Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.
Document Type
Article
Publication Date
10-9-2015
JAX Source
PLoS Genet 2015 Oct 9; 11(10):e1005504.
Volume
11
Issue
10
First Page
1005504
Last Page
1005504
ISSN
1553-7404
PMID
26452100
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. PLoS Genet 2015 Oct 9; 11(10):e1005504.
Recommended Citation
Gralinski L,
Ferris M,
Aylor D,
Whitmore A,
Green R,
Frieman M,
Deming D,
Menachery V,
Miller D,
Buus R,
Bell T,
Churchill GA,
Threadgill D,
Katze M,
McMillan L,
Valdar W,
Heise M,
Pardo-Manuel de Villena F,
Baric R.
Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. PLoS Genet 2015 Oct 9; 11(10):e1005504.