Pedigree-based measurement of thede novomutation rate in the gray mouse lemur reveals a high mutation rate, few mutations in CpG sites, and a weak sex bias

Abstract

Pedigree-based measurement of the de novo mutation rate in the gray mouse lemur 3 reveals a high mutation rate, few mutations in CpG sites, and a weak sex bias 4 5 Abstract 1617 Spontaneous germline mutations are the raw material on which evolution acts and knowledge 18 of their frequency and genomic distribution is therefore crucial for understanding how evolution 19 operates at both long and short timescales. At present, the rate and spectrum of de novo 20 mutations have been directly characterized in only a few lineages, and it is therefore critical to 21 examine a wide range of species to determine the generality of patterns that have been 22identified so far. Our study provides the first direct mutation rate estimate for strepsirrhine 23 primates (i.e., the lemurs and lorises) which comprise nearly half of the primate clade. Using 24 high-coverage linked-read sequencing of a family pedigree (n = 8) of gray mouse lemurs 25 (Microcebus murinus), we estimate the mutation rate to be 1.64 × 10 -8 (95% CI: 1.41 × 10 −8 to 26 1.98 × 10 −8 ) mutations per basepair per generation. This estimate is higher than those for most 27 previously characterized mammals, including other primates. Contrary to expectation, we 28 found only a modest overrepresentation of mutations at CpG-sites and of paternal mutations. 29Comparing mutation rates across taxa, we show that expectations based on the drift barrier 30 hypothesis are met at a broad phylogenetic scale but not within primates. Finally, we 31 compared pedigree-based mutation rates with phylogenetically-based substitution rate 32 estimates for mouse lemurs and six other primate lineages and found considerable differences 33 between the two rate estimates. This finding has implications for divergence-time estimation 34 and calls for further study. 35 2016; Feng, et al. 2017;Pfeifer 2017;Thomas, et al. 2018; Koch, et al. 2019). 57Phylogenetically-based approaches, on the other hand, are dependent on external calibrations 58 to obtain substitution rates in units of absolute time. In a typical study, divergence between 59 homologous genomic regions across a phylogeny is calibrated with fossils or other external 60 criteria at specific nodes in order to determine substitution rates (Thorne, et al. 1998; 61 Sanderson 2002;Thorne and Kishino 2002;Drummond, et al. 2006;Yang 2006), relying on 62 the assumption that the rate at which substitutions accumulate between species is equal to the 63 mutation rate for neutral sites (Kimura 1983). Thus, in principle, phylogenetically-based and 64 pedigree-based methods should produce equivalent estimates of the mutation rate. 65 66

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

“…Assuming the average parental age in our sample (3.8 years) is representative of the average age of reproduction in the cat, we estimate a per-year mutation rate of 2.2 × 10 -9 per bp. This is much higher than the human rate of 0.43 × 10 -9 per bp per year (Jónsson et al 2017), or the per-year rate from any reported primate (Besenbacher et al 2019;Campbell et al 2020;Wang et al 2020;Wu et al 2020). This higher rate is driven by the similar number of mutations at puberty, but a much shorter generation time in the cat.…”

Cryptic Patterns of Speciation in Cryptic Primates: Microendemic Mouse Lemurs and the Multispecies Coalescent

“…Several factors likely contribute to this large difference. First, the MSC estimate uses a de novo mutation rate sampled from a distribution based on available pedigree-based mutation rates in primates, including mouse lemurs (Campbell et al, 2019). This rate is nearly two-fold higher than the estimated substitution rate for M. murinus (dos Reis et al, 2018).…”

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

“…Up until now, the germline mutation rate has only been estimated using pedigrees in a few non-human primate species, including chimpanzee ( Pan troglodytes ) [ 18 , 26 , 27 ], gorilla ( Gorilla gorilla ) [ 27 ], orangutan ( Pongo abelii ) [ 27 ], African green monkey ( Chlorocebus sabaeus ) [ 28 ], owl monkey ( Aotus nancymaae ) [ 19 ], the baboon ( Papio anubis ) [ 29 ], and recently rhesus macaque ( Macaca mulatta ) [ 30 ]. The mutation rate of grey mouse lemur ( Microcebus murinus ) [ 31 ] has also been estimated in preprinted studies. To precisely call de novo mutations in the offspring, collecting and comparing the genomic information of the pedigrees is the first essential step for detecting mutations only present in offspring but not in either parent.…”