Population genomics of the mouse. (360G-Wellcome-088114_Z_08_C)

The mouse is the leading model mammal in genetics and biomedical research, yet little is known about how variation in its genome translates to variation in reproductive fitness. This is important because the fitness effects of nucleotide variants are closely related to the nature of quantitative genetic variation, such as susceptibility to genetic disease in humans. We propose to study the population genetics of Mus m. castaneus, a highly variable subspecies from the ancestral range of the house mouse subspecies complex. We shall generate accurate, whole genome nucleotide polymorphism data for the genomes of a sample of wild-caught individuals. Using this data in conjunction with the mouse genome annotation and the rat genome, we shall apply new methods developed by the PI and others that analyse within population polymorphism and between species divergence to infer the fitness consequences of nucleotide variation. We propose to estimate the frequency distributions of effects of new mu tations for both coding and noncoding DNA, and the frequency of adaptive substitutions in the genome. We shall analyse the spatial correspondence between selected-site divergence and neutral diversity to estimate both the rate and strength of selection associated with selective sweeps.