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...