Somatic mutation rates scale with lifespan across mammals

TLDR

Somatic mutation rates and patterns are largely unknown outside humans, and comparative studies can illuminate their diversity and evolutionary links to cancer and ageing. The authors sequenced 208 intestinal crypts from 56 individuals spanning 16 mammalian species to map the landscape of somatic mutations. They found that endogenous mutational processes dominate across species, with mutation rates per year inversely correlated with lifespan and a roughly three‑fold variation in lifetime burden despite 30‑fold lifespan and 40,000‑fold body‑mass differences, indicating evolutionary constraints that may influence ageing.

Abstract

Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans 1–7 . Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans 8 , although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined—including variation of around 30-fold in lifespan and around 40,000-fold in body mass—the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.