Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic 1 outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well 2 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 3 of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment 4 response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable 5 effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive 6 effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus 7 resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed 8 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) 9 population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null 10 Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, 11 accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.
12Keywords: treatment response, multiparental population, causal effect, Bayesian model, multiple imputation
ARTICLE SUMMARY
14Seasonal and pandemic influenza viruses comprise an important public health burden, but the architecture of host genetic resistance to 15 viruses is poorly understood. We conducted an influenza challenge in a diallel cross of eight inbred mouse strains. Roughly 60% of variation 16 in disease at 4 days post-infection was explained by genetic and non-genetic diallel effects, with about 34% of variation independent of the 17 host resistance factor, Mx1. The dominance of Mx1 resistance was highly dependent on subspecies Mx1 allelic origin, and similar Mx1 18 effect patterns were found in the related Collaborative Cross strains, motivating integrated infection studies in these populations.