西亚试剂：A Systematic Survey of Loss-of-Function

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

Daniel G. MacArthur1,2,*, Suganthi Balasubramanian3,4, Adam Frankish1, Ni Huang1, James Morris1, Klaudia Walter1, Luke Jostins1, Lukas Habegger3,4, Joseph K. Pickrell5, Stephen B. Montgomery6,7, Cornelis A. Albers1,8, Zhengdong D. Zhang9, Donald F. Conrad10, Gerton Lunter11, Hancheng Zheng12, Qasim Ayub1, Mark A. DePristo13, Eric Banks13, Min Hu1, Robert E. Handsaker13,14, Jeffrey A. Rosenfeld15, Menachem Fromer13, Mike Jin3, Xinmeng Jasmine Mu3,4, Ekta Khurana3,4, Kai Ye16, Mike Kay1, Gary Ian Saunders1, Marie-Marthe Suner1, Toby Hunt1, If H. A. Barnes1, Clara Amid1,17, Denise R. Carvalho-Silva1, Alexandra H. Bignell1, Catherine Snow1, Bryndis Yngvadottir1, Suzannah Bumpstead1, David N. Cooper18, Yali Xue1, Irene Gallego Romero1,5, 1000 Genomes Project Consortium, Jun Wang12, Yingrui Li12, Richard A. Gibbs19, Steven A. McCarroll13,14, Emmanouil T. Dermitzakis7, Jonathan K. Pritchard5,20, Jeffrey C. Barrett1, Jennifer Harrow1, Matthew E. Hurles1, Mark B. Gerstein3,4,21,†, Chris Tyler-Smith1,†

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