Genomic Sequencing to Establish a Macaque Genotype and Phenotype Research Resource

摘要 恒河猴是学术生物医学中研究最多的非人灵长类动物 研究。由于它们在基因组、生理、解剖和行为上与人类有很高的相似性， 猕猴通常是一种不可或缺的临床前模型。短尾猴和短尾猴近距离的进化史 人类明显具有相似的疾病易感性和遗传关联(例如，S/艾滋病、黄斑 退化、肥胖、心血管疾病、与年龄相关的认知能力下降等)。《俄勒冈国家报》 灵长类研究中心(ONPRC)是4000多只印度原产恒河猴的家园，目前 一个跨越10代的血统繁育群体的成员。这个殖民地支持38个联邦政府资助的 ONPRC的研究研究，其他研究机构的另外60项研究，以及几项 协作性的大规模表型研究。然而，由于缺乏全基因组的基因分型工具 对于猕猴来说，关于ONPRC猕猴群体的基因组数据仍然非常稀少。这款R24将 开发一种新的、有效的方法来大规模描述这一被广泛研究的基因组 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，以生成 该群体的致密基因组图谱。然后，我们将利用基因测序(GBS)这一方法 通常用于植物基因组研究，但仍很少用于生物医学研究，与 全基因组计算，以获得另外1,000名受试者的完整基因组数据。通过利用 为了准确推算全基因组的基因类型，我们将建立一个非常低的- 为后代的持续表征提供成本方法，确保生物医学的持久资源 研究。为了方便广泛使用我们所产生的数据，我们将开发一个数据库，使公众能够 近乎实时地获取所产生的基因数据。该数据库还将包括有关 同样的动物，使其成为第一个同时提供NHP基因和表型的公共可获取资源 数据。临床/表型数据可以分析疾病关联，用于识别 感兴趣，或下载基因组数据进行比较分析。最后，因为角色的特点 研究对象包括活的动物，研究人员还可以根据存在的情况确定潜在的研究对象 或缺乏特定的基因组变异、临床数据或两者兼而有之。后一种选择将提供机会 确定有研究兴趣的珍稀动物，这是NHP模型疾病开发的一个重要目标。我们预计 这一资源将吸引希望利用基因或临床/表型数据的新研究人员 NHP研究的入门，无论是在ONPRC还是在其他地方。作为这项工作的结果，我们将建立 第一个具有基因组特征的纯种猕猴研究群体，开发了一种可持续的方法 为了继续描述后代，并建立工具、资源和方法 支持在其他恒河猴繁育群体中进行基因组归属。

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.