The 2024/25 application process is now open
Visit the MRC DTP/CASE at LSTM pages for further information and how to apply
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Abstract |
Insecticide-based control of mosquitoes has driven the recent huge gains in malaria control, yet insecticide resistance necessitates both new control approaches and ways to combine approaches that drastically reduce the overall likelihood of resistance. Our recent research has demonstrated a new form of genetic control, called gene drive, that can spread a genetic element rapidly in a population and cause its suppression. The gene drive, based on a modified CRISPR element, effectively acts as a very specific form of genomic parasite designed to recognise and disrupt a target sequence in any essential mosquito gene, copying itself in the process. We have shown that gene drives are also subject to resistance, in the form of sequence variation at the target site. Both forms of control show similarities in the dynamics of selection and spread of resistance yet show completely independent modes of action. After initial suppression, insecticide programs can leave a residual resistant population that shows drastically reduced genomic variation (‘selective sweeps’) making it more susceptible to subsequent control by gene drive. Conversely, it should be possible to engineer gene drives in a way that, after causing long term suppression, any residual population is newly susceptible to insecticide. Target site resistance to pyrethroids is widespread in many African populations of mosquitoes after the extended use of pyrethroid-treated bednets. The genetics of this resistance centre on a particular gene (vgsc) encoding a voltage-gated sodium channel, with many of the key point mutations being known. As a first step we have developed a gene drive that targets the vgsc gene to investigate the feasibility of deliberately affecting this gene’s function with a gene drive. Future steps as part of this project will look at the feasibility of targeting resistant versus susceptible alleles of this gene as well as other nearby regions of interest. Sites in these regions are attractive as gene drive targets since many of them show little genetic variation. This project will also investigate the feasibility of targeting these with gene drives that are designed to modify the targeted population through the introduction of ‘cargo’ genes that encode an effector that affect the mosquito’s intrinsic ability to harbour the malaria parasite.
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Where does the project lie on the Translational Pathway? |
T1 – Basic Research T3 Evidence into Practice |
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Expected Outputs |
If successful, the project will open up a new paradigm for combined genetic- and chemical-based control. The project will produce high quality REF returnable 3*/4* publications and will provide the evidence base for large scale research council, philanthropic (e.g. OP and Gates) and industry funding. |
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Training Opportunities |
CRISPR genome editing; execution of large cage studies; bioinformatics training; insect husbandry; professional development course |
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Skills Required |
An aptitude for molecular biology, genetics and vector control. Some bioinformatic skills would be desirable but not essential. |
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Key Publications associated with this project |
https://www.nature.com/articles/s41467-019-09694-w
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https://onlinelibrary.wiley.com/doi/epdf/10.1002/bies.202100279
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https://pubmed.ncbi.nlm.nih.gov/35022402/
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