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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