Genomic Sequencing of Japanese Macaques to Enhance NHP Model Discovery

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SUMMARY The FDA approved the first gene therapy treatment for an inherited disease in late 2017. Since then, an accelerating number of reports describe progress in the development of gene or cell-based therapies to prevent or forestall a range of devastating genetic diseases. The exciting advances in these and other precision medicine approaches have resulted in the rapidly growing demand for genetically similar, large animal models for the pre- clinical study of promising treatments. In that regard, nonhuman primates (NHPs) have emerged as a premier model for the study of human genetic diseases and cutting-edge treatments. In addition to their similar genetics, physiology, anatomy and behavior, the uniquely similar eye, ear and brain structures make macaques particularly important for advancing new therapies to address neurodegenerative disease and sensory impairment. Born out of that need, NIH funded the development of the macaque Genotype and Phenotype (mGAP) Resource, which currently includes genomic sequence and variant data from more than 3.4K rhesus macaques housed in NIH supported colonies. Using state-of-the-art variant discovery methods, mGAP also provides access to discovered single nucleotide variant data, with annotations including predicted protein effects, pathogenicity scores, allele frequency, cross-species conservation metrics and genotype data. The breadth of the primarily US-based mGAP user base underscores the value of this data for clinical and research applications. This current project aims to expand the mGAP data set to include genomic data from a unique Japanese macaque (JM; M. fuscata) colony, founded almost 60 years ago with breeders obtained from the Hiroshima Prefecture and donated to the Oregon National Primate Research Center by the government of Japan. Subsequent generations of breeding among the free-range JM troop has yielded multiple natural models of human disease, including the only known spontaneous model of demyelinating disease similar to multiple sclerosis (MS), a model of Batten Disease (BD), and a dominant drusen model of early-onset macular degeneration (MD). This project will capitalize on the unique history and value of the JM colony by producing whole-genome sequence and variant discovery on the current and future breeders in this colony. The data will enable 1) the discovery and analysis of JM sequence variants, 2) public access to comprehensive genomic data from this unique colony, 3) genetic mapping of the valuable MS and MD models, 4) identification of potential new models based on genome-wide discovery of pathogenic variants, and 5) informed genetic management of the JM colony to insure genetic health and retention of valuable model alleles. All of the generated sequence, variant and associated model data will be made publicly available by the addition of new JM-specific data tracks in the well-established mGAP Resource website.