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

被引：113

作者：

Gralinski, Lisa E. ^{[1
]}

Ferris, Martin T. ^{[2
]}

Aylor, David L. ^{[2
]}

Whitmore, Alan C. ^{[2
]}

Green, Richard ^{[3
]}

Frieman, Matthew B. ^{[1
]}

Deming, Damon ^{[1
]}

Menachery, Vineet D. ^{[1
]}

Miller, Darla R. ^{[2
,4
]}

Buus, Ryan J. ^{[2
,4
]}

Bell, Timothy A. ^{[2
,4
]}

Churchill, Gary A. ^{[5
]}

Threadgill, David W. ^{[6
]}

Katze, Michael G. ^{[3
]}

McMillan, Leonard ^{[7
]}

Valdar, William ^{[2
]}

Heise, Mark T. ^{[2
]}

de Villena, Fernando Pardo-Manuel ^{[2
,4
]}

Baric, Ralph S. ^{[1
]}

机构：

[1] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[3] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA

[4] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[5] Jackson Lab, Bar Harbor, ME 04609 USA

[6] Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX USA

[7] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC USA

来源：

PLOS GENETICS | 2015年 / 11卷 / 10期

基金：

美国国家卫生研究院;

关键词：

ACUTE RESPIRATORY SYNDROME; SYNDROME-CORONAVIRUS INFECTION; QUANTITATIVE TRAIT LOCI; MANNOSE-BINDING LECTIN; GENETIC-ANALYSIS; IMMUNE-RESPONSES; LABORATORY MOUSE; SYSTEMS GENETICS; VIRUS-INFECTION; MICE;

D O I：

10.1371/journal.pgen.1005504

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：21

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