Reproductive longevity predicts mutation rates in primates

Abstract

Mutation rates vary between species across several orders of magnitude, with larger organisms having the highest per-generation mutation rates. Hypotheses for this pattern typically invoke physiological or population-genetic constraints imposed on the molecular machinery preventing mutations 1 . However, continuing germline cell division in multicellular eukaryotes means that organisms with longer generation times and of larger size will leave more mutations to their offspring simply as a by-product of their increased lifespan 2,3 . Here, we deeply sequence the genomes of 30 owl monkeys (Aotus nancymaae) from 6 multi-generation pedigrees to demonstrate that paternal age is the major factor determining the number of de novo mutations in this species. We find that owl monkeys have an average mutation rate of 0.81 x 10 -8 per site per generation, roughly 32% lower than the estimate in humans. Based on a simple model of reproductive longevity that does not require any changes to the mutational machinery, we show that this is the expected mutation rate in owl monkeys. We further demonstrate that our model predicts species-specific mutation rates in other primates, including study-specific mutation rates in humans based on the average paternal age. Our results suggest that variation in life history traits alone can explain variation in the per-generation mutation rate among primates, and perhaps among a wide range of multicellular organisms. MainThe rate at which new mutations arise is a key parameter of life on Earth, contributing to both individual disease risk and the evolution of novel traits. The mutation rate per generation varies among taxa, from as low as 1x10 -10 per base in Archaea to more than 1x10 -8 in mammals 1 . Two classes of models have been proposed to explain this variation. In one, the physiological and biochemical costs of increased fidelity during DNA replication limit the minimum mutation rate achievable 4,5 . Selection for faster replication in smaller organisms constrains the accuracy with which the cellular machinery can copy DNA, resulting in an inverse relationship between body size and mutation rate. Alternatively, a population-genetic model invokes the limits to natural selection in organisms with smaller population sizes [6][7][8] . This model posits a higher rate of mutation in larger organisms because of their generally smaller population size 9 .One difficulty in teasing apart the forces driving the evolution of the mutation rate among multicellular organisms is the fact that lifespan varies as much as the per-generation mutation rate. In multicellular organisms, the number of mutations passed on to offspring in a single generation is a combination of the errors made in each round of germline replication and the accumulation of unrepaired DNA damage. One hundred years after the first observation of increased disease incidence in the children of older parents 2,10 , whole-genome sequencing in humans revealed the precise contribution of parental age to the number of de novo muta...

Pedigree-based measurement of thede novomutation rate in the gray mouse lemur reveals a high mutation rate, few mutations in CpG sites, and a weak sex bias

“…CpG sites have generally been found to have higher mutation rates relative to other site classes, a pattern discovered several decades ago using sequence comparisons (Bird, 1980) and ascribed to the frequent deamination of methylated cytosines (Friedberg et al, 2005). Only a four-fold enrichment of mutations at CpG sites (11 mutations, 8.2% of all mutations) was found in mouse lemur, which is less than the at least ten-fold enrichment (12-25% of total mutations) found in other primate studies (Besenbacher et al, 2019;Gao et al, 2019;Thomas et al, 2018;Venn et al, 2014). It is thus reassuring that findings from our relaxed-clock analyses of different substitution types are consistent with the observed mutation spectrum (Fig.…”

“…Using the long phasing blocks generated by the linked-read method, we were able to determine the parent-of-origin for 94 out of 134 (70%) de novo mutations. The number of mutations confidently assigned to a parent are notably higher in our analysis compared to previous studies that used short read sequencing alone, such as 35% (Venn et al, 2014) or 38% (Thomas et al, 2018). Among the assigned mutations, 54% (n = 51) were found on the offsprings' paternal haplotype while the remaining 46% (n = 43) were found on the offsprings' maternal haplotype; a ratio of male-to-female mutations of approximately 1.2.…”

“…1). The number of mutations with an assigned parent-of-origin is higher (70%) in the present study than in analyses that only used standard short reads (Thomas et al, 2018;Venn et al, 2014). And although a number of factors such as sequencing depth, heterozygosity, and recombination rate may vary across investigations and limit the value of cross-study comparisons, the prospect of successfully phasing more mutations while also eliminating the need to sequence across more than two generations with linked-read data is appealing.…”

“…Our estimates of the Ti:Tv and SW:WS ratios at 1.03 each are lower than values found in other animals. For instance, Ti:Tv ratio in previous pedigree-based studies varied between 1.97 and 2.67 (Agier and Fischer, 2012;Assaf et al, 2017;Besenbacher et al, 2019;Kong et al, 2012;Smeds et al, 2016;Thomas et al, 2018;Venn et al, 2014). The finding of a lower Ti:Tv ratio is likely a consequence of the relatively low number of C>T transitions, especially at CpG sites.…”

“…While phylogenetic methods were the standard before recent developments in sequencing technology that have made whole-genome sequencing widely accessible, pedigree-based mutation rates are now increasingly being estimated for non-model species. By comparing the genomes of individuals with known genealogical relationships -typically, parent to offspringinvestigators can count mutations as they appear (Feng et al, 2017;Koch et al, 2019;Pfeifer, 2017;Scally and Durbin, 2012;Smeds et al, 2016;Thomas et al, 2018). Phylogenetic approaches, on the other hand, use external calibrations such as fossils or geological events to obtain substitution rates in units of absolute time (Drummond et al, 2006;Sanderson, 2002;Thorne and Kishino, 2002;Thorne et al, 1998).…”