The germline mutational process in rhesus macaque and its implications for phylogenetic dating

Abstract

32Understanding the rate and pattern of germline mutations is of fundamental importance for 33 understanding evolutionary processes. Here we analyzed 19 parent-offspring trios of rhesus macaques 34 (Macaca mulatta) at high sequencing coverage of ca. 76X per individual, and estimated an average 35 r a t e of 0.73 × 10 −8 de novo mutations per site per generation (95 % CI: 0.65 × 10 −8 -0.81 × 36 10 −8 ). By phasing 50 % of the mutations to parental origins, we found that the mutation rate is 37 positively correlated with the paternal age. The paternal lineage contributed an average of 80 % of 38 the de novo mutations, with a trend of an increasing male contribution for older fathers. About 1.9 39 % of de novo mutations were shared between siblings, with no parental bias, suggesting that they 40 arose from early development (postzygotic) stages. Finally, the divergence times between closely 41 related primates calculated based on the yearly mutation rate of rhesus macaque generally 42 reconcile with divergence estimated with molecular clock methods, except for the 43 Cercopithecidae/Hominoidea molecular divergence dated at 54 Mya using our new estimate of the 44 yearly mutation rate. 45

The challenge and promise of estimating the de novo mutation rate from whole‐genome comparisons among closely related individuals

“…Pedigree-based studies in humans and nonhuman primates have confirmed the paternal origin of a majority of DNMs, consistent with the hypothesis that the number of mutations increase with the father's age (Bergeron et al, 2020;Jónsson et al, 2017;Lindsay et al, 2019;Rahbari et al, 2016;Venn et al, 2014;Wang et al, 2020). The paternal mutation bias may be a more general feature of mammals, as it is also prevalent in domestic cats (Wang et al, 2021) and mice (Lindsay et al, 2019).…”

“…Despite the fact that spermatogonial stem cells are characterized by highly efficient DNA repair and one of the lowest spontaneous mutation rates in the human body (Aitken et al, 2020), this idea has dominated the mutation rate literature for years. Pedigree‐based studies in humans and nonhuman primates have confirmed the paternal origin of a majority of DNMs, consistent with the hypothesis that the number of mutations increase with the father's age (Bergeron et al, 2020; Jónsson et al, 2017; Lindsay et al, 2019; Rahbari et al, 2016; Venn et al, 2014; Wang et al, 2020). The paternal mutation bias may be a more general feature of mammals, as it is also prevalent in domestic cats (Wang et al, 2021) and mice (Lindsay et al, 2019).…”

De novomutations in domestic cat are consistent with an effect of reproductive longevity on both the rate and spectrum of mutations

“…The spectrum of mutations in the cat was remarkably similar to those found in most primates, with a preponderance of C>T and A>G transitions (Kong et al 2012;Venn et al 2014;Thomas et al 2018;Besenbacher et al 2019;Bergeron et al 2020;Wang et al 2020;Wu et al 2020;see Campbell et al 2020 for an exception in the mouse lemur). We showed that differences in the mutation spectrum between the cat and the human can in large part be explained by differences in age according to a model of reproductive longevity.…”

The germline mutational process in rhesus macaque and its implications for phylogenetic dating

“…The analysis pipeline and scripts are available via Github [ 69 ] and Zenodo [ 70 ]. Other supporting data are available via the GigaScience database GigaDB [ 74 ].…”