De novo Mutations in Domestic Cat are Consistent with an Effect of Reproductive Longevity on Both the Rate and Spectrum of Mutations

Abstract

The mutation rate is a fundamental evolutionary parameter with direct and appreciable effects on the health and function of individuals. Here, we examine this important parameter in the domestic cat, a beloved companion animal as well as a valuable biomedical model. We estimate a mutation rate of 0.86 × 10−8 per bp per generation for the domestic cat (at an average parental age of 3.8 years). We find evidence for a significant paternal age effect, with more mutations transmitted by older sires. Our analyses suggest that the cat and the human have accrued similar numbers of mutations in the germline before reaching sexual maturity. The per-generation mutation rate in the cat is 28% lower than what has been observed in humans, but is consistent with the shorter generation time in the cat. Using a model of reproductive longevity, which takes into account differences in the reproductive age and time to sexual maturity, we are able to explain much of the difference in per-generation rates between species. We further apply our reproductive longevity model in a novel analysis of mutation spectra and find that the spectrum for the cat resembles the human mutation spectrum at a younger age of reproduction. Together, these results implicate changes in life-history as a driver of mutation rate evolution between species. As the first direct observation of the paternal age effect outside of rodents and primates, our results also suggest a phenomenon that may be universal among mammals.

Examining the Effects of Hibernation on Germline Mutation Rates in Grizzly Bears

“…Second, advanced paternal age better predicted the appearance of disease mutations than advanced maternal age—implying that mutation was male biased ( Haldane 1946 ; Penrose 1955 ). Both of these patterns have been confirmed by studies that have sequenced large numbers of human pedigrees ( Kong et al 2012 ; Goldmann et al 2016 ; Rahbari et al 2016 ; Jónsson et al 2017 ), as well as by studies in other mammals ( Venn et al 2014 ; Thomas et al 2018 ; Besenbacher et al 2019 ; Lindsay et al 2019 ; Wang et al 2020 , 2022 ; Wu et al 2020 ; Bergeron et al 2021 ).…”

“…In order to test for an effect of hibernation, we calculated the expected per-generation mutation rate under two models that consider mutation accumulation up to the point of conception, but with no hibernation. First, we used a “total longevity” model (cf., Wang et al 2022 ), where the mutation rate is dependent solely on the age at conception (Materials and Methods). That is, mutation accumulation is constant from birth to conception, with a rate of accumulation in males and females independently estimated from human data (eqs 5 and 6 ).…”

“…This model separates parental mutation accumulation into two stages: pre and post puberty. Modeling pre-puberty separately allows us to account for the higher rate of mutation in this stage (e.g., Jónsson et al 2018 ; Sasani et al 2019 ), as well as for the fact that pre-puberty mutation accumulation seems to be relatively constant across species with very different ages at puberty ( Thomas et al 2018 ; Wang et al 2020 , 2022 ). Post puberty, we assume that bears follow the same process of mutation accumulation as humans (Materials and Methods).…”

“…Our predictions of the per-generation mutation rate with no hibernation were made under two distinct models. Although both models assume that many of the underlying mutation parameters are the same among species, we previously found them to be conserved among multiple mammals ( Thomas et al 2018 ; Wang et al 2020 , 2022 ).…”

“…The per-generation mutation rate evolves between species. Whole-genome sequencing has revealed that the mutation rate per generation ( Lynch 2010 ) ( Chintalapati and Moorjani 2020 ; Wang et al 2022 ). Prior to the advent of large-scale DNA sequencing, early studies of disease mutations in humans uncovered two general patterns in the accumulation of mutations.…”