PROJECT SUMMARY Much of our understanding of the genetic basis of adaptation derives from studies of simple traits in which a large proportion of the phenotypic variation is controlled by one or a few genes of major effect. However, much of evolution involves changes in complex traits that are controlled by many genes of small to modest effect. Complex traits also underlie most phenotypic differences among humans, including those related to human health. The proposed research will study the genetic basis of environmental adaptation in house mice, Mus musculus, the best mammalian model for humans. House mice have recently expanded into the Americas from their native range in Western Europe. By combining studies of genetic and phenotypic variation in natural populations with crosses in the lab, this project will make explicit links between genotype and phenotype for several complex traits. This work will utilize recent large-scale surveys of 20 populations of house mice collected across the Americas from 55 S latitude to 54 N latitude. New inbred lines of mice from different environments will be used to measure phenotypes in a common laboratory environment and to perform controlled crosses. Mice from colder environments in the Americas have evolved to become larger (Bergmann's rule) and have shorter extremities (Allen's rule), conforming to two of the best-documented eco- geographic patterns in mammals. In addition, mice from different environments differ in many metabolic traits, including activity levels, body mass index, and aspects of blood chemistry. Here, we build on a recent genome-scan for selection among 50 mice in Eastern North America in four ways. (1) Exomes will be sequenced at moderate coverage and whole genomes will be sequenced at low coverage in an additional 150 mice from two transects, one in Western North America and one in South America, to identify loci underlying environmental adaptation using models that account for population structure. Replicated patterns in separate transects will provide additional evidence of selection. (2) Patterns of gene expression will be studied in both wild-caught mice and in laboratory crosses. Identification of cis-acting expression quantitative trait loci (cis- eQTL) will help pinpoint genes underlying adaptation. (3) Loci underlying phenotypic differences will be mapped using laboratory crosses of progeny derived from mice from different environments. (4) Finally, association studies will be conducted in two populations to more precisely map specific genes underlying phenotypic traits. Associations will also be used in combination with estimates of allele age to test polygenic modes of adaptation for several traits. Together, laboratory crosses and association studies will provide links between genotype and phenotype with resolution at the level of individual genes. The combination of quantitative-genetic and population-genetic approaches in this study will identify loci underlying polygenic adaptation in mice and will identify the genetic basis of traits likely to be relevant for understanding metabolic differences among humans.