The genomic basis of environmental adaptation in house mice

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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 and 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 28 populations of house mice collected across the Americas from 55° S latitude to 54° N latitude. New inbred lines of mice from different environments form a critical resource for the proposed work. Mice from colder environments 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. We have two major goals for the next five years. First, we will identify the genetic architecture and specific loci underlying complex adaptive traits using (1) QTL mapping with wild-derived inbred lines of mice from different environments, (2) expression studies, including the identification of cis-eQTL, to identify specific genes within broad QTL intervals, (3) studies of chromatin accessibility to identify potential regulatory changes, (4) association studies of traits in large samples of mice from natural populations, and (5) studies of inbred lines reared in different laboratory environments to measure the effects of environmental perturbations on both gene expression and organismal- level traits. Second, we will expand on our previous work studying patterns of SNP variation of wild mice by using a combination of long-read PacBio sequencing of mice from natural populations and long-read PacBio sequencing and Hi-C scaffolding of genomes from wild-derived inbred strains to study structural variation across the genome, including (1) copy-number variation contributing to environmental adaptation, (2) transposable element insertion polymorphisms underlying adaptive differences, and (3) larger structural variants such as inversion polymorphisms. The impact of structural variation on gene expression will be assessed using RNAseq from the same animals. Together this combination of approaches will provide an unparalleled picture of the genomic details underlying polygenic adaptation in mice and will identify the genetic basis of traits likely to be relevant for understanding differences among humans.