Genomic Sequencing to Establish a Macaque Genotype and Phenotype Research Resource

SUMMARYRhesus macaques are the most commonly studied non-human primate (NHP) in academic biomedicalresearch. 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 andhumans is evident in their similar disease susceptibilities and genetic associations (e.g., S/HIV, maculardegeneration, obesity, cardiovascular disease, age-associated cognitive decline, etc.). The Oregon NationalPrimate Research Center (ONPRC) is home to more than 4,000 Indian-origin rhesus macaques, the currentmembers of a pedigreed breeding colony that spans 10 generations. This colony supports 38 federally fundedresearch studies at the ONPRC, an additional 60+ studies at other research institutions, and severalcollaborative, large scale phenotyping studies. However given the absence of genome-wide genotyping toolsfor macaques, genomic data on the ONPRC rhesus macaque colony remain extremely sparse. This R24 willdevelop a novel and efficient approach for the large-scale genomic characterization of this heavily studiedcolony. We will obtain 30X whole genome sequence data on at least 200 selected individuals to generate adense genomic map of the colony. We will then utilize genotype-by-sequencing (GBS), an approachcommonly used in genomic studies of plants but still rarely used in biomedical research, in concert withgenome-wide imputation to obtain complete genomic data in an additional 1,000 subjects. By leveraging thedense 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 biomedicalresearch. To facilitate widespread use of the data we generate, we will develop a database that enables publicaccess in near real-time to the genotype data produced. The database will also include clinical data on thesame animals, making it the first publically accessible resource to provide both NHP genotype and phenotypedata. The clinical/phenotypic data can be analyzed for disease associations, for the identification of animals ofinterest, or to download with genomic data for comparative analyses. Finally, because the characterizedsubjects include living animals, researchers can also identify potential study subjects based upon the presenceor absence of particular genomic variants, clinical data or both. The latter option will provide opportunity toidentify rare animals of research interest, an important goal for NHP model disease development. We expectthat this resource will attract new investigators who wish to leverage the genotype or clinical/phenotype data asan entree to NHP research, be it at the ONPRC or elsewhere. As a result of this work, we will establish thefirst genomically characterized, pedigreed rhesus macaque research colony, develop a sustainable approachfor the continued characterization of future generations, and establish the tools, resources and methods tosupport genome imputation in other rhesus macaque breeding colonies.