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ps. Apparently the link has not been working consistently, so please use: events.simonsfoundation.org/2m9OK2 to register.

Tx! (sorry, had missed this) It's not clear most germline mutation rates are tracking cell divisions (see e.g., Spisak et al. 2024 PLoS Biol). But to the extent they are, then I guess it would also depend on the corr between rates of cell divisions in germline and in somatic dev. across species.

oops, we will fix, thanks!

Thanks to Ziyue Gao, William Milligan & Jonathan Pritchard for helpful comments on the manuscript. 16/16

Ultimately, making sense of what sets the mutation rate of a cell type in a given species will require theory that integrates recent findings about mutagenesis and developmental constraints with population processes of selection and genetic drift. 15/n

From this view, not all somatic cell types will show the same scaling as the germline. In some, mutations are likely inconsequential and mutation rates will only be constrained indirectly, by pleiotropic effects, while in others, the fitness consequences of mutations will differ among species. 14/n

and highest in short-lived, differentiated cells, with somatic stem cells lying in between. 13/n

We suggest a possible synthesis, focused on properties of cell types, notably their rate of replacement and contribution to organismal fitness. In this view, mutation rate should be lowest in the germline, where mutations become constitutive in the offspring and selection is esp. strong, ... 12/n

To consider these questions, we briefly review existing theories about selection on germline mutations, notably the drift-barrier hypothesis (Lynch 2010) and recent extensions by Zhu et al. 2024 (Box 2) & models about harmful effects of somatic mutations (including recent ideas in Alon 2023). 11/n

So what drives what: Does selection against mutator alleles in the germline reduce mutation rates in the soma because of shared repair mechanisms? Do selection pressures that arise from aging and cancers influence germline mutations through pleiotropic effects? Both? 10/n

This scaling is expected to arise when mutations inflict a similar fitness cost per year across species (see our Box 2). Intriguingly, however, it does not seem to apply to all somatic cell types (e.g., blood). 9/n

A similar scaling, in which mutation rates per year are inversely proportional to intrinsic lifespan, was recently reported by Cagan et al. (2022), for intestinal crypts. 8/n

The specific value of the rate in a species may be set by limits to the efficacy of selection (Lynch 2010); alternatively, driving the rate down even further may inflict other costs, such that optimum is under (indirect) stabilizing selection (Kondrashov 1995). 7/n

Instead, the similarity points to strong selection pressures on the mutation rate per bp per generation. As expected if the net effect of mutations is deleterious (Kimura 1967), there appears to be directional selection to decrease the mutation rate as much as possible. 6/n

Such constancy is not expected from genetic drift alone, given the vast phylogenetic distances represented, nor is it likely to arise as a simple byproduct of life history or developmental constraints, since these differ dramatically among species. 5/n

In fact, they appear to be eerily similar. The per generation mutation rate seems to lay between 10-9 and 10-8 per bp in all animal taxa surveyed to date–despite vast differences in environments, life histories, and three orders of magnitude variation in the generation time: 4/n

A mathematically equivalent way to say it is that mutation rates per generation seem similar. 3/n

Evolutionary biologists have noted for decades that short-lived species evolve faster; specifically that the per year mutation rate scales inversely with generation time (e.g., Laird et al. 1969; Wu & Li 1985; Martin & Palumbi 1993; Wilson Sayres et al. 2011). 2/n