Cell-lineage selection interacts with development and life history to shape the rates and identity of heritable mutations

Mutation rates determine the supply of heritable variation and are central to evolutionary theory, yet they are usually treated as properties of molecular mutational processes. We hypothesised that mutation rates are also shaped by selection among cell lineages within organisms and that the strength of this process depends on developmental and life-history traits. To test the extent of this idea, we combined mathematical modelling with experiments in Drosophila melanogaster and treated mutation rates as emergent properties of interactions among molecular mutagenesis, development, life history, and cell-lineage selection. The model predicts that even modest effects of mutations on cellular fitness can substantially alter the probability that mutations are transmitted, and that these effects depend strongly on developmental architecture, germline dynamics, and time to reproduction. In Drosophila , we experimentally demonstrate biased transmission of a mutation affecting cellular proliferation and show that this bias changes over the reproductive lifespan of the individual. Extending the model genome-wide reveals that the cellular distribution of fitness effects and its interaction with developmental parameters influence both the estimated mutation rate and the composition of transmitted mutations, producing transmission biases that favour mutations with particular cellular fitness effects. These results suggest that developmental and life-history parameters determine how cellular fitness effects translate into transmission bias; therefore, estimates of heritable mutational input can vary from species to species even under constant molecular mutagenesis. By filtering mutations before they enter populations, developmental and life-history evolution can modify both the rate and the nature of heritable variation and thereby influence evolutionary trajectories.