ESPEYB20 13. Editors' Choice Section (12 abstracts)
13.2. Somatic mutation rates scale with lifespan across mammals
Cagan A , Baez-Ortega A , Brzozowska N , Abascal F , Coorens THH , Sanders MA , Lawson ARJ , Harvey LMR , Bhosle S , Jones D , Alcantara RE , Butler TM , Hooks Y , Roberts K , Anderson E , Lunn S , Flach E , Spiro S , Januszczak I , Wrigglesworth E , Jenkins H , Dallas T , Masters N , Perkins MW , Deaville R , Druce M , Bogeska R , Milsom MD , Neumann B , Gorman F , Constantino-Casas F , Peachey L , Bochynska D , Smith ESJ , Gerstung M , Campbell PJ , Murchison EP , Stratton MR & Martincorena I
Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, UK. ac36@sanger.ac.uk Nature 2022;604:517–524. https://www.nature.com/articles/s41586-022-04618-z
In Brief: To document variations in rates of somatic mutations, the authors performed whole-genome sequencing of DNA from cells of intestinal crypts across 16 diverse mammalian species, spanning huge 40 000-fold variations in body mass and 30-fold variations in lifespan. The somatic mutation rates per year varied greatly across species and showed a much stronger inverse relationship with species lifespan than with species body mass.
Comment: Peto’s paradox describes the observation that larger species do not have higher rates of cancer than smaller species, despite containing several thousand-fold more cells, each of which is prone to developing an oncogenic somatic mutation. The prevailing hypothesised explanation was that larger organisms have developed efficient cancer suppression mechanisms. This landmark paper turns that hypothesis on its head by performing detailed genomic analyses across 16 diverse species, including colobus monkey, cat, cow, dog, ferret, giraffe, harbour porpoise, horse, human, lion, mouse, naked mole-rat, rabbit, rat, ring-tailed lemur and tiger. They found wide differences in somatic mutation rates per genome, highest in mice (796 substitutions per year) and fortunately it was lowest in humans (47 substitutions per year). Notably, there was an almost perfect correlation between somatic mutation rate and species lifespan, which attenuated the weaker relationship between somatic mutation rate and body mass.
Somatic mutations may occur in cells due to a number of reasons, including endogenous DNA damage, errors during cell division, or damage by environmental mutagens. The authors studied intestinal crypt cells as these are less affected by environmental factors and so indicate endogenous processes. The findings imply that somatic mutations are evolutionarily constrained according to lifespan and this involves a number of mechanisms such as DNA damage repair, and avoidance of DNA polymerase slippage and DNA assembly errors. Remarkably, by the end of their lifespan, species differ relatively little in their estimated mutation load per cell. Together with the tight correlation with lifespan, these findings further imply that somatic mutation rate is the major determinant of differences in lifespan across species.
From a developmental perspective, as well as the obvious insights into the mechanisms of ageing, it is recently recognised that DNA damage repair and efficiency and accuracy of DNA replication may also influence early life cell and tissue growth rate. For example, the same mechanisms that protect against DNA damage to delay menopause also contribute to the establishment of a larger oocyte pool at birth (1).
Reference: 1. Ruth KS, Day FR, Hussain J, et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021 Aug;596(7872):393–397.
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ESPE Yearbook of Paediatric Endocrinology
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