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

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…

• NS
  National Science Foundation
• WT
  Wellcome Trust

  Awards: 090532, 098051, 090532/Z/09/Z, 090532/Z/09/
• BI
  Broad Institute
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• NN
  National Natural Science Foundation of China

  Awards: 30890032, 30725008
• NO
  Nederlandse Organisatie voor Wetenschappelijk Onderzoek
• GO
  Government of Jiangxi Province
• NI
  National Institutes of Health
• MR
  Medical Research Council

  Award: 098051
• BA
  Biotechnology and Biological Sciences Research Council

  Award: BB/I02593X/1
• NH
  National Health and Medical Research Council
• NH
  National High-tech Research and Development Program
• NK
  National Key Research and Development Program of China
• NI
  National Institute of Mental Health