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 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 journalArticle

47 Citations (Scopus)

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 languageEnglish (US)
Article numbere1005504
JournalPLoS Genetics
Volume11
Issue number10
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

SARS Virus
severe acute respiratory syndrome
genome
Genome
loci
Blood Vessels
blood vessels
Pathology
Inflammation
pathology
Lung
Untranslated RNA
Chromosomes, Human, Pair 3
Ubiquitin-Protein Ligases
Gene Regulatory Networks
inflammation
lungs
gene
Virus Replication
ubiquitin-protein ligase

ASJC Scopus subject areas

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

Cite this

Gralinski, L. E., Ferris, M. T., Aylor, D. L., Whitmore, A. C., Green, R., Frieman, M. B., ... 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

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 journalArticle

Gralinski, LE, Ferris, MT, Aylor, DL, Whitmore, AC, Green, R, Frieman, MB, Deming, D, Menachery, V, 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
Gralinski LE, Ferris MT, Aylor DL, Whitmore AC, Green R, Frieman MB et al. Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. PLoS Genetics. 2015 Jan 1;11(10). e1005504. https://doi.org/10.1371/journal.pgen.1005504
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. / Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross. In: PLoS Genetics. 2015 ; Vol. 11, No. 10.
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