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While the role of viral variants has long been known to play a key role in causing variation in disease severity, it is also clear that host genetic variation plays a critical role in determining virus-induced disease responses. However, a variety of factors, including confounding environmental variables, rare genetic variants requiring extremely large cohorts, the temporal dynamics of infections, and ethical limitation on human studies, have made the identification and dissection of variant host genes and pathways difficult within human populations. This difficulty has led to the development of a variety of experimental approaches used to identify host genetic contributions to disease responses. In this chapter, we describe the history of genetic associations within the human population, the development of experimentally tractable systems, and the insights these specific approaches provide. We conclude with a discussion of recent advances that allow for the investigation of the role of complex genetic networks that underlie host responses to infection, with the goal of drawing connections to human infections. In particular, we highlight the need for robust animal models with which to directly control and assess the role of host genetics on viral infection outcomes.
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