Changes in Neuronal Signaling and Cell Stress Response Pathways are Associated with a Multigenic Response of Drosophila melanogaster to DDT Selection.

The adaptation of insect populations to insecticidal control is a continual threat to human health and sustainable agricultural practices, but many complex genomic mechanisms involved in this adaption remain poorly understood. This study applied a systems approach to investigate the interconnections between structural and functional variance in response to dichlorodiphenyltrichloroethane (DDT) within the Drosophila melanogaster strain 91-R. Directional selection in 6 selective sweeps coincided with constitutive gene expression differences in DDT resistant flies, including the most highly upregulated transcript, Unc-115 b, which plays a central role in axon guidance, and the most highly downregulated transcript, the angiopoietin-like CG31832, which is involved in directing vascular branching and dendrite outgrowth but likely may be under trans-regulatory control. Direct functions and protein-protein interactions mediated by differentially expressed transcripts control changes in cell migration, signal transduction, and gene regulatory cascades that impact the nervous system. Although changes to cellular stress response pathways involve 8 different cytochrome P450s, stress response, and apoptosis is controlled by a multifacetted regulatory mechanism. These data demonstrate that DDT selection in 91-R may have resulted in genome-wide adaptations that impacts genetic and signal transduction pathways that converge to modify stress response, cell survival, and neurological functions. This study implicates the involvement of a multigenic mechanism in the adaptation to a chemical insecticide, which impact interconnected regulatory cascades. We propose that DDT selection within 91-R might act systemically, wherein pathway interactions function to reinforce the epistatic effects of individual adaptive changes on an additive or nonadditive basis.