Wild-derived mice: from genetic diversity to variation in immune responses

Classical inbred mouse strains have historically been instrumental in mapping immunological traits. However, most of the classical strains originate from a relatively limited number of founder animals, largely within the Mus musculus domesticus subspecies. Therefore, their genetic diversity is ultimately limited. For this reason, it is not feasible to use these mice for exhaustive interrogation of immune signaling pathways. In order to investigate networks through forward genetic analysis, larger genetic diversity is required than is introduced under laboratory conditions. Recently, inbred strains from other mouse subspecies were established such as Mus musculus castaneus and Mus musculus musculus, which diverged from a shared common ancestor with Mus musculus domesticus more than one million years ago. A direct genomic comparison clearly demonstrates the evolutionary divergence that has occurred between wild-derived mice and the classical inbred strains. When compared to classical inbred strains, wild-derived mice exhibit polymorphisms every 100-200 base pairs. Studying the molecular basis of these traits provides us with insight into how the immune system can evolve regulatory features to accommodate environment-specific constraints. Because most wild-derived strains are able to breed with classical inbred mice, they represent a rich source of evolutionarily significant diversity for forward genetic studies. These organisms are an emerging, though still largely unexplored, model for the identification and study of novel immunological genes.