PROJECT SUMMARY We propose a research program in evolutionary genetics and genomics that emphasizes two distinct themes. The first theme focuses on the island rule – the widespread phenomenon of populations evolving unusual body sizes after colonizing islands. Advances in our laboratory have established mice from Gough Island, the largest wild house mice in the world, as a tractable system for understanding genetic mechanisms responsible for the evolution of extreme body size. Through comprehensive characterization of novel congenic strains, we will identify genes and mutations involved in this instance of the island rule. To elucidate causes and consequences of gigantism, we will extend this unique system to genetically dissect another trait associated with evolution on islands: exploratory behavior. This research direction will reveal genetic principles of complex trait evolution in novel environments. The second theme centers on recombination, a process that diversifies offspring genomes and ensures proper chromosomal segregation during meiosis in many species. Using single-cell methods that enable us to quantify recombination in individuals, we have discovered that house mice evolved substantial differences in genomic crossover number over short timescales, with females and males showing discordant trajectories. Motivated by this advance, we will reconstruct the evolutionary dynamics of the recombination landscape in house mice across genomic scales (from hotspots to whole genomes) and temporal scales (from thousands to millions of years). To identify cellular processes involved in the evolution of recombination, we will integrate high- resolution, sex-specific positioning of crossovers with cellular profiling of key meiotic phenotypes. This research direction will unveil mechanisms that drive the evolution of a primary determinant of genetic variation. These distinct themes of research showcase a program that exploits the power of genetics and genomics in house mice to address fundamental evolutionary questions with breadth and depth. Beyond their evolutionary significance, the traits of interest are connected to common human diseases. Defects in recombination are the leading genetic cause of birth defects, body size is related to the metabolic syndrome, and exploratory activity is associated with neurological disorders. Our research offers potential to illuminate these conditions by deciphering natural variation in the premier genetic model organism for human disease.