The evolution of mutation rates in the light of development and cell-lineage selection

Mutation rates drive the pace and potential of evolutionary change. However, to better understand the evolutionary implications of mutation rates, there is a need to uncover the causes of their diversification. In multicellular organisms, all mutations first arise in a single cell in a developmental context. Whether a mutation enters a populations gene pool can therefore depend on developmental events that affect the likelihood of mutant cell lineages of producing gametes. For this reason, the evolution of mutation rates in populations is governed not only by changes in the rates at which mutations occur at the molecular level, but also by changes in developmental features of organisms and how mutations impact cellular fitness during development. We present a theoretical framework that, supported by empirical data from mammals and experiments on the fruit fly, demonstrate how generational mutation rates can be shaped by changes in developmental parameters and intraorganismal selective processes even when molecular mutation rates are presumed constant. Our model highlights how the diversity of mutation rates observed across animals may be the byproduct of organismal development rather than the result of direct selection against mutator alleles. As such, development not only introduces phenotypic biases, it also shapes the rates and trajectories of genetic diversity and is thus at the core of evolutionary theory.