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A Multitrait Locus Regulates Sarbecovirus Pathogenesis
Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infe...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426612/ https://www.ncbi.nlm.nih.gov/pubmed/35862771 http://dx.doi.org/10.1128/mbio.01454-22 |
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author | Schäfer, Alexandra Leist, Sarah R. Gralinski, Lisa E. Martinez, David R. Winkler, Emma S. Okuda, Kenichi Hawkins, Padraig E. Gully, Kendra L. Graham, Rachel L. Scobey, D. Trevor Bell, Timothy A. Hock, Pablo Shaw, Ginger D. Loome, Jennifer F. Madden, Emily A. Anderson, Elizabeth Baxter, Victoria K. Taft-Benz, Sharon A. Zweigart, Mark R. May, Samantha R. Dong, Stephanie Clark, Matthew Miller, Darla R. Lynch, Rachel M. Heise, Mark T. Tisch, Roland Boucher, Richard C. Pardo Manuel de Villena, Fernando Montgomery, Stephanie A. Diamond, Michael S. Ferris, Martin T. Baric, Ralph S. |
author_facet | Schäfer, Alexandra Leist, Sarah R. Gralinski, Lisa E. Martinez, David R. Winkler, Emma S. Okuda, Kenichi Hawkins, Padraig E. Gully, Kendra L. Graham, Rachel L. Scobey, D. Trevor Bell, Timothy A. Hock, Pablo Shaw, Ginger D. Loome, Jennifer F. Madden, Emily A. Anderson, Elizabeth Baxter, Victoria K. Taft-Benz, Sharon A. Zweigart, Mark R. May, Samantha R. Dong, Stephanie Clark, Matthew Miller, Darla R. Lynch, Rachel M. Heise, Mark T. Tisch, Roland Boucher, Richard C. Pardo Manuel de Villena, Fernando Montgomery, Stephanie A. Diamond, Michael S. Ferris, Martin T. Baric, Ralph S. |
author_sort | Schäfer, Alexandra |
collection | PubMed |
description | Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. |
format | Online Article Text |
id | pubmed-9426612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-94266122022-08-31 A Multitrait Locus Regulates Sarbecovirus Pathogenesis Schäfer, Alexandra Leist, Sarah R. Gralinski, Lisa E. Martinez, David R. Winkler, Emma S. Okuda, Kenichi Hawkins, Padraig E. Gully, Kendra L. Graham, Rachel L. Scobey, D. Trevor Bell, Timothy A. Hock, Pablo Shaw, Ginger D. Loome, Jennifer F. Madden, Emily A. Anderson, Elizabeth Baxter, Victoria K. Taft-Benz, Sharon A. Zweigart, Mark R. May, Samantha R. Dong, Stephanie Clark, Matthew Miller, Darla R. Lynch, Rachel M. Heise, Mark T. Tisch, Roland Boucher, Richard C. Pardo Manuel de Villena, Fernando Montgomery, Stephanie A. Diamond, Michael S. Ferris, Martin T. Baric, Ralph S. mBio Research Article Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. American Society for Microbiology 2022-07-12 /pmc/articles/PMC9426612/ /pubmed/35862771 http://dx.doi.org/10.1128/mbio.01454-22 Text en Copyright © 2022 Schäfer et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Schäfer, Alexandra Leist, Sarah R. Gralinski, Lisa E. Martinez, David R. Winkler, Emma S. Okuda, Kenichi Hawkins, Padraig E. Gully, Kendra L. Graham, Rachel L. Scobey, D. Trevor Bell, Timothy A. Hock, Pablo Shaw, Ginger D. Loome, Jennifer F. Madden, Emily A. Anderson, Elizabeth Baxter, Victoria K. Taft-Benz, Sharon A. Zweigart, Mark R. May, Samantha R. Dong, Stephanie Clark, Matthew Miller, Darla R. Lynch, Rachel M. Heise, Mark T. Tisch, Roland Boucher, Richard C. Pardo Manuel de Villena, Fernando Montgomery, Stephanie A. Diamond, Michael S. Ferris, Martin T. Baric, Ralph S. A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title | A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title_full | A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title_fullStr | A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title_full_unstemmed | A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title_short | A Multitrait Locus Regulates Sarbecovirus Pathogenesis |
title_sort | multitrait locus regulates sarbecovirus pathogenesis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426612/ https://www.ncbi.nlm.nih.gov/pubmed/35862771 http://dx.doi.org/10.1128/mbio.01454-22 |
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