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

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 - PLoS Genet. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Phenotypic relationships.Heat map of the relationships between lung pathology, titer and weight loss in the preCC. Yellow indicates positive correlation and blue indicates negative correlation.
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pgen.1005504.g003: Phenotypic relationships.Heat map of the relationships between lung pathology, titer and weight loss in the preCC. Yellow indicates positive correlation and blue indicates negative correlation.

Mentions: Multiple aspects of lung pathology were assessed in surviving preCC animals including disease and immune infiltrates in the airways, vasculature, alveoli and parenchyma and signs of DAD (S2 Table). A wide variety of lung pathologies were found across the preCC mice including denudation of airway epithelial cells, airway debris, eosinophilia, hyaline membrane formation and vascular cuffing (Fig 2A–2F). Quantification of the overall pathology score along with select data ranges are shown in S2 Fig. Hyaline membrane formation and pulmonary edema with accompanying inflammation in the alveoli was a hallmark of SARS-CoV infection in human cases and is also evident in aged mouse models of disease [11]. In contrast to young founder strain animals, robust hyaline membrane formation was observed in 13% of preCC mice at day four post-infection, demonstrating that improved animal models are one likely outcome of infection studies in the CC. Phenotypic correlations of varying strengths were observed between aspects of lung pathology, inflammation, viral load at day four post infection, as well as weight loss across the course of the study (Fig 3).


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

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 - PLoS Genet. (2015)

Phenotypic relationships.Heat map of the relationships between lung pathology, titer and weight loss in the preCC. Yellow indicates positive correlation and blue indicates negative correlation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4599853&req=5

pgen.1005504.g003: Phenotypic relationships.Heat map of the relationships between lung pathology, titer and weight loss in the preCC. Yellow indicates positive correlation and blue indicates negative correlation.
Mentions: Multiple aspects of lung pathology were assessed in surviving preCC animals including disease and immune infiltrates in the airways, vasculature, alveoli and parenchyma and signs of DAD (S2 Table). A wide variety of lung pathologies were found across the preCC mice including denudation of airway epithelial cells, airway debris, eosinophilia, hyaline membrane formation and vascular cuffing (Fig 2A–2F). Quantification of the overall pathology score along with select data ranges are shown in S2 Fig. Hyaline membrane formation and pulmonary edema with accompanying inflammation in the alveoli was a hallmark of SARS-CoV infection in human cases and is also evident in aged mouse models of disease [11]. In contrast to young founder strain animals, robust hyaline membrane formation was observed in 13% of preCC mice at day four post-infection, demonstrating that improved animal models are one likely outcome of infection studies in the CC. Phenotypic correlations of varying strengths were observed between aspects of lung pathology, inflammation, viral load at day four post infection, as well as weight loss across the course of the study (Fig 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus