Reproductive life history may modulate selection on the germline mutation rate

Abstract

AbstractA long lifespan is a potential liability from the point of view of mutation accumulation, allowing more time for cancer-causing mutations to accumulate in somatic tissues. In practice, however, long-lived organisms do not seem to suffer more cancer mortality than short-lived organisms, a pattern known as “Peto’s Paradox.” One suggested resolution to Peto’s Paradox is that long lifespans may facilitate the evolution of better somatic DNA repair. This comes into some conflict with the predictions of the drift-barrier hypothesis of mutation rate evolution, which infers that germline DNA repair efficacy should be best in short-lived organisms with high genetic diversity and efficient natural selection. Here, we show that this conflict can be resolved by modeling the tendency of long generation times to increase the strength of selection against mutator alleles that affect clocklike mutational processes. By considering the empirical joint distribution of generation time and effective population size, we show that stronger selection against mutator alleles in long-lived organisms is likely to be partially but not completely offset by their tendency to have low effective population sizes. This model resolves a conflict between the predictions of theories of germline and somatic mutation rate evolution, leading to the prediction that both germline and somatic DNA repair should be most efficient in long-lived organisms despite their lower genetic diversity.Significance StatementAll cells accumulate mutations due to DNA damage and replication errors. Mutations affecting the germline can harm future offspring, while mutations in other tissues can threaten longevity. Previous theories have predicted that somatic DNA repair should be most effective in long-lived organisms, but that germline DNA repair should instead be most effective in organisms with high genetic diversity that tend to be short-lived. We model how reproductive age should affect germline mutation rate evolution and show that this may reverse the prediction that high-diversity species should have more efficient selection for effective germline DNA repair. By demonstrating how population sizeandlifespan likely shape selection on mutagenesis, we are able to harmonize predictions about germline and somatic mutation rate evolution.