Large-Scale Discovery of Functional Genetic Variation in Rhesus Macaques

描述(申请人提供)：恒河猴(猕猴)是生物医学研究中使用最广泛的非人类灵长类动物。恒河猴在努力了解艾滋病毒-艾滋病的发病机制、开发针对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、糖尿病和骨质疏松症等代谢性疾病以及生殖生物学的研究。恒河猴在干细胞生物学分析中很重要。在与酒精中毒、毒瘾、焦虑症和抑郁症相关的研究中，本种也经常被用作动物模型。这个拟议的项目将通过产生大量关于恒河猴功能遗传变异的新信息，极大地提高这种灵长类物种对所有类型生物医学研究的价值和意义。现在公认的是，人与人之间的遗传差异会影响他们罹患包括传染病在内的上述常见疾病的风险。基因变异也会影响疾病的进展和不同人对特定治疗的反应。我们将通过在恒河猴基因组的功能基因中识别大量新的DNA序列变异，促进疾病易感性和治疗反应的遗传基础的研究。为了做到这一点，我们将对96只无关的恒河猴的外显子(所有功能基因外显子)进行测序，这96只恒河猴既有印度血统的，也有中国血统的。我们还将为这96种动物中的8种提供全基因组序列。外显子组和全基因组数据将被用来识别该物种存在的新的DNA序列变异。我们还将对所有96只动物的淋巴细胞的RNA进行测序，以开始评估该组织内基因表达的个体差异，并将差异RNA表达与相关基因的DNA序列差异联系起来。所有产生的数据将通过适当的NCB1数据库(如Short Read Archive、DBVAR和DBSNP)公开提供，并建立我们自己的可供公众搜索的恒河猴遗传变异在线数据库。

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.