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

Lisa E. Gralinski; Martin T. Ferris; David L. Aylor; Alan C. Whitmore; Richard Green; Matthew B. Frieman; Damon Deming; Vineet D. Menachery; Darla R. Miller; Ryan J. Buus; Timothy A. Bell; Gary A. Churchill; David W. Threadgill; Michael G. Katze; Leonard McMillan; William Valdar; Mark T. Heise; Fernando Pardo-Manuel de Villena; Ralph S. Baric

doi:10.1371/journal.pgen.1005504

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

Lisa E. Gralinski, Martin T. Ferris, David L. Aylor, Alan C. Whitmore, Richard Green, Matthew B. Frieman, Damon Deming, Vineet D. Menachery, Darla R. Miller, Ryan J. Buus, Timothy A. Bell, Gary A. Churchill, David W. Threadgill, Michael G. Katze, Leonard McMillan, William Valdar, Mark T. Heise, Fernando Pardo-Manuel de Villena, Ralph S. Baric

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

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	https://doi.org/10.1371/journal.pgen.1005504
State	Published - 2015
Externally published	Yes

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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10.1371/journal.pgen.1005504

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Gralinski, L. E., Ferris, M. T., Aylor, D. L., Whitmore, A. C., Green, R., Frieman, M. B., Deming, D., Menachery, V. D., Miller, D. R., Buus, R. J., Bell, T. A., Churchill, G. A., Threadgill, D. W., Katze, M. G., McMillan, L., Valdar, W., Heise, M. T., Pardo-Manuel de Villena, F., & Baric, R. S. (2015). Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. PLoS genetics, 11(10), [e1005504]. https://doi.org/10.1371/journal.pgen.1005504

Gralinski, LE, Ferris, MT, Aylor, DL, Whitmore, AC, Green, R, Frieman, MB, Deming, D, Menachery, VD, Miller, DR, Buus, RJ, Bell, TA, Churchill, GA, Threadgill, DW, Katze, MG, McMillan, L, Valdar, W, Heise, MT, Pardo-Manuel de Villena, F & Baric, RS 2015, 'Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross', PLoS genetics, vol. 11, no. 10, e1005504. https://doi.org/10.1371/journal.pgen.1005504

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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.",

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

Abstract

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