Genomic surveillance of malaria vectors to develop mechanistic understanding of insecticide resistance and its impact on population structure

Abstract

Vector control remains central to reducing malaria transmission, yet its long-term effectiveness is increasingly compromised by the rapid evolution of insecticide resistance in mosquito populations. In this thesis, population genomics, genome-wide association analyses, and experimental evolution are applied to examine how insecticide-based interventions shape mosquito population dynamics, resistance mechanisms, and adaptive potential. The role of genomic surveillance in resistance management and intervention assessment is discussed alongside the key findings of the three research chapters summarised below.

First chapter: genomic analyses embedded within a large-scale cluster-randomised vector control trial show that substantial reductions in indoor mosquito density following net deployment did not correspond to detectable decline in effective population size. These findings indicate that vector populations can retain considerable evolutionary capacity despite apparent short-term intervention success. The study further demonstrates that intervention chemistry strongly influences selection, with pyrethroid-only nets favouring increase in frequency of swept haplotypes around a cytochrome P450-locus associated with pyrethroid resistance, while with pyrethroid nets coupled PBO, a P450 inhibitor, a drop in frequency was observed in the same locus.

Second chapter: Genome-wide analysis of deltamethrin resistance in Anopheles funestus from western Kenya, where established major-effect pyrethroid-resistance loci (e.g., rp1 and Cyp9k1) were already at very high frequency, indicates that the remaining variation in resistance is not attributable to additional loci of large effect, but instead reflects polygenic contributions spanning detoxification enzymes, redox homeostasis, neuronal signalling, and membrane trafficking. These findings support a surveillance strategy in which validated high-effect markers are complemented with region-specific, multi-locus panels to capture residual and emerging resistance variation once major selective sweeps have occurred.

Third chapter: experimental laboratory evolution of dinotefuran tolerance demonstrates that resistance to neonicotinoids can arise rapidly in few generations of exposure. Tolerance evolved convergently across oral and topical exposure routes and was underpinned by broad transcriptional reprogramming involving detoxification, cuticular components, synaptic homeostasis, and strong evidence of an altered receptor stoichiometry indicating that new insecticide classes are also vulnerable to rapid adaptive responses.

Combined, these studies show that insecticide resistance is dynamic, context-dependent, and shaped by intervention chemistry, and that traditional surveillance approaches capture only part of this complexity. Integrating genomic surveillance into vector control programmes provides a powerful means to evaluate intervention effectiveness, detect emerging resistance mechanisms early, and support more informed, sustainable resistance management strategies.

Date of Award	26 Jun 2026
Original language	English
Awarding Institution	Liverpool School of Tropical Medicine
Supervisor	Martin Donnelly (Supervisor), Eric Lucas (Supervisor) & Eric Ochomo (Supervisor)