Disease as a Mediator of Somatic Mutation - Fitspan Coevolution: Model Analysis and Empirical Tests

Multicellular organisms are confronted not only with germline mutations, but also mutations emerging in somatic cells. Somatic mutations can lead to various conditions, diseases, and cancers in particular. Somatic mutation rate is limited by evolved protection mechanisms, notably those repairing damaged DNA or eliminating 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 (SMR) and fitness lifespan (hereafter called ‘fitspan’), the latter measured as the age at which inclusive fitness becomes negligible. Evolution in the model is driven by the fitness costs of disease, because as organisms age: disease is more extensive, disease prevention mechanisms are less effective and more costly, and fitness payoffs of disease prevention are lower. 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. I then compare model predictions 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, and (3) the model is consistent with the idea that the linear relation between somatic mutation accumulation and age is the net result of mutational washing-out. I argue that the findings here generalize to other decreases in condition with age that are submitted to selection, including aging itself.