Interpreting the dependence of mutation rates on age and time

Abstract

Mutations can arise from the chance misincorporation of nucleotides during DNA replication or from DNA lesions that 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 absolute time. 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 the higher incidence of cancer in rapidly renewing tissues, an observation ascribed to replication errors, could instead reflect exogenous or endogenous mutagens. We further find that only mutations that arise from inefficiently repaired lesions will accrue according to absolute time; thus, in the absence of selection on mutation rates, the phylogenetic "molecular clock" should not be expected to run steadily across species.