Identification of a large set of rare complete human knockouts

Nat Genet. 2015 May;47(5):448-52. doi: 10.1038/ng.3243. Epub 2015 Mar 25.


Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).

MeSH terms

  • Brain / metabolism
  • Female
  • Gene Expression
  • Gene Frequency
  • Gene Ontology
  • Genome, Human
  • Heterozygote
  • Homozygote
  • Humans
  • INDEL Mutation*
  • Male
  • Open Reading Frames
  • Organ Specificity
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA