Diet unmasks genetic variants that regulate lifespan in outbred Drosophila

Several evolutionary forces are thought to maintain genetic variation for fitness-related traits, such as lifespan, but experimental support is limited. Using a powerful experimental design, we identified lifespan-associated variants by exposing outbred Drosophila melanogaster to standard and high-sugar diets and tracking genome-wide allele frequency changes as the flies aged. We mapped alleles associated with early vs late life tradeoffs, late-onset effects, and genotype-by-environment (GxE) interactions - all of which are predicted by long-standing theories to maintain genetic variation for lifespan. We also validated an environmentally-dependent role for nAChRalpha4 in regulating lifespan; the ortholog of this gene is one of the few lifespan-associated genes in humans (CHRNA3). Our results provide insight into the highly polygenic and context-dependent genetic architecture of lifespan, as well as the evolutionary processes that shape this key trait.