Large-Scale Discovery of Functional Genetic Variation in Rhesus Macaques

描述（申请人提供）：恒河猴（Macaca mulatta）是生物医学研究中应用最广泛的非人灵长类动物。恒河猴在了解艾滋病毒-艾滋病发病机制、开发抗艾滋病毒感染的新疗法和新疫苗方面至关重要。此外，恒河猴通常用于基础神经生物学、代谢疾病（如糖尿病和骨质疏松症）和生殖生物学的研究。恒河猴是干细胞生物学分析的重要对象。该物种也经常被用作与酒精中毒、药物成瘾、焦虑症和抑郁症有关的研究的动物模型。该计划将通过产生大量关于恒河猴功能遗传变异的新信息，极大地增加这一灵长类物种在所有类型的生物医学研究中的价值和意义。现在已经确定，人与人之间的遗传差异会影响他们患上述常见疾病（包括传染病）的风险。遗传变异也会影响疾病的进展和不同人对特定治疗的反应。我们将通过鉴定恒河猴基因组中功能基因的大量新的DNA序列变异，促进疾病易感性和治疗反应的遗传基础研究。为了实现这一目标，我们将对96只无亲缘关系的印度和中国猕猴的外显子（所有功能基因外显子）进行测序。我们还将对这96只动物中的8只进行全基因组测序。外显子组和全基因组数据将用于鉴定该物种中存在的新的DNA序列变异。我们还将对所有96只动物淋巴细胞的RNA进行测序，以开始评估该组织中基因表达的个体差异，并将差异RNA表达与相关基因的DNA序列变化联系起来。所有生成的数据将通过适当的NCBl数据库（例如Short Read Archive， dbVAR和dbSNP）以及创建我们自己的公共可搜索的恒河猴遗传变异在线数据库公开提供。

DESCRIPTION (provided by applicant): Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research. Rhesus are critically important in efforts to understand the pathogenesis of HIV-AIDS, to develop novel treatments and new vaccines against HIV infection. In addition, rhesus macaques are commonly used in studies of basic neurobiology, metabolic diseases such as diabetes and osteoporosis, and reproductive biology. Rhesus monkeys are important in analyses of stem cell biology. This species is also frequently used as an animal model in studies related to alcoholism, drug addiction, anxiety disorders and depression. This proposed project will dramatically increase the value and significance of this primate species for all types of biomedical research by generating a substantial amount of new information about functional genetic variation among rhesus macaques. It is now well established that genetic differences among people influence their risk of developing common diseases such as those listed above, including infectious diseases. Genetic variation can also influence the progression of disease and the responses of different people to a specific treatment. We will facilitate research on the genetic basis of disease susceptibility and response to treatment by identifying large numbers of new DNA sequence variants in functional genes within the rhesus genome. To accomplish this, we will sequence the exome (all functional gene exons) from 96 unrelated rhesus macaques, both Indian-origin and Chinese-origin animals. We will also produce whole genome sequences for 8 of those 96 animals. The exome and whole genome data will be used to identify new DNA sequence variation present in this species. We will also sequence RNA from the lymphocytes of all 96 animals to begin assessment of individual variation in gene expression within that tissue, and to correlate differential RNA expression with DNA sequence variation in the relevant genes. All the data generated will be made publically available through appropriate NCBl databases (e.g. Short Read Archive, dbVAR and dbSNP) and by creating our own public searchable on-line database of rhesus genetic variation.