UNIVERSITY OF ARIZONA
The primary aim of this administrative supplement is to describe patterns of genetic variation across the genome in wild house mice (Mus musculus). These data will be used to address questions concerning the distribution of variation among subspecies, the origin of classical inbred strains of laboratory mice, the suitability of wild mice for genetic association studies, and the ways in which natural selection shapes patterns of genetic variation, especially on genes involved in male reproduction. These topics form the specific aims of the parent grant, ?Natural selection and DNA sequence variation in mice.? Two recent developments motivate this request. The first is a new Affymetrix SNP genotyping array for the mouse with over 600,000 SNPs. The second is the design and improvement of the ?next-generation? sequencing technologies. Both of these new methods will enable us to address the questions raised in the parent grant on a genomic scale. First, we propose to genotype 10 wild mice each from M. m. musculus, M. m. castaneus, and M. m. domesticus and to analyze these data together with similar data from 100 classical inbred strains to understand the distribution of variation among the major groups of house mice and the origins of classical inbred strains. Second, we propose to sequence the testes transcriptome from 8 wild-derived inbred lines each of M/ m. musculus, M. m. castaneus, and M. m. domesticus using the Solexa/Illumina sequencing technology. This will enable us to describe the distribution of neutral, advantageous, and deleterious variants segregating across a substantial fraction of the genome. It will also enable us to identify specific targets of selection for genes underlying male reproductive traits. This work is relevant to human health in several ways. First, it lays the foundation for developing wild mice for genetic association studies of complex traits, including those serving as models for human disease. Second, the population-genetic inferences from mice complement similar studies in humans and will help us understand the forces maintaining disease variants in natural populations.