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Mutations beget more mutations – The baseline mutation rate and runaway accumulation

There is a sizable literature on mutation rate evolution (Drake 1991; Makova and Li 2002; Lynch 2011; Scally and Durbin 2012; Sung, et al. 2012) but few studies incorporate the recent genomic data from somatic tissues that suggest the operation of mutators. These data show that the mutation burden among cancer samples may vary by several orders of magnitude (Kandoth, et al. 2013; Lawrence, et al. 2013). We now propose a runaway model, applicable to both the germline and the soma, whereby the accumulation of mutator mutations forms a positive-feedback loop. In this loop, any mutator mutation would increase the probability of acquiring the next mutator, thus triggering a runaway escalation in mutation rate. The process can be initiated more readily if there are many weak, rather than a few strong, mutators. Interestingly, even a small increase in the mutation rate at birth could trigger the runaway process, resulting in unfit progeny in slowly reproducing species. In such species, the need to minimize the risk of this uncontrolled accumulation would entail a mutation rate that may seem unnecessarily low. In comparison, species that starts and ends reproduction much sooner do not face the risk and may set the baseline mutation rate higher. The mutation rate would evolve as the generation time changes, therefore explaining many puzzling evolutionary phenomena (Elango, et al. 2006; Thomas, et al. 2010; Langergraber, et al. 2012; Thomas, et al. 2018; Besenbacher, et al. 2019).