Overdominance occurs when individuals carrying two different alleles at a specific locus have higher Darwinian fitness than both homozygotes, who carry only one allele. It is involved in a range of observations in genetics and evolution (e.g. genetic diversity, inbreeding depression, heterosis) and has been controversial for over a century. Empirical studies on the frequency of spontaneous mutations causing overdominance are scarce and there has been no systematic effort to screen for overdominant alleles in any natural population. We propose to (1) test a recent theory predicting that the rate of spontaneous mutations with overdominant effect on fitness increases with maladaptation, and (2) screen for overdominance alleles in a natural population. We propose to use the most appropriate model system for answering each of these questions: Saccharomyces yeast for spontaneous mutations, and Daphnia for segregating alleles. Cutting-edge methods in experimental evolution and quantitative genetics will be used. This project will contribute to the scientific competitiveness of Europe by strengthening a new area of research in France (the scientist in charge will maintain permanent projects using experimental evolution with yeast), providing large libraries of yeast and Daphnia genotypes, and producing high-impact publications.