Pervasive sex-dependent effects in the genetic architecture of starvation resistance in Drosophila melanogaster

Genetic variants can have sex-specific, sex-biased, or sexually antagonistic fitness effects, yet their roles in fitness-related traits remain unclear. Using pooled phenotype sorting and sequencing of male Drosophila melanogaster from natural populations, we identified starvation resistance–associated variants, many in regulatory regions or altering protein sequences. RNA interference experiments showed that 85.7% (66 of 77) of the candidate genes with nonlethal knockdown effects influenced starvation resistance. Of these, 49 had sex-dependent effects, including 12 with sexually antagonistic effects—all increasing resistance in females but decreasing it in males. These patterns were not explained by sex-biased expression or knockdown efficiency. Analysis of the Lnk gene revealed that both nonsynonymous mutations and expression changes had sex-dependent effects. Our findings indicate that polygenic architecture, sex-dependent effects, and pleiotropy jointly shape evolutionary outcomes and that some variants maintained by these forces may enable rapid responses to environmental change.