The persistent threat of infection has contributed to variation in mortality and survival, shaping mammalian genomes throughout history. Genetic variation that now exists controls infection outcomes, although the specific genes and variants are not well known. Common methods for genome-wide mapping often assume predominantly additive genetic action, for reasons of power and simplicity. However, non-additive effects may arise from mutations in critical pathways, such as those that regulate the host resistance to influenza A virus. Notably, complex, non-additive genetic architecture is difficult to characterize in human studies, and certain effects may remain elusive except in model organisms, such as mice. Thus, the identification of novel non-additive genetic effects in host-pathogen interactions is an area of open research, and this dissertation focuses specifically on understanding the role of dominance, parent-of-origin, and additive genetic variation the host control of influenza infection. In this research, I use experimental crosses of inbred strains of mice, both standard and recombinant inbreds, to introduce genetic diversity and increase levels of heterozygosity.

Using replicable, genetically diverse populations, I model and characterize genetic variation that controls the host pathogenic response to influenza. In Chapter 1, I provide a basic introduction for influenza virus, diallels, and reciprocal cross breeding designs for genetic studies, and I review systems and statistical genetics analysis with recombinant inbred strains known as the Collaborative Cross. In Chapter 2, I describe the genetic architecture of the host response to influenza in a diallel, and the dissection of Mx1 subspecies-specific dominance. In Chapter 3, I describe novel parent-of-origin effects on pathology and on gene regulation in the response to influenza in F1 reciprocal cross mice. Chapter 4 covers the discovery of a novel genomic locus that controls pathology of influenza infection in the lung, via quantitative trait locus mapping in Collaborative Cross F1 mice. I conclude in Chapter 5 with a recap and future directions. In summary, this work provides a path forward for interrogating and understanding the complex genetic architecture of genome-wide contributions to host pathology following influenza infection, using quantitative, statistical, and systems approaches in inbred and hybrid mice.