Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
Date
2015Journal
PLoS GeneticsPublisher
Public Library of ScienceType
Article
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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.Sponsors
Lineberger Comprehensive Cancer Center, University of North Carolina; National Cancer Institute, NCI; National Institute of Allergy and Infectious Diseases, NIAID; National Institutes of Health, NIH: U01CA134240; National Institutes of Health, NIH: U19 AI100625; National Institutes of Health, NIH: U54AI081680Identifier to cite or link to this item
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84946606810&doi=10.1371%2fjournal.pgen.1005504&partnerID=40&md5=a61cbd21f395f0f1cf613b050ecf2336; http://hdl.handle.net/10713/12409ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1005504
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