Abstract
BACKGROUND: Rhesus macaques play a valuable role in biomedical research, and their genetic characterization is critical for effective colony management. Levels of genetic diversity, genomic admixture, and genetic substructure can all impact the suitability of macaques for biomedical research. The Southwest National Primate Research Center (SNPRC) houses one of the largest rhesus macaque colonies in the United States. Their genetic management includes the ongoing assessment of genetic diversity, ancestral origin (India or China), and deep sequencing of the major histocompatibility complex (MHC). A goal of the SNPRC has been the reduction of levels of admixture between Indian- and Chinese-origin macaques and the prevalence of simian immunodeficiency virus (SIV) refractory MHC haplotypes while maintaining overall genetic and MHC haplotype diversity. This has been achieved by targeted sequencing of the MHC and removing animals with haplotypes more prevalent in Chinese-origin macaques from breeding.
RESULTS: We investigated the impact of management strategies on admixture, population genetic structure, genetic diversity, and inbreeding using whole exome sequencing of founding and colony-born animals (n = 488). Admixture analysis of founders showed one animal to be of Chinese origin and an additional 37 considered admixed (> 15% Chinese ancestry; range 16.3-84.5%) with population substructure closely reflecting primate research center source. The levels of Chinese ancestry in the colony declined over time, though genetic diversity remains high (heterozygosity = 0.320). We characterized the MHC through targeted sequencing of 1,069 SNPRC macaques born over a twelve-year period. MHC management strategies reduced the prevalence of SIV-refractory MHC haplotypes, with Mamu-B*008 reaching significance (p = 0.027), while overall haplotype diversity was maintained (Mamu-A, h = 0.907; Mamu-B, h = 0.952). Finally, we performed genome-wide scans for genetic selection over time. We identify numerous genomic regions where allele frequencies have shifted significantly, supporting the presence of short-term adaptation under colony management.
CONCLUSIONS: We show that colony management strategies have been successful without reducing genetic diversity of the MHC or exonic regions. We also show that colony genetic substructure is related to animal colony source and that mergers and migrations have reduced inbreeding and increased overall genetic diversity.