Genomic Sequencing to Establish a Macaque Genotype and Phenotype Research Resource

点击翻译按钮获取中文摘要

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.