猕猴（Macaca mulatta）亚种及其近缘种比较基因组学研究

Rhesus monkeys (Macaca mulatta) and its closely-related species (M. fascicularis, M. cyclopis and M. fuscata) are the most widely used nonhuman primates in basic and applied biomedical research. Furthermore, they have a broad geographic distribution that reaches from Afghanistan and India across Asia to the Chinese shore of the Pacific Ocean, and Japan (M. fuscata) and Taiwan island (M. cyclopis), offering a good opportunity to study evolutionary and adaptation processes during speciation and diversification. In rhesus macaques there are 6-15 subspecies recognized and there is extensive genetic diversity in rhesus macaques and related species with different origin, which are considered to underpin the observed phenotypic differences between them, such as ecological adaptation, morphology, immune responses and disease progression. For example, compared with Indian rhesus macaques (M. mulatta mulatta), simian immunodeficiency virus (SIV) pathogenesis in Chinese rhesus macaques (M. mulatta lasiota) are more similar to HIV-1 infections in untreated adult humans. Therefore, developing a global map of genomic variation within subspecies and close-related species of M. mulatta has important implications for biomedical research, drug development and evolutionary studies. Currently, the genetic divergence and differentiation between rhesus macaques in China (M. mulatta lasiota) and Indian (M. mulatta mulatta) has been analyzed through whole-genome analysis to assess their potential biomedical value. The results have shown that variation in the number of positively selected genes and frequencies of disease-related alleles, indicating that such differences should be considered when selecting macaques for use as disease models. However, for most of published papers, the target individuals are from captive groups in southern China and their geographical origins are ambiguous. At present, there is no comprehensive study on genome-scale variation among wild populations of M. mulatta. Therefore, developing a global map of genomic variation among macaques with clear provenance is now necessary to contextualize the results of biomedical research and drug development. In particular, it is essential to be able to control for the genetic background of captive groups in biomedical studies. We plan to integrate genome resequencing data from subspecies of M. mulatta, M. fuscata and M. cyclopis, using the massively parallel sequencing. My aims are: (1) to dissect genetic variants that are responsible for phenotypic divergence among macaques; (2) evaluate variation in disease and drug-target genes among subspecies of M. mulatta and its closely-related species; (3) detect variation in selection pressure across genome regions in macaques of different geographical origin.

猕猴（Macaca mulatta）及其近缘种是进行非人灵长类生态基因组学研究的理想对象。猕猴种内的遗传多样性非常丰富，共划分了6-13个亚种，但其基因组变异水平及其与生态适应的关系尚未完全开展研究工作。猕猴及其近缘种在疫苗实验和人类疾病医药实验中都是重要的动物模型。猕猴的遗传差异也导致不同亚种间免疫反应和疫病过程不尽相同。对猕猴各个亚种和地理种群及其近缘种开展比较基因组学研究，无论从生态基因组学和生物医药研究方面，均具有重要的意义。本研究拟对猕猴6-8个亚种及其近缘种日本猕猴和台湾猕猴开展基因组重测序研究。统计各个种/亚种单核苷酸突变、短插入缺失、结构变异和拷贝数变异情况，评估种/亚种间遗传变异差异，探讨遗传变异在不同种/亚种中受选择压力的差异，及其与生态适应的关系。同时检查人类疫病同源基因和药靶基因的变异情况，为生物医药实验动物选择和分析表型差异提供重要的生物信息。

猕猴（Macaca mulatta）是生物医学研究中最重要的非人灵长类动物模型。我们首次对81个中国野生猕猴进行了种群基因组学研究，这81个猕猴样本分布在中国的17个样品采集点，覆盖了我国猕猴的绝大多数分布区。通过解析中国猕猴的种群遗传结构，我们将中国猕猴划分为5个种群，代表了目前猕猴的亚种分布。通过模拟发现这些亚种在大约109 千年前到18 千年前发生了分化，并在后期伴随有基因交流。另外，猕猴分布区最北端的华北亚种（M. m. tcheliensis）和分布区最南端的海南亚种（M. m. brevicaudus）分别是中国猕猴中体型最大的和最小的，与贝格曼法则（Bergman’s rule）一致。通过选择消除分析，在华北亚种和海南亚种中都检测到了和骨骼发育相关的基因受到选择。另外，华北亚种（M. m. tcheliensis）中的2个参与糖异生过程的基因(Fbp1, Fbp2)也检测到明显的选择信号，这可能和华北亚种在冬季食物资源匮乏时，仍然能够维持稳定的血糖水平密切相关。在海南亚种（M. M. brevicaudus）表现出与心血管功能和对温度刺激反应有关的受选择基因，这些基因可能参与海南亚种对炎热环境的适应。另外，我们还在中国猕猴中检测到118个和人类疾病相关的SNPs位点，其中大部分位点为亚种特有或者部分亚种特有。这些数据为生物医学实验中猕猴的选择提供了资源。中国猕猴的种群历史及其局部适应为猕猴的演化提供了新的视角，并为生物医学研究提供了有价值的基础信息。