A systematic survey of loss-of-function variants in human protein-coding genes

Zheng, X.; Zhou, Y.; Zheng Bradley, X.; Zöllner, S.; Zilversmit, M.; Dg, MacArthur; MacArthur, Daniel G.; Jk, Pickrell; Sb, Montgomery; Ma, DePristo; Jin, M.; Dr, Carvalho Silva; Consortium, Genomes Project; Balasubramanian, Suganthi; Altshuler, D.; Rm, Durbin; Gr, Abecasis; Dr, Bentley; Chakravarti, A.; Ag, Clark; Frankish, Adam; Fs, Collins; Fm, De La Vega; Donnelly, P.; Egholm, M.; Flicek, P.; Sb, Gabriel; Huang, Ni; Bm, Knoppers; Es, Lander; Lehrach, H.; Er, Mardis; Ga, McVean; Ca, Albers; Da, Nickerson; Morris, James; Peltonen, L.; Aj, Schafer; St, Sherry; Zd, Zhang; Wang, J.; Wilson, R.; Deiros, D.; Walter, Klaudia; Metzker, M.; Df, Conrad; Muzny, D.; Reid, J.; Wheeler, D.; Li, J.; Jian, M.; Jostins, Luke; Li, G.; Li, R.; Liang, H.; Tian, G.; Wang, B.; Wang, W.; Yang, H.; Zhang, X.; Habegger, Lukas; Dl, Altshuler; Ambrogio, L.; Bloom, T.; Cibulskis, K.; Tj, Fennell; Db, Jaffe; Shefler, E.; Pickrell, Joseph K.; Cl, Sougnez; Zhang, Zhengdong D.; Gormley, N.; Humphray, S.; Kingsbury, Z.; Re, Handsaker; Kokko Gonzales, P.; Montgomery, Stephen B.; Stone, J.; Kj, McKernan; Gl, Costa; Ja, Rosenfeld; Zhang, Z. D.; Jk, Ichikawa; Cc, Lee; Albers, Cornelis A.; Sudbrack, R.; Ta, Borodina; Dahl, A.; An, Davydov; Marquardt, P.; Mertes, F.; Nietfeld, W.; Rosenstiel, P.; Schreiber, S.; Xj, Mu; Av, Soldatov; Timmermann, Bernd; Tolzmann, M.; Affourtit, J.; Ashworth, D.; Attiya, S.; Conrad, Donald F.; Bachorski, M.; Buglione, E.; Burke, A.; Caprio, A.; Celone, C.; Clark, S.; Conners, D.; Lunter, Gerton; Desany, B.; Gu, L.; Gi, Saunders; Guccione, L.; Kao, K.; Kebbler, J.; Knowlton, J.; Zheng, Hancheng; Mm, Suner; Labrecque, M.; McDade, L.; Mealmaker, C.; Minderman, M.; Nawrocki, A.; Niazi, F.; Ayub, Qasim; Pareja, K.; Ramenani, R.; Ih, Barnes; Riches, D.; Song, W.; Turcotte, C.; Wang, S.; Rk, Wilson; DePristo, Mark A.; Dooling, D.; Fulton, L.; Fulton, R.; Weinstock, G.; Burton, J.; Dm, Carter; Ah, Bignell; Banks, Eric; Churcher, C.; Coffey, A.; Cox, A.; Palotie, A.; Quail, M.; Skelly, T.; Stalker, J.; Hu, Min; Hp, Swerdlow; Turner, D.; De Witte, A.; Giles, S.; Bainbridge, M.; Challis, D.; Sabo, A.; Handsaker, Robert E.; Dn, Cooper; Yu, F.; Yu, J.; Fang, X.; Guo, X.; Li, Y.; Luo, R.; Tai, S.; Rosenfeld, Jeffrey A.; Wu, H.; Ig, Romero; Jin, Mike; Gt, Marth; Ep, Garrison; Huang, W.; Indap, A.; Fromer, Menachem; Kural, D.; Wp, Lee; Wf, Leong; Ar, Quinlan; Stewart, C.; Mp, Stromberg; An, Ward; Wu, J.; Lee, C.; Re, Mills; Shi, X.; Mj, Daly; Ad, Ball; Bl, Browning; Kv, Garimella; Mu, Xinmeng Jasmine; Sr, Grossman; Ra, Gibbs; Hanna, M.; Hartl, C.; Am, Kernytsky; Jm, Korn; Li, H.; Khurana, Ekta; Jr, Maguire; McKenna, A.; Jc, Nemesh; Aa, Philippakis; Re, Poplin; Price, A.; Ma, Rivas; Ye, Kai; Pc, Sabeti; Sf, Schaffner; Ia, Shlyakhter; Ev, Ball; Mort, M.; Ad, Phillips; Pd, Stenson; Kay, Mike; Sebat, J.; Makarov, V.; Sc, Yoon; Cd, Bustamante; Boyko, A.; Degenhardt, J.; Gravel, S.; Rn, Gutenkunst; Saunders, Gary Ian; Kaganovich, M.; Keinan, A.; Lacroute, P.; Ma, X.; Reynolds, A.; Clarke, L.; Cunningham, F.; Suner, Marie-Marthe; Herrero, J.; Keenen, S.; Kulesha, E.; Leinonen, R.; Wm, McLaren; Radhakrishnan, R.; Hunt, Toby; Re, Smith; Zalunin, V.; Jo, Korbel; Am, Stütz; Bauer, M.; Rk, Cheetham; Cox, T.; Eberle, M.; Barnes, If H. A.; James, T.; Kahn, S.; Murray, L.; Fu, Y.; Fc, Hyland; Jm, Manning; Amid, Clara; Sf, McLaughlin; He, Peckham; Sakarya, O.; Ya, Sun; Ef, Tsung; Ma, Batzer; Mk, Konkel; Ja, Walker; Carvalho-Silva, Denise R.; Mw, Albrecht; Vs, Amstislavskiy; Herwig, R.; Dv, Parkhomchuk; Agarwala, R.; Hm, Khouri; Bignell, Alexandra H.; Ao, Morgulis; Je, Paschall; Ld, Phan; Ke, Rotmistrovsky; Sa, McCarroll; Rd, Sanders; Mf, Shumway; Snow, Catherine; Xiao, C.; Auton, A.; Iqbal, Z.; Jl, Marchini; Moutsianas, L.; Myers, S.; Tumian, A.; Yngvadottir, Bryndis; Knight, J.; Winer, R.; Dw, Craig; Sm, Beckstrom Sternberg; Christoforides, A.; Aa, Kurdoglu; Jv, Pearson; Bumpstead, Suzannah; Sa, Sinari; Wd, Tembe; Haussler, D.; As, Hinrichs; Sj, Katzman; Kern, A.; Rm, Kuhn; Przeworski, M.; Cooper, David Neil; Rd, Hernandez; Howie, B.; Jl, Kelley; Sc, Melton; Anderson, P.; Blackwell, T.; Chen, W.; Xue, Yali; Wo, Cookson; Ding, J.; Hm, Kang; Lathrop, M.; Liang, L.; Mf, Moffatt; Scheet, P.; Sidore, C.; Romero, Irene Gallego; Genomes Project, C.; Snyder, M.; 1000, Genomes Project Consortium; Zhan, X.; Awadalla, P.; Casals, F.; Idaghdour, Y.; Keebler, J.; Wang, Jun; Ea, Stone; Jorde, L.; Xing, J.; Ee, Eichler; Aksay, G.; Alkan, C.; Li, Yingrui; Hajirasouliha, I.; Hormozdiari, F.; Jm, Kidd; Sc, Sahinalp; Ph, Sudmant; Chen, K.; Chinwalla, A.; Ding, L.; Gibbs, Richard A.; Dc, Koboldt; Md, McLellan; Jw, Wallis; Mc, Wendl; Zhang, Q.; Balasubramaniam, S.; McCarroll, Steven A.; Chen, Y.; Danecek, P.; Jin, H.; Tm, Keane; Et, Dermitzakis; Sq, Le; Lindsay, S.; Dermitzakis, Emmanouil T.; Long, Q.; Parts, L.; Zhang, Y.; Jc, Barrett; Abyzov, A.; Bjornson, R.; Du, J.; Pritchard, Jonathan K.; Grubert, F.; Haraksingh, R.; Jee, J.; Hy, Lam; Leng, J.; Me, Hurles; Ae, Urban; Barrett, Jeffrey C.; Zhang, Z.; Coafra, C.; Dinh, H.; Kovar, C.; Lee, S.; Nazareth, L.; Wilkinson, J.; Mb, Gerstein; Scott, C.; Gharani, N.; Harrow, Jennifer; Js, Kaye; Kent, A.; Li, T.; Al, McGuire; Pn, Ossorio; Cn, Rotimi; Hurles, Matthew E.; Su, Y.; Lh, Toji; Ld, Brooks; Al, Felsenfeld; Je, McEwen; Abdallah, A.; Cr, Juenger; Gerstein, Mark B.; Nc, Clemm; Duncanson, A.; Ed, Green; Ms, Guyer; Jl, Peterson; Cartwright R. A. Wang, J.; Tyler-Smith, Chris; Jk, Pritchard

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A systematic survey of loss-of-function variants in human protein-coding genes

Journal article published in 2012 by X. Zheng, Y. Zhou, X. Zheng Bradley, S. Zöllner, M. Zilversmit, MacArthur Dg, Daniel G. MacArthur, Pickrell Jk, Montgomery Sb, DePristo Ma, M. Jin, Carvalho Silva Dr, Genomes Project Consortium, Suganthi Balasubramanian, D. Altshuler and other authors.

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Abstract

Defective Gene Detective Identifying genes that give rise to diseases is one of the major goals of sequencing human genomes. However, putative loss-of-function genes, which are often some of the first identified targets of genome and exome sequencing, have often turned out to be sequencing errors rather than true genetic variants. In order to identify the true scope of loss-of-function genes within the human genome, MacArthur et al. (p. 823 ; see the Perspective by Quintana-Murci ) extensively validated the genomes from the 1000 Genomes Project, as well as an additional European individual, and found that the average person has about 100 true loss-of-function alleles of which approximately 20 have two copies within an individual. Because many known disease-causing genes were identified in “normal” individuals, the process of clinical sequencing needs to reassess how to identify likely causative alleles.

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A systematic survey of loss-of-function variants in human protein-coding genes

Abstract