Publication Date
7-5-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-49922-6
PMID
38969634
PMCID
PMC11226599
PubMedCentral® Posted Date
7-5-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Macaca mulatta, Disease Models, Animal, Humans, Genetic Variation, Gene Frequency, Optic Atrophy, Autosomal Dominant, Polymorphism, Single Nucleotide, Phenotype, Machine Learning, Genotype, Mutation, Missense, Next-generation sequencing, Neurodevelopmental disorders, Genetic variation, Animal disease models
Abstract
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.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Diseases Commons, Genetic Phenomena Commons, Genetic Processes Commons, Genetics Commons, Medical Biochemistry Commons, Medical Specialties Commons, Molecular Genetics Commons
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