The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

Abstract

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.

Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host

“…The details of sequencing and single-nucleotide variants discovery for this population have previously been described 8 . The population-level VCF file for this study was examined for relevant variation in these two genes.…”

“…2b). By contrast, analysis of the whole-genome sequences of 15 baboons and more than 130 rhesus macaques demonstrated that only the full-length ICAM-2 protein was found in all individuals (data not shown) 8 . The ICAM-2 deletion may be specific to C. atys , as it is not present in any other known primate sequences, including other natural SIV hosts, such as the African green monkey, drill and colobus monkey.…”

“…This suggests that this mutation occurred after the hominoid–Old World monkey divergence approximately 25 million years ago 12 . Second, there is a G-to-A nucleotide substitution in the non-natural host Old World monkeys (baboons and macaques) that creates a truncated protein in these species 8 (Extended Data Fig. 6b).…”

The value of new genome references

“…Comparisons among individuals within the same species are used to understand the extent of variation within the species[54, 55]. The data for these analyses can be WGS or sample sequences like genotyping assays using chips designed for other species.…”

Whole genome sequencing predicts novel human disease models in rhesus macaques

“…Cornish et al highlight the importance of both the completeness of the reference assembly and accuracy of gene annotation for variant detection and functional prediction, demonstrating considerable improvement in the second generation MacaM genome over the earlier rheMac2 build [14]. Most recently, a study of 133 Rhesus macaques found approximately 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans [16]. Each of these studies identified examples of mutations predicted to adversely affect key proteins, which suggests that many naturally occurring disease models may be present in the population.…”