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 D., 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. and Tyler-Smith, Chris (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science, 335 6070: 823-828. doi:10.1126/science.1215040

Author 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 D.
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
Title A systematic survey of loss-of-function variants in human protein-coding genes
Journal name Science   Check publisher's open access policy
ISSN 1095-9203
Publication date 2012-02-17
Year available 2012
Sub-type Article (original research)
DOI 10.1126/science.1215040
Open Access Status Not yet assessed
Volume 335
Issue 6070
Start page 823
End page 828
Total pages 6
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 536 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 570 times in Scopus Article | Citations
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