Genome-wide patterns and properties of de novo mutations in humans

Nat Genet. 2015 Jul;47(7):822-826. doi: 10.1038/ng.3292. Epub 2015 May 18.


Mutations create variation in the population, fuel evolution and cause genetic diseases. Current knowledge about de novo mutations is incomplete and mostly indirect. Here we analyze 11,020 de novo mutations from the whole genomes of 250 families. We show that de novo mutations in the offspring of older fathers are not only more numerous but also occur more frequently in early-replicating, genic regions. Functional regions exhibit higher mutation rates due to CpG dinucleotides and show signatures of transcription-coupled repair, whereas mutation clusters with a unique signature point to a new mutational mechanism. Mutation and recombination rates independently associate with nucleotide diversity, and regional variation in human-chimpanzee divergence is only partly explained by heterogeneity in mutation rate. Finally, we provide a genome-wide mutation rate map for medical and population genetics applications. Our results provide new insights and refine long-standing hypotheses about human mutagenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Animals
  • Evolution, Molecular
  • Female
  • Genome, Human
  • Germ-Line Mutation*
  • Humans
  • Male
  • Models, Genetic
  • Mutation Rate
  • Pan troglodytes / genetics
  • Paternal Age