Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross

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  • Gralinski, Lisa E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Ferris, Martin T.
    • Affiliation: School of Medicine, Department of Genetics
  • Aylor, David L.
    • Affiliation: School of Medicine, Department of Genetics
  • Whitmore, Alan C.
    • Affiliation: School of Medicine, Department of Genetics
  • Green, Richard
    • Other Affiliation: University of Washington
  • Frieman, Matthew B.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Deming, Damon
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Menachery, Vineet D.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Miller, Darla R.
    • Affiliation: School of Medicine, Department of Genetics
  • Buus, Ryan J.
    • Affiliation: School of Medicine, Department of Genetics
  • Bell, Timothy A.
    • Affiliation: School of Medicine, Department of Genetics
  • Churchill, Gary A.
    • Other Affiliation: The Jackson Laboratory
  • Threadgill, David W.
    • Other Affiliation: Texas A&M University
  • Katze, Michael G.
    • Other Affiliation: University of Washington
  • McMillan, Leonard
    • Affiliation: College of Arts and Sciences, Department of Computer Science
  • Valdar, William
    • Affiliation: School of Medicine, Department of Genetics
  • Heise, Mark T.
    • Affiliation: School of Medicine, Department of Genetics
  • de Villena, Fernando Pardo-Manuel
    • Affiliation: School of Medicine, Department of Genetics
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Abstract
  • New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.
Date of publication
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  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Genetics
Journal volume
  • 11
Journal issue
  • 10
Language
  • English
ISSN
  • 1553-7390

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