Non-Additive Transcriptional Regulation Underpins Additive Survival Trait In Populations Of Drosophila Selected For Increased Post Infection Survival

Understanding how immunity evolves requires integrating organismal resistance with the underlying genetic and regulatory mechanisms. Using Drosophila melanogaster populations experimentally selected for increased survival post infection with Enterococcus faecalis , we dissected the quantitative genetic basis of post-infection survival and the transcriptional architecture associated with it. F1 hybrid analyses revealed an additive genetic basis for survivorship in both sexes, consistent with a polygenic response to selection. In contrast, gene expression showed extensive sex-specific regulation and hybrid misexpression. Males strongly upregulated antimicrobial peptides yet suffered greater mortality, suggesting a costly or inefficient immune strategy. Females relied on distinct effector pathways and exhibited superior survivorship. Notably, transcriptional induction of the melanization precursor PPO1 did not correspond to increased phenoloxidase enzyme activity, revealing a post-transcriptional constraint on immune deployment. Together, these results show that while the genetic basis of survivorship is additive, the evolved immune phenotype is shaped by sex-specific regulatory divergence, hybrid incompatibilities, and functional bottlenecks. This emphasizes the need to integrate quantitative genetic, transcriptomic, and functional assays to understand the evolution of immune defense.