Abstract
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. 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.
| Original language | English |
|---|---|
| Pages (from-to) | 517–524 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 604 |
| Issue number | 7906 |
| DOIs | |
| Publication status | Published - 13 Apr 2022 |
Bibliographical note
Funding Information:We thank the staff of the Wellcome Sanger Institute for help in this project, including the Scientific Operations, Informatics and CASM support teams. This research was made possible by the worldwide information network of zoos and aquariums that are members of Species360, and is authorized by Species360 research data use and grant agreement 60633. We thank D. Conde and J. Staerk for help accessing Species360 data; and J. P. de Magalhaes, J. DeGregori, J. Vijg and M. Lynch for their comments on the manuscript. This research was funded by Wellcome (grant number 206194), the Dunhill Medical Trust (RPGF2002\188) and the Deutsche José Carreras Leukämie-Stiftung. I.M. is funded by Cancer Research UK (C57387/A21777) and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow.
Funding Information:
We thank the staff of the Wellcome Sanger Institute for help in this project, including the Scientific Operations, Informatics and CASM support teams. This research was made possible by the worldwide information network of zoos and aquariums that are members of Species360, and is authorized by Species360 research data use and grant agreement 60633. We thank D. Conde and J. Staerk for help accessing Species360 data; and J. P. de Magalhaes, J. DeGregori, J. Vijg and M. Lynch for their comments on the manuscript. This research was funded by Wellcome (grant number 206194), the Dunhill Medical Trust (RPGF2002\188) and the Deutsche Jos? Carreras Leuk?mie-Stiftung. I.M. is funded by Cancer Research UK (C57387/A21777) and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow.
Publisher Copyright:
© 2022, The Author(s).