Interpreting the Dependence of Mutation Rates on Age and Time

PLoS Biol. 2016 Jan 13;14(1):e1002355. doi: 10.1371/journal.pbio.1002355. eCollection 2016 Jan.


Mutations can originate from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that arise between replication cycles and are not repaired correctly. We introduce a model that relates the source of mutations to their accumulation with cell divisions, providing a framework for understanding how mutation rates depend on sex, age, and cell division rate. We show that the accrual of mutations should track cell divisions not only when mutations are replicative in origin but also when they are non-replicative and repaired efficiently. One implication is that observations from diverse fields that to date have been interpreted as pointing to a replicative origin of most mutations could instead reflect the accumulation of mutations arising from endogenous reactions or exogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, unless life history traits co-vary, the phylogenetic "molecular clock" should not be expected to run steadily across species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Cell Division
  • DNA Replication
  • Humans
  • Models, Genetic*
  • Mutation Rate*
  • Time Factors

Grant support

ZG was supported in part by the William Rainey Harper Fellowship from the University of Chicago. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.