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Genome-wide detection and characterization of positive selection in human populations.

ABSTRACT: With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

SUBMITTER: Sabeti PC

PROVIDER: S-EPMC2687721 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Genome-wide detection and characterization of positive selection in human populations.

Sabeti Pardis C PC Varilly Patrick P Fry Ben B Lohmueller Jason J Hostetter Elizabeth E Cotsapas Chris C Xie Xiaohui X Byrne Elizabeth H EH McCarroll Steven A SA Gaudet Rachelle R Schaffner Stephen F SF Lander Eric S ES Frazer Kelly A KA Ballinger Dennis G DG Cox David R DR Hinds David A DA Stuve Laura L LL Gibbs Richard A RA Belmont John W JW Boudreau Andrew A Hardenbol Paul P Leal Suzanne M SM Pasternak Shiran S Wheeler David A DA Willis Thomas D TD Yu Fuli F Yang Huanming H Zeng Changqing C Gao Yang Y Hu Haoran H Hu Weitao W Li Chaohua C Lin Wei W Liu Siqi S Pan Hao H Tang Xiaoli X Wang Jian J Wang Wei W Yu Jun J Zhang Bo B Zhang Qingrun Q Zhao Hongbin H Zhao Hui H Zhou Jun J Gabriel Stacey B SB Barry Rachel R Blumenstiel Brendan B Camargo Amy A Defelice Matthew M Faggart Maura M Goyette Mary M Gupta Supriya S Moore Jamie J Nguyen Huy H Onofrio Robert C RC Parkin Melissa M Roy Jessica J Stahl Erich E Winchester Ellen E Ziaugra Liuda L Altshuler David D Shen Yan Y Yao Zhijian Z Huang Wei W Chu Xun X He Yungang Y Jin Li L Liu Yangfan Y Shen Yayun Y Sun Weiwei W Wang Haifeng H Wang Yi Y Wang Ying Y Xiong Xiaoyan X Xu Liang L Waye Mary M Y MM Tsui Stephen K W SK Xue Hong H Wong J Tze-Fei JT Galver Luana M LM Fan Jian-Bing JB Gunderson Kevin K Murray Sarah S SS Oliphant Arnold R AR Chee Mark S MS Montpetit Alexandre A Chagnon Fanny F Ferretti Vincent V Leboeuf Martin M Olivier Jean-François JF Phillips Michael S MS Roumy Stéphanie S Sallée Clémentine C Verner Andrei A Hudson Thomas J TJ Kwok Pui-Yan PY Cai Dongmei D Koboldt Daniel C DC Miller Raymond D RD Pawlikowska Ludmila L Taillon-Miller Patricia P Xiao Ming M Tsui Lap-Chee LC Mak William W Song You Qiang YQ Tam Paul K H PK Nakamura Yusuke Y Kawaguchi Takahisa T Kitamoto Takuya T Morizono Takashi T Nagashima Atsushi A Ohnishi Yozo Y Sekine Akihiro A Tanaka Toshihiro T Tsunoda Tatsuhiko T Deloukas Panos P Bird Christine P CP Delgado Marcos M Dermitzakis Emmanouil T ET Gwilliam Rhian R Hunt Sarah S Morrison Jonathan J Powell Don D Stranger Barbara E BE Whittaker Pamela P Bentley David R DR Daly Mark J MJ de Bakker Paul I W PI Barrett Jeff J Chretien Yves R YR Maller Julian J McCarroll Steve S Patterson Nick N Pe'er Itsik I Price Alkes A Purcell Shaun S Richter Daniel J DJ Sabeti Pardis P Saxena Richa R Schaffner Stephen F SF Sham Pak C PC Varilly Patrick P Altshuler David D Stein Lincoln D LD Krishnan Lalitha L Smith Albert Vernon AV Tello-Ruiz Marcela K MK Thorisson Gudmundur A GA Chakravarti Aravinda A Chen Peter E PE Cutler David J DJ Kashuk Carl S CS Lin Shin S Abecasis Gonçalo R GR Guan Weihua W Li Yun Y Munro Heather M HM Qin Zhaohui Steve ZS Thomas Daryl J DJ McVean Gilean G Auton Adam A Bottolo Leonardo L Cardin Niall N Eyheramendy Susana S Freeman Colin C Marchini Jonathan J Myers Simon S Spencer Chris C Stephens Matthew M Donnelly Peter P Cardon Lon R LR Clarke Geraldine G Evans David M DM Morris Andrew P AP Weir Bruce S BS Tsunoda Tatsuhiko T Johnson Todd A TA Mullikin James C JC Sherry Stephen T ST Feolo Michael M Skol Andrew A Zhang Houcan H Zeng Changqing C Zhao Hui H Matsuda Ichiro I Fukushima Yoshimitsu Y Macer Darryl R DR Suda Eiko E Rotimi Charles N CN Adebamowo Clement A CA Ajayi Ike I Aniagwu Toyin T Marshall Patricia A PA Nkwodimmah Chibuzor C Royal Charmaine D M CD Leppert Mark F MF Dixon Missy M Peiffer Andy A Qiu Renzong R Kent Alastair A Kato Kazuto K Niikawa Norio N Adewole Isaac F IF Knoppers Bartha M BM Foster Morris W MW Clayton Ellen Wright EW Watkin Jessica J Gibbs Richard A RA Belmont John W JW Muzny Donna D Nazareth Lynne L Sodergren Erica E Weinstock George M GM Wheeler David A DA Yakub Imtaz I Gabriel Stacey B SB Onofrio Robert C RC Richter Daniel J DJ Ziaugra Liuda L Birren Bruce W BW Daly Mark J MJ Altshuler David D Wilson Richard K RK Fulton Lucinda L LL Rogers Jane J Burton John J Carter Nigel P NP Clee Christopher M CM Griffiths Mark M Jones Matthew C MC McLay Kirsten K Plumb Robert W RW Ross Mark T MT Sims Sarah K SK Willey David L DL Chen Zhu Z Han Hua H Kang Le L Godbout Martin M Wallenburg John C JC L'Archevêque Paul P Bellemare Guy G Saeki Koji K Wang Hongguang H An Daochang D Fu Hongbo H Li Qing Q Wang Zhen Z Wang Renwu R Holden Arthur L AL Brooks Lisa D LD McEwen Jean E JE Guyer Mark S MS Wang Vivian Ota VO Peterson Jane L JL Shi Michael M Spiegel Jack J Sung Lawrence M LM Zacharia Lynn F LF Collins Francis S FS Kennedy Karen K Jamieson Ruth R Stewart John J

Nature 20071001 7164

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover allel ...[more]

PMID: 17943131

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Project description:Comparative genomics studies investigating the signals of positive selection among groups of closely related species are still rare and limited in taxonomic breadth. Such studies show great promise in advancing our knowledge about the proportion and the identity of genes experiencing diversifying selection. However, methodological challenges have led to high levels of false positives in past studies. Here, we use the well-annotated genome of the purple sea urchin, Strongylocentrotus purpuratus, as a reference to investigate the signals of positive selection at 6520 single-copy orthologs from nine sea urchin species belonging to the family Strongylocentrotidae paying careful attention to minimizing false positives.We identified 1008 (15.5%) candidate positive selection genes (PSGs). Tests for positive selection along the nine terminal branches of the phylogeny identified 824 genes that showed lineage-specific adaptive diversification (1.67% of branch-sites tests performed). Positively selected codons were not enriched at exon borders or near regions containing missing data, suggesting a limited contribution of false positives caused by alignment or annotation errors. Alignments were validated at 10 loci with re-sequencing using Sanger methods. No differences were observed in the rates of synonymous substitution (d S), GC content, and codon bias between the candidate PSGs and those not showing positive selection. However, the candidate PSGs had 68% higher rates of nonsynonymous substitution (d N) and 33% lower levels of heterozygosity, consistent with selective sweeps and opposite to that expected by a relaxation of selective constraint. Although positive selection was identified at reproductive proteins and innate immunity genes, the strongest signals of adaptive diversification were observed at extracellular matrix proteins, cell adhesion molecules, membrane receptors, and ion channels. Many candidate PSGs have been widely implicated as targets of pathogen binding, inactivation, mimicry, or exploitation in other groups (notably mammals).Our study confirmed the widespread action of positive selection across sea urchin genomes and allowed us to reject the possibility that annotation and alignment errors (including paralogs) were responsible for creating false signals of adaptive molecular divergence. The candidate PSGs identified in our study represent promising targets for future research into the selective agents responsible for their adaptive diversification and their contribution to speciation.

Project description:: Detection of selection footprints provides insight into the evolution process and the underlying mechanisms controlling the phenotypic diversity of traits that have been exposed to selection. Selection focused on certain characters, mapping certain genomic regions often shows a loss of genetic diversity with an increased level of homozygosity. Therefore, the runs of homozygosity (ROHs), homozygosity by descent (HBD), and effective population size (Ne) are effective tools for exploring the genetic diversity, understanding the demographic history, foretelling the signature of directional selection, and improving the breeding strategies to use and conserve genetic resources. We characterized the ROH, HBD, Ne, and signature of selection of six Chinese goat populations using single nucleotide polymorphism (SNP) 50K Illumina beadchips. Our results show an inverse relationship between the length and frequency of ROH. A long ROH length, higher level of inbreeding, long HBD segment, and smaller Ne in Guangfeng (GF) goats suggested intensive selection pressure and recent inbreeding in this breed. We identified six reproduction-related genes within the genomic regions with a high ROH frequency, of which two genes overlapped with a putative selection signature. The estimated pair-wise genetic differentiation (FST) among the populations is 9.60% and the inter- and intra-population molecular variations are 9.68% and 89.6%, respectively, indicating low to moderate genetic differentiation. Our selection signatures analysis revealed 54 loci harboring 86 putative candidate genes, with a strong signature of selection. Further analysis showed that several candidate genes, including MARF1, SYCP2, TMEM200C, SF1, ADCY1, and BMP5, are involved in goat fecundity. We identified 11 candidate genes by using cross-population extended haplotype homozygosity (XP-EHH) estimates, of which MARF1 and SF1 are under strong positive selection, as they are differentiated in high and low reproduction groups according to the three approaches used. Gene ontology enrichment analysis revealed that different biological pathways could be involved in the variation of fecundity in female goats. This study provides a new insight into the ROHs patterns for maintenance of within breed diversity and suggests a role of positive selection for genetic variation influencing fecundity in Chinese goat.

Dataset Information

Genome-wide detection and characterization of positive selection in human populations.

Publications

Genome-wide detection and characterization of positive selection in human populations.

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