A Systematic Survey of Loss-of-Function Variants in Human Protein-Coding Genes

被引：880

作者：

MacArthur, Daniel G. ^{[1
,2
]}

Balasubramanian, Suganthi ^{[3
,4
]}

Frankish, Adam ^{[1
]}

Huang, Ni ^{[1
]}

Morris, James ^{[1
]}

Walter, Klaudia ^{[1
]}

Jostins, Luke ^{[1
]}

Habegger, Lukas ^{[3
,4
]}

Pickrell, Joseph K. ^{[5
]}

Montgomery, Stephen B. ^{[6
,7
,8
]}

Albers, Cornelis A. ^{[1
,9
,10
]}

Zhang, Zhengdong D. ^{[11
]}

Conrad, Donald F. ^{[12
]}

Lunter, Gerton ^{[13
]}

Zheng, Hancheng ^{[14
]}

Ayub, Qasim ^{[1
]}

DePristo, Mark A. ^{[15
]}

Banks, Eric ^{[15
]}

Hu, Min ^{[1
]}

Handsaker, Robert E. ^{[15
,16
]}

Rosenfeld, Jeffrey A. ^{[17
]}

Fromer, Menachem ^{[15
]}

Jin, Mike ^{[3
]}

Mu, Xinmeng Jasmine ^{[3
,4
]}

Khurana, Ekta ^{[3
,4
]}

Ye, Kai ^{[18
]}

Kay, Mike ^{[1
]}

Saunders, Gary Ian ^{[1
]}

Suner, Marie-Marthe ^{[1
]}

Hunt, Toby ^{[1
]}

Barnes, If H. A. ^{[1
]}

Amid, Clara ^{[1
,19
]}

Carvalho-Silva, Denise R. ^{[1
]}

Bignell, Alexandra H. ^{[1
]}

Snow, Catherine ^{[1
]}

Yngvadottir, Bryndis ^{[1
]}

Bumpstead, Suzannah ^{[1
]}

Cooper, David N. ^{[20
]}

Xue, Yali ^{[1
]}

Romero, Irene Gallego ^{[1
,5
]}

Wang, Jun ^{[14
]}

Li, Yingrui ^{[14
]}

Gibbs, Richard A. ^{[21
]}

McCarroll, Steven A. ^{[15
,16
]}

Dermitzakis, Emmanouil T. ^{[8
]}

Pritchard, Jonathan K. ^{[5
,22
]}

Barrett, Jeffrey C. ^{[1
]}

Harrow, Jennifer ^{[1
]}

Hurles, Matthew E. ^{[1
]}

Gerstein, Mark B. ^{[3
,4
,23
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[2] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia

[3] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA

[4] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA

[5] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[6] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[8] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland

[9] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England

[10] NHS Blood & Transplant, Cambridge CB2 0PT, England

[11] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA

[12] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[13] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[14] BGI Shenzhen, Shenzhen 518083, Peoples R China

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

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

[17] Univ Med & Dent New Jersey, IST High Performance & Res Comp, Newark, NJ 07103 USA

[18] Leiden Univ, Med Ctr, Mol Epidemiol Sect, NL-2300 RC Leiden, Netherlands

[19] European Bioinformat Inst, European Mol Biol Lab, Hinxton CB10 1SD, England

[20] Cardiff Univ, Sch Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales

[21] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[22] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA

[23] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA

来源：

SCIENCE | 2012年 / 335卷 / 6070期

基金：

英国生物技术与生命科学研究理事会; 瑞士国家科学基金会; 英国惠康基金; 英国医学研究理事会; 中国国家自然科学基金;

关键词：

POSITIVE SELECTION; ANNOTATION; MECHANISMS; NUMBER; FORM;

D O I：

10.1126/science.1215040

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：

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain similar to 100 genuine LoF variants with similar to 20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

引用

页码：823 / 828

页数：6

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