Determinants of mutation rate variation in the human germline

Annu Rev Genomics Hum Genet. 2014;15:47-70. doi: 10.1146/annurev-genom-031714-125740. Epub 2014 Jun 5.


Because germline mutations are the source of all evolutionary adaptations and heritable diseases, characterizing their properties and the rate at which they arise across individuals is of fundamental importance for human genetics. After decades during which estimates were based on indirect approaches, notably on inferences from evolutionary patterns, it is now feasible to count de novo mutations in transmissions from parents to offspring. Surprisingly, this direct approach yields a mutation rate that is twofold lower than previous estimates, calling into question our understanding of the chronology of human evolution and raising the possibility that mutation rates have evolved relatively rapidly. Here, we bring together insights from studies of human genetics and molecular evolution, focusing on where they conflict and what the discrepancies tell us about important open questions. We begin by outlining various methods for studying the properties of mutations in humans. We review what we have learned from their applications about genomic factors that influence mutation rates and the effects of sex, age, and other sources of interindividual variation. We then consider the mutation rate as a product of evolution and discuss how and why it may have changed over time in primates.

Keywords: CpG; evolution; generation time effect; germline mutation; human; paternal age effect.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA / genetics*
  • Evolution, Molecular*
  • Genome, Human
  • Genomics
  • Germ-Line Mutation*
  • Humans
  • Mutation Rate*


  • DNA