Somatic mutations are implicated in important life processes such as cancer and ageing, yet they still are not well understood. Now, a new study, published as preprint in bioRxiv, has increased our knowledge by analysing somatic mutations in 16 mammalian species. Their findings have shed more light on the role of somatic mutations.
The effect of somatic mutations
Throughout life, healthy cells will accumulate somatic mutations. Despite the fact that somatic mutations drive cancer development and are thought to contribute to ageing, we know relatively little about them.
It has only become possible to accurately study somatic mutation in normal tissues relatively recently, thanks to the development of technologies such as single-cell sequencing. Consequently, our current knowledge of somatic mutations is mostly limited to human tissues. Knowing the rates of mutagenesis in other species could enable us to uncover the role of somatic mutations in cancer and ageing in humans.
How somatic mutations influence cancer and ageing
Somatic mutations are known to increase the risk of cancer as each mutation has the chance of being oncogenic. As larger species have more cells subject to these mutations, you would expect cancer risk to increase with body size. However, there appears to be no correlation between body mass and cancer risk across species. This raises the question of whether larger animals have evolved to have lower somatic mutation rates, thereby reducing cancer risk.
No one actually knows the underlying cause of ageing, but scientists have long predicted that somatic mutations may play a role. If this hypothesis is true, species that have shorter lifespans should have higher somatic mutation rates and vice versa. Unfortunately, this theory has not yet been tested due to the aforementioned difficulties of studying somatic mutations.
This current study set out to answer these questions by carrying out comparative analyses of somatic mutagenesis across species.
Whole genome sequencing tissue samples
In the study, the team analysed tissue samples from 16 mammalian species across a range of sizes – from a naked mole-rat to a giraffe! They carried out whole genome sequencing of 208 intestinal crypt tissue samples from 56 individual mammals.
The team’s analysis found that all samples showed a clear accumulation of mutations with age. This is in agreement with previous research on somatic mutation rates in humans.
Investigating mutational rates
Similar mutational processes were observed across the species, but the mutation rate per genome per year varied widely. The number of single base substitutions (SBS) ranged from 47 SBS per year in humans to 796 SBS per year in mice.
To explore the relationship between rate and lifespan, the team used mortality data from animals in zoos. Interestingly, they found a strong inverse correlation between somatic mutation rates per year and lifespan across species. These results suggest that the theory of somatic mutations contributing to ageing is correct.
Next, the team explored the relationship between somatic mutation rates and body mass. They discovered that the correlation between the two variables was very weak. The variation in mutation rates across species appeared to be controlled by lifespan, rather than body size. This was nicely demonstrated through comparison of select mammals. For example, giraffes and naked mole-rats had very similar somatic mutation rates of 99 and 93 SBS per year respectively. This is despite there being a 23,000-fold difference in adult body mass. However, both these species have a very similar average lifespan (24 years for giraffes and 25 years for naked mole-rats) which supports the team’s suggestion that life expectancy controls mutation rate.
The lack of correlation between mutations and body mass found in this study opposes the theory that lower cancer risk in larger mammals is due to lower somatic mutation rates. The findings suggest that other mechanisms may be responsible for the lower incidence of cancer observed in larger animals.
Conclusion and future work
The findings reported in this study suggest that somatic mutational rates do play a role in ageing, something that has long been suggested but never experimentally shown. In the future, the actual mechanisms by which mutations contribute to age should be investigated. The researchers clarify that even if somatic mutations are an underlying cause of ageing, ageing is a complex process and other forms of molecular damage are expected to display similar inverse correlations with lifespan.
The results have also shown that mutational rate does not correlate with body mass. This suggests that large mammals have not evolved to have lower mutational rates in order to reduce cancer risk. Therefore, other adaptations must play a role in modulating cancer risk, an avenue that should be explored in further studies.
Overall, this study is the first to describe and analyse somatic mutations at such a large scale. The findings have greatly increased our knowledge of somatic mutations and pave the way for future investigations into mutations, ageing and cancer – and how the three interrelate.
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