigeonpea, we sequenced the mitochondrial genomes of three C. cajan lines (the male-sterile line ICPA 2039, the maintainer line ICPB 2039, and the hybrid line ICPH 2433) and of the wild relative (Cajanus cajanifolius ICPW 29). A single, circular-mapping molecule of length 545.7 kb was assembled and annotated for the ICPA 2039 line. Sequence annotation predicted 51 genes, including 34 protein-coding and 17 RNA genes. Comparison of the mitochondrial genomes from different Cajanus genotypes identified 31 ORFs, which differ between lines within which CMS is present or absent. Among these chimeric ORFs, 13 were identified by comparison of the related male-sterile and maintainer lines. These ORFs display features that are known to trigger CMS in other plant species and to represent the most promising candidates for CMS-related mitochondrial rearrangements in pigeonpea. PMID:23792890

Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

PubMed

Guo, Xingyi; Shi, Jiajun; Cai, Qiuyin; Shu, Xiao-Ou; He, Jing; Wen, Wanqing; Allen, Jamie; Pharoah, Paul; Dunning, Alison; Hunter, David J; Kraft, Peter; Easton, Douglas F; Zheng, Wei; Long, Jirong

2018-03-01

Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

WordSeeker: concurrent bioinformatics software for discovering genome-wide patterns and word-based genomic signatures

PubMed Central

2010-01-01

Background An important focus of genomic science is the discovery and characterization of all functional elements within genomes. In silico methods are used in genome studies to discover putative regulatory genomic elements (called words or motifs). Although a number of methods have been developed for motif discovery, most of them lack the scalability needed to analyze large genomic data sets. Methods This manuscript presents WordSeeker, an enumerative motif discovery toolkit that utilizes multi-core and distributed computational platforms to enable scalable analysis of genomic data. A controller task coordinates activities of worker nodes, each of which (1) enumerates a subset of the DNA word space and (2) scores words with a distributed Markov chain model. Results A comprehensive suite of performance tests was conducted to demonstrate the performance, speedup and efficiency of WordSeeker. The scalability of the toolkit enabled the analysis of the entire genome of Arabidopsis thaliana; the results of the analysis were integrated into The Arabidopsis Gene Regulatory Information Server (AGRIS). A public version of WordSeeker was deployed on the Glenn cluster at the Ohio Supercomputer Center. Conclusion WordSeeker effectively utilizes concurrent computing platforms to enable the identification of putative functional elements in genomic data sets. This capability facilitates the analysis of the large quantity of sequenced genomic data. PMID:21210985

Machine Learning Leveraging Genomes from Metagenomes Identifies Influential Antibiotic Resistance Genes in the Infant Gut Microbiome

PubMed Central

Olm, Matthew R.; Morowitz, Michael J.

2018-01-01

ABSTRACT Antibiotic resistance in pathogens is extensively studied, and yet little is known about how antibiotic resistance genes of typical gut bacteria influence microbiome dynamics. Here, we leveraged genomes from metagenomes to investigate how genes of the premature infant gut resistome correspond to the ability of bacteria to survive under certain environmental and clinical conditions. We found that formula feeding impacts the resistome. Random forest models corroborated by statistical tests revealed that the gut resistome of formula-fed infants is enriched in class D beta-lactamase genes. Interestingly, Clostridium difficile strains harboring this gene are at higher abundance in formula-fed infants than C. difficile strains lacking this gene. Organisms with genes for major facilitator superfamily drug efflux pumps have higher replication rates under all conditions, even in the absence of antibiotic therapy. Using a machine learning approach, we identified genes that are predictive of an organism’s direction of change in relative abundance after administration of vancomycin and cephalosporin antibiotics. The most accurate results were obtained by reducing annotated genomic data to five principal components classified by boosted decision trees. Among the genes involved in predicting whether an organism increased in relative abundance after treatment are those that encode subclass B2 beta-lactamases and transcriptional regulators of vancomycin resistance. This demonstrates that machine learning applied to genome-resolved metagenomics data can identify key genes for survival after antibiotics treatment and predict how organisms in the gut microbiome will respond to antibiotic administration. IMPORTANCE The process of reconstructing genomes from environmental sequence data (genome-resolved metagenomics) allows unique insight into microbial systems. We apply this technique to investigate how the antibiotic resistance genes of bacteria affect their ability to

Landscape genomics reveals altered genome wide diversity within revegetated stands of Eucalyptus microcarpa (Grey Box).

PubMed

Jordan, Rebecca; Dillon, Shannon K; Prober, Suzanne M; Hoffmann, Ary A

2016-12-01

In order to contribute to evolutionary resilience and adaptive potential in highly modified landscapes, revegetated areas should ideally reflect levels of genetic diversity within and across natural stands. Landscape genomic analyses enable such diversity patterns to be characterized at genome and chromosomal levels. Landscape-wide patterns of genomic diversity were assessed in Eucalyptus microcarpa, a dominant tree species widely used in revegetation in Southeastern Australia. Trees from small and large patches within large remnants, small isolated remnants and revegetation sites were assessed across the now highly fragmented distribution of this species using the DArTseq genomic approach. Genomic diversity was similar within all three types of remnant patches analysed, although often significantly but only slightly lower in revegetation sites compared with natural remnants. Differences in diversity between stand types varied across chromosomes. Genomic differentiation was higher between small, isolated remnants, and among revegetated sites compared with natural stands. We conclude that small remnants and revegetated sites of our E. microcarpa samples largely but not completely capture patterns in genomic diversity across the landscape. Genomic approaches provide a powerful tool for assessing restoration efforts across the landscape. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Assembly of the draft genome of buckwheat and its applications in identifying agronomically useful genes

PubMed Central

Yasui, Yasuo; Hirakawa, Hideki; Ueno, Mariko; Matsui, Katsuhiro; Katsube-Tanaka, Tomoyuki; Yang, Soo Jung; Aii, Jotaro; Sato, Shingo; Mori, Masashi

2016-01-01

Buckwheat (Fagopyrum esculentum Moench; 2n = 2x = 16) is a nutritionally dense annual crop widely grown in temperate zones. To accelerate molecular breeding programmes of this important crop, we generated a draft assembly of the buckwheat genome using short reads obtained by next-generation sequencing (NGS), and constructed the Buckwheat Genome DataBase. After assembling short reads, we determined 387,594 scaffolds as the draft genome sequence (FES_r1.0). The total length of FES_r1.0 was 1,177,687,305 bp, and the N50 of the scaffolds was 25,109 bp. Gene prediction analysis revealed 286,768 coding sequences (CDSs; FES_r1.0_cds) including those related to transposable elements. The total length of FES_r1.0_cds was 212,917,911 bp, and the N50 was 1,101 bp. Of these, the functions of 35,816 CDSs excluding those for transposable elements were annotated by BLAST analysis. To demonstrate the utility of the database, we conducted several test analyses using BLAST and keyword searches. Furthermore, we used the draft genome as a reference sequence for NGS-based markers, and successfully identified novel candidate genes controlling heteromorphic self-incompatibility of buckwheat. The database and draft genome sequence provide a valuable resource that can be used in efforts to develop buckwheat cultivars with superior agronomic traits. PMID:27037832

Genomic Sequence around Butterfly Wing Development Genes: Annotation and Comparative Analysis

PubMed Central

Conceição, Inês C.; Long, Anthony D.; Gruber, Jonathan D.; Beldade, Patrícia

2011-01-01

Background Analysis of genomic sequence allows characterization of genome content and organization, and access beyond gene-coding regions for identification of functional elements. BAC libraries, where relatively large genomic regions are made readily available, are especially useful for species without a fully sequenced genome and can increase genomic coverage of phylogenetic and biological diversity. For example, no butterfly genome is yet available despite the unique genetic and biological properties of this group, such as diversified wing color patterns. The evolution and development of these patterns is being studied in a few target species, including Bicyclus anynana, where a whole-genome BAC library allows targeted access to large genomic regions. Methodology/Principal Findings We characterize ∼1.3 Mb of genomic sequence around 11 selected genes expressed in B. anynana developing wings. Extensive manual curation of in silico predictions, also making use of a large dataset of expressed genes for this species, identified repetitive elements and protein coding sequence, and highlighted an expansion of Alcohol dehydrogenase genes. Comparative analysis with orthologous regions of the lepidopteran reference genome allowed assessment of conservation of fine-scale synteny (with detection of new inversions and translocations) and of DNA sequence (with detection of high levels of conservation of non-coding regions around some, but not all, developmental genes). Conclusions The general properties and organization of the available B. anynana genomic sequence are similar to the lepidopteran reference, despite the more than 140 MY divergence. Our results lay the groundwork for further studies of new interesting findings in relation to both coding and non-coding sequence: 1) the Alcohol dehydrogenase expansion with higher similarity between the five tandemly-repeated B. anynana paralogs than with the corresponding B. mori orthologs, and 2) the high conservation of non

Contrasting Patterns of Nucleotide Substitution Rates Provide Insight into Dynamic Evolution of Plastid and Mitochondrial Genomes of Geranium

PubMed Central

Park, Seongjun; Ruhlman, Tracey A.; Weng, Mao-Lun; Hajrah, Nahid H.; Sabir, Jamal S.M.

2017-01-01

Abstract Geraniaceae have emerged as a model system for investigating the causes and consequences of variation in plastid and mitochondrial genomes. Incredible structural variation in plastid genomes (plastomes) and highly accelerated evolutionary rates have been reported in selected lineages and functional groups of genes in both plastomes and mitochondrial genomes (mitogenomes), and these phenomena have been implicated in cytonuclear incompatibility. Previous organelle genome studies have included limited sampling of Geranium, the largest genus in the family with over 400 species. This study reports on rates and patterns of nucleotide substitutions in plastomes and mitogenomes of 17 species of Geranium and representatives of other Geraniaceae. As detected across other angiosperms, substitution rates in the plastome are 3.5 times higher than the mitogenome in most Geranium. However, in the branch leading to Geranium brycei/Geranium incanum mitochondrial genes experienced significantly higher dN and dS than plastid genes, a pattern that has only been detected in one other angiosperm. Furthermore, rate accelerations differ in the two organelle genomes with plastomes having increased dN and mitogenomes with increased dS. In the Geranium phaeum/Geranium reflexum clade, duplicate copies of clpP and rpoA genes that experienced asymmetric rate divergence were detected in the single copy region of the plastome. In the case of rpoA, the branch leading to G. phaeum/G. reflexum experienced positive selection or relaxation of purifying selection. Finally, the evolution of acetyl-CoA carboxylase is unusual in Geraniaceae because it is only the second angiosperm family where both prokaryotic and eukaryotic ACCases functionally coexist in the plastid. PMID:28854633

Molluscan Evolutionary Genomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simison, W. Brian; Boore, Jeffrey L.

2005-12-01

In the last 20 years there have been dramatic advances in techniques of high-throughput DNA sequencing, most recently accelerated by the Human Genome Project, a program that has determined the three billion base pair code on which we are based. Now this tremendous capability is being directed at other genome targets that are being sampled across the broad range of life. This opens up opportunities as never before for evolutionary and organismal biologists to address questions of both processes and patterns of organismal change. We stand at the dawn of a new 'modern synthesis' period, paralleling that of the earlymore » 20th century when the fledgling field of genetics first identified the underlying basis for Darwin's theory. We must now unite the efforts of systematists, paleontologists, mathematicians, computer programmers, molecular biologists, developmental biologists, and others in the pursuit of discovering what genomics can teach us about the diversity of life. Genome-level sampling for mollusks to date has mostly been limited to mitochondrial genomes and it is likely that these will continue to provide the best targets for broad phylogenetic sampling in the near future. However, we are just beginning to see an inroad into complete nuclear genome sequencing, with several mollusks and other eutrochozoans having been selected for work about to begin. Here, we provide an overview of the state of molluscan mitochondrial genomics, highlight a few of the discoveries from this research, outline the promise of broadening this dataset, describe upcoming projects to sequence whole mollusk nuclear genomes, and challenge the community to prepare for making the best use of these data.« less

Condensation patterns of prophase/prometaphase chromosome are correlated with H4K5 histone acetylation and genomic DNA contents in plants.

PubMed

Feitoza, Lidiane; Costa, Lucas; Guerra, Marcelo

2017-01-01

Mitotic prophase chromosome condensation plays an essential role in nuclear division being therefore regulated by highly conserved mechanisms. However, degrees of chromatin condensation in prophase-prometaphase cells may vary along the chromosomes resulting in specific condensation patterns. We examined different condensation patterns (CPs) of prophase and prometaphase chromosomes and investigated their relationship with genome size and distribution of histone H4 acetylated at lysine 5 (H4K5ac) in 17 plant species. Our results showed that most species with small genomes (2C < 5 pg) (Arachis pusilla, Bixa orellana, Costus spiralis, Eleutherine bulbosa, Indigofera campestris, Phaseolus lunatus, P. vulgaris, Poncirus trifoliata, and Solanum lycopersicum) displayed prophase chromosomes with late condensing terminal regions that were highly enriched in H4K5ac, and early condensing regions with apparently non-acetylated proximal chromatin. The species with large genomes (Allium cepa, Callisia repens, Araucaria angustifolia and Nothoscordum pulchellum) displayed uniformly condensed and acetylated prophase/prometaphase chromosomes. Three species with small genomes (Eleocharis geniculata, Rhynchospora pubera, and R. tenuis) displayed CP and H4K5ac labeling patterns similar to species with large genomes, whereas a forth species (Emilia sonchifolia) exhibited a gradual chromosome labeling, being more acetylated in the terminal regions and less acetylated in the proximal ones. The nucleolus organizer chromatin was the only chromosomal region that in prometaphase or metaphase could be hyperacetylated, hypoacetylated or non-acetylated, depending on the species. Our data indicate that the CP of a plant chromosome complement is influenced but not exclusively determined by nuclear and chromosomal DNA contents, whereas the CP of individual chromosomes is clearly correlated with H4K5ac distribution.

Condensation patterns of prophase/prometaphase chromosome are correlated with H4K5 histone acetylation and genomic DNA contents in plants

PubMed Central

Feitoza, Lidiane; Costa, Lucas

2017-01-01

Mitotic prophase chromosome condensation plays an essential role in nuclear division being therefore regulated by highly conserved mechanisms. However, degrees of chromatin condensation in prophase-prometaphase cells may vary along the chromosomes resulting in specific condensation patterns. We examined different condensation patterns (CPs) of prophase and prometaphase chromosomes and investigated their relationship with genome size and distribution of histone H4 acetylated at lysine 5 (H4K5ac) in 17 plant species. Our results showed that most species with small genomes (2C < 5 pg) (Arachis pusilla, Bixa orellana, Costus spiralis, Eleutherine bulbosa, Indigofera campestris, Phaseolus lunatus, P. vulgaris, Poncirus trifoliata, and Solanum lycopersicum) displayed prophase chromosomes with late condensing terminal regions that were highly enriched in H4K5ac, and early condensing regions with apparently non-acetylated proximal chromatin. The species with large genomes (Allium cepa, Callisia repens, Araucaria angustifolia and Nothoscordum pulchellum) displayed uniformly condensed and acetylated prophase/prometaphase chromosomes. Three species with small genomes (Eleocharis geniculata, Rhynchospora pubera, and R. tenuis) displayed CP and H4K5ac labeling patterns similar to species with large genomes, whereas a forth species (Emilia sonchifolia) exhibited a gradual chromosome labeling, being more acetylated in the terminal regions and less acetylated in the proximal ones. The nucleolus organizer chromatin was the only chromosomal region that in prometaphase or metaphase could be hyperacetylated, hypoacetylated or non-acetylated, depending on the species. Our data indicate that the CP of a plant chromosome complement is influenced but not exclusively determined by nuclear and chromosomal DNA contents, whereas the CP of individual chromosomes is clearly correlated with H4K5ac distribution. PMID:28854212

Use of a draft genome of coffee (Coffea arabica) to identify SNPs associated with caffeine content.

PubMed

Tran, Hue T M; Ramaraj, Thiruvarangan; Furtado, Agnelo; Lee, Leonard Slade; Henry, Robert J

2018-03-07

Arabica coffee (Coffea arabica) has a small gene pool limiting genetic improvement. Selection for caffeine content within this gene pool would be assisted by identification of the genes controlling this important trait. Sequencing of DNA bulks from 18 genotypes with extreme high- or low-caffeine content from a population of 232 genotypes was used to identify linked polymorphisms. To obtain a reference genome, a whole genome assembly of arabica coffee (variety K7) was achieved by sequencing using short read (Illumina) and long-read (PacBio) technology. Assembly was performed using a range of assembly tools resulting in 76 409 scaffolds with a scaffold N50 of 54 544 bp and a total scaffold length of 1448 Mb. Validation of the genome assembly using different tools showed high completeness of the genome. More than 99% of transcriptome sequences mapped to the C. arabica draft genome, and 89% of BUSCOs were present. The assembled genome annotated using AUGUSTUS yielded 99 829 gene models. Using the draft arabica genome as reference in mapping and variant calling allowed the detection of 1444 nonsynonymous single nucleotide polymorphisms (SNPs) associated with caffeine content. Based on Kyoto Encyclopaedia of Genes and Genomes pathway-based analysis, 65 caffeine-associated SNPs were discovered, among which 11 SNPs were associated with genes encoding enzymes involved in the conversion of substrates, which participate in the caffeine biosynthesis pathways. This analysis demonstrated the complex genetic control of this key trait in coffee. © 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Genomic analysis identifies masqueraders of full-term cerebral palsy.

PubMed

Takezawa, Yusuke; Kikuchi, Atsuo; Haginoya, Kazuhiro; Niihori, Tetsuya; Numata-Uematsu, Yurika; Inui, Takehiko; Yamamura-Suzuki, Saeko; Miyabayashi, Takuya; Anzai, Mai; Suzuki-Muromoto, Sato; Okubo, Yukimune; Endo, Wakaba; Togashi, Noriko; Kobayashi, Yasuko; Onuma, Akira; Funayama, Ryo; Shirota, Matsuyuki; Nakayama, Keiko; Aoki, Yoko; Kure, Shigeo

2018-05-01

Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full-term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders. A total of 107 patients-all full-term births-without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole-exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1 , CYP2U1 , SPAST , GNAO1 , CACNA1A , AMPD2 , STXBP1 , and SCN2A . Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice-site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments. The high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full-term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy.

The genomic evolution of H1 influenza A viruses from swine detected in the United States between 2009 and 2016.

PubMed

Gao, Shibo; Anderson, Tavis K; Walia, Rasna R; Dorman, Karin S; Janas-Martindale, Alicia; Vincent, Amy L

2017-08-01

Transmission of influenza A virus (IAV) from humans to swine occurs with relative frequency and is a critical contributor to swine IAV diversity. Subsequent to the introduction of these human seasonal lineages, there is often reassortment with endemic viruses and antigenic drift. To address whether particular genome constellations contributed to viral persistence following the introduction of the 2009 H1N1 human pandemic virus to swine in the USA, we collated and analysed 616 whole genomes of swine H1 isolates. For each gene, sequences were aligned, the best-known maximum likelihood phylogeny was inferred, and each virus was assigned a clade based upon its evolutionary history. A time-scaled Bayesian approach was implemented for the haemagglutinin (HA) gene to determine the patterns of genetic diversity over time. From these analyses, we observed an increase in genome diversity across all H1 lineages and clades, with the H1-γ and H1-δ1 genetic clades containing the greatest number of unique genome patterns. We documented 74 genome patterns from 2009 to 2016, of which 3 genome patterns were consistently detected at a significantly higher level than others across the entire time period. Eight genome patterns increased significantly, while five genome patterns were shown to decline in detection over time. Viruses with genome patterns identified as persisting in the US swine population may possess a greater capacity to infect and transmit in swine. This study highlights the emerging genetic diversity of US swine IAV from 2009 to 2016, with implications for swine and public health and vaccine control efforts.

Copy Number Variations in Tilapia Genomes.

PubMed

Li, Bi Jun; Li, Hong Lian; Meng, Zining; Zhang, Yong; Lin, Haoran; Yue, Gen Hua; Xia, Jun Hong

2017-02-01

Discovering the nature and pattern of genome variation is fundamental in understanding phenotypic diversity among populations. Although several millions of single nucleotide polymorphisms (SNPs) have been discovered in tilapia, the genome-wide characterization of larger structural variants, such as copy number variation (CNV) regions has not been carried out yet. We conducted a genome-wide scan for CNVs in 47 individuals from three tilapia populations. Based on 254 Gb of high-quality paired-end sequencing reads, we identified 4642 distinct high-confidence CNVs. These CNVs account for 1.9% (12.411 Mb) of the used Nile tilapia reference genome. A total of 1100 predicted CNVs were found overlapping with exon regions of protein genes. Further association analysis based on linear model regression found 85 CNVs ranging between 300 and 27,000 base pairs significantly associated to population types (R 2  > 0.9 and P > 0.001). Our study sheds first insights on genome-wide CNVs in tilapia. These CNVs among and within tilapia populations may have functional effects on phenotypes and specific adaptation to particular environments.

Genome comparison of two Magnaporthe oryzae field isolates reveals genome variations and potential virulence effectors

PubMed Central

2013-01-01

Background Rice blast caused by the fungus Magnaporthe oryzae is an important disease in virtually every rice growing region of the world, which leads to significant annual decreases of grain quality and yield. To prevent disease, resistance genes in rice have been cloned and introduced into susceptible cultivars. However, introduced resistance can often be broken within few years of release, often due to mutation of cognate avirulence genes in fungal field populations. Results To better understand the pattern of mutation of M. oryzae field isolates under natural selection forces, we used a next generation sequencing approach to analyze the genomes of two field isolates FJ81278 and HN19311, as well as the transcriptome of FJ81278. By comparing the de novo genome assemblies of the two isolates against the finished reference strain 70–15, we identified extensive polymorphisms including unique genes, SNPs (single nucleotide polymorphism) and indels, structural variations, copy number variations, and loci under strong positive selection. The 1.75 MB of isolate-specific genome content carrying 118 novel genes from FJ81278, and 0.83 MB from HN19311 were also identified. By analyzing secreted proteins carrying polymorphisms, in total 256 candidate virulence effectors were found and 6 were chosen for functional characterization. Conclusions We provide results from genome comparison analysis showing extensive genome variation, and generated a list of M. oryzae candidate virulence effectors for functional characterization. PMID:24341723

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

USDA-ARS?s Scientific Manuscript database

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...

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin

PubMed Central

Troggio, Michela; Šurbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the ‘Golden Delicious’ genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies. PMID:23826289

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin.

PubMed

Troggio, Michela; Surbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the 'Golden Delicious' genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies.

Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer. | Office of Cancer Genomics

Cancer.gov

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low passage tumor cells derived from a patient with a treatmentresistant HPV-negative HNSCC.

Comparative whole genome DNA methylation profiling of cattle sperm and somatic tissues reveals striking hypomethylated patterns in sperm

USDA-ARS?s Scientific Manuscript database

Using whole-genome bisulfite sequencing (WGBS), we profiled the DNA methylome of cattle sperms through comparison with three bovine somatic tissues (mammary grand, brain and blood). Large differences between them were observed in the methylation patterns of global CpGs, pericentromeric satellites, p...

ChIP-Seq Analysis for Identifying Genome-Wide Histone Modifications Associated with Stress-Responsive Genes in Plants.

PubMed

Li, Guosheng; Jagadeeswaran, Guru; Mort, Andrew; Sunkar, Ramanjulu

2017-01-01

Histone modifications represent the crux of epigenetic gene regulation essential for most biological processes including abiotic stress responses in plants. Thus, identification of histone modifications at the genome-scale can provide clues for how some genes are 'turned-on' while some others are "turned-off" in response to stress. This chapter details a step-by-step protocol for identifying genome-wide histone modifications associated with stress-responsive gene regulation using chromatin immunoprecipitation (ChIP) followed by sequencing of the DNA (ChIP-seq).

The Chloroplast Genome of Pellia endiviifolia: Gene Content, RNA-Editing Pattern, and the Origin of Chloroplast Editing

PubMed Central

Grosche, Christopher; Funk, Helena T.; Maier, Uwe G.; Zauner, Stefan

2012-01-01

RNA editing is a post-transcriptional process that can act upon transcripts from mitochondrial, nuclear, and chloroplast genomes. In chloroplasts, single-nucleotide conversions in mRNAs via RNA editing occur at different frequencies across the plant kingdom. These range from several hundred edited sites in some mosses and ferns to lower frequencies in seed plants and the complete lack of RNA editing in the liverwort Marchantia polymorpha. Here, we report the sequence and edited sites of the chloroplast genome from the liverwort Pellia endiviifolia. The type and frequency of chloroplast RNA editing display a pattern highly similar to that in seed plants. Analyses of the C to U conversions and the genomic context in which the editing sites are embedded provide evidence in favor of the hypothesis that chloroplast RNA editing evolved to compensate mutations in the first land plants. PMID:23221608

Genome-wide association study identifies a locus associated with rotator cuff injury

PubMed Central

Roos, Thomas R.; Roos, Andrew K.; Avins, Andrew L.; Ahmed, Marwa A.; Kleimeyer, John P.; Fredericson, Michael; Ioannidis, John P. A.; Dragoo, Jason L.

2017-01-01

Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome-wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31x10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others. PMID:29228018

AGAPE (Automated Genome Analysis PipelinE) for Pan-Genome Analysis of Saccharomyces cerevisiae

PubMed Central

Song, Giltae; Dickins, Benjamin J. A.; Demeter, Janos; Engel, Stacia; Dunn, Barbara; Cherry, J. Michael

2015-01-01

The characterization and public release of genome sequences from thousands of organisms is expanding the scope for genetic variation studies. However, understanding the phenotypic consequences of genetic variation remains a challenge in eukaryotes due to the complexity of the genotype-phenotype map. One approach to this is the intensive study of model systems for which diverse sources of information can be accumulated and integrated. Saccharomyces cerevisiae is an extensively studied model organism, with well-known protein functions and thoroughly curated phenotype data. To develop and expand the available resources linking genomic variation with function in yeast, we aim to model the pan-genome of S. cerevisiae. To initiate the yeast pan-genome, we newly sequenced or re-sequenced the genomes of 25 strains that are commonly used in the yeast research community using advanced sequencing technology at high quality. We also developed a pipeline for automated pan-genome analysis, which integrates the steps of assembly, annotation, and variation calling. To assign strain-specific functional annotations, we identified genes that were not present in the reference genome. We classified these according to their presence or absence across strains and characterized each group of genes with known functional and phenotypic features. The functional roles of novel genes not found in the reference genome and associated with strains or groups of strains appear to be consistent with anticipated adaptations in specific lineages. As more S. cerevisiae strain genomes are released, our analysis can be used to collate genome data and relate it to lineage-specific patterns of genome evolution. Our new tool set will enhance our understanding of genomic and functional evolution in S. cerevisiae, and will be available to the yeast genetics and molecular biology community. PMID:25781462

OrthoMCL: Identification of Ortholog Groups for Eukaryotic Genomes

PubMed Central

Li, Li; Stoeckert, Christian J.; Roos, David S.

2003-01-01

The identification of orthologous groups is useful for genome annotation, studies on gene/protein evolution, comparative genomics, and the identification of taxonomically restricted sequences. Methods successfully exploited for prokaryotic genome analysis have proved difficult to apply to eukaryotes, however, as larger genomes may contain multiple paralogous genes, and sequence information is often incomplete. OrthoMCL provides a scalable method for constructing orthologous groups across multiple eukaryotic taxa, using a Markov Cluster algorithm to group (putative) orthologs and paralogs. This method performs similarly to the INPARANOID algorithm when applied to two genomes, but can be extended to cluster orthologs from multiple species. OrthoMCL clusters are coherent with groups identified by EGO, but improved recognition of “recent” paralogs permits overlapping EGO groups representing the same gene to be merged. Comparison with previously assigned EC annotations suggests a high degree of reliability, implying utility for automated eukaryotic genome annotation. OrthoMCL has been applied to the proteome data set from seven publicly available genomes (human, fly, worm, yeast, Arabidopsis, the malaria parasite Plasmodium falciparum, and Escherichia coli). A Web interface allows queries based on individual genes or user-defined phylogenetic patterns (http://www.cbil.upenn.edu/gene-family). Analysis of clusters incorporating P. falciparum genes identifies numerous enzymes that were incompletely annotated in first-pass annotation of the parasite genome. PMID:12952885

Structural and functional insights of β-glucosidases identified from the genome of Aspergillus fumigatus

NASA Astrophysics Data System (ADS)

Dodda, Subba Reddy; Aich, Aparajita; Sarkar, Nibedita; Jain, Piyush; Jain, Sneha; Mondal, Sudipa; Aikat, Kaustav; Mukhopadhyay, Sudit S.

2018-03-01

Thermostable glucose tolerant β-glucosidase from Aspergillus species has attracted worldwide interest for their potentiality in industrial applications and bioethanol production. A strain of Aspergillus fumigatus (AfNITDGPKA3) identified by our laboratory from straw retting ground showed higher cellulase activity, specifically the β-glucosidase activity, compared to other contemporary strains. Though A. fumigatus has been known for high cellulase activity, detailed identification and characterization of the cellulase genes from their genome is yet to be done. In this work we have been analyzed the cellulase genes from the genome sequence database of Aspergillus fumigatus (Af293). Genome analysis suggests two cellobiohydrolase, eleven endoglucanase and seventeen β-glucosidase genes present. β-Glucosidase genes belong to either Glycohydro1 (GH1 or Bgl1) or Glycohydro3 (GH3 or Bgl3) family. The sequence similarity suggests that Bgl1 and Bgl3 of A. fumagatus are phylogenetically close to those of A. fisheri and A. oryzae. The modelled structure of the Bgl1 predicts the (β/α)8 barrel type structure with deep and narrow active site, whereas, Bgl3 shows the (α/β)8 barrel and (α/β)6 sandwich structure with shallow and open active site. Docking results suggest that amino acids Glu544, Glu466, Trp408,Trp567,Tyr44,Tyr222,Tyr770,Asp844,Asp537,Asn212,Asn217 of Bgl3 and Asp224,Asn242,Glu440, Glu445, Tyr367, Tyr365,Thr994,Trp435,Trp446 of Bgl1 are involved in the hydrolysis. Binding affinity analyses suggest that Bgl3 and Bgl1 enzymes are more active on the substrates like 4-methylumbelliferyl glycoside (MUG) and p-nitrophenyl-β-D-1, 4-glucopyranoside (pNPG) than on cellobiose. Further docking with glucose suggests that Bgl1 is more glucose tolerant than Bgl3. Analysis of the Aspergillus fumigatus genome may help to identify a β-glucosidase enzyme with better property and the structural information may help to develop an engineered recombinant enzyme.

Genomic and Transcriptomic Associations Identify a New Insecticide Resistance Phenotype for the Selective Sweep at the Cyp6g1 Locus of Drosophila melanogaster.

PubMed

Battlay, Paul; Schmidt, Joshua M; Fournier-Level, Alexandre; Robin, Charles

2016-08-09

Scans of the Drosophila melanogaster genome have identified organophosphate resistance loci among those with the most pronounced signature of positive selection. In this study, the molecular basis of resistance to the organophosphate insecticide azinphos-methyl was investigated using the Drosophila Genetic Reference Panel, and genome-wide association. Recently released full transcriptome data were used to extend the utility of the Drosophila Genetic Reference Panel resource beyond traditional genome-wide association studies to allow systems genetics analyses of phenotypes. We found that both genomic and transcriptomic associations independently identified Cyp6g1, a gene involved in resistance to DDT and neonicotinoid insecticides, as the top candidate for azinphos-methyl resistance. This was verified by transgenically overexpressing Cyp6g1 using natural regulatory elements from a resistant allele, resulting in a 6.5-fold increase in resistance. We also identified four novel candidate genes associated with azinphos-methyl resistance, all of which are involved in either regulation of fat storage, or nervous system development. In Cyp6g1, we find a demonstrable resistance locus, a verification that transcriptome data can be used to identify variants associated with insecticide resistance, and an overlap between peaks of a genome-wide association study, and a genome-wide selective sweep analysis. Copyright © 2016 Battlay et al.

Comparison of gene expression in segregating families identifies genes and genomic regions involved in a novel adaptation, zinc hyperaccumulation.

PubMed

Filatov, Victor; Dowdle, John; Smirnoff, Nicholas; Ford-Lloyd, Brian; Newbury, H John; Macnair, Mark R

2006-09-01

One of the challenges of comparative genomics is to identify specific genetic changes associated with the evolution of a novel adaptation or trait. We need to be able to disassociate the genes involved with a particular character from all the other genetic changes that take place as lineages diverge. Here we show that by comparing the transcriptional profile of segregating families with that of parent species differing in a novel trait, it is possible to narrow down substantially the list of potential target genes. In addition, by assuming synteny with a related model organism for which the complete genome sequence is available, it is possible to use the cosegregation of markers differing in transcription level to identify regions of the genome which probably contain quantitative trait loci (QTLs) for the character. This novel combination of genomics and classical genetics provides a very powerful tool to identify candidate genes. We use this methodology to investigate zinc hyperaccumulation in Arabidopsis halleri, the sister species to the model plant, Arabidopsis thaliana. We compare the transcriptional profile of A. halleri with that of its sister nonaccumulator species, Arabidopsis petraea, and between accumulator and nonaccumulator F(3)s derived from the cross between the two species. We identify eight genes which consistently show greater expression in accumulator phenotypes in both roots and shoots, including two metal transporter genes (NRAMP3 and ZIP6), and cytoplasmic aconitase, a gene involved in iron homeostasis in mammals. We also show that there appear to be two QTLs for zinc accumulation, on chromosomes 3 and 7.

Microfluidic screening and whole-genome sequencing identifies mutations associated with improved protein secretion by yeast.

PubMed

Huang, Mingtao; Bai, Yunpeng; Sjostrom, Staffan L; Hallström, Björn M; Liu, Zihe; Petranovic, Dina; Uhlén, Mathias; Joensson, Haakan N; Andersson-Svahn, Helene; Nielsen, Jens

2015-08-25

There is an increasing demand for biotech-based production of recombinant proteins for use as pharmaceuticals in the food and feed industry and in industrial applications. Yeast Saccharomyces cerevisiae is among preferred cell factories for recombinant protein production, and there is increasing interest in improving its protein secretion capacity. Due to the complexity of the secretory machinery in eukaryotic cells, it is difficult to apply rational engineering for construction of improved strains. Here we used high-throughput microfluidics for the screening of yeast libraries, generated by UV mutagenesis. Several screening and sorting rounds resulted in the selection of eight yeast clones with significantly improved secretion of recombinant α-amylase. Efficient secretion was genetically stable in the selected clones. We performed whole-genome sequencing of the eight clones and identified 330 mutations in total. Gene ontology analysis of mutated genes revealed many biological processes, including some that have not been identified before in the context of protein secretion. Mutated genes identified in this study can be potentially used for reverse metabolic engineering, with the objective to construct efficient cell factories for protein secretion. The combined use of microfluidics screening and whole-genome sequencing to map the mutations associated with the improved phenotype can easily be adapted for other products and cell types to identify novel engineering targets, and this approach could broadly facilitate design of novel cell factories.

A Bioinformatics Approach for Detecting Repetitive Nested Motifs using Pattern Matching.

PubMed

Romero, José R; Carballido, Jessica A; Garbus, Ingrid; Echenique, Viviana C; Ponzoni, Ignacio

2016-01-01

The identification of nested motifs in genomic sequences is a complex computational problem. The detection of these patterns is important to allow the discovery of transposable element (TE) insertions, incomplete reverse transcripts, deletions, and/or mutations. In this study, a de novo strategy for detecting patterns that represent nested motifs was designed based on exhaustive searches for pairs of motifs and combinatorial pattern analysis. These patterns can be grouped into three categories, motifs within other motifs, motifs flanked by other motifs, and motifs of large size. The methodology used in this study, applied to genomic sequences from the plant species Aegilops tauschii and Oryza sativa , revealed that it is possible to identify putative nested TEs by detecting these three types of patterns. The results were validated through BLAST alignments, which revealed the efficacy and usefulness of the new method, which is called Mamushka.

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.

PubMed

Kim, Young Jin; Go, Min Jin; Hu, Cheng; Hong, Chang Bum; Kim, Yun Kyoung; Lee, Ji Young; Hwang, Joo-Yeon; Oh, Ji Hee; Kim, Dong-Joon; Kim, Nam Hee; Kim, Soeui; Hong, Eun Jung; Kim, Ji-Hyun; Min, Haesook; Kim, Yeonjung; Zhang, Rong; Jia, Weiping; Okada, Yukinori; Takahashi, Atsushi; Kubo, Michiaki; Tanaka, Toshihiro; Kamatani, Naoyuki; Matsuda, Koichi; Park, Taesung; Oh, Bermseok; Kimm, Kuchan; Kang, Daehee; Shin, Chol; Cho, Nam H; Kim, Hyung-Lae; Han, Bok-Ghee; Lee, Jong-Young; Cho, Yoon Shin

2011-09-11

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

Assembly of the draft genome of buckwheat and its applications in identifying agronomically useful genes.

PubMed

Yasui, Yasuo; Hirakawa, Hideki; Ueno, Mariko; Matsui, Katsuhiro; Katsube-Tanaka, Tomoyuki; Yang, Soo Jung; Aii, Jotaro; Sato, Shingo; Mori, Masashi

2016-06-01

Buckwheat (Fagopyrum esculentum Moench; 2n = 2x = 16) is a nutritionally dense annual crop widely grown in temperate zones. To accelerate molecular breeding programmes of this important crop, we generated a draft assembly of the buckwheat genome using short reads obtained by next-generation sequencing (NGS), and constructed the Buckwheat Genome DataBase. After assembling short reads, we determined 387,594 scaffolds as the draft genome sequence (FES_r1.0). The total length of FES_r1.0 was 1,177,687,305 bp, and the N50 of the scaffolds was 25,109 bp. Gene prediction analysis revealed 286,768 coding sequences (CDSs; FES_r1.0_cds) including those related to transposable elements. The total length of FES_r1.0_cds was 212,917,911 bp, and the N50 was 1,101 bp. Of these, the functions of 35,816 CDSs excluding those for transposable elements were annotated by BLAST analysis. To demonstrate the utility of the database, we conducted several test analyses using BLAST and keyword searches. Furthermore, we used the draft genome as a reference sequence for NGS-based markers, and successfully identified novel candidate genes controlling heteromorphic self-incompatibility of buckwheat. The database and draft genome sequence provide a valuable resource that can be used in efforts to develop buckwheat cultivars with superior agronomic traits. © The Author 2016. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Genome Surfing As Driver of Microbial Genomic Diversity.

PubMed

Choudoir, Mallory J; Panke-Buisse, Kevin; Andam, Cheryl P; Buckley, Daniel H

2017-08-01

Historical changes in population size, such as those caused by demographic range expansions, can produce nonadaptive changes in genomic diversity through mechanisms such as gene surfing. We propose that demographic range expansion of a microbial population capable of horizontal gene exchange can result in genome surfing, a mechanism that can cause widespread increase in the pan-genome frequency of genes acquired by horizontal gene exchange. We explain that patterns of genetic diversity within Streptomyces are consistent with genome surfing, and we describe several predictions for testing this hypothesis both in Streptomyces and in other microorganisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

The First Endogenous Herpesvirus, Identified in the Tarsier Genome, and Novel Sequences from Primate Rhadinoviruses and Lymphocryptoviruses

PubMed Central

Aswad, Amr; Katzourakis, Aris

2014-01-01

Herpesviridae is a diverse family of large and complex pathogens whose genomes are extremely difficult to sequence. This is particularly true for clinical samples, and if the virus, host, or both genomes are being sequenced for the first time. Although herpesviruses are known to occasionally integrate in host genomes, and can also be inherited in a Mendelian fashion, they are notably absent from the genomic fossil record comprised of endogenous viral elements (EVEs). Here, we combine paleovirological and metagenomic approaches to both explore the constituent viral diversity of mammalian genomes and search for endogenous herpesviruses. We describe the first endogenous herpesvirus from the genome of the Philippine tarsier, belonging to the Roseolovirus genus, and characterize its highly defective genome that is integrated and flanked by unambiguous host DNA. From a draft assembly of the aye-aye genome, we use bioinformatic tools to reveal over 100,000 bp of a novel rhadinovirus that is the first lemur gammaherpesvirus, closely related to Kaposi's sarcoma-associated virus. We also identify 58 genes of Pan paniscus lymphocryptovirus 1, the bonobo equivalent of human Epstein-Barr virus. For each of the viruses, we postulate gene function via comparative analysis to known viral relatives. Most notably, the evidence from gene content and phylogenetics suggests that the aye-aye sequences represent the most basal known rhadinovirus, and indicates that tumorigenic herpesviruses have been infecting primates since their emergence in the late Cretaceous. Overall, these data show that a genomic fossil record of herpesviruses exists despite their extremely large genomes, and expands the known diversity of Herpesviridae, which will aid the characterization of pathogenesis. Our analytical approach illustrates the benefit of intersecting evolutionary approaches with metagenomics, genetics and paleovirology. PMID:24945689

Genome-wide analysis of the WRKY transcription factors in aegilops tauschii.

PubMed

Ma, Jianhui; Zhang, Daijing; Shao, Yun; Liu, Pei; Jiang, Lina; Li, Chunxi

2014-01-01

The WRKY transcription factors (TFs) play important roles in responding to abiotic and biotic stress in plants. However, due to its unfinished genome sequencing, relatively few WRKY TFs with full-length coding sequences (CDSs) have been identified in wheat. Instead, the Aegilops tauschii genome, which is the D-genome progenitor of the hexaploid wheat genome, provides important resources for the discovery of new genes. In this study, we performed a bioinformatics analysis to identify WRKY TFs with full-length CDSs from the A. tauschii genome. A detailed evolutionary analysis for all these TFs was conducted, and quantitative real-time PCR was carried out to investigate the expression patterns of the abiotic stress-related WRKY TFs under different abiotic stress conditions in A. tauschii seedlings. A total of 93 WRKY TFs were identified from A. tauschii, and 79 of them were found to be newly discovered genes compared with wheat. Gene phylogeny, gene structure and chromosome location of the 93 WRKY TFs were fully analyzed. These studies provide a global view of the WRKY TFs from A. tauschii and a firm foundation for further investigations in both A. tauschii and wheat. © 2015 S. Karger AG, Basel.

Population-scale whole genome sequencing identifies 271 highly polymorphic short tandem repeats from Japanese population.

PubMed

Hirata, Satoshi; Kojima, Kaname; Misawa, Kazuharu; Gervais, Olivier; Kawai, Yosuke; Nagasaki, Masao

2018-05-01

Forensic DNA typing is widely used to identify missing persons and plays a central role in forensic profiling. DNA typing usually uses capillary electrophoresis fragment analysis of PCR amplification products to detect the length of short tandem repeat (STR) markers. Here, we analyzed whole genome data from 1,070 Japanese individuals generated using massively parallel short-read sequencing of 162 paired-end bases. We have analyzed 843,473 STR loci with two to six basepair repeat units and cataloged highly polymorphic STR loci in the Japanese population. To evaluate the performance of the cataloged STR loci, we compared 23 STR loci, widely used in forensic DNA typing, with capillary electrophoresis based STR genotyping results in the Japanese population. Seventeen loci had high correlations and high call rates. The other six loci had low call rates or low correlations due to either the limitations of short-read sequencing technology, the bioinformatics tool used, or the complexity of repeat patterns. With these analyses, we have also purified the suitable 218 STR loci with four basepair repeat units and 53 loci with five basepair repeat units both for short read sequencing and PCR based technologies, which would be candidates to the actual forensic DNA typing in Japanese population.

Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility

PubMed Central

Cook, James P; Morris, Andrew P

2016-01-01

Genome-wide association studies (GWAS) have traditionally been undertaken in homogeneous populations from the same ancestry group. However, with the increasing availability of GWAS in large-scale multi-ethnic cohorts, we have evaluated a framework for detecting association of genetic variants with complex traits, allowing for population structure, and developed a powerful test of heterogeneity in allelic effects between ancestry groups. We have applied the methodology to identify and characterise loci associated with susceptibility to type 2 diabetes (T2D) using GWAS data from the Resource for Genetic Epidemiology on Adult Health and Aging, a large multi-ethnic population-based cohort, created for investigating the genetic and environmental basis of age-related diseases. We identified a novel locus for T2D susceptibility at genome-wide significance (P<5 × 10−8) that maps to TOMM40-APOE, a region previously implicated in lipid metabolism and Alzheimer's disease. We have also confirmed previous reports that single-nucleotide polymorphisms at the TCF7L2 locus demonstrate the greatest extent of heterogeneity in allelic effects between ethnic groups, with the lowest risk observed in populations of East Asian ancestry. PMID:27189021

Contrasting Patterns of Nucleotide Substitution Rates Provide Insight into Dynamic Evolution of Plastid and Mitochondrial Genomes of Geranium.

PubMed

Park, Seongjun; Ruhlman, Tracey A; Weng, Mao-Lun; Hajrah, Nahid H; Sabir, Jamal S M; Jansen, Robert K

2017-06-01

Geraniaceae have emerged as a model system for investigating the causes and consequences of variation in plastid and mitochondrial genomes. Incredible structural variation in plastid genomes (plastomes) and highly accelerated evolutionary rates have been reported in selected lineages and functional groups of genes in both plastomes and mitochondrial genomes (mitogenomes), and these phenomena have been implicated in cytonuclear incompatibility. Previous organelle genome studies have included limited sampling of Geranium, the largest genus in the family with over 400 species. This study reports on rates and patterns of nucleotide substitutions in plastomes and mitogenomes of 17 species of Geranium and representatives of other Geraniaceae. As detected across other angiosperms, substitution rates in the plastome are 3.5 times higher than the mitogenome in most Geranium. However, in the branch leading to Geranium brycei/Geranium incanum mitochondrial genes experienced significantly higher dN and dS than plastid genes, a pattern that has only been detected in one other angiosperm. Furthermore, rate accelerations differ in the two organelle genomes with plastomes having increased dN and mitogenomes with increased dS. In the Geranium phaeum/Geranium reflexum clade, duplicate copies of clpP and rpoA genes that experienced asymmetric rate divergence were detected in the single copy region of the plastome. In the case of rpoA, the branch leading to G. phaeum/G. reflexum experienced positive selection or relaxation of purifying selection. Finally, the evolution of acetyl-CoA carboxylase is unusual in Geraniaceae because it is only the second angiosperm family where both prokaryotic and eukaryotic ACCases functionally coexist in the plastid. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Genomic differentiation among wild cyanophages despite widespread horizontal gene transfer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gregory, Ann C.; Solonenko, Sergei A.; Ignacio-Espinoza, J. Cesar

Genetic recombination is a driving force in genome evolution. Among viruses it has a dual role. For genomes with higher fitness, it maintains genome integrity in the face of high mutation rates. Conversely, for genomes with lower fitness, it provides immediate access to sequence space that cannot be reached by mutation alone. Understanding how recombination impacts the cohesion and dissolution of individual whole genomes within viral sequence space is poorly understood across double-stranded DNA bacteriophages (a.k.a phages) due to the challenges of obtaining appropriately scaled genomic datasets. Here in this study we explore the role of recombination in both maintainingmore » and differentiating whole genomes of 142 wild double-stranded DNA marine cyanophages. Phylogenomic analysis across the 51 core genes revealed ten lineages, six of which were well represented. These phylogenomic lineages represent discrete genotypic populations based on comparisons of intra- and inter- lineage shared gene content, genome-wide average nucleotide identity, as well as detected gaps in the distribution of pairwise differences between genomes. McDonald-Kreitman selection tests identified putative niche-differentiating genes under positive selection that differed across the six well-represented genotypic populations and that may have driven initial divergence. Concurrent with patterns of recombination of discrete populations, recombination analyses of both genic and intergenic regions largely revealed decreased genetic exchange across individual genomes between relative to within populations. Lastly, these findings suggest that discrete double-stranded DNA marine cyanophage populations occur in nature and are maintained by patterns of recombination akin to those observed in bacteria, archaea and in sexual eukaryotes.« less

Genomic differentiation among wild cyanophages despite widespread horizontal gene transfer

DOE PAGES

Gregory, Ann C.; Solonenko, Sergei A.; Ignacio-Espinoza, J. Cesar; ...

2016-11-16

Genetic recombination is a driving force in genome evolution. Among viruses it has a dual role. For genomes with higher fitness, it maintains genome integrity in the face of high mutation rates. Conversely, for genomes with lower fitness, it provides immediate access to sequence space that cannot be reached by mutation alone. Understanding how recombination impacts the cohesion and dissolution of individual whole genomes within viral sequence space is poorly understood across double-stranded DNA bacteriophages (a.k.a phages) due to the challenges of obtaining appropriately scaled genomic datasets. Here in this study we explore the role of recombination in both maintainingmore » and differentiating whole genomes of 142 wild double-stranded DNA marine cyanophages. Phylogenomic analysis across the 51 core genes revealed ten lineages, six of which were well represented. These phylogenomic lineages represent discrete genotypic populations based on comparisons of intra- and inter- lineage shared gene content, genome-wide average nucleotide identity, as well as detected gaps in the distribution of pairwise differences between genomes. McDonald-Kreitman selection tests identified putative niche-differentiating genes under positive selection that differed across the six well-represented genotypic populations and that may have driven initial divergence. Concurrent with patterns of recombination of discrete populations, recombination analyses of both genic and intergenic regions largely revealed decreased genetic exchange across individual genomes between relative to within populations. Lastly, these findings suggest that discrete double-stranded DNA marine cyanophage populations occur in nature and are maintained by patterns of recombination akin to those observed in bacteria, archaea and in sexual eukaryotes.« less

Efficient genome-wide association in biobanks using topic modeling identifies multiple novel disease loci.

PubMed

McCoy, Thomas H; Castro, Victor M; Snapper, Leslie A; Hart, Kamber L; Perlis, Roy H

2017-08-31

Biobanks and national registries represent a powerful tool for genomic discovery, but rely on diagnostic codes that may be unreliable and fail to capture the relationship between related diagnoses. We developed an efficient means of conducting genome-wide association studies using combinations of diagnostic codes from electronic health records (EHR) for 10845 participants in a biobanking program at two large academic medical centers. Specifically, we applied latent Dirichilet allocation to fit 50 disease topics based on diagnostic codes, then conducted genome-wide common-variant association for each topic. In sensitivity analysis, these results were contrasted with those obtained from traditional single-diagnosis phenome-wide association analysis, as well as those in which only a subset of diagnostic codes are included per topic. In meta-analysis across three biobank cohorts, we identified 23 disease-associated loci with p<1e-15, including previously associated autoimmune disease loci. In all cases, observed significant associations were of greater magnitude than for single phenome-wide diagnostic codes, and incorporation of less strongly-loading diagnostic codes enhanced association. This strategy provides a more efficient means of phenome-wide association in biobanks with coded clinical data.

Comparison of genome-wide selection strategies to identify furfural tolerance genes in Escherichia coli.

PubMed

Glebes, Tirzah Y; Sandoval, Nicholas R; Gillis, Jacob H; Gill, Ryan T

2015-01-01

Engineering both feedstock and product tolerance is important for transitioning towards next-generation biofuels derived from renewable sources. Tolerance to chemical inhibitors typically results in complex phenotypes, for which multiple genetic changes must often be made to confer tolerance. Here, we performed a genome-wide search for furfural-tolerant alleles using the TRackable Multiplex Recombineering (TRMR) method (Warner et al. (2010), Nature Biotechnology), which uses chromosomally integrated mutations directed towards increased or decreased expression of virtually every gene in Escherichia coli. We employed various growth selection strategies to assess the role of selection design towards growth enrichments. We also compared genes with increased fitness from our TRMR selection to those from a previously reported genome-wide identification study of furfural tolerance genes using a plasmid-based genomic library approach (Glebes et al. (2014) PLOS ONE). In several cases, growth improvements were observed for the chromosomally integrated promoter/RBS mutations but not for the plasmid-based overexpression constructs. Through this assessment, four novel tolerance genes, ahpC, yhjH, rna, and dicA, were identified and confirmed for their effect on improving growth in the presence of furfural. © 2014 Wiley Periodicals, Inc.

Pattern analysis uncovers a chronic ethanol-induced disruption of the switch-like dynamics of C/EBP-β and C/EBP-α genome-wide binding during liver regeneration

PubMed Central

Kuttippurathu, Lakshmi; Patra, Biswanath; Cook, Daniel; Hoek, Jan B.

2017-01-01

Chronic ethanol intake impairs liver regeneration through a system-wide alteration in the regulatory networks driving the response to injury. Our study focused on the initial phase of response to 2/3rd partial hepatectomy (PHx) to investigate how adaptation to chronic ethanol intake affects the genome-wide binding profiles of the transcription factors C/EBP-β and C/EBP-α. These factors participate in complementary and often opposing functions for maintaining cellular differentiation, regulating metabolism, and governing cell growth during liver regeneration. We analyzed ChIP-seq data with a comparative pattern count (COMPACT) analysis, which exhaustively enumerates temporal patterns of discretized binding profiles to identify dominant as well as subtle patterns that may not be apparent from conventional clustering analyses. We found that adaptation to chronic ethanol intake significantly alters the genome-wide binding profile of C/EBP-β and C/EBP-α before and following PHx. A subset of these ethanol-induced changes include C/EBP-β binding to promoters of genes involved in the profibrogenic transforming growth factor-β pathway, and both C/EBP-β and C/EBP-α binding to promoters of genes involved in the cell cycle, apoptosis, homeostasis, and metabolic processes. The shift in C/EBP binding loci, coupled with an ethanol-induced increase in C/EBP-β binding at 6 h post-resection, indicates that ethanol adaptation may change both the amount and nature of C/EBP binding postresection. Taken together, our results suggest that chronic ethanol consumption leads to a spatially and temporally reorganized activity at many genomic loci, resulting in a shift in the dynamic balance and coordination of cellular processes underlying regenerative response. PMID:27815535

A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

PubMed

Arango, Natalia Paez; Brusco, Lauren; Mills Shaw, Kenna R; Chen, Ken; Eterovic, Agda Karina; Holla, Vijaykumar; Johnson, Amber; Litzenburger, Beate; Khotskaya, Yekaterina B; Sanchez, Nora; Bailey, Ann; Zheng, Xiaofeng; Horombe, Chacha; Kopetz, Scott; Farhangfar, Carol J; Routbort, Mark; Broaddus, Russell; Bernstam, Elmer V; Mendelsohn, John; Mills, Gordon B; Meric-Bernstam, Funda

2017-06-27

Molecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment. 1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform. 527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials. Expanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

PubMed

Savage, Jeanne E; Jansen, Philip R; Stringer, Sven; Watanabe, Kyoko; Bryois, Julien; de Leeuw, Christiaan A; Nagel, Mats; Awasthi, Swapnil; Barr, Peter B; Coleman, Jonathan R I; Grasby, Katrina L; Hammerschlag, Anke R; Kaminski, Jakob A; Karlsson, Robert; Krapohl, Eva; Lam, Max; Nygaard, Marianne; Reynolds, Chandra A; Trampush, Joey W; Young, Hannah; Zabaneh, Delilah; Hägg, Sara; Hansell, Narelle K; Karlsson, Ida K; Linnarsson, Sten; Montgomery, Grant W; Muñoz-Manchado, Ana B; Quinlan, Erin B; Schumann, Gunter; Skene, Nathan G; Webb, Bradley T; White, Tonya; Arking, Dan E; Avramopoulos, Dimitrios; Bilder, Robert M; Bitsios, Panos; Burdick, Katherine E; Cannon, Tyrone D; Chiba-Falek, Ornit; Christoforou, Andrea; Cirulli, Elizabeth T; Congdon, Eliza; Corvin, Aiden; Davies, Gail; Deary, Ian J; DeRosse, Pamela; Dickinson, Dwight; Djurovic, Srdjan; Donohoe, Gary; Conley, Emily Drabant; Eriksson, Johan G; Espeseth, Thomas; Freimer, Nelson A; Giakoumaki, Stella; Giegling, Ina; Gill, Michael; Glahn, David C; Hariri, Ahmad R; Hatzimanolis, Alex; Keller, Matthew C; Knowles, Emma; Koltai, Deborah; Konte, Bettina; Lahti, Jari; Le Hellard, Stephanie; Lencz, Todd; Liewald, David C; London, Edythe; Lundervold, Astri J; Malhotra, Anil K; Melle, Ingrid; Morris, Derek; Need, Anna C; Ollier, William; Palotie, Aarno; Payton, Antony; Pendleton, Neil; Poldrack, Russell A; Räikkönen, Katri; Reinvang, Ivar; Roussos, Panos; Rujescu, Dan; Sabb, Fred W; Scult, Matthew A; Smeland, Olav B; Smyrnis, Nikolaos; Starr, John M; Steen, Vidar M; Stefanis, Nikos C; Straub, Richard E; Sundet, Kjetil; Tiemeier, Henning; Voineskos, Aristotle N; Weinberger, Daniel R; Widen, Elisabeth; Yu, Jin; Abecasis, Goncalo; Andreassen, Ole A; Breen, Gerome; Christiansen, Lene; Debrabant, Birgit; Dick, Danielle M; Heinz, Andreas; Hjerling-Leffler, Jens; Ikram, M Arfan; Kendler, Kenneth S; Martin, Nicholas G; Medland, Sarah E; Pedersen, Nancy L; Plomin, Robert; Polderman, Tinca J C; Ripke, Stephan; van der Sluis, Sophie; Sullivan, Patrick F; Vrieze, Scott I; Wright, Margaret J; Posthuma, Danielle

2018-06-25

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

The genomic evolution of H1 influenza A viruses from swine detected in the United States between 2009 and 2016

PubMed Central

Gao, Shibo; Anderson, Tavis K.; Walia, Rasna R.; Dorman, Karin S.; Janas-Martindale, Alicia

2017-01-01

Transmission of influenza A virus (IAV) from humans to swine occurs with relative frequency and is a critical contributor to swine IAV diversity. Subsequent to the introduction of these human seasonal lineages, there is often reassortment with endemic viruses and antigenic drift. To address whether particular genome constellations contributed to viral persistence following the introduction of the 2009 H1N1 human pandemic virus to swine in the USA, we collated and analysed 616 whole genomes of swine H1 isolates. For each gene, sequences were aligned, the best-known maximum likelihood phylogeny was inferred, and each virus was assigned a clade based upon its evolutionary history. A time-scaled Bayesian approach was implemented for the haemagglutinin (HA) gene to determine the patterns of genetic diversity over time. From these analyses, we observed an increase in genome diversity across all H1 lineages and clades, with the H1-γ and H1-δ1 genetic clades containing the greatest number of unique genome patterns. We documented 74 genome patterns from 2009 to 2016, of which 3 genome patterns were consistently detected at a significantly higher level than others across the entire time period. Eight genome patterns increased significantly, while five genome patterns were shown to decline in detection over time. Viruses with genome patterns identified as persisting in the US swine population may possess a greater capacity to infect and transmit in swine. This study highlights the emerging genetic diversity of US swine IAV from 2009 to 2016, with implications for swine and public health and vaccine control efforts. PMID:28758634

Convergent Genomic Studies Identify Association of GRIK2 and NPAS2 with Chronic Fatigue Syndrome

PubMed Central

Smith, Alicia K.; Fang, Hong; Whistler, Toni; Unger, Elizabeth R.; Rajeevan, Mangalathu S.

2011-01-01

Background There is no consistent evidence of specific gene(s) or molecular pathways that contribute to the pathogenesis, therapeutic intervention or diagnosis of chronic fatigue syndrome (CFS). While multiple studies support a role for genetic variation in CFS, genome-wide efforts to identify associated loci remain unexplored. We employed a novel convergent functional genomics approach that incorporates the findings from single-nucleotide polymorphism (SNP) and mRNA expression studies to identify associations between CFS and novel candidate genes for further investigation. Methods We evaluated 116,204 SNPs in 40 CFS and 40 nonfatigued control subjects along with mRNA expression of 20,160 genes in a subset of these subjects (35 CFS subjects and 27 controls) derived from a population-based study. Results Sixty-five SNPs were nominally associated with CFS (p < 0.001), and 165 genes were differentially expressed (≥4-fold; p ≤ 0.05) in peripheral blood mononuclear cells of CFS subjects. Two genes, glutamate receptor, ionotropic, kinase 2 (GRIK2) and neuronal PAS domain protein 2 (NPAS2), were identified by both SNP and gene expression analyses. Subjects with the G allele of rs2247215 (GRIK2) were more likely to have CFS (p = 0.0005), and CFS subjects showed decreased GRIK2 expression (10-fold; p = 0.015). Subjects with the T allele of rs356653 (NPAS2) were more likely to have CFS (p = 0.0007), and NPAS2 expression was increased (10-fold; p = 0.027) in those with CFS. Conclusion Using an integrated genomic strategy, this study suggests a possible role for genes involved in glutamatergic neurotransmission and circadian rhythm in CFS and supports further study of novel candidate genes in independent populations of CFS subjects. PMID:21912186

Genome skimming identifies polymorphism in tern populations and species

PubMed Central

2012-01-01

Background Terns (Charadriiformes: Sterninae) are a lineage of cosmopolitan shorebirds with a disputed evolutionary history that comprises several species of conservation concern. As a non-model system in genetics, previous study has left most of the nuclear genome unexplored, and population-level studies are limited to only 15% of the world's species of terns and noddies. Screening of polymorphic nuclear sequence markers is needed to enhance genetic resolution because of supposed low mitochondrial mutation rate, documentation of nuclear insertion of hypervariable mitochondrial regions, and limited success of microsatellite enrichment in terns. Here, we investigated the phylogenetic and population genetic utility for terns and relatives of a variety of nuclear markers previously developed for other birds and spanning the nuclear genome. Markers displaying a variety of mutation rates from both the nuclear and mitochondrial genome were tested and prioritized according to optimal cross-species amplification and extent of genetic polymorphism between (1) the main tern clades and (2) individual Royal Terns (Thalasseus maxima) breeding on the US East Coast. Results Results from this genome skimming effort yielded four new nuclear sequence-based markers for tern phylogenetics and 11 intra-specific polymorphic markers. Further, comparison between the two genomes indicated a phylogenetic conflict at the base of terns, involving the inclusion (mitochondrial) or exclusion (nuclear) of the Angel Tern (Gygis alba). Although limited mitochondrial variation was confirmed, both nuclear markers and a short tandem repeat in the mitochondrial control region indicated the presence of considerable genetic variation in Royal Terns at a regional scale. Conclusions These data document the value of intronic markers to the study of terns and allies. We expect that these and additional markers attained through next-generation sequencing methods will accurately map the genetic origin and

Phylogenetic and Evolutionary Patterns in Microbial Carotenoid Biosynthesis Are Revealed by Comparative Genomics

PubMed Central

Klassen, Jonathan L.

2010-01-01

Background Carotenoids are multifunctional, taxonomically widespread and biotechnologically important pigments. Their biosynthesis serves as a model system for understanding the evolution of secondary metabolism. Microbial carotenoid diversity and evolution has hitherto been analyzed primarily from structural and biosynthetic perspectives, with the few phylogenetic analyses of microbial carotenoid biosynthetic proteins using either used limited datasets or lacking methodological rigor. Given the recent accumulation of microbial genome sequences, a reappraisal of microbial carotenoid biosynthetic diversity and evolution from the perspective of comparative genomics is warranted to validate and complement models of microbial carotenoid diversity and evolution based upon structural and biosynthetic data. Methodology/Principal Findings Comparative genomics were used to identify and analyze in silico microbial carotenoid biosynthetic pathways. Four major phylogenetic lineages of carotenoid biosynthesis are suggested composed of: (i) Proteobacteria; (ii) Firmicutes; (iii) Chlorobi, Cyanobacteria and photosynthetic eukaryotes; and (iv) Archaea, Bacteroidetes and two separate sub-lineages of Actinobacteria. Using this phylogenetic framework, specific evolutionary mechanisms are proposed for carotenoid desaturase CrtI-family enzymes and carotenoid cyclases. Several phylogenetic lineage-specific evolutionary mechanisms are also suggested, including: (i) horizontal gene transfer; (ii) gene acquisition followed by differential gene loss; (iii) co-evolution with other biochemical structures such as proteorhodopsins; and (iv) positive selection. Conclusions/Significance Comparative genomics analyses of microbial carotenoid biosynthetic proteins indicate a much greater taxonomic diversity then that identified based on structural and biosynthetic data, and divides microbial carotenoid biosynthesis into several, well-supported phylogenetic lineages not evident previously. This

A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.

PubMed

Lutz, Sharon M; Cho, Michael H; Young, Kendra; Hersh, Craig P; Castaldi, Peter J; McDonald, Merry-Lynn; Regan, Elizabeth; Mattheisen, Manuel; DeMeo, Dawn L; Parker, Margaret; Foreman, Marilyn; Make, Barry J; Jensen, Robert L; Casaburi, Richard; Lomas, David A; Bhatt, Surya P; Bakke, Per; Gulsvik, Amund; Crapo, James D; Beaty, Terri H; Laird, Nan M; Lange, Christoph; Hokanson, John E; Silverman, Edwin K

2015-12-03

Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)). In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.

MEPD: a Medaka gene expression pattern database

PubMed Central

Henrich, Thorsten; Ramialison, Mirana; Quiring, Rebecca; Wittbrodt, Beate; Furutani-Seiki, Makoto; Wittbrodt, Joachim; Kondoh, Hisato

2003-01-01

The Medaka Expression Pattern Database (MEPD) stores and integrates information of gene expression during embryonic development of the small freshwater fish Medaka (Oryzias latipes). Expression patterns of genes identified by ESTs are documented by images and by descriptions through parameters such as staining intensity, category and comments and through a comprehensive, hierarchically organized dictionary of anatomical terms. Sequences of the ESTs are available and searchable through BLAST. ESTs in the database are clustered upon entry and have been blasted against public data-bases. The BLAST results are updated regularly, stored within the database and searchable. The MEPD is a project within the Medaka Genome Initiative (MGI) and entries will be interconnected to integrated genomic map databases. MEPD is accessible through the WWW at http://medaka.dsp.jst.go.jp/MEPD. PMID:12519950

Genome-wide association study identifies novel breast cancer susceptibility loci

PubMed Central

Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Marchand, Loic Le; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.; Luccarini, Craig; Conroy, Don; Shah, Mitul; Munday, Hannah; Jordan, Clare; Perkins, Barbara; West, Judy; Redman, Karen; Driver, Kristy; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armes, Jane; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Begley, Glenn; Beilby, John; Bennett, Ian; Bennett, Barbara; Berry, Geoffrey; Blackburn, Anneke; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chenevix-Trench, Georgia; Clarke, Christine; Colley, Alison; Cotton, Dick; Cui, Jisheng; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Field, Michael; Firgaira, Frank; Fleming, Jean; Forbes, John; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Harris, Marion; Hart, Stewart; Hayward, Nick; Hopper, John; Humphrey, Evelyn; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kirk, Judy; Kollias, James; Kovalenko, Sergey; Lakhani, Sunil; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Maclurcan, Mariette; Mann, Graham; Marsh, Deborah; McCredie, Margaret; McKay, Michael; McLachlan, Sue Anne; Meiser, Bettina; Milne, Roger; Mitchell, Gillian; Newman, Beth; O'Loughlin, Imelda; Osborne, Richard; Peters, Lester; Phillips, Kelly; Price, Melanie; Reeve, Jeanne; Reeve, Tony; Richards, Robert; Rinehart, Gina; Robinson, Bridget; Rudzki, Barney; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Scott, Clare; Scott, Elizabeth; Scott, Rodney; Seshadri, Ram; Shelling, Andrew; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Taylor, Donna; Tennant, Christopher; Thorne, Heather; Townshend, Sharron; Tucker, Kathy; Tyler, Janet; Venter, Deon; Visvader, Jane; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Watson, Elizabeth; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Young, Mary Ann; Bowtell, David; Green, Adele; deFazio, Anna; Chenevix-Trench, Georgia; Gertig, Dorota; Webb, Penny

2009-01-01

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. PMID:17529967

GeNemo: a search engine for web-based functional genomic data.

PubMed

Zhang, Yongqing; Cao, Xiaoyi; Zhong, Sheng

2016-07-08

A set of new data types emerged from functional genomic assays, including ChIP-seq, DNase-seq, FAIRE-seq and others. The results are typically stored as genome-wide intensities (WIG/bigWig files) or functional genomic regions (peak/BED files). These data types present new challenges to big data science. Here, we present GeNemo, a web-based search engine for functional genomic data. GeNemo searches user-input data against online functional genomic datasets, including the entire collection of ENCODE and mouse ENCODE datasets. Unlike text-based search engines, GeNemo's searches are based on pattern matching of functional genomic regions. This distinguishes GeNemo from text or DNA sequence searches. The user can input any complete or partial functional genomic dataset, for example, a binding intensity file (bigWig) or a peak file. GeNemo reports any genomic regions, ranging from hundred bases to hundred thousand bases, from any of the online ENCODE datasets that share similar functional (binding, modification, accessibility) patterns. This is enabled by a Markov Chain Monte Carlo-based maximization process, executed on up to 24 parallel computing threads. By clicking on a search result, the user can visually compare her/his data with the found datasets and navigate the identified genomic regions. GeNemo is available at www.genemo.org. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

An application of partial least squares for identifying dietary patterns in bone health.

PubMed

Yang, Tiffany C; Aucott, Lorna S; Duthie, Garry G; Macdonald, Helen M

2017-12-01

In a large cohort of older women, a mechanism-driven statistical technique for assessing dietary patterns that considers a potential nutrient pathway found two dietary patterns associated with lumbar spine and femoral neck bone mineral density. A "healthy" dietary pattern was observed to be beneficial for bone mineral density. Dietary patterns represent a broader, more realistic representation of how foods are consumed, compared to individual food or nutrient analyses. Partial least-squares (PLS) is a data-reduction technique for identifying dietary patterns that maximizes correlation between foods and nutrients hypothesized to be on the path to disease, is more hypothesis-driven than previous methods, and has not been applied to the study of dietary patterns in relation to bone health. Women from the Aberdeen Prospective Osteoporosis Screening Study (2007-2011, n = 2129, age = 66 years (2.2)) provided dietary intake using a food frequency questionnaire; 37 food groups were created. We applied PLS to the 37 food groups and 9 chosen response variables (calcium, potassium, vitamin C, vitamin D, protein, alcohol, magnesium, phosphorus, zinc) to identify dietary patterns associated with bone mineral density (BMD) cross-sectionally. Multivariable regression was used to assess the relationship between the retained dietary patterns and BMD at the lumbar spine and femoral neck, adjusting for age, body mass index, physical activity level, smoking, and national deprivation category. Five dietary patterns were identified, explaining 25% of the variation in food groups and 77% in the response variables. Two dietary patterns were positively associated with lumbar spine (per unit increase in factor 2: 0.012 g/cm 2 [95% CI: 0.006, 0.01]; factor 4: 0.007 g/cm 2 [95% CI: 0.00001, 0.01]) and femoral neck (factor 2: 0.006 g/cm 2 [95% CI: 0.002, 0.01]; factor 4: 0.008 g/cm 2 [95% CI: 0.003, 0.01)]) BMD. Dietary pattern 2 was characterized by high intakes of milk

Genome sequence and genetic diversity of the common carp, Cyprinus carpio.

PubMed

Xu, Peng; Zhang, Xiaofeng; Wang, Xumin; Li, Jiongtang; Liu, Guiming; Kuang, Youyi; Xu, Jian; Zheng, Xianhu; Ren, Lufeng; Wang, Guoliang; Zhang, Yan; Huo, Linhe; Zhao, Zixia; Cao, Dingchen; Lu, Cuiyun; Li, Chao; Zhou, Yi; Liu, Zhanjiang; Fan, Zhonghua; Shan, Guangle; Li, Xingang; Wu, Shuangxiu; Song, Lipu; Hou, Guangyuan; Jiang, Yanliang; Jeney, Zsigmond; Yu, Dan; Wang, Li; Shao, Changjun; Song, Lai; Sun, Jing; Ji, Peifeng; Wang, Jian; Li, Qiang; Xu, Liming; Sun, Fanyue; Feng, Jianxin; Wang, Chenghui; Wang, Shaolin; Wang, Baosen; Li, Yan; Zhu, Yaping; Xue, Wei; Zhao, Lan; Wang, Jintu; Gu, Ying; Lv, Weihua; Wu, Kejing; Xiao, Jingfa; Wu, Jiayan; Zhang, Zhang; Yu, Jun; Sun, Xiaowen

2014-11-01

The common carp, Cyprinus carpio, is one of the most important cyprinid species and globally accounts for 10% of freshwater aquaculture production. Here we present a draft genome of domesticated C. carpio (strain Songpu), whose current assembly contains 52,610 protein-coding genes and approximately 92.3% coverage of its paleotetraploidized genome (2n = 100). The latest round of whole-genome duplication has been estimated to have occurred approximately 8.2 million years ago. Genome resequencing of 33 representative individuals from worldwide populations demonstrates a single origin for C. carpio in 2 subspecies (C. carpio Haematopterus and C. carpio carpio). Integrative genomic and transcriptomic analyses were used to identify loci potentially associated with traits including scaling patterns and skin color. In combination with the high-resolution genetic map, the draft genome paves the way for better molecular studies and improved genome-assisted breeding of C. carpio and other closely related species.

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

Identification, characterization, and utilization of genome-wide simple sequence repeats to identify a QTL for acidity in apple

PubMed Central

2012-01-01

Background Apple is an economically important fruit crop worldwide. Developing a genetic linkage map is a critical step towards mapping and cloning of genes responsible for important horticultural traits in apple. To facilitate linkage map construction, we surveyed and characterized the distribution and frequency of perfect microsatellites in assembled contig sequences of the apple genome. Results A total of 28,538 SSRs have been identified in the apple genome, with an overall density of 40.8 SSRs per Mb. Di-nucleotide repeats are the most frequent microsatellites in the apple genome, accounting for 71.9% of all microsatellites. AT/TA repeats are the most frequent in genomic regions, accounting for 38.3% of all the G-SSRs, while AG/GA dimers prevail in transcribed sequences, and account for 59.4% of all EST-SSRs. A total set of 310 SSRs is selected to amplify eight apple genotypes. Of these, 245 (79.0%) are found to be polymorphic among cultivars and wild species tested. AG/GA motifs in genomic regions have detected more alleles and higher PIC values than AT/TA or AC/CA motifs. Moreover, AG/GA repeats are more variable than any other dimers in apple, and should be preferentially selected for studies, such as genetic diversity and linkage map construction. A total of 54 newly developed apple SSRs have been genetically mapped. Interestingly, clustering of markers with distorted segregation is observed on linkage groups 1, 2, 10, 15, and 16. A QTL responsible for malic acid content of apple fruits is detected on linkage group 8, and accounts for ~13.5% of the observed phenotypic variation. Conclusions This study demonstrates that di-nucleotide repeats are prevalent in the apple genome and that AT/TA and AG/GA repeats are the most frequent in genomic and transcribed sequences of apple, respectively. All SSR motifs identified in this study as well as those newly mapped SSRs will serve as valuable resources for pursuing apple genetic studies, aiding the apple breeding

Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy.

PubMed

Marenholz, Ingo; Grosche, Sarah; Kalb, Birgit; Rüschendorf, Franz; Blümchen, Katharina; Schlags, Rupert; Harandi, Neda; Price, Mareike; Hansen, Gesine; Seidenberg, Jürgen; Röblitz, Holger; Yürek, Songül; Tschirner, Sebastian; Hong, Xiumei; Wang, Xiaobin; Homuth, Georg; Schmidt, Carsten O; Nöthen, Markus M; Hübner, Norbert; Niggemann, Bodo; Beyer, Kirsten; Lee, Young-Ae

2017-10-20

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanisms in food allergy.

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

NASA Technical Reports Server (NTRS)

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

2005-01-01

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

The evolutionary processes of mitochondrial and chloroplast genomes differ from those of nuclear genomes

NASA Astrophysics Data System (ADS)

Korpelainen, Helena

2004-11-01

This paper first introduces our present knowledge of the origin of mitochondria and chloroplasts, and the organization and inheritance patterns of their genomes, and then carries on to review the evolutionary processes influencing mitochondrial and chloroplast genomes. The differences in evolutionary phenomena between the nuclear and cytoplasmic genomes are highlighted. It is emphasized that varying inheritance patterns and copy numbers among different types of genomes, and the potential advantage achieved through the transfer of many cytoplasmic genes to the nucleus, have important implications for the evolution of nuclear, mitochondrial and chloroplast genomes. Cytoplasmic genes transferred to the nucleus have joined the more strictly controlled genetic system of the nuclear genome, including also sexual recombination, while genes retained within the cytoplasmic organelles can be involved in selection and drift processes both within and among individuals. Within-individual processes can be either intra- or intercellular. In the case of heteroplasmy, which is attributed to mutations or biparental inheritance, within-individual selection on cytoplasmic DNA may provide a mechanism by which the organism can adapt rapidly. The inheritance of cytoplasmic genomes is not universally maternal. The presence of a range of inheritance patterns indicates that different strategies have been adopted by different organisms. On the other hand, the variability occasionally observed in the inheritance mechanisms of cytoplasmic genomes reduces heritability and increases environmental components in phenotypic features and, consequently, decreases the potential for adaptive evolution.

The genome landscape of indigenous African cattle.

PubMed

Kim, Jaemin; Hanotte, Olivier; Mwai, Okeyo Ally; Dessie, Tadelle; Bashir, Salim; Diallo, Boubacar; Agaba, Morris; Kim, Kwondo; Kwak, Woori; Sung, Samsun; Seo, Minseok; Jeong, Hyeonsoo; Kwon, Taehyung; Taye, Mengistie; Song, Ki-Duk; Lim, Dajeong; Cho, Seoae; Lee, Hyun-Jeong; Yoon, Duhak; Oh, Sung Jong; Kemp, Stephen; Lee, Hak-Kyo; Kim, Heebal

2017-02-20

The history of African indigenous cattle and their adaptation to environmental and human selection pressure is at the root of their remarkable diversity. Characterization of this diversity is an essential step towards understanding the genomic basis of productivity and adaptation to survival under African farming systems. We analyze patterns of African cattle genetic variation by sequencing 48 genomes from five indigenous populations and comparing them to the genomes of 53 commercial taurine breeds. We find the highest genetic diversity among African zebu and sanga cattle. Our search for genomic regions under selection reveals signatures of selection for environmental adaptive traits. In particular, we identify signatures of selection including genes and/or pathways controlling anemia and feeding behavior in the trypanotolerant N'Dama, coat color and horn development in Ankole, and heat tolerance and tick resistance across African cattle especially in zebu breeds. Our findings unravel at the genome-wide level, the unique adaptive diversity of African cattle while emphasizing the opportunities for sustainable improvement of livestock productivity on the continent.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

PubMed Central

Imamura, Minako; Takahashi, Atsushi; Yamauchi, Toshimasa; Hara, Kazuo; Yasuda, Kazuki; Grarup, Niels; Zhao, Wei; Wang, Xu; Huerta-Chagoya, Alicia; Hu, Cheng; Moon, Sanghoon; Long, Jirong; Kwak, Soo Heon; Rasheed, Asif; Saxena, Richa; Ma, Ronald C. W.; Okada, Yukinori; Iwata, Minoru; Hosoe, Jun; Shojima, Nobuhiro; Iwasaki, Minaka; Fujita, Hayato; Suzuki, Ken; Danesh, John; Jørgensen, Torben; Jørgensen, Marit E.; Witte, Daniel R.; Brandslund, Ivan; Christensen, Cramer; Hansen, Torben; Mercader, Josep M.; Flannick, Jason; Moreno-Macías, Hortensia; Burtt, Noël P.; Zhang, Rong; Kim, Young Jin; Zheng, Wei; Singh, Jai Rup; Tam, Claudia H. T.; Hirose, Hiroshi; Maegawa, Hiroshi; Ito, Chikako; Kaku, Kohei; Watada, Hirotaka; Tanaka, Yasushi; Tobe, Kazuyuki; Kawamori, Ryuzo; Kubo, Michiaki; Cho, Yoon Shin; Chan, Juliana C. N.; Sanghera, Dharambir; Frossard, Philippe; Park, Kyong Soo; Shu, Xiao-Ou; Kim, Bong-Jo; Florez, Jose C.; Tusié-Luna, Teresa; Jia, Weiping; Tai, E Shyong; Pedersen, Oluf; Saleheen, Danish; Maeda, Shiro; Kadowaki, Takashi

2016-01-01

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10−8), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities. PMID:26818947

Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.

PubMed

Raelson, John V; Little, Randall D; Ruether, Andreas; Fournier, Hélène; Paquin, Bruno; Van Eerdewegh, Paul; Bradley, W E C; Croteau, Pascal; Nguyen-Huu, Quynh; Segal, Jonathan; Debrus, Sophie; Allard, René; Rosenstiel, Philip; Franke, Andre; Jacobs, Gunnar; Nikolaus, Susanna; Vidal, Jean-Michel; Szego, Peter; Laplante, Nathalie; Clark, Hilary F; Paulussen, René J; Hooper, John W; Keith, Tim P; Belouchi, Abdelmajid; Schreiber, Stefan

2007-09-11

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

A Mitochondrial Genome of Rhyparochromidae (Hemiptera: Heteroptera) and a Comparative Analysis of Related Mitochondrial Genomes.

PubMed

Li, Teng; Yang, Jie; Li, Yinwan; Cui, Ying; Xie, Qiang; Bu, Wenjun; Hillis, David M

2016-10-19

The Rhyparochromidae, the largest family of Lygaeoidea, encompasses more than 1,850 described species, but no mitochondrial genome has been sequenced to date. Here we describe the first mitochondrial genome for Rhyparochromidae: a complete mitochondrial genome of Panaorus albomaculatus (Scott, 1874). This mitochondrial genome is comprised of 16,345 bp, and contains the expected 37 genes and control region. The majority of the control region is made up of a large tandem-repeat region, which has a novel pattern not previously observed in other insects. The tandem-repeats region of P. albomaculatus consists of 53 tandem duplications (including one partial repeat), which is the largest number of tandem repeats among all the known insect mitochondrial genomes. Slipped-strand mispairing during replication is likely to have generated this novel pattern of tandem repeats. Comparative analysis of tRNA gene families in sequenced Pentatomomorpha and Lygaeoidea species shows that the pattern of nucleotide conservation is markedly higher on the J-strand. Phylogenetic reconstruction based on mitochondrial genomes suggests that Rhyparochromidae is not the sister group to all the remaining Lygaeoidea, and supports the monophyly of Lygaeoidea.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations

PubMed Central

Liang, Jingjing; Le, Thu H.; Edwards, Digna R. Velez; Tayo, Bamidele O.; Gaulton, Kyle J.; Lu, Yingchang; Jensen, Richard A.; Chen, Guanjie; Schwander, Karen; McKenzie, Colin A.; Fox, Ervin; Nalls, Michael A.; Young, J. Hunter; Lane, Jacqueline M.; Zhou, Jie; Tang, Hua; Fornage, Myriam; Musani, Solomon K.; Wang, Heming; Forrester, Terrence; Chu, Pei-Lun; Evans, Michele K.; Morrison, Alanna C.; Martin, Lisa W.; Wiggins, Kerri L.; Hui, Qin; Zhao, Wei; Jackson, Rebecca D.; Faul, Jessica D.; Reiner, Alex P.; Bray, Michael; Denny, Joshua C.; Mosley, Thomas H.; Palmas, Walter; Guo, Xiuqing; Polak, Joseph F.; Taylor, Ken D.; Boerwinkle, Eric; Bottinger, Erwin P.; Liu, Kiang; Risch, Neil; Hunt, Steven C.; Kooperberg, Charles; Zonderman, Alan B.; Becker, Diane M.; Cai, Jianwen; Loos, Ruth J. F.; Psaty, Bruce M.; Weir, David R.; Kardia, Sharon L. R.; Arnett, Donna K.; Won, Sungho; Edwards, Todd L.; Redline, Susan; Cooper, Richard S.; Rao, D. C.; Rotimi, Charles; Levy, Daniel; Chakravarti, Aravinda

2017-01-01

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension. PMID:28498854

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