Evolution of Mutational Susceptibility to Genetic Diseases

Cancer is a genetic disease, remnant from a time before multicellularity, when individual cells prioritized their own growth over cooperative constraints. While research has primarily focused on the identification and effects of mutations in cancer driver genes, it remains unclear whether natural selection has acted on the on the root cause: the probability of these mutations occurring in the first place. We investigate how susceptibility to somatic mutations has evolved in cancer driver genes by reconstructing ancestral genomes across primate phylogenies. By computing the probability of a sequence mutating under COSMIC mutational signatures, we find a decline in susceptibility to key signatures SBS1 and SBS5 along the primate lineage from the human–orangutan common ancestor to modern humans. Signatures associated with mismatch repair deficiency (SBS15, SBS6, SBS44) also show consistent decreases. In the most recent episode this trend is especially pronounced at sites neighbouring synonymous positions, suggesting optimization that reduces mutation risk while preserving protein function. To distinguish cancer-specific selection from neutral drift, we develop a model of neutral evolution calibrated for each phylogeny branch using estimated gene specific mutation rates from Bayesian inference. Extending our analysis to germline mutational processes, we observe distinct patterns of SBS1 and SBS5 susceptibility in genes under different levels of inferred germline selection pressure. This work introduces a novel framework for understanding how mutation probabilities evolve, shaping cancer risk across lineages and influencing susceptibility to genetic diseases. It will further shed new light on Peto’s paradox and may ultimately contribute to advancements in cancer prevention, early detection, and therapeutic strategies.

Evolution of Mutational Susceptibility to Genetic Diseases

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Maria Kelly

"Evolution of Mutational Susceptibility to Genetic Diseases"

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