De novomutations 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 age of 3.8 years). We find evidence for a strong 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 slightly lower than what has been observed in humans, but 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 primates, our results also suggest a phenomenon that may be universal among mammals.

Human generation times across the past 250,000 years

“…Our study builds upon advances in understanding the characteristics of de novo mutations (14) and in estimating genome-wide genealogies (15) to create a model for generation times that can be applied to ancient populations. While it is clear that the frequency of individual mutation types can evolve rapidly (16,17), even small changefs to the generation interval can reshape the overall mutation spectrum (21,22). Our results are consistent with previous estimates of the average generation time over the past 40-45 thousand years (10,11), but offer unprecedented resolution of sex-specific generation times across 250,000 years of human history.…”

Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates

“…To find DNMs, we must first find where in the genome each of the short sequencing reads comes from. The Burrows-Wheeler Aligner (BWA; Li and Durbin, 2009) is an algorithm developed to map short reads (50-250 bp) to a reference genome and has been used in the majority of studies on direct mutation rate estimation (Bergeron et al, 2021; Besenbacher et al, 2019; Harland et al, 2017; Jónsson et al, 2017; Kessler et al, 2020; Koch et al, 2019; Malinsky et al, 2018; Maretty et al, 2017; Milholland et al, 2017; Pfeifer, 2017; Sasani et al, 2019; Smeds et al, 2016; Tatsumoto et al, 2017; Thomas et al, 2018; Turner et al, 2017; Wang et al, 2021b, 2020; Wu et al, 2020). In particular, the BWA-MEM algorithm is fast, accurate, and can be implemented with an insert size option to improve the matching of paired reads.…”

“…To ensure the homozygosity of the parents, some studies filter away sites where alternative alleles are present in the parents’ reads. AD refers to the number of reads supporting the alternative allele, with previously utilized thresholds include AD > 0 (Besenbacher et al, 2019; Harland et al, 2017; Koch et al, 2019; Pfeifer, 2017; Sasani et al, 2019; Smeds et al, 2016; Wang et al, 2021b), AD > 1 (Jónsson et al, 2017; Wang et al, 2020), or AD > 4 (Maretty et al, 2017). Even more conservative, one study used a lowQ AD2 > 1, i.e.…”

“…GQ is the difference between the PL 2nd most likely and PL 1st most likely , with a maximum reported of 99. Applied GQ thresholds vary between 20 (Jónsson et al, 2017;Sasani et al, 2019) and 70 (Wang et al, 2021b(Wang et al, , 2020. Instead of using GQ, some studies used the difference between PL 2nd most likely and PL 1st most likely , which is not limited to a maximum of 99, and applied more conservative criteria for the offspring heterozygous genotype than for the homozygous parents (Maretty et al, 2017 Variants can also be filtered using allelic depth: the number of reads supporting the reference allele and the alternative allele.…”

“…1.52 2 ♂: 4.55 and ♀: 1.45 (Campbell et al, 2021) Mouse (Mus musculus) 0.57 0.39 8 15 unspecified ~ 0.47 (Milholland et al, 2017) (Lindsay et al, 2019) Cattle (Bos taurus) 1.17 5 unspecified (Harland et al, 2017) Wolf (Canis lupus) 0.45 4 ♂: 4.00 and ♀: 2.25 (Koch et al, 2019) Domestic cat (Felis catus) 0.86 11 ♂: 4.70 and ♀: 2.90 (Wang et al, 2021b) Platypus (Ornithorhynchus anatinus) 0.70 2 unspecified (Martin et al, 2018) Collared flycatcher (Ficedula albicollis) 0.46 7 unspecified (Smeds et al, 2016) Herring (Clupea harengus) 0.20 12 unspecified (Feng et al, 2017) Cichlid (Astatotilapia calliptera, Aulonocara stuartgranti and Lethrino ps lethrinus) 0.35 9 unspecified (Malinsky et al, 2018) (and accounting for the diploid length of the genome, as mutations can be transmitted by both the mother and father). As mutations are rare events, detecting all the true DNMs (or having a high sensitivity) while avoiding errors (or increasing precision) from a single generation remains challenging.…”