Targeted capture sequencing of rhesus macaques for genes associated with inherited human retinal and neurodevelopmental diseases.

To understand and develop treatments for human diseases, valid animal models are essential. To leverage the pool of spontaneous genetic variation within rhesus macaque (Macaca mulatta) populations across eight primate centers in the United States, we conducted targeted sequencing on 1,845 individuals for 374 genes associated with inherited human retinal and neurodevelopmental disorders. We detected over 47,000 high-quality single nucleotide variants (SNVs), a significant portion of which are shared with human populations. Integrating rhesus and human allele frequencies with established variant prediction scores, we devised a machine learning-based integrative score for predicting the pathogenicity of missense variant, outperforming established methods. Notably, we uncovered a marked number of loss-of-function variants and putative deleterious variants, opening new avenues for developing rhesus macaque disease models. Through phenotypic analysis of macaques carrying a pathogenic OPA1:p.A8S variant, we identified a genetic model for autosomal dominant optic atrophy in rhesus macaques. Lastly, we established a publicly accessible website hosting variant and genotype data from over two thousand rhesus macaques, serving as an invaluable resource for biomedical research.