Somatic mutation rates scale with lifespan across mammals

Alex Cagan (), Adrian Baez-Ortega, Natalia Brzozowska, Federico Abascal, Tim H. H. Coorens, Mathijs A. Sanders, Andrew R. J. Lawson, Luke M. R. Harvey, Shriram Bhosle, David Jones, Raul E. Alcantara, Timothy M. Butler, Yvette Hooks, Kirsty Roberts, Elizabeth Anderson, Sharna Lunn, Edmund Flach, Simon Spiro, Inez Januszczak, Ethan Wrigglesworth, Hannah Jenkins, Tilly Dallas, Nic Masters, Matthew W. Perkins, Robert Deaville, Megan Druce, Ruzhica Bogeska, Michael D. Milsom, Björn Neumann, Frank Gorman, Fernando Constantino-Casas, Laura Peachey, Diana Bochynska, Ewan St. John Smith, Moritz Gerstung, Peter J. Campbell, Elizabeth P. Murchison, Michael R. Stratton and Iñigo Martincorena ()
Additional contact information
Alex Cagan: Wellcome Sanger Institute
Adrian Baez-Ortega: Wellcome Sanger Institute
Natalia Brzozowska: Wellcome Sanger Institute
Federico Abascal: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
Mathijs A. Sanders: Wellcome Sanger Institute
Andrew R. J. Lawson: Wellcome Sanger Institute
Luke M. R. Harvey: Wellcome Sanger Institute
Shriram Bhosle: Wellcome Sanger Institute
David Jones: Wellcome Sanger Institute
Raul E. Alcantara: Wellcome Sanger Institute
Timothy M. Butler: Wellcome Sanger Institute
Yvette Hooks: Wellcome Sanger Institute
Kirsty Roberts: Wellcome Sanger Institute
Elizabeth Anderson: Wellcome Sanger Institute
Sharna Lunn: Wellcome Sanger Institute
Edmund Flach: Zoological Society of London
Simon Spiro: Zoological Society of London
Inez Januszczak: Zoological Society of London
Ethan Wrigglesworth: Zoological Society of London
Hannah Jenkins: Zoological Society of London
Tilly Dallas: Zoological Society of London
Nic Masters: Zoological Society of London
Matthew W. Perkins: Zoological Society of London
Robert Deaville: Zoological Society of London
Megan Druce: German Cancer Research Center (DKFZ)
Ruzhica Bogeska: German Cancer Research Center (DKFZ)
Michael D. Milsom: German Cancer Research Center (DKFZ)
Björn Neumann: University of Cambridge
Frank Gorman: University of Cambridge
Fernando Constantino-Casas: University of Cambridge
Laura Peachey: University of Cambridge
Diana Bochynska: University of Cambridge
Ewan St. John Smith: University of Cambridge
Moritz Gerstung: European Bioinformatics Institute (EMBL-EBI)
Peter J. Campbell: Wellcome Sanger Institute
Elizabeth P. Murchison: University of Cambridge
Michael R. Stratton: Wellcome Sanger Institute
Iñigo Martincorena: Wellcome Sanger Institute

Nature, 2022, vol. 604, issue 7906, 517-524

Abstract: Abstract The 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.

Date: 2022
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DOI: 10.1038/s41586-022-04618-z

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