Investigating the genetic basis of putative behavioural mechanisms of insecticide resistance in the malaria mosquito

Huge successes in reducing the malaria burden haven been achieved over the last 20-years, predominantly due to deployment of the effective combination of insecticides and bednets as a method of mosquito control.

Given the variety and heterogeneity of these new selection pressures, evolution is likely to be occurring at multiple loci, many of which may be unknown, throughout the genomes of malaria vector species. The availability of data from the Anopheles genomes project (Ag1000G) on genetic variation in thousands of wild-caught malaria vectors provides a unique opportunity to study the full genomic landscape of recent selection, to discover new adaptations to insecticide resistance, and to compare the genomic characteristics of adaptation between unlike species and populations.

Of the many selection signals recognised, several of these mapped to loci known previously to be involved in target-site and metabolic resistance to insecticides, verifying the validity of the approach. Interestingly though other selection signals mapped to genes whose function is challenging to reconcile with metabolic turnover of insecticide or with being direct target sites of insecticides.

One such gene, which is the focus for this project, may have roles in either altered synaptic transmission of nerve signals or, potentially, altered visual signalling, which may point to altered behaviour that ultimately leads to less insecticide exposure.

To this end the ability to recreate, on a standardised genetic background, different alleles of genes observed in the wild and assay their contribution to insecticide resistance and behaviour in the laboratory is game changing. We have developed a suite of genome editing tools based on CRISPR that allow us to introduce, with high ability, genetic mutations of choice precisely into the mosquito genome.

This project will thus integrate information emerging from this sector on the prevalence of novel genetic signals of selection and then design and test genetic constructs for integration into a standard mosquito strain to recapitulate and measure their effect on mosquito behaviour.