SOMATIC EVOLUTION ACROSS SPECIES

Why study somatic evolution across species?

Ageing

There is enormous diversity in the rates of ageing and lifespans across species. Comparing somatic mutational processes and clonal dynamics in species with diverse lifespans could provide insights into the complex factors that contribute to ageing and potentially guide future interventions for age-related diseases.

Cancer

Cancer risk does not increase proportionally with lifespan or body-size across species. This observation, known as ‘Peto’s Paradox’, suggests that larger, longer-lived species have evolved superior cancer suppression mechanisms. Studying somatic mutation and clonal dynamics in these species could lead to the discovery of their cancer resistance mechanisms, opening the door for novel therapeutic strategies.

Environmental Monitoring

Environmental pollutants are a significant contributor to early mortality, especially in underprivileged communities. The distinctive mutational signatures created by many pollutants could be leveraged for genomic surveillance of sentinel species, offering a fast and effective tool to monitor the presence and impact of pollutants, similar to the ‘canary in the coal mine’.

High Resolution Scans of Histological Sections Prepared for Laser Capture Microdissection:

Selected Publications

Cagan et al, 2023 ‘Somatic mutation rates scale with lifespan across mammals’ Nature (2022)

We developed a pipeline integrating histology, laser capture microscopy and low-input genome sequencing to compare somatic mutational processes in 208 intestinal crypts from 56 individuals in 16 mammalian species with diverse lifespans and body-sizes. Somatic mutations were dominated by endogenous processes common across species. Strikingly, a strong inverse relationship between somatic mutation rates and lifespan suggests that somatic mutation rates are evolutionarily constrained, partially explain variation in cancer risk across species, and may play a role in ageing.

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Moore, Cagan, Coorens et al. ‘The mutational landscape of human somatic and germline cells’ Nature (2021)

This study compared the mutational landscape in 29 cell types across the human body, including direct quantification of paternal de novo mutation rates from spermatogonial stem cells. Two ubiquitous mutational signatures accounted for the majority of acquired mutations in most cell types, though their absolute and relative contributions varied substantially. Fascinatingly, spermatogonia, the cells responsible for most genetic variation in human populations, exhibited the lowest mutation rates, implying that germ cells possess superior mechanisms of genomic maintenance compared to their somatic counterparts.

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