Disease as a mediator of somatic mutation-life history coevolution

Abstract

Multicellular organisms are confronted not only with mutation in germline, but also mutations emerging in somatic cells. Somatic mutations can lead cancers and possibly contribute to aging phenotypes. Prevailing wisdom suggests somatic mutations are limited by evolved defences, either targeting DNA or post-mutational cellular states. Here, I analyse simple models for metazoans and humans in particular, incorporating the possibility that mutation rate trades off of organism longevity, defined as the age at which natural selection becomes negligible. The models assume selection acts to reduce mutation rate and prevent disease, both of which contribute to selecting for longer lifespan. We detail equilibrium conditions and find coevolutionary oscillations under certain parameter combinations. Notably, disease prevention can lead to mutational tolerance and this can contribute to explaining empirical cross-species patterns in longevity vs. mutation rate. We conclude that mutational disease and cancer in particular have required characteristics to be mediators of mutation rate-lifespan coevolution. The mutational tolerance that results from this coevolution can contribute to explaining the incidences of other diseases and conditions, including aging.