Species differences in somatic mutations shed light on aging

Somatic mutations in healthy cells promote the development of cancer and have been thought to contribute to aging. The decade-long hypothesis on somatic mutation rates correlates cancer risk with body mass. Another theory cites the role of these mutations in aging.

Until recently, it was difficult to study somatic mutations in normal tissues because it is difficult to detect mutations in single cells or small clones. But, interestingly, recent technological advances have allowed the study of normal tissues for somatic mutations.

In healthy tissue, the pattern and rates of these mutations remain largely unknown, except for humans.

Study: Scale of somatic mutation rates with mammalian lifespan. Image Credit: Konstantin Faraktinov/Shutterstock

The study

A recent study published in the journal Nature aimed to elucidate, through comparative analysis, the diversity of mutagenesis across different species, and the long-established hypothesis regarding the evolution of somatic mutation rates, as well as their role in cancer and aging.

To study the somatic mutation landscape in 16 mammalian species, whole genome sequencing was performed on 208 gut crypts from 56 multicellular living beings – belonging to different species with wide variations in lifespan and anatomical dimensions. These species included humans, black and white colobus monkeys, ferrets, mice, cats, dogs, naked mole rats, rats, ring-tailed lemurs, harbor porpoises, rabbits, cows , horses, giraffes, lions and tigers. .


Results from whole genome sequencing of colorectal crypts showed significant similarities in the mutational spectrum of these organisms, despite differences in their diet and life histories. Moreover, the analysis suggested that the three signatures dominating somatic mutagenesis in humans, namely SBS1, SBSB and SBSC, were also dominant in other mammals but with variable contribution.

On this basis, one could argue that somatic mutagenesis in different mammalian species is dominated by a set of preserved mutational processes.

Variant allele fraction (VAF) distributions for somatic substitutions in each crypt for each species.  Each distribution refers to the variants in a single sequenced crypt.Variant allele fraction (VAF) distributions for somatic substitutions in each crypt for each species. Each distribution refers to the variants in a single sequenced crypt.

The most significant finding of this study was the inverse scale or somatic mutation and lifespan rates – a well-established prediction of the theory of aging Going through somatic mutation.

Mechanistic and evolutionary models of aging predict that its process depends on several factors. It indicates that various forms of molecular and cellular damage contribute to the aging of the organism due to its evolutionary constraints on selection, which again act on the rate of aging. This finding was supported by studies that reported more efficient DNA repair in species with longer lifespans.

Moreover, somatic mutations affect aging in various ways. This study highlights the possibility that somatic mutations may contribute to aging through clonal expansions of functionally altered cells in human tissues, for example – the possible association of mutations in liver disease and insulin resistance.

This phenomenon can be further understood through an in-depth understanding of somatic mutations and clonal expansions in age-related diseases and phenotypes. Similar inverse correlations with different forms of aging-related molecular damage and lifespans are expected and already reported, such as telomere shortening and protein turnover.

There is a need to consider other non-casual inverse correlations between lifespan and somatic mutations. One such interpretation is the possible scaling of cell division rates with lifespan and explaining the observed rates of somatic mutation. However, available cell division rate estimates reject this hypothesis. Another explanation could be that the rate of cell division in humans is not a detrimental factor in somatic mutation rates.

Another possible cause for the observed inverse correlation could be that selection reduces germline mutation rates in species with relatively longer reproductive spans. Selective pressure on germline mutations might have some influence on somatic mutation rates. Yet, germline mutation rates are unlikely to firmly determine somatic mutation rates since, in humans, somatic mutation rates are 10–20 times higher than germline mutation rates and show variability in different cell types.


Therefore, it can be concluded that somatic mutation rates have themselves been limited by an evolutionary process, possibly due to the selection of multiple DNA repair pathways.

Overall, this study gives a detailed account of mutational processes and contrasts common and variable characteristics in mammals. Further research will help expand our knowledge of somatic mutations and their influence on disease, aging and evolution.

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