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Abstract

The genome is in constant evolution. Despite this constant change, the genome also has to maintain essential functions. Discovering the evolutionary process underlying genome evolution is thus a central goal not only in evolutionary genetics, but also in medicine. I will discuss two studies in the mouse, where we take a systems genetics approach to understand how the genome evolves in the mouse. First I will discuss the evolution of the “Longshanks mouse”, a unique genetic resource created by my collaborator Campbell Rolian at the University of Calgary. By subjecting mouse to twenty generations of strong selection for increased tibia length, he was able to generate mice with tibia as much as 25% longer than their unselected relatives. We have sequenced genomes of the selection pedigree to allow us to not only identify the loci that changed under selection, but also “replay the evolutionary tape” and uncover how the genome reshapes itself locus by locus. I will also discuss our molecular genetics investigations into key developmental genes that contribute to such drastic evolutionary response. In a second part I will discuss our novel approach of generating in vitro “crosses” using in interspecific F1 hybrid mouse embryonic stem (ES) cells. Starting from an F1 hybrid ES cell line between Mus spretus and the laboratory mouse Mus musculus domesticus, we have developed a simple tissue culture system to generate mitotic recombinants with genome-wide random breakpoints. By bypassing hybrid sterility and inviability, we can now generate “Impossible Hybrid” mouse stem cells and directly investigate which genetic changes underlie species differences. We will present our proof-of-concept results, where we show how to efficiently generate recombinant ES cell lines entirely in vitro without crosses. By coupling in vitro crosses with FACS , I will discuss our forward genetic mapping experiments for stem cell traits that are now routine and can be performed in as few as 6 days. This approach will make it possible to create large genetic mapping panels of potentially any size from mouse, or indeed human or other mammals with a robust tissue culture system. In doing so we identify an experimental way towards studying evolutionary systems biology in a mammalian system. Through these two examples I hope to highlight how we envision a new phase for mouse systems genetics in evolutionary and biomedical areas.