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Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice

View ORCID ProfilePaul L. Maurizio, View ORCID ProfileMartin T. Ferris, View ORCID ProfileGregory R. Keele, View ORCID ProfileDarla R. Miller, View ORCID ProfileGinger D. Shaw, Alan C. Whitmore, Ande West, Clayton R. Morrison, View ORCID ProfileKelsey E. Noll, Kenneth S. Plante, Adam S. Cockrell, View ORCID ProfileDavid W. Threadgill, View ORCID ProfileFernando Pardo-Manuel de Villena, Ralph S. Baric, Mark T. Heise, View ORCID ProfileWilliam Valdar
doi: https://doi.org/10.1101/214205
Paul L. Maurizio
*Curriculum in Bioinformatics and Computational Biology
†Department of Genetics
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Martin T. Ferris
†Department of Genetics
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Gregory R. Keele
*Curriculum in Bioinformatics and Computational Biology
†Department of Genetics
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Darla R. Miller
†Department of Genetics
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Ginger D. Shaw
†Department of Genetics
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Alan C. Whitmore
†Department of Genetics
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Ande West
†Department of Genetics
‡Department of Epidemiology
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Clayton R. Morrison
†Department of Genetics
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Kelsey E. Noll
†Department of Genetics
§Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, 27599-7435
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Kenneth S. Plante
†Department of Genetics
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Adam S. Cockrell
‡Department of Epidemiology
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David W. Threadgill
**Institute of Genome Sciences and Society, Texas A&M University, College Station, Texas 77433-2470
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Fernando Pardo-Manuel de Villena
†Department of Genetics
††Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7265
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Ralph S. Baric
‡Department of Epidemiology
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Mark T. Heise
†Department of Genetics
††Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7265
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William Valdar
†Department of Genetics
††Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27599-7265
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  • For correspondence: william.valdar@unc.edu
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1. ABSTRACT

Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8×8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

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Posted November 06, 2017.
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Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice
Paul L. Maurizio, Martin T. Ferris, Gregory R. Keele, Darla R. Miller, Ginger D. Shaw, Alan C. Whitmore, Ande West, Clayton R. Morrison, Kelsey E. Noll, Kenneth S. Plante, Adam S. Cockrell, David W. Threadgill, Fernando Pardo-Manuel de Villena, Ralph S. Baric, Mark T. Heise, William Valdar
bioRxiv 214205; doi: https://doi.org/10.1101/214205
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Diallel analysis reveals Mx1-dependent and Mx1-independent effects on response to influenza A virus in mice
Paul L. Maurizio, Martin T. Ferris, Gregory R. Keele, Darla R. Miller, Ginger D. Shaw, Alan C. Whitmore, Ande West, Clayton R. Morrison, Kelsey E. Noll, Kenneth S. Plante, Adam S. Cockrell, David W. Threadgill, Fernando Pardo-Manuel de Villena, Ralph S. Baric, Mark T. Heise, William Valdar
bioRxiv 214205; doi: https://doi.org/10.1101/214205

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