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

abstract

  • 1.ABSTRACTInfluenza 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 88 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 theMx1locus 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 protectiveMx1haplotypes was observed to differ by subspecies origin: relative to thedomesticusnullMx1allele,musculusacts dominantly whereascastaneusacts additively. After controlling forMx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

altmetric score

  • 0.75

author list (cited authors)

  • Maurizio, P. L., Ferris, M. T., Keele, G. R., Miller, D. R., Shaw, G. D., Whitmore, A. C., ... Valdar, W.

citation count

  • 0

complete list of authors

  • Maurizio, Paul L||Ferris, Martin T||Keele, Gregory R||Miller, Darla R||Shaw, Ginger D||Whitmore, Alan C||West, Ande||Morrison, Clayton R||Noll, Kelsey E||Plante, Kenneth S||Cockrell, Adam S||Threadgill, David W||de Villena, Fernando Pardo-Manuel||Baric, Ralph S||Heise, Mark T||Valdar, William

publication date

  • November 2017