This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Malaria control relies on the use of insecticides whose effectiveness is threatened by the spread of resistance in Anopheles mosquitoes, which transmit the disease. The increasing range of available insecticide formulations provides a means to overcome the problem of resistance by choosing compounds to which mosquitoes remain susceptible. Molecular surveillance using genetic markers offers the promise of rapid and effective surveillance of resistance, allowing malaria control programmes to make informed choices regarding the most effective interventions to deploy. Recent work has shown that the genetic causes of resistance are variable between regions of Africa, both in terms of the genes involved, and the individual mutations identified around each gene. Furthermore, genetic markers of resistance are only currently known for a few insecticides, with many of the new products remaining understudied. These shortcomings severely limit the breadth of application of existing genetic panels of resistance. There is a pressing need to expand both the geographic range of studies, and the range of insecticides for which resistance can be screened genetically. In the major malaria vector An. gambiae, most research on the genetic markers of resistance has been performed in West and East Africa, with a crucial knowledge gap remaining in southern Africa. This project will perform genome-wide association studies of resistance in southern Africa. The first insecticide will be an established, widely used pyrethroid treatment of bednets, such as permethrin. The second will be an insecticide used in the most recent generation of control products, such as chlorphenapyr, for which early signs of resistance have already been detected in An. gambiae. In the first part of the project, the student will undertake field work in southern Africa and identify locations with resistance to the insecticides of interest. They will collect An. gambiae samples from these locations and expose them to the insecticides, obtaining resistant and susceptible individuals which will be whole-genome sequenced. In collaboration with the An. gambiae 1000 genomes project at the Wellcome Sanger Institute, these large scale genomic data will then be bioinformatically analysed using genome-wide association study methods and population genetics to detect genes and mutations associated with resistance to the insecticides. The student will then incorporate these markers of resistance into monitoring panels to detect and track the spread of resistance. In the second part of the project, the student will collect further mosquitoes from a wide range of sites and apply their newly developed monitoring panel to the collected samples, providing a map of resistance marker frequency. They will also measure expression of resistance-associated genes in mosquitoes from each location, and correlate this with the presence of the resistance markers, providing an understanding of the link between genotype and resistance phenotype. The outcomes of the project will be: 1. an improved understanding of the genomics of resistance in An. gambiae, both to established and novel public health insecticides, 2. a molecular panel for screening insecticide resistance in southern Africa, and 3. an understanding of the association between resistance markers and gene expression. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Expected Outputs | The project will produce at least three high-impact publications (1. genome-wide association study of resistance in southern Africa, 2. development and application of marker panel to map resistance markers across the region, 3. association between resistance marker frequency and gene expression). Building on the results of the project, funding will be sought to develop a surveillance network across southern Africa, and to extend the study of the genetics of chlorphenapyr resistance to other regions of Africa. The project will result in improved understanding of the geographical distribution of resistance in southern Africa, and more targeted malaria control interventions. |
| Training Opportunities | The student will spend 3 months at the Wellcome Sanger Institute in Cambridge to work with the bioinformaticians from the Anopheles gambiae 1000 genomes project and develop their skills in genomic analysis and interpretation. |
| Skills Required | The student should have experience and expertise in mosquito field work and insectary work. A background of having worked on insecticide resistance would also be valuable, but not essential. |
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Key Publications associated with this project |
Lucas, ER et al. 2023. “Genome-Wide Association Studies Reveal Novel Loci Associated with Pyrethroid and Organophosphate Resistance in Anopheles Gambiae and Anopheles Coluzzii.” Nature Communications 14 (1): 1–11. |
| Nagi, SC et al. 2024. “Parallel Evolution in Mosquito Vectors – a Duplicated Esterase Locus Is Associated with Resistance to Pirimiphos-Methyl in Anopheles Gambiae.” Molecular Biology and Evolution 41 (7): msae140. | |
| Lucas, ER et al. 2024. “Copy Number Variants Underlie the Major Selective Sweeps in Insecticide Resistance Genes in Anopheles Arabiensis from Tanzania.” bioRxiv : The Preprint Server for Biology, March. https://doi.org/10.1101/2024.03.11.583874. | |
| Lucas, ER et al. 2019. “A High Throughput Multi-Locus Insecticide Resistance Marker Panel for Tracking Resistance Emergence and Spread in Anopheles gambiae.” Scientific Reports 9: 13335. |