Somatic mutation rates scale with lifespan across mammals

Abstract

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including ~30-fold variation in lifespan and ~40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of ~3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a determinant of lifespan.

Constrained optimisation of divisional load in hierarchically-organised tissues during homeostasis

“…Therefore, based on our optimisation criteria, we would expect that in longer lived organisms (with the same homeostatic TDC number) SCs should divide more slowly and there should be a greater number of amplification steps to minimise division accumulation. A recent measurement of somatic mutation rate across animals with different lifespans supports this hypothesis, with longer lived animals having a lower rate of somatic mutation accumulation (Cagan et al, 2021). Furthermore, we find that underestimating the timescale of optimisation relative to lifetime leads to a large increase in divisional load at ages beyond the optimisation timescale.…”

The Dynamics of Somatic Mutagenesis During Life in Humans

“…As has been recently reviewed in detail, accumulation of somatic mutations might also impact aging for example by affecting the functioning of cells by influencing tightly controlled gene-regulatory networks and increasing cell-to-cell transcriptional heterogeneity (transcriptional noise) (Vijg and Dong, 2020). This is further supported by the observation that the mutation load at the end of life is similar between different mammals with wildly different lifespans (Cagan et al, 2021). Defects in DNA repair have also been associated with accelerated aging (Tiwari and Wilson, 2019).…”

What Clonal Hematopoiesis Can Teach Us About MDS

“…The patterns of aging-related somatic mutagenesis are conserved even across mammalian species with the mutation rate inversely correlated with species lifespan. This suggests that beyond risk of cancer, somatic mutation rate may be a determinant of lifespan ( 14 ). Mathematical reconstruction of HSPC lineage histories suggests that CH mutations may arise as early as childhood (even in utero ) with some mutations undergoing a gradual expansion throughout life ( 11 , 15 ).…”

“…Our ability to detect CH mutations and the observed prevalence of CH is dependent on the sensitivity of sequencing as determined by sequencing depth. For example, analysis of whole exome sequencing data sequenced at a depth of under 100-fold coverage generally reports age‐dependent single nucleotide variants (SNVs) or small insertions/deletions (indels) in approximately 6% of subjects over 65 years of age ( 2 , 3 , 14 ). In contrast, next-generation sequencing (NGS) technologies with advanced error-correction methods such as unique molecular indices, can accurately detect mutations below 0.5% variant allele fraction (VAF) when performed at a high depth ( 16 ).…”