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Nature. 2013 Jan 10;493(7431):216-20. doi: 10.1038/nature11690. Epub 2012 Nov 28.

Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.

Collaborators (396)

Gabriel SB, Altshuler DM, Gonçalo R A, Allayee H, Cresci S, Daly MJ, de Bakker PI, DePristo MA, Do R, Donnelly P, Farlow DN, Fennell T, Garimella K, Hazen SL, Hu Y, Jordan DM, Jun G, Kathiresan S, Kang HM, Kiezun A, Lettre G, Li B, Li M, Newton-Cheh CH, Padmanabhan S, Peloso G, Pulit S, Rader DJ, Reich D, Reilly MP, Rivas MA, Schwartz S, Hutchinson F, Scott L, Siscovick DS, Spertus JA, Stitziel NO, Stoletzki N, Sunyaev SR, Voight BF, Willer CJ, Rich SS, Akylbekova E, Atwood LD, Ballantyne CM, Barbalic M, Barr R, Benjamin EJ, Bis J, Boerwinkle E, Bowden DW, Brody J, Budoff M, Burke G, Buxbaum S, Carr J, Chen DT, Chen IY, Chen WM, Concannon P, Crosby J, Cupples LA, D'Agostino R, DeStefano AL, Dreisbach A, Dupuis J, Durda J, Ellis J, Folsom AR, Fornage M, Fox CS, Fox E, Funari V, Ganesh SK, Gardin J, Goff D, Gordon O, Grody W, Gross M, Guo X, Hall IM, Heard-Costa NL, Heckbert SR, Heintz N, Herrington DM, Hickson D, Huang J, Hwang SJ, Jacobs DR, Jenny NS, Johnson AD, Johnson CW, Kawut S, Kronmal R, Kurz R, Lange EM, Lange LA, Larson M, Lawson M, Lewis CE, Levy D, Li D, Lin H, Liu C, Liu J, Liu K, Liu X, Liu Y, Longstreth WT, Loria C, Lumley T, Lunetta K, Mackey AJ, Mackey R, Manichaikul A, Maxwell T, McKnight B, Meigs JB, Morrison AC, Musani SK, Mychaleckyj JC, Nettleton JA, North K, O'Donnell CJ, O'Leary D, Ong F, Palmas W, Pankow JS, Pankratz ND, Paul S, Perez M, Person SD, Polak J, Post WS, Psaty BM, Quinlan AR, Raffel LJ, Ramachandran VS, Reiner AP, Rice K, Rotter JI, Sanders JP, Schreiner P, Seshadri S, Shea S, Sidney S, Silverstein K, Siscovick DS, Smith NL, Sotoodehnia N, Srinivasan A, Taylor HA, Taylor K, Thomas F, Tracy RP, Tsai MY, Volcik KA, Wassel CL, Watson K, Wei G, White W, Wiggins KL, Wilk JB, Williams O, Wilson G, Wilson JG, Wolf P, Zakai NA, Hardy J, Meschia JF, Nalls M, Rich SS, Singleton A, Worrall B, Bamshad MJ, Barnes KC, Abdulhamid I, Accurso F, Anbar R, Beaty T, Bigham A, Black P, Bleecker E, Buckingham K, Cairns AM, Chen WM, Caplan D, Chatfield B, Chidekel A, Cho M, Christiani DC, Crapo JD, Crouch J, Daley D, Dang A, Dang H, De Paula A, DeCelie-Germana J, Dozor A, Drumm M, Dyson M, Emerson J, Emond MJ, Ferkol T, Fink R, Foster C, Froh D, Gao L, Gershan W, Gibson RL, Godwin E, Gondor M, Gutierrez H, Hansel NN, Hassoun PM, Hiatt P, Hokanson JE, Howenstine M, Hummer LK, Kanga J, Kim Y, Knowles MR, Konstan M, Lahiri T, Laird N, Lange C, Lin L, Lin X, Louie TL, Lynch D, Make B, Martin TR, Mathai SC, Mathias RA, McNamara J, McNamara S, Meyers D, Millard S, Mogayzel P, Moss R, Murray T, Nielson D, Noyes B, O'Neal W, Orenstein D, O'Sullivan B, Pace R, Pare P, Parker H, Passero MA, Perkett E, Prestridge A, Rafaels NM, Ramsey B, Regan E, Ren C, Retsch-Bogart G, Rock M, Rosen A, Rosenfeld M, Ruczinski I, Sanford A, Schaeffer D, Sell C, Sheehan D, Silverman EK, Sin D, Spencer T, Stonebraker J, Tabor HK, Varlotta L, Vergara CI, Weiss R, Wigley F, Wise RA, Wright FA, Wurfel MM, Zanni R, Zou F, Nickerson DA, Rieder MJ, Green P, Shendure J, Akey JM, Bamshad MJ, Bustamante CD, Crosslin DR, Eichler EE, Fox PK, Fu W, Gordon A, Gravel S, Jarvik GP, Johnsen JM, Kan M, Kenny EE, Kidd JM, Lara-Garduno F, Leal SM, Liu DJ, McGee S, O'Connor TD, Paeper B, Robertson PD, Smith JD, Tennessen JA, Turner EH, Wang G, Jackson R, North K, Peters U, Carlson CS, Anderson G, Anton-Culver H, Assimes TL, Auer PL, Hutchinson F, Beresford S, Hutchinson F, Bizon C, Black H, Brunner R, Brzyski R, Burwen D, Caan B, Carty CL, Chlebowski R, Cummings S, Curb JD, Eaton CB, Ford L, Franceschini N, Fullerton SM, Gass M, Geller N, Heiss G, Howard BV, Hsu L, Hutter CM, Ioannidis J, Jiao S, Johnson KC, Kooperberg C, Kuller L, LaCroix A, Lakshminarayan K, Lane D, Lange EM, Lange LA, Lasser N, LeBlanc E, Lewis CE, Li KP, Limacher M, Lin DY, Logsdon BA, Ludlam S, Manson JE, Margolis K, Martin L, McGowan J, Monda KL, Kotchen JM, Nathan L, Ockene J, O'Sullivan MJ, Phillips LS, Prentice RL, Reiner AP, Hutchinson F, Robbins J, Robinson JG, Rossouw JE, Sangi-Haghpeykar H, Sarto GE, Shumaker S, Simon MS, Stefanick ML, Stein E, Tang H, Taylor KC, Thomson CA, Thornton TA, Van Horn L, Vitolins M, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Zeng D, Applebaum-Bowden D, Feolo M, Gan W, Paltoo DN, Rossouw JE, Sholinsky P, Sturcke A.

Author information

  • 1Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. wqfu@u.washington.edu

Erratum in

  • Nature. 2013 Mar 14;495(7440):270. Rieder, Mark J [added].

Abstract

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

Comment in

PMID:
23201682
[PubMed - indexed for MEDLINE]
PMCID:
PMC3676746
Free PMC Article

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