The mutational constraint spectrum quantified from variation in 141,456 humans

Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769…

• NS
  National Science Foundation
• S
  Sanofi
• BP
  BioMarin Pharmaceutical
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  Award: 177853
• NI
  National Institutes of Health

  Awards: HG006493, R01 GM104371, HG008900, U24 HG008956, HD081256, MH115957, UM1 HG008900
• SG
  Sanofi Genzyme
• NI
  National Institute on Aging
• NH
  National Heart, Lung, and Blood Institute

  Awards: UM1 HG008900, U24 HG008956, UM1 HG006493, HG006493
• NI
  National Institute of Mental Health

  Award: MH115957
• NH
  National Human Genome Research Institute

  Awards: HG006493, HG008956, UM1 HG008900, UM1 HG006493, HG008900, U24 HG008956
• NC
  National Cancer Institute
• NI
  National Institute of General Medical Sciences

  Awards: R01 GM104371, GM115208
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases

  Award: U54 DK105566
• CF
  Common Fund