Dominance reversal protects large-effect resistance polymorphisms in temporally varying environments

Large-effect functional genetic variation is commonly found in natural populations, even though natural selection should erode such variants. Theory suggests that under fluctuating selective pressures, beneficial reversal of dominance - where alleles are dominant when beneficial and recessive when deleterious - can protect these loci from selection, allowing them to persist. However, empirical evidence for this mechanism remains elusive because testing requires direct measurements of selection and dominance in natural conditions. Here, we show that insecticide-resistant alleles at the Ace locus in Drosophila melanogaster persist worldwide at intermediate frequencies and exhibit beneficial reversal of dominance. By combining laboratory and large-scale field mesocosm experiments with insecticide manipulation, and mathematical modeling, we show that the benefits of the resistant Ace alleles are dominant while their fitness costs recessive. We further show that fluctuating insecticide selection generates chromosome-scale genomic perturbations at sites linked to the resistant Ace alleles, revealing broader genomic consequences of this mechanism. Overall, our results suggest that beneficial reversal of dominance contributes to the maintenance of functional genetic variation and impacts patterns of genomic diversity via linked fluctuating selection.