Interpreting the dependence of mutation rates on age and time

TL;DR

This paper presents a model linking mutation accumulation to cell divisions, age, and time, challenging traditional views on mutation origins and implications for cancer and molecular clock assumptions.

Contribution

The paper introduces a comprehensive model connecting mutation sources to their accumulation patterns across cell divisions, age, and species.

Findings

Mutations can accrue from both replicative errors and unrepaired lesions.

Cancer incidence in rapidly renewing tissues may be influenced by mutagens, not just replication errors.

Molecular clocks may not run steadily across species due to mutation repair efficiency.

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.