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.
| Original language | English (US) |
|---|---|
| Article number | e1005504 |
| Journal | PLoS Genetics |
| Volume | 11 |
| Issue number | 10 |
| DOIs | |
| State | Published - Jan 1 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research
Cite this
Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. / Gralinski, Lisa E.; Ferris, Martin T.; Aylor, David L.; Whitmore, Alan C.; Green, Richard; Frieman, Matthew B.; Deming, Damon; Menachery, Vineet; Miller, Darla R.; Buus, Ryan J.; Bell, Timothy A.; Churchill, Gary A.; Threadgill, David W.; Katze, Michael G.; McMillan, Leonard; Valdar, William; Heise, Mark T.; Pardo-Manuel de Villena, Fernando; Baric, Ralph S.
In: PLoS Genetics, Vol. 11, No. 10, e1005504, 01.01.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
AU - Gralinski, Lisa E.
AU - Ferris, Martin T.
AU - Aylor, David L.
AU - Whitmore, Alan C.
AU - Green, Richard
AU - Frieman, Matthew B.
AU - Deming, Damon
AU - Menachery, Vineet
AU - Miller, Darla R.
AU - Buus, Ryan J.
AU - Bell, Timothy A.
AU - Churchill, Gary A.
AU - Threadgill, David W.
AU - Katze, Michael G.
AU - McMillan, Leonard
AU - Valdar, William
AU - Heise, Mark T.
AU - Pardo-Manuel de Villena, Fernando
AU - Baric, Ralph S.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pgen.1005504
DO - 10.1371/journal.pgen.1005504
M3 - Article
VL - 11
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 10
M1 - e1005504
ER -