Giving the Genes a Shuffle: Using Natural Variation to Understand Host Genetic Contributions to Viral Infections

The laboratory mouse has proved an invaluable model to identify host factors that regulate the progression and outcome of virus-induced disease. The paradigm is to use single-gene knockouts in inbred mouse strains or genetic mapping studies using biparental mouse populations. However, genetic variation among these mouse strains is limited compared with the diversity seen in human populations. To address this disconnect, a multiparental mouse population has been developed to specifically dissect the multigenetic regulation of complex disease traits. The Collaborative Cross (CC) population of recombinant inbred mouse strains is a well-suited systems-genetics tool to identify susceptibility alleles that control viral and microbial infection outcomes and immune responses and to test the promise of personalized medicine.
Highlights Viral infections are complex traits that are influenced by viral and environmental as well as host factors. Complete knockouts of genes are rare in humans whereas natural variation at the nucleotide level is abundant. Thus, successful translation from mice to humans is more likely working with natural variation in mouse populations. The Collaborative Cross is a mouse genetic reference population that is well suited to be utilized to identify networks of host genetics key players that influence complex traits such as viral infections. Indefinitely reproducible mouse strains with fully sequenced genomes offer the chance for wide collaborations across pathogens. Additionally, it offers the ability to identify cross-pathogen susceptibility or resistance alleles.