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

Author

Listed:
  • Jun Wang

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Meng Wang

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Ala Moshiri

    (School of Medicine, UC Davis, Sacramento)

  • R. Alan Harris

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Muthuswamy Raveendran

    (Baylor College of Medicine
    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
    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
    Baylor College of Medicine)

  • Sara M. Thomasy

    (School of Medicine, UC Davis, Sacramento
    University of California-Davis
    University of California-Davis)

  • Jeffrey Rogers

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Rui Chen

    (Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • 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 Martin, 2024. "Genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49922-6
    DOI: 10.1038/s41467-024-49922-6
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    References listed on IDEAS

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    1. Vincent Ranwez & Sébastien Harispe & Frédéric Delsuc & Emmanuel J P Douzery, 2011. "MACSE: Multiple Alignment of Coding SEquences Accounting for Frameshifts and Stop Codons," PLOS ONE, Public Library of Science, vol. 6(9), pages 1-10, September.
    2. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
    3. Noah Dukler & Mehreen R. Mughal & Ritika Ramani & Yi-Fei Huang & Adam Siepel, 2022. "Extreme purifying selection against point mutations in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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