Analysis of protein-coding genetic variation in 60,706 humans

被引：7333

作者：

Lek, Monkol ^{[1
,2
,3
,4
]}

Karczewski, Konrad J. ^{[1
,2
]}

Minikel, Eric V. ^{[1
,2
,5
]}

Samocha, Kaitlin E. ^{[1
,2
,5
,6
]}

Banks, Eric ^{[2
]}

Fennell, Timothy ^{[20
]}

O'Donnell-Luria, Anne H. ^{[1
,2
,7
]}

Ware, James S. ^{[2
,8
,9
,10
,11
]}

Hill, Andrew J. ^{[1
,2
,12
]}

Cummings, Beryl B. ^{[1
,2
,5
]}

Tukiainen, Taru ^{[1
,2
]}

Birnbaum, Daniel P. ^{[2
]}

Kosmicki, Jack A. ^{[1
,2
,6
,13
]}

Duncan, Laramie E. ^{[1
,2
,6
]}

Estrada, Karol ^{[1
,2
]}

Zhao, Fengmei ^{[12
]}

Zou, James ^{[2
]}

Pierce-Hollman, Emma ^{[1
,2
]}

Berghout, Joanne ^{[14
,15
]}

Cooper, David N. ^{[16
]}

Deflaux, Nicole ^{[17
]}

DePristo, Mark ^{[18
]}

Do, Ron ^{[19
,20
,21
,22
]}

Flannick, Jason ^{[2
,23
]}

Fromer, Menachem ^{[1
,6
,19
,20
,24
]}

Gauthier, Laura ^{[18
]}

Goldstein, Jackie ^{[1
,2
,6
]}

Gupta, Namrata ^{[2
]}

Howrigan, Daniel ^{[1
,2
,6
]}

Kiezun, Adam ^{[18
]}

Kurki, Mitja I. ^{[2
,25
]}

Moonshine, Ami Levy ^{[18
]}

Natarajan, Pradeep ^{[2
,26
,27
,28
]}

Orozeo, Lorena ^{[29
]}

Peloso, Gina M. ^{[2
,27
,28
]}

Poplin, Ryan ^{[18
]}

Rivas, Manuel A. ^{[2
]}

Ruano-Rubio, Valentin ^{[18
]}

Rose, Samuel A. ^{[6
]}

Ruderfer, Douglas M. ^{[19
,20
,24
]}

Shakir, Khalid ^{[18
]}

Stenson, Peter D. ^{[16
]}

Stevens, Christine ^{[2
]}

Thomas, Brett P. ^{[1
,2
]}

Tiao, Grace ^{[18
]}

Tusie-Luna, Maria T. ^{[30
]}

Weisburd, Ben ^{[2
]}

Won, Hong-Hee ^{[31
]}

Yu, Dongmei ^{[6
,25
,27
,32
]}

Altshuler, David M. ^{[2
,33
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Univ Sydney, Sch Paediat & Child Hlth, Sydney, NSW 2145, Australia

[4] Childrens Hosp VVestmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia

[5] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[7] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[8] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[9] Imperial Coll London, Natl Heart & Lung Inst, London SW7 2AZ, England

[10] Royal Brompton Hosp, NIHR Royal Brompton Cardiovasc Biomed Res Unit, London SW3 6NP, England

[11] Imperial Coll London, MRC Clin Sci Ctr, London SW7 2AZ, England

[12] Univ Washington, Genome Sci, Seattle, WA 98195 USA

[13] Harvard Med Sch, Program Bioinformat & Integrat Genom, Boston, MA 02115 USA

[14] Jackson Lab, Mouse Genome Informat, 600 Main St, Bar Harbor, ME 04609 USA

[15] Univ Arizona, Ctr Biomed Informat & Biostat, Tucson, AZ 85721 USA

[16] Cardiff Univ, Inst Med Genet, Cardiff CF10 3XQ, S Glam, Wales

[17] Google, Mountain View, CA 94043 USA

[18] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[19] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[20] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA

[21] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[22] Icahn Sch Med Mt Sinai, Ctr Stat Genet, New York, NY 10029 USA

[23] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[24] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[25] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[26] Harvard Med Sch, Boston, MA 02115 USA

[27] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[28] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[29] Inst Nacl Med Genom, Immunogen & Metab Dis Lab, Mexico City 14610, DF, Mexico

[30] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mol Biol & Genom Med Unit, Mexico City 14080, DF, Mexico

[31] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol SAIHST, Seoul, South Korea

[32] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[33] Vertex Pharmaceut, Boston, MA 02210 USA

[34] Univ Hosp, Dept Cardiol, I-43100 Parma, Italy

[35] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[36] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[37] Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England

[38] Hosp Mar Med Res Inst, Cardiovasc Epidemiol & Genet, Barcelona 08003, Spain

[39] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[40] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[41] SUNY Upstate Med Univ, Psychiat Genet Epidemiol & Neurobiol Lab, Syracuse, NY 13210 USA

[42] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA

[43] SUNY Upstate Med Univ, Dept Neurobiol & Physiol, Syracuse, NY 13210 USA

[44] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden

[45] Univ Eastern Finland, Dept Med, Kuopio 70211, Finland

[46] Kuopio Univ Hosp, Kuopio 70211, Finland

[47] Univ Oxford, Wellcome Trust Ctr Human Genet, S Parks Rd, Oxford OX1 2JD, England

[48] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, S Parks Rd, Oxford OX1 2JD, England

[49] Oxford Univ Hosp Fdn Trust, Oxford NIHR Biomed Res Ctr, Oxford OX1 2JD, England

[50] Cedars Sinai Med Ctr, Inflammatory Bowel Dis & Immunobiol Res Inst, Los Angeles, CA 90048 USA

来源：

NATURE | 2016年 / 536卷 / 7616期

关键词：

HUMAN-POPULATION HISTORY; SEQUENCE VARIANTS; MUTATION; GUIDELINES; EVOLUTION; FRAMEWORK;

D O I：

10.1038/nature19057

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

引用

页码：285 / +

页数：13

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