Somatic mutation rates scale with lifespan across mammals
Author:
Cagan AlexORCID, Baez-Ortega Adrian, Brzozowska Natalia, Abascal FedericoORCID, Coorens Tim H. H.ORCID, Sanders Mathijs A., Lawson Andrew R. J.ORCID, Harvey Luke M. R., Bhosle ShriramORCID, Jones DavidORCID, Alcantara Raul E., Butler Timothy M.ORCID, Hooks Yvette, Roberts Kirsty, Anderson Elizabeth, Lunn Sharna, Flach Edmund, Spiro SimonORCID, Januszczak Inez, Wrigglesworth Ethan, Jenkins Hannah, Dallas Tilly, Masters Nic, Perkins Matthew W., Deaville Robert, Druce Megan, Bogeska Ruzhica, Milsom Michael D.ORCID, Neumann Björn, Gorman Frank, Constantino-Casas Fernando, Peachey Laura, Bochynska DianaORCID, Smith Ewan St. JohnORCID, Gerstung MoritzORCID, Campbell Peter J.ORCID, Murchison Elizabeth P.ORCID, Stratton Michael R.ORCID, Martincorena IñigoORCID
Abstract
AbstractThe rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1–7. 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 humans8, 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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference73 articles.
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