Abstract:

I will present a broad overview of numerous findings that we have made, and are in the process of making, over the course of several years working on mice and rats that have developed a resistance to the anticoagulant rodenticide warfarin (and derivatives). This resistance evolved rather quickly after the introduction of the compound in the 1950’s with aim to control rodent populations. I will present some historical information on the warfarin discovery (also known as Coumadin TM). I will present on the impact of warfarin in medicine including how dosing problems with the drug swerved as a poster child for promoting the need for personalized medicine. I will discuss how warfarin resistance in rodents has become a classical textbook example of evolution in action and overdominance. I present evidence that an astounding amount of independent evolutionary innovation (towards resistance) has occurred by both point mutation and interbreeding between species. I present new data showing that warfarin resistance is multigenic, rather than merely involving one main gene (a vitamin K epoxide reductase, Vkorc1), and how Network-guided GWAS and the emerging additional genes begin to reveal how natural selection in the wild rapidly assembles complex adaptive traits by selecting on new mutations of main effect as well as on rare ancestral standing genetic variants of currently unknown yet detectable effect. I will present on future ideas on how the study of the genetics underlying the physiological response to warfarin remains a promising study system with relevance to both evolutionary biology and medicine.