Title: “The long-legged mice and the Impossible Hybrid - the genetics of evolutionary change”

Abstract: The genome is in constant evolution. Despite this on-going change, the genome also has to maintain essential functions. Discovering the evolutionary process underlying genome evolution is thus a central goal in evolutionary genetics and medicine. I will discuss two studies, where we take a systems genetics approach to understand how the genome evolves in the mouse. First, I will discuss the “Longshanks mouse”, a unique genetic resource created by Campbell Rolian at the University of Calgary. We combined whole genome sequencing, modelling and molecular genetics to dissect this mammalian evolve-and-resequence experiment. Next, I will present our novel approach of generating in vitro “crosses” in interspecific F1 hybrid mouse embryonic stem (ES) cells. By inducing mitotic recombinants with genome-wide random breakpoints, we have developed a simple tissue culture system that allows genetic mapping between the reference strain BL6 (mostly Mus musculus domesticus) and M. castaneus, M. spretus and M. caroli that span 1, 2 and 6 million years of divergence. I will discuss how we use in vitro recombination to generate “Impossible Hybrid” mouse stem cells and directly investigate which genetic changes underlie species differences. I will end by discussing current genotyping and phenotyping bottlenecks in large-scale genetic studies; I will introduce haplotagging, a rapid technique for linked-read sequencing, and computational approaches for morphometrics. Together, these studies illustrate our research program of identifying and mining these special systems in the mouse for their unique insights in our overall goal to link genotype to phenotype in an evolving genome.