Mutation rate variation as the neutral byproduct of developmental and life-history diversification

Understanding why species differ in their rates of mutation is central to explaining patterns of molecular and phenotypic evolution. Mutation rates are often assumed to evolve primarily through selection acting on molecular mechanisms that control DNA replication, repair, and damage. Prominently, the drift-barrier hypothesis proposes that selection tends to purge mutator alleles as they tend to increase deleterious mutation rates, leading to a negative correlation between population size (Ne) and generational mutation rate (μpop). Here, we propose and test an alternative, yet compatible, framework-the life-history hypothesis of mutation rate variation-which posits that generational mutation rates diversify passively as a byproduct of diversification in developmental and life-history traits, without requiring selection acting on mutator alleles. Using developmental models integrated with evolutionary simulations, we show that the empirically observed negative correlation between effective population size Ne and μpop can arise neutrally from covariation with body size and developmental parameters. Our results also reveal that the life-history hypothesis can easily capture variation in μpop at short-to-medium evolutionary timescales, where the drift-barrier hypothesis would require a high rate of emergence of mutator alleles and a high fraction of deleterious mutations. Comparative phylogenetic analyses of mammalian clades further support this view, revealing that covariation between body mass, generation time, and μpop among closely related species is sufficient to explain the observed variation in mutation rates. Together, these findings suggest that developmental and organismal properties play a central role in shaping mutation rate diversity, providing a unified framework linking molecular evolution to the evolution of life histories in multicellular organisms.