Single nucleotide polymorphisms are the most common type of genetic variation, but how these variants contribute to the evolutionary adaptation of complex phenotypes is largely unknown. Experimental evolution and genome-wide association studies have demonstrated that variation in the PPARg-homologEip75Bis associated with longevity and life-history differences in the fruit flyDrosophila melanogaster. Using RNAi knockdown, we first demonstrate that reduced expression ofEip75Bin adults affects lifespan, egg-laying rate and egg volume. We then tested the effect of a naturally occurring SNP variant within a cis-regulatory domain ofEip75Bby applying two complementary approaches: a Mendelian randomization approach using lines of theDrosophilaGenetic Reference Panel, and allelic replacement using precise CRISPR/Cas9-induced genome editing. Our experiments reveal that this natural polymorphism has a significant pleiotropic effect on fecundity and egg-to-adult viability, but not on longevity or other life-history traits. These results provide a rare functional validation at the nucleotide level and identify a natural allelic variant affecting fitness and life-history adaptation.
