Next‐Generation Short‐Read Sequencing Reveals Impacts on Major Histocompatibility Complex Diversity Resulting From Differences in Captive Rhesus Macaque ( Macaca Mulatta ) Colony Expansion Strategies

ABSTRACT The Caribbean Primate Research Center's (CPRC) specific‐pathogen‐free (SPF) rhesus macaque ( Macaca mulatta ) colony was established between 1998 and 2002 with 87 founders from Cayo Santiago. Colony expansion continued with the rederivation of animals from their SPF predecessors, while additional animals were still being relocated from Cayo Santiago. The CPRC's major histocompatibility complex (MHC) database, generated through next‐generation short‐read sequencing, provides insights into the long‐term MHC immunogenetics of its SPF colony. This database was used to examine the composition of Mamu‐A, Mamu‐B (Class I), and Mamu‐DRB (Class II) across five 5‐year SPF birth cohorts from 1998 to 2022. Population structure at these loci was compared with that of 27 non‐syntenic short tandem repeats (STRs) to examine longitudinal differences in MHC and STR composition during the colony's transition from establishment to expansion. There was no significant relationship between the average observed (OH) and expected (EH) heterozygosity values of the STRs and those of the MHC. STRs exhibited greater and more consistent heterogeneity. Besides being lower than the STRs, the longitudinal changes in the MHC's EH were more pronounced. The pattern of pairwise differentiation (F ST ) at the MHC differed significantly from that of the STRs, where the MHC showed greater differentiation between birth cohorts, whereas STR differentiation was negligible. Increasing rederivation from SPF predecessors while reducing Cayo Santiago translocations made subsequent birth cohorts more genetically divergent and less heterogeneous at the MHC. Recruitment strategies are the primary driver of longitudinal diversity patterns at the MHC, while variation at non‑syntenic STRs was uncorrelated with MHC diversity. This divergence in STR and MHC variation underscores that MHC loci remain under selection even in a genetically managed population, highlighting the importance of direct MHC assessment and considering both MHC and STR diversity in management decisions.