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

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-Mart

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