Genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models

Jun Wang, Meng Wang, Ala Moshiri, R. Alan Harris, Muthuswamy Raveendran, Tracy Nguyen, Soohyun Kim, Laura Young, Keqing Wang, Roger Wiseman, David H. O’Connor, Zach Johnson, Melween Martinez, Michael J. Montague, Ken Sayers, Martha Lyke, Eric Vallender, Tim Stout, Yumei Li, Sara M. Thomasy, Jeffrey Rogers and Rui Chen ()
Additional contact information
Jun Wang: Baylor College of Medicine
Meng Wang: Baylor College of Medicine
Ala Moshiri: School of Medicine, UC Davis, Sacramento
R. Alan Harris: Baylor College of Medicine
Muthuswamy Raveendran: Baylor College of Medicine
Tracy Nguyen: University of California-Davis
Soohyun Kim: University of California-Davis
Laura Young: University of California-Davis
Keqing Wang: Baylor College of Medicine
Roger Wiseman: University of Wisconsin-Madison
David H. O’Connor: University of Wisconsin-Madison
Zach Johnson: Emory University
Melween Martinez: University of Puerto Rico
Michael J. Montague: University of Pennsylvania
Ken Sayers: Texas Biomedical Research Institute
Martha Lyke: Texas Biomedical Research Institute
Eric Vallender: Tulane university
Tim Stout: Baylor College of Medicine
Yumei Li: Baylor College of Medicine
Sara M. Thomasy: School of Medicine, UC Davis, Sacramento
Jeffrey Rogers: Baylor College of Medicine
Rui Chen: Baylor College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49922-6

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