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Genomic Study of Mammalian Species Links Somatic Mutation Rate to Lifespan

NEW YORK – An international research team has linked differences in lifespan between 16 mammalian species to somatic mutation rates, arguing against the notion that those rates primarily shift in relation to a species' size.

"The most notable finding of this study is the inverse scaling of somatic mutation rates with lifespan — a long-standing prediction of the somatic mutation theory of aging," the authors reported. These and other findings are "consistent with somatic mutations contributing to aging and with somatic mutation rates being evolutionarily constrained," they wrote.

For their analysis, the researchers profiled somatic mutation patterns across 16 mammalian species, using whole-genome sequencing data generated on more than 200 colorectal crypt samples from 56 individual animals. The findings, published in Nature on Wednesday, suggested that the somatic mutations present in different animals by the end of their lifespan were more similar than anticipated, despite dramatic species-related differences in the number of mutations accumulated each year.

"That this diverse range of mammals end their lives with a similar number of mutations in their cells is an exciting and intriguing discovery," senior author Inigo Martincorena, a researcher at the Wellcome Sanger Institute, said in a statement.

Although the lifespans observed varied as much as 30-fold from one mammalian species to the next, the team explained, lifespan consistently waned as somatic mutation rates rose. Conversely, long-lived animals had lower somatic mutation rates, bringing all the species to comparable somatic mutational burdens by the ends of their lives.

"This suggests that somatic mutations may play a role in aging, although alternative explanations may be possible," co-first author Alex Cagan, also a researcher at the Sanger Institute, said in a statement. "Over the next few years, it will be fascinating to extend these studies into even more diverse species, such as insects or plants."

The types of mutations identified in the colorectal epithelium samples were relatively consistent, with three main mutational signatures that appeared to line up with DNA damage and repair-related mutation signatures reported in humans and other animals in the past. These ranged from DNA substitutions stemming from oxidative damage to DNA polymerase enzyme errors and deamination of methylated cytosine bases, though the proportion of mutations explained by each signature varied between species.

"Altogether, this study provides a detailed description of somatic mutation across mammals, identifying common and variable features and shedding light on long-standing hypotheses," the authors concluded. "Scaled across the tree of life and across tissues, in species with markedly different physiologies, life histories, genome compositions, and mutagenic exposures, similar studies promise to transform our understanding of somatic mutation and its effect on evolution, aging, and disease."

In a related comment in Nature, Massachusetts General Hospital researchers Alexander Gorelick and Kamila Naxerova discussed potential implications of the new research, and a related analysis published in Nature in December, for understanding processes such as aging and cancer, calling the studies "a wonderful reminder of how much our conceptual thinking about human health and disease can be enriched by expanding our horizon to consider other species."

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