tetano
Editor, Senior Moderator
G3 (Bethesda). 2017 Nov 29. pii: g3.300438.2017. doi: 10.1534/g3.117.300438. [Epub ahead of print]
[h=1]Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice.[/h] Maurizio PL[SUP]1[/SUP], Ferris MT[SUP]2[/SUP], Keele GR[SUP]1[/SUP], Miller DR[SUP]1[/SUP], Shaw GD[SUP]1[/SUP], Whitmore AC[SUP]1[/SUP], West A[SUP]1[/SUP], Morrison CR[SUP]1[/SUP], Noll KE[SUP]1[/SUP], Plante KS[SUP]1[/SUP], Cockrell AS[SUP]1[/SUP], Threadgill DW[SUP]3[/SUP], Pardo-Manuel de Villena F[SUP]1[/SUP], Baric RS[SUP]1[/SUP], Heise MT[SUP]1[/SUP], Valdar W[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Bayesian model; causal effect; multiparental population; multiple imputation; treatment response
PMID: 29187420 DOI: 10.1534/g3.117.300438
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[h=1]Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice.[/h] Maurizio PL[SUP]1[/SUP], Ferris MT[SUP]2[/SUP], Keele GR[SUP]1[/SUP], Miller DR[SUP]1[/SUP], Shaw GD[SUP]1[/SUP], Whitmore AC[SUP]1[/SUP], West A[SUP]1[/SUP], Morrison CR[SUP]1[/SUP], Noll KE[SUP]1[/SUP], Plante KS[SUP]1[/SUP], Cockrell AS[SUP]1[/SUP], Threadgill DW[SUP]3[/SUP], Pardo-Manuel de Villena F[SUP]1[/SUP], Baric RS[SUP]1[/SUP], Heise MT[SUP]1[/SUP], Valdar W[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] Bayesian model; causal effect; multiparental population; multiple imputation; treatment response
PMID: 29187420 DOI: 10.1534/g3.117.300438
Free full text