COMPARATIVE MOLECULAR POPULATION GENETICS OF DROSOPHILA

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There is considerable debate over whether most mutations leading to naturally occurring polymorphisms are neutral, slightly deleterious, or advantageous. These seemingly subtle differences in average selection coefficient have a major impact on our world view about what processes drive molecular evolution. Many of the experiments proposed follow from the finding of a significant positive correlation between levels of DNA restriction site polymorphism and the regional rate of recombination in Drosophila melanogaster. Mutations of different selective effects are predicted to behave differently in regions of high versus low recombination. These different behaviors are used to test hypotheses concerning the relative distribution of selective effects of naturally occurring variation in natural populations of D. melanogaster and D. simulans. The data obtained will provide new insight into the impact of differences in the rate of recombination on the level and distribution of DNA variation, and will allow tests of alternative hypotheses to account for the general correlation between levels of DNA variation and recombination rates. Comparison of noncoding site variation at X-linked vs. third chromosomal genes will allow discrimination of the relative contributions of "selective sweeps" associated with the fixation of advantageous mutations versus "background selection" associated with the elimination of deleterious mutations. Contrasts between results obtained in Zimbabwe and Maryland may provide insight into the level of selection that accompanied the founding of temperate regions by D. melanogaster. The hypothesis that regional levels of linkage disequilibrium are a simple function of regional rates of recombination will be tested. The lack of such a relationship would suggest strong epistatic selection. The distribution of selective effects of new mutations will also be examined by comparison of levels of polymorphism within and differentiation between D. simulans and D. melanogaster. Relative rate tests of three genes with high recombination rates, using D. yakuba as the outgroup, will provide a framework in which to test for differences in mutation rate and effective population size, as well as differences in selective effects between replacement, synonymous and noncoding variation. The level and distribution of polymorphism will provide additional discrimination of population size and mutation rate differences. The importance of a population genetic approach to these questions is that it provides information on historical levels of selection, not simply those acting at present. Understanding the forces that influence genetic change in populations over time and space is fundamental to a deeper understanding of the dynamics of human genetic disease and to an understanding of why our genome is variable.