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

Daniel G. MacArthur, Suganthi Balasubramanian, Adam Frankish, Ni Huang, James Morris, Klaudia Walter, Luke Jostins, Lukas Habegger, Joseph K. Pickrell, Stephen B. Montgomery, Cornelis A. Albers, Zhengdong Zhang, Donald F. Conrad, Gerton Lunter, Hancheng Zheng, Qasim Ayub, Mark A. DePristo, Eric Banks, Min Hu, Robert E. HandsakerJeffrey A. Rosenfeld, Menachem Fromer, Mike Jin, Xinmeng Jasmine Mu, Ekta Khurana, Kai Ye, Mike Kay, Gary Ian Saunders, Marie Marthe Suner, Toby Hunt, If H A Barnes, Clara Amid, Denise R. Carvalho-Silva, Alexandra H. Bignell, Catherine Snow, Bryndis Yngvadottir, Suzannah Bumpstead, David N. Cooper, Yali Xue, Irene Gallego Romero, Jun Wang, Yingrui Li, Richard A. Gibbs, Steven A. McCarroll, Emmanouil T. Dermitzakis, Jonathan K. Pritchard, Jeffrey C. Barrett, Jennifer Harrow, Matthew E. Hurles, Mark B. Gerstein, Chris Tyler-Smith

Research output: Contribution to journalArticle

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Abstract

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 ∼100 genuine LoF variants with ∼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.

Original languageEnglish (US)
Pages (from-to)823-828
Number of pages6
JournalScience
Volume335
Issue number6070
DOIs
StatePublished - Feb 17 2012

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Human Genome
Genes
Recessive Genes
Proteins
Alleles
Genome
Surveys and Questionnaires

ASJC Scopus subject areas

  • General

Cite this

MacArthur, D. G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., ... Tyler-Smith, C. (2012). A systematic survey of loss-of-function variants in human protein-coding genes. Science, 335(6070), 823-828. https://doi.org/10.1126/science.1215040

A systematic survey of loss-of-function variants in human protein-coding genes. / MacArthur, Daniel G.; Balasubramanian, Suganthi; Frankish, Adam; Huang, Ni; Morris, James; Walter, Klaudia; Jostins, Luke; Habegger, Lukas; Pickrell, Joseph K.; Montgomery, Stephen B.; Albers, Cornelis A.; Zhang, Zhengdong; Conrad, Donald F.; Lunter, Gerton; Zheng, Hancheng; Ayub, Qasim; DePristo, Mark A.; Banks, Eric; Hu, Min; Handsaker, Robert E.; Rosenfeld, Jeffrey A.; Fromer, Menachem; Jin, Mike; Mu, Xinmeng Jasmine; Khurana, Ekta; Ye, Kai; Kay, Mike; Saunders, Gary Ian; Suner, Marie Marthe; Hunt, Toby; Barnes, If H A; Amid, Clara; Carvalho-Silva, Denise R.; Bignell, Alexandra H.; Snow, Catherine; Yngvadottir, Bryndis; Bumpstead, Suzannah; Cooper, David N.; Xue, Yali; Romero, Irene Gallego; Wang, Jun; Li, Yingrui; Gibbs, Richard A.; McCarroll, Steven A.; Dermitzakis, Emmanouil T.; Pritchard, Jonathan K.; Barrett, Jeffrey C.; Harrow, Jennifer; Hurles, Matthew E.; Gerstein, Mark B.; Tyler-Smith, Chris.

In: Science, Vol. 335, No. 6070, 17.02.2012, p. 823-828.

Research output: Contribution to journalArticle

MacArthur, DG, Balasubramanian, S, Frankish, A, Huang, N, Morris, J, Walter, K, Jostins, L, Habegger, L, Pickrell, JK, Montgomery, SB, Albers, CA, Zhang, Z, Conrad, DF, Lunter, G, Zheng, H, Ayub, Q, DePristo, MA, Banks, E, Hu, M, Handsaker, RE, Rosenfeld, JA, Fromer, M, Jin, M, Mu, XJ, Khurana, E, Ye, K, Kay, M, Saunders, GI, Suner, MM, Hunt, T, Barnes, IHA, Amid, C, Carvalho-Silva, DR, Bignell, AH, Snow, C, Yngvadottir, B, Bumpstead, S, Cooper, DN, Xue, Y, Romero, IG, Wang, J, Li, Y, Gibbs, RA, McCarroll, SA, Dermitzakis, ET, Pritchard, JK, Barrett, JC, Harrow, J, Hurles, ME, Gerstein, MB & Tyler-Smith, C 2012, 'A systematic survey of loss-of-function variants in human protein-coding genes', Science, vol. 335, no. 6070, pp. 823-828. https://doi.org/10.1126/science.1215040
MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012 Feb 17;335(6070):823-828. https://doi.org/10.1126/science.1215040
MacArthur, Daniel G. ; Balasubramanian, Suganthi ; Frankish, Adam ; Huang, Ni ; Morris, James ; Walter, Klaudia ; Jostins, Luke ; Habegger, Lukas ; Pickrell, Joseph K. ; Montgomery, Stephen B. ; Albers, Cornelis A. ; Zhang, Zhengdong ; Conrad, Donald F. ; Lunter, Gerton ; Zheng, Hancheng ; Ayub, Qasim ; DePristo, Mark A. ; Banks, Eric ; Hu, Min ; Handsaker, Robert E. ; Rosenfeld, Jeffrey A. ; Fromer, Menachem ; Jin, Mike ; Mu, Xinmeng Jasmine ; Khurana, Ekta ; Ye, Kai ; Kay, Mike ; Saunders, Gary Ian ; Suner, Marie Marthe ; Hunt, Toby ; Barnes, If H A ; Amid, Clara ; Carvalho-Silva, Denise R. ; Bignell, Alexandra H. ; Snow, Catherine ; Yngvadottir, Bryndis ; Bumpstead, Suzannah ; Cooper, David N. ; Xue, Yali ; Romero, Irene Gallego ; Wang, Jun ; Li, Yingrui ; Gibbs, Richard A. ; McCarroll, Steven A. ; Dermitzakis, Emmanouil T. ; Pritchard, Jonathan K. ; Barrett, Jeffrey C. ; Harrow, Jennifer ; Hurles, Matthew E. ; Gerstein, Mark B. ; Tyler-Smith, Chris. / A systematic survey of loss-of-function variants in human protein-coding genes. In: Science. 2012 ; Vol. 335, No. 6070. pp. 823-828.
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abstract = "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 ∼100 genuine LoF variants with ∼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.",
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AU - MacArthur, Daniel G.

AU - Balasubramanian, Suganthi

AU - Frankish, Adam

AU - Huang, Ni

AU - Morris, James

AU - Walter, Klaudia

AU - Jostins, Luke

AU - Habegger, Lukas

AU - Pickrell, Joseph K.

AU - Montgomery, Stephen B.

AU - Albers, Cornelis A.

AU - Zhang, Zhengdong

AU - Conrad, Donald F.

AU - Lunter, Gerton

AU - Zheng, Hancheng

AU - Ayub, Qasim

AU - DePristo, Mark A.

AU - Banks, Eric

AU - Hu, Min

AU - Handsaker, Robert E.

AU - Rosenfeld, Jeffrey A.

AU - Fromer, Menachem

AU - Jin, Mike

AU - Mu, Xinmeng Jasmine

AU - Khurana, Ekta

AU - Ye, Kai

AU - Kay, Mike

AU - Saunders, Gary Ian

AU - Suner, Marie Marthe

AU - Hunt, Toby

AU - Barnes, If H A

AU - Amid, Clara

AU - Carvalho-Silva, Denise R.

AU - Bignell, Alexandra H.

AU - Snow, Catherine

AU - Yngvadottir, Bryndis

AU - Bumpstead, Suzannah

AU - Cooper, David N.

AU - Xue, Yali

AU - Romero, Irene Gallego

AU - Wang, Jun

AU - Li, Yingrui

AU - Gibbs, Richard A.

AU - McCarroll, Steven A.

AU - Dermitzakis, Emmanouil T.

AU - Pritchard, Jonathan K.

AU - Barrett, Jeffrey C.

AU - Harrow, Jennifer

AU - Hurles, Matthew E.

AU - Gerstein, Mark B.

AU - Tyler-Smith, Chris

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