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.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

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

doi

10.1371/journal.pgen.1005504

subject

Has Abstract

pub_date

2015-10-09 00:00:00

pages

e1005504

issue

10

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-15-00734

journal_volume

11

pub_type

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