Genomic Sequencing to Establish a Macaque Genotype and Phenotype Research Resource

总结 恒河猴是学术生物医学研究中最常研究的非人灵长类动物（NHP）。 research.由于它们在基因组、生理、解剖和行为上与人类高度相似， 猕猴通常作为不可缺少的临床前模型。猕猴的进化史与 人类在其相似的疾病易感性和遗传关联方面是明显的（例如，S/HIV，黄斑 退化、肥胖、心血管疾病、年龄相关的认知衰退等）。俄勒冈州国家队 灵长类动物研究中心（ONPRC）是4,000多只印度恒河猴的家园，目前 一个跨越10代的纯种繁殖群体的成员。这个殖民地支持38个联邦资助的 在ONPRC进行研究，在其他研究机构进行另外60多项研究， 协作的大规模表型研究。然而，由于缺乏全基因组基因分型工具 对于猕猴，关于ONPRC恒河猴群的基因组数据仍然极其稀少。R24将 开发一种新的和有效的方法，用于大规模的基因组表征，这一大量研究 殖民地我们将获得至少200个选定个体的30倍全基因组序列数据， 密集的殖民地基因组图谱。然后，我们将利用基因型测序（GBS）， 通常用于植物的基因组研究，但很少用于生物医学研究， 全基因组插补以获得另外1，000名受试者的完整基因组数据。通过利用 密集的系谱结构，为全基因组基因型的准确插补，我们将建立一个非常低的， 成本方法，以继续表征后代，确保生物医学的持久资源 research.为方便市民广泛使用我们所收集的资料，我们会建立一个资料库， 接近实时地访问所产生的基因型数据。该数据库还将包括关于 相同的动物，使其成为第一个提供NHP基因型和表型的动物学可及资源 数据可以分析临床/表型数据的疾病相关性，用于鉴定 感兴趣，或下载基因组数据进行比较分析。最后，由于特征 受试者包括活体动物，研究人员还可以根据存在的情况识别潜在的研究受试者。 或不存在特定基因组变体、临床数据或两者。后一种选择将提供机会， 鉴定研究感兴趣的稀有动物，这是NHP疾病模型开发的一个重要目标。我们预计 该资源将吸引希望利用基因型或临床/表型数据的新研究人员， NHP研究的入场券，无论是在ONPRC还是其他地方。作为这项工作的结果，我们将建立 第一个基因组特征，纯种恒河猴研究群体，发展可持续的方法 为继续表征后代，并建立工具，资源和方法， 支持其他恒河猴繁殖群体的基因组估算。

SUMMARY Rhesus macaques are the most commonly studied non-human primate (NHP) in academic biomedical research. Due to their high level of genomic, physiological, anatomical and behavioral similarity to humans, macaques often serve as an indispensable preclinical model. The close evolutionary history of macaques and humans is evident in their similar disease susceptibilities and genetic associations (e.g., S/HIV, macular degeneration, obesity, cardiovascular disease, age-associated cognitive decline, etc.). The Oregon National Primate Research Center (ONPRC) is home to more than 4,000 Indian-origin rhesus macaques, the current members of a pedigreed breeding colony that spans 10 generations. This colony supports 38 federally funded research studies at the ONPRC, an additional 60+ studies at other research institutions, and several collaborative, large scale phenotyping studies. However given the absence of genome-wide genotyping tools for macaques, genomic data on the ONPRC rhesus macaque colony remain extremely sparse. This R24 will develop a novel and efficient approach for the large-scale genomic characterization of this heavily studied colony. We will obtain 30X whole genome sequence data on at least 200 selected individuals to generate a dense genomic map of the colony. We will then utilize genotype-by-sequencing (GBS), an approach commonly used in genomic studies of plants but still rarely used in biomedical research, in concert with genome-wide imputation to obtain complete genomic data in an additional 1,000 subjects. By leveraging the dense pedigree structure for the accurate imputation of genome-wide genotypes, we will establish a very low- cost method for the continued characterization of future generations, ensuring a lasting resource for biomedical research. To facilitate widespread use of the data we generate, we will develop a database that enables public access in near real-time to the genotype data produced. The database will also include clinical data on the same animals, making it the first publically accessible resource to provide both NHP genotype and phenotype data. The clinical/phenotypic data can be analyzed for disease associations, for the identification of animals of interest, or to download with genomic data for comparative analyses. Finally, because the characterized subjects include living animals, researchers can also identify potential study subjects based upon the presence or absence of particular genomic variants, clinical data or both. The latter option will provide opportunity to identify rare animals of research interest, an important goal for NHP model disease development. We expect that this resource will attract new investigators who wish to leverage the genotype or clinical/phenotype data as an entree to NHP research, be it at the ONPRC or elsewhere. As a result of this work, we will establish the first genomically characterized, pedigreed rhesus macaque research colony, develop a sustainable approach for the continued characterization of future generations, and establish the tools, resources and methods to support genome imputation in other rhesus macaque breeding colonies.