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.

Variation in the molecular clock of primates

“…(Because CGI are often hypomethylated, we remove these regions from this analysis, and, unless specified otherwise, refer to transitions at CpG sites outside of CGIs as "CpG transitions.") Mathematical modeling of different substitution mechanisms predicts that mutations that are nonreplicative in origin and highly inefficiently repaired should depend on absolute time, rather than on the number of cell divisions, and hence should be more clocklike among species (21). In contrast, mutations that arise from replication errors, or are nonreplicative in origin but well repaired, should depend on the generation time and other life history traits, and therefore their substitution rates could vary considerably across primates (21,33).…”

“…Mathematical modeling of different substitution mechanisms predicts that mutations that are nonreplicative in origin and highly inefficiently repaired should depend on absolute time, rather than on the number of cell divisions, and hence should be more clocklike among species (21). In contrast, mutations that arise from replication errors, or are nonreplicative in origin but well repaired, should depend on the generation time and other life history traits, and therefore their substitution rates could vary considerably across primates (21,33). Thus, a priori, we expect CpG transitions outside CGI to be more clocklike than other types of substitutions (assuming similar rates of deamination across species).…”

“…To this end, we use a model introduced by Amster and Sella (33) to describe mutations that are replicative in origin, which should also apply to mutations that are nonreplicative but well repaired (21). This model relates substitution rates to sex-specific life history and reproductive traits, and thus predicts how substitution rates are expected to differ among species.…”

“…For example, in mammals, CpG transitions show the least amount of variation in substitution rates among species (6). A plausible explanation is the source of mutations, as transitions at methylated CpG sites are thought to occur primarily through spontaneous deamination; if they arise at a constant rate and their repair is inefficient relative to the cell cycle length, as is thought to be the case, then their mutation rate should depend largely on absolute time, rather than the number of cell divisions (20)(21)(22).…”

DNA sequence diversity and the efficiency of natural selection in animal mitochondrial DNA

“…interaction between genetic diversity and the efficiency of selection that will tend to make the slope of the relationship between log(π N /π S ) and log(π S ) steeper. However, the importance of this effect remains unclear: although some studies have found evidence to suggest that there is a negative correlation between N e and μ (Piganeau and EyreWalker, 2009;Lynch, 2010;Cutter et al, 2013), the theory predicts a relatively small effect of N e on μ that could be masked by the impact of other influences on μ, such as rate of sperm production and exposure to mutagens (Gao et al, 2016). In addition, the theory suggests that the mutation rate of a species is reduced as far as possible by selection, with genetic drift preventing selection from further reducing the rate (Lynch, 2011).…”