Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
Identifieur interne : 001332 ( Pmc/Curation ); précédent : 001331; suivant : 001333Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
Auteurs : Lisa E. Gralinski [États-Unis] ; Martin T. Ferris [États-Unis] ; David L. Aylor [États-Unis] ; Alan C. Whitmore [États-Unis] ; Richard Green [États-Unis] ; Matthew B. Frieman [États-Unis] ; Damon Deming [États-Unis] ; Vineet D. Menachery [États-Unis] ; Darla R. Miller [États-Unis] ; Ryan J. Buus [États-Unis] ; Timothy A. Bell [États-Unis] ; Gary A. Churchill [États-Unis] ; David W. Threadgill [États-Unis] ; Michael G. Katze [États-Unis] ; Leonard Mcmillan [États-Unis] ; William Valdar [États-Unis] ; Mark T. Heise [États-Unis] ; Fernando Pardo-Manuel De Villena [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- PLoS Genetics [ 1553-7390 ] ; 2015.
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,
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DOI: 10.1371/journal.pgen.1005504
PubMed: 26452100
PubMed Central: 4599853
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Gralinski</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Ferris, Martin T" sort="Ferris, Martin T" uniqKey="Ferris M" first="Martin T." last="Ferris">Martin T. Ferris</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Aylor, David L" sort="Aylor, David L" uniqKey="Aylor D" first="David L." last="Aylor">David L. 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Whitmore</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Green, Richard" sort="Green, Richard" uniqKey="Green R" first="Richard" last="Green">Richard Green</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea></affiliation></author><author><name sortKey="Frieman, Matthew B" sort="Frieman, Matthew B" uniqKey="Frieman M" first="Matthew B." last="Frieman">Matthew B. Frieman</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Deming, Damon" sort="Deming, Damon" uniqKey="Deming D" first="Damon" last="Deming">Damon Deming</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Menachery, Vineet D" sort="Menachery, Vineet D" uniqKey="Menachery V" first="Vineet D." last="Menachery">Vineet D. Menachery</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Miller, Darla R" sort="Miller, Darla R" uniqKey="Miller D" first="Darla R." last="Miller">Darla R. Miller</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Buus, Ryan J" sort="Buus, Ryan J" uniqKey="Buus R" first="Ryan J." last="Buus">Ryan J. Buus</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Bell, Timothy A" sort="Bell, Timothy A" uniqKey="Bell T" first="Timothy A." last="Bell">Timothy A. Bell</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Churchill, Gary A" sort="Churchill, Gary A" uniqKey="Churchill G" first="Gary A." last="Churchill">Gary A. Churchill</name><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>The Jackson Laboratory, Bar Harbor, Maine, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Jackson Laboratory, Bar Harbor, Maine</wicri:regionArea></affiliation></author><author><name sortKey="Threadgill, David W" sort="Threadgill, David W" uniqKey="Threadgill D" first="David W." last="Threadgill">David W. Threadgill</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas</wicri:regionArea></affiliation></author><author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, University of Washington, Seattle, Washington</wicri:regionArea></affiliation></author><author><name sortKey="Mcmillan, Leonard" sort="Mcmillan, Leonard" uniqKey="Mcmillan L" first="Leonard" last="Mcmillan">Leonard Mcmillan</name><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Valdar, William" sort="Valdar, William" uniqKey="Valdar W" first="William" last="Valdar">William Valdar</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Pardo Manuel De Villena, Fernando" sort="Pardo Manuel De Villena, Fernando" uniqKey="Pardo Manuel De Villena F" first="Fernando" last="Pardo-Manuel De Villena">Fernando Pardo-Manuel De Villena</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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, <italic>Trim55</italic>, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in <italic>Trim55</italic> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Lai, St" uniqKey="Lai S">ST Lai</name></author><author><name sortKey="Poon, Ll" uniqKey="Poon L">LL Poon</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author><author><name sortKey="Yam, Ly" uniqKey="Yam L">LY Yam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Sk" uniqKey="Lau S">SK Lau</name></author><author><name sortKey="Woo, Pc" uniqKey="Woo P">PC Woo</name></author><author><name sortKey="Li, Ks" uniqKey="Li K">KS Li</name></author><author><name sortKey="Huang, Y" uniqKey="Huang Y">Y 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosgen</journal-id><journal-title-group><journal-title>PLoS Genetics</journal-title></journal-title-group><issn pub-type="ppub">1553-7390</issn><issn pub-type="epub">1553-7404</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26452100</article-id><article-id pub-id-type="pmc">4599853</article-id><article-id pub-id-type="doi">10.1371/journal.pgen.1005504</article-id><article-id pub-id-type="publisher-id">PGENETICS-D-15-00734</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross</article-title><alt-title alt-title-type="running-head">Novel TRIM Function Identified in SARS-CoV GWAS</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gralinski</surname><given-names>Lisa E.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ferris</surname><given-names>Martin T.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Aylor</surname><given-names>David L.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="author-notes" rid="currentaff001"><sup>¤a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Whitmore</surname><given-names>Alan C.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Green</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Frieman</surname><given-names>Matthew B.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="currentaff002"><sup>¤b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Deming</surname><given-names>Damon</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="author-notes" rid="currentaff003"><sup>¤c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Menachery</surname><given-names>Vineet D.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Miller</surname><given-names>Darla R.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buus</surname><given-names>Ryan J.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bell</surname><given-names>Timothy A.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Churchill</surname><given-names>Gary A.</given-names></name><xref ref-type="aff" rid="aff005"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Threadgill</surname><given-names>David W.</given-names></name><xref ref-type="aff" rid="aff006"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Katze</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>McMillan</surname><given-names>Leonard</given-names></name><xref ref-type="aff" rid="aff007"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Valdar</surname><given-names>William</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Heise</surname><given-names>Mark T.</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pardo-Manuel de Villena</surname><given-names>Fernando</given-names></name><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff004"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baric</surname><given-names>Ralph S.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref rid="cor001" ref-type="corresp">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Epidemiology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Microbiology, University of Washington, Seattle, Washington, United States of America</addr-line></aff><aff id="aff004"><label>4</label><addr-line>Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></aff><aff id="aff005"><label>5</label><addr-line>The Jackson Laboratory, Bar Harbor, Maine, United States of America</addr-line></aff><aff id="aff006"><label>6</label><addr-line>Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America</addr-line></aff><aff id="aff007"><label>7</label><addr-line>Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Panthier</surname><given-names>Jean-Jacques</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Institut Pasteur; URA CNRS 2578, FRANCE</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: LEG MTF DLA GAC DWT MGK MTH FPMdV RSB. Performed the experiments: LEG MTF ACW RG MBF DD RJB TAB. Analyzed the data: LEG MTF DLA ACW RG LM WV. Contributed reagents/materials/analysis tools: DRM GAC LM WV FPMdV. Wrote the paper: LEG MTF VDM GAC RSB.</p></fn><fn fn-type="current-aff" id="currentaff001"><label>¤a</label><p>Current address: Department of Biological Sciences, NC State University, Raleigh, North Carolina, United States of America,</p></fn><fn fn-type="current-aff" id="currentaff002"><label>¤b</label><p>Current address: Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America</p></fn><fn fn-type="current-aff" id="currentaff003"><label>¤c</label><p>Current address: Federal Drug Administration, Silver Spring, Maryland, United States of America</p></fn><corresp id="cor001">* E-mail: <email>rbaric@email.unc.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>9</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="collection"><month>10</month><year>2015</year></pub-date><volume>11</volume><issue>10</issue><elocation-id>e1005504</elocation-id><history><date date-type="received"><day>24</day><month>3</month><year>2015</year></date><date date-type="accepted"><day>15</day><month>8</month><year>2015</year></date></history><permissions><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="pgen.1005504.pdf"></self-uri><abstract><p>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, <italic>Trim55</italic>, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in <italic>Trim55</italic> 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.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>New emerging pathogens are a significant threat to human health with at least six highly pathogenic viruses, including four respiratory viruses, having spread from animal hosts into the human population within the past 15 years. With the emergence of new pathogens, new and better animal models are needed in order to better understand the disease these pathogens cause; to assist in the rapid development of therapeutics; and importantly to evaluate the role of natural host genetic variation in regulating disease outcome. We used incipient lines of the Collaborative Cross, a newly available recombinant inbred mouse panel, to identify polymorphic host genes that contribute to SARS-CoV pathogenesis. We discovered new animal models that better capture the range of disease found in human SARS patients and also found four novel susceptibility loci governing various aspects of SARS-induced pathogenesis. By integrating statistical, genetic and bioinformatic approaches we were able to narrow candidate genome regions to highly likely candidate genes. We narrowed one locus to a single candidate gene, <italic>Trim55</italic>, and confirmed its role in the inflammatory response to SARS-CoV infection through the use of knockout mice. This work identifies a novel function for <italic>Trim55</italic> and also demonstrates the utility of the CC as a platform for identifying the genetic contributions of complex traits.</p></abstract><funding-group><funding-statement>This work was supported by funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health U19 AI100625 (RSB and MTH) and U54AI081680 (RSB, MTH and MK), as well as the National Cancer Institute, National Institutes of Health U01CA134240 (DT and FPMV). Essential support for access to the pre-CC mice was provided by the Dean of the UNC School of Medicine, the Lineberger Comprehensive Cancer Center at UNC, and the University Cancer Research Fund from the state of North Carolina. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="6"></fig-count><table-count count="1"></table-count><page-count count="21"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>Most relevant data are within the paper and its Supporting Information files. Microarray data are available at the National Center for Biotechnology Information’s Gene Expression Omnibus database and are accessible through GEO accession SE64660. Genotyping data have been posted to the CC Status website at <ext-link ext-link-type="uri" xlink:href="http://csbio.unc.edu/CCstatus/index.py?run=pubs">http://csbio.unc.edu/CCstatus/index.py?run=pubs</ext-link>.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>Most relevant data are within the paper and its Supporting Information files. Microarray data are available at the National Center for Biotechnology Information’s Gene Expression Omnibus database and are accessible through GEO accession SE64660. Genotyping data have been posted to the CC Status website at <ext-link ext-link-type="uri" xlink:href="http://csbio.unc.edu/CCstatus/index.py?run=pubs">http://csbio.unc.edu/CCstatus/index.py?run=pubs</ext-link>.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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