PROJECT SUMMARY This R24 application addresses NIH priorities to expand genetic analysis of nonhuman primate (NHP) colonies, to make the resulting genomic variant data publically accessible, and to promote NHP model discovery. These goals reflect the urgent need for the identification of genetically appropriate, large-animal models to support the development of precision medicine approaches, including gene or cell-based therapies, for the treatment of human disease. In that regard, NHPs, especially rhesus macaques, have emerged as a premier pre-clinical model, owing to their similar genetic content, physiology and anatomy, particularly the uniquely similar eye, ear and brain structures important for the treatment of neurodegenerative disease and sensory impairment. We have shown that rhesus macaques carry thousands of variants that are either identical to human pathogenic alleles associated with genetic disease, or are predicted to be functionally damaging and likely contributing to disease. This R24 research resource will efficiently identify such predicted pathogenic variants, by sequencing the genomes of prolific breeders that together produced more than 4,200 of the macaques currently living in three large, NIH supported rhesus macaque breeding colonies. By including multiple breeding centers in this study, there are increased opportunities to identify rare sequence variants, and if needed, to establish breeding programs to propagate critical disease models. By working with veterinary specialists, investigators and clinicians to characterize the most urgently needed disease models, we will continue to identify new naturally occurring NHP genetic models that can be utilized for the study and treatment of human diseases associated with hearing impairment, blindness, neurodegeneration or developmental disorders, among others. All of the genome sequences, variants and model data generated by this project will be made available through our web- accessible, macaque Genotype And Phenotype (mGAP) research resource, the only public resource to provide individual-linked genotype data for rhesus macaques housed at the NIH National Primate Research Centers (NPRCs). mGAP has already attracted use by a broad range of investigators and clinicians. In addition to deploying new mGAP functions, variants and macaque annotations, we will also analyze and host rhesus macaque genomic data sets produced by other NIH-funded studies. Accordingly, mGAP will continue to serve as a central resource for sharing genomic variant data on rhesus macaques housed at NPRCs nationwide, supporting advanced genetic management of NIH rhesus macaque colonies, and expanding opportunities for the development of new medical treatments to prevent or alleviate human disease.

PROJECT NARRATIVE The successful development of promising precision medicine therapies often requires use of animal models that are genetically and anatomically similar to humans. This proposal will speed the discovery of natural genetic disease models already existing in nonhuman primates through the large-scale genome sequencing and analysis of macaque breeding colonies.