Reproductive Longevity Predicts Mutation Rates in Primates

Abstract

Summary 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 × 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.

Comparison of the full distribution of fitness effects of new amino acid mutations across great apes

“…In this work we have assumed the same mutation rate per site and generation across all great apes. However, there is evidence that both the generation time and the mutation rate per year vary across great apes (Amster and Sella 2016;Jónsson et al 2017;Thomas et al 2018;Besenbacher et al 2019). We checked how more realistic estimates of mutation rate per generation could explain our results.…”

Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

“…Although A3G retrocopies are expected to lack stop codons upon their birth from an intact A3G gene, absence of stop codons in older A3G retrocopies could indicate functional retention. We adapted a previously published approach (Young et al, 2018) to simulate the rate of decay of ORFs in the absence of selection based on ORF length and conservative and liberal bounds on NWM background mutation frequency and generation time (Campbell and Eichler, 2013;Tacutu et al, 2018;Thomas et al, 2018). We found that that less than 5% of A3G ORFs were expected to remain intact after 20 million years (less than 1% after 40 million years) ( Figure 5).…”

“…Combinations of several substitution, insertion, deletion rate and sexual maturation time were used for the simulation. We used substitution, insertion and deletion rate of 1.16x10 -8 , 2x10 -10 and 5.5x10 -10 per site per generation for human (Campbell and Eichler, 2013), substitution, insertion and deletion rate of 5.4x10 -9 , 1.55x10 -10 and 1.55x10 -10 per site per generation for mouse (Uchimura et al, 2015), and substitution rate of 8.1x10 -9 for Night monkey (Aotus nancymaae) (Thomas et al, 2018). Sexual maturation time of human, mouse and New World monkeys were estimated to be 25, 0.3 and 1-9 years (http://genomics.senescence.info; https://animaldiversity.org).…”

Origins and long-term patterns of copy-number variation in rhesus macaques

“…Recent work in humans and other primates have unveiled patterns of mutation for single nucleotide variants using pedigrees of related individuals. For instance, studies in primates have found a strong paternal age effect on the number of de novo single nucleotide mutations: older fathers tend to pass on more mutations (Kong et al 2012;Venn et al 2014;Jonsson et al 2017; Thomas et al 2018). This is likely due to a combination of errors accruing from both ongoing spermatogenesis and unrepaired DNA damage.…”