biostudies-literatureWang JU.S. Department of Health & Human Services | NIH | National Eye InstituteU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Eye Institute (NEI)U.S. Department of Health & Human Services | NIH | NIH Office of the DirectorU.S. Department of Health & Human Services | NIH | NIH Office of the Director (OD)5658https://www.ebi.ac.uk/biostudies/studies/S-EPMC11226599biostudies-literatureUnknown15(1)Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.Nature communicationsGenetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models.PMC11226599S10OD032189P40OD012217P30EY01257675N93021C00006U24EY029904Vallender ENguyen TThomasy SMRaveendran MStout TWang JWang KMontague MJWang MHarris RAKim SJohnson ZLi YMoshiri AMartinez MWiseman RRogers JSayers KYoung LO'Connor DHChen RLyke MfalseGenetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models.Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.2024-01-01T00:00:00Z2024 Jul2025-04-22T15:35:47.534Z2025-04-06T01:24:18.633ZS-EPMC112265993896963410.1038/s41467-024-49922-6