title: Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.
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.
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Gralinski
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Ferris
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Aylor
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Whitmore
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Green
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Frieman
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Damon
authors.initials: D
authors.lastname: Deming
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Vineet D
authors.initials: VD
authors.lastname: Menachery
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Darla R
authors.initials: DR
authors.lastname: Miller
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Buus
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bell
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
authors.affiliation: Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Leonard
authors.initials: L
authors.lastname: McMillan
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Valdar
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Heise
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pardo-Manuel de Villena
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000821:virology; D051379:Mice; D010641:Phenotype; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics* / Q000472:pathogenicity; D045169:Severe Acute Respiratory Syndrome / Q000235:genetics* / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000235:genetics