title: Interpreting the Dependence of Mutation Rates on Age and Time.
abstract: 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.
authors.affiliation: Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.
authors.forename: Minyoung J
authors.initials: MJ
authors.lastname: Wyman
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.
authors.forename: Guy
authors.initials: G
authors.lastname: Sella
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.|Department of Systems Biology, Columbia University, New York, New York, United States of America.
authors.forename: Molly
authors.initials: M
authors.lastname: Przeworski
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002455:Cell Division; D004261:DNA Replication; D006801:Humans; D008957:Models, Genetic; D059645:Mutation Rate; D013997:Time Factors