Lyke M M, Bagwell A, Newman D, Galindo S, Church T, Christensen C, Gray S B, Cox L A, Ross C N, Kaushal D, Cheeseman I H, Cole S A
Southwest National Primate Research Center, San Antonio, TX.
Texas Biomedical Research Institute, San Antonio, TX.
bioRxiv. 2025 May 28:2025.05.26.654976. doi: 10.1101/2025.05.26.654976.
Rhesus macaques are the preferred non-human primate model for HIV/AIDS-related research. Specific major histocompatibility complex (MHC) haplotypes and genetic ancestry are linked to slow disease progression of Simian Immunodeficiency Virus (SIV) infections in macaques. To maximize their utility for HIV/AIDS research, the Southwest National Primate Research Center (SNPRC) has introduced targeted breeding strategies to reduce the prevalence of SIV-refractory MHC haplotypes and levels of admixture between Indian- and Chinese-origin macaques.
We characterized the MHC region in SNPRC macaques by targeted deep sequencing of 1,458 animals born over a ten-year period. Following the implementation of MHC management strategies, the prevalence of SIV-refractory MHC haplotypes reduced significantly while overall haplotype diversity was maintained. 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 some Chinese ancestry, though population substructure more closely reflected primate research center source than geographical origin. The levels of Chinese ancestry declined significantly over time, though genetic diversity remains high. 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 within the colony.
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.
恒河猴是与HIV/AIDS相关研究的首选非人灵长类动物模型。特定的主要组织相容性复合体（MHC）单倍型和遗传血统与猕猴中猿猴免疫缺陷病毒（SIV）感染的疾病缓慢进展有关。为了最大限度地发挥它们在HIV/AIDS研究中的作用，西南国家灵长类动物研究中心（SNPRC）引入了定向育种策略，以降低SIV难治性MHC单倍型的流行率以及印度和中国原产猕猴之间的混合水平。
我们通过对十年内出生的1458只动物进行靶向深度测序，对SNPRC猕猴的MHC区域进行了表征。在实施MHC管理策略后，SIV难治性MHC单倍型的流行率显著降低，同时总体单倍型多样性得以维持。我们使用奠基动物和群体出生动物（n = 488）的全外显子组测序，研究了管理策略对混合、群体遗传结构、遗传多样性和近亲繁殖的影响。对奠基动物的混合分析显示有一些中国血统，尽管群体亚结构更紧密地反映了灵长类动物研究中心的来源而非地理起源。随着时间的推移，中国血统水平显著下降，尽管遗传多样性仍然很高。最后，我们对随时间的遗传选择进行了全基因组扫描。我们确定了许多等位基因频率发生显著变化的基因组区域，支持群体内存在短期适应性。
我们表明群体管理策略取得了成功，同时没有降低MHC或外显子区域的遗传多样性。我们还表明群体遗传亚结构与动物群体来源有关，并且合并和迁移减少了近亲繁殖并增加了总体遗传多样性。
