Pervasive sex-dependent effects in the genetic architecture of starvation resistance in <i>Drosophila melanogaster</i>

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 <i>Drosophila melanogaster</i> 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 <i>Lnk</i> 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.