Disease as a mediator of somatic mutation-life history coevolution

Abstract

Multicellular organisms are confronted not only with germline mutations, but also with mutations emerging in somatic cells. Somatic mutations can lead to diverse pathologies, including cancer. Somatic mutation rate (SMR) can be constrained by evolved protection mechanisms, notably those repairing damaged DNA, or eliminating or slowing the growth of mutated cells. However, in a broader context, life history traits such as body mass, age of first reproduction and reproductive lifespan can also be subject to selection due to the negative fitness impacts of disease. Here, I analyze a simple coevolutionary model of somatic mutation rate and lifespan. The trait dynamics are formulated as an evolutionary-response system through an explicit, frequency-dependent invasion-fitness function. Evolution in the model is driven in part by the negative fitness impacts of disease, represented phenomenologically as increasing with both SMR and lifespan. I investigate relations between selective forces and (co)evolutionary responses, notably showing the possibility of either monotone or oscillatory non-equilibrium dynamics and fast or slow returns to equilibrium. Model predictions are then compared to recently published data on body mass, lifespan and somatic mutation rate. I show that the model (1) can explain the non-linear empirical relationship between somatic mutation and lifespan, (2) predicts the evolution of longer lifespans through a heretofore ignored feedback loop, (3) predicts opposite body-mass scaling of cumulative mutational burden and lifespan-normalized mutation rate, and (4) is compatible with observed linear mutation accumulation with age reflecting a hypothesized washing-out of highly mutated cells. I discuss the findings and their generality to somatic diseases, notably cancers and to aging itself.