A Systematic Assessment of Signatures of Positive Selection Events in Natural Populations of the House Mouse

The frequency and the structure of positive selection events in natural populations are of central importance, but one of the least known variables in evolutionary biology. The aim of this study is to investigate these basic parameters in a population based approach. Positive selection events leave population genetical signatures (selective sweeps) behind, which can be systematically identified with molecular studies. Positive selection can lead to the fixation of a favorable mutation in a population. Due to an effect called hitchhiking, variability in the neutral flanking regions which are physically linked to the target of selection is lost. This footprint of reduced neutral variability can be employed to systematically screen for positively selected (adaptive) mutations and allows to estimate their frequency in a given population. Differences in recombination rates along the chromosomes can influence the evolution of neutral loci via hitchhiking effects even on a large time scale, which would influence the results. Generally, these effects should be stronger in regions of low recombination than in regions of high recombination. The detailed information on physical and genetic maps in the house mouse allows now to assess the correlation between neutral variability and recombination rates at given chromosomal regions. I have tested microsatellite loci from chromosomal regions which show differences in recombination rates and found no evidence for a correlation between microsatellite variability and recombination rates in samples from five wild mice populations (Mus musculus musculus and M. m. domesticus). This suggests that the high average mutation rate of microsatellites in mammals counter balances the effects of long range hitchhiking in the mouse genome. Approaches, in which the variability of neutral markers is used to identify regions which have recently been under positive selection, is termed hitchhiking mapping. Since higher eukaryotic genomes may contain about 40,000 selectable loci and the detection of polymorphic variants requires testing of multiple individuals (at least 20) for several populations, a complete genome scan would require millions of genotypes to be determined. I present here a pooling strategy that allows to reduce the number of genotyping reactions significantly. The presented high throughput routine enabled me to investigate almost 1,000 microsatellite loci in different populations of the house mouse. Among the composite patterns that are obtained in this way, it is possible to visually select those with population specifical reduced variability. In a second step, these candidates were then re-typed in individuals of a carefully chosen population background and statistically tested for significance. A detailed analysis of the candidate loci identified by a single comparison yield results on the frequency of selective sweeps, the strength of selection acting in natural populations and the origin of selected variants. The two investigated populations of the house mouse (M. m. domesticus) have split upon arrival in Middle Europe about 3,000 years ago. The massive invasion of house mice into Europe is well documented based on fossil records. Strong independent subsequent bottlenecks can be ruled out because of a comparable high genome wide variability in both populations. Thus, complex demographic influences on the results can be excluded. Identified candidate regions between the two focal populations were further characterized by genotyping additional microsatellites in the flanking regions of the identified candidates. The significant deviation of the candidate regions from the neutral state is supported by several statistical tests. Based on these results, I find that there was at least one positive selection event per 100 generations in each lineage. Since none of the detected sweep valleys is broad, on average they are about 50 kb, I conclude that positive selection in general is driven by alleles providing weak beneficial impact. Estimated selection coefficients vary between 0.0007 and 0.021. Furthermore, it seems that beneficial variants are generally taken from the standing variation and that positive selection is a continuously acting background effect in all population.