Abstract
Resistance to pyrethroid insecticides is a major concern for malaria vector control. Pyrethroids target the voltage‐gated sodium channel (VGSC), an essential component of the mosquito nervous system. Substitutions in the amino acid sequence can induce a resistance phenotype. We use whole‐genome sequence data from phase 2 of the Anopheles gambiae 1000 Genomes Project (Ag1000G) to provide a comprehensive account of genetic variation in the Vgsc gene across 13 African countries. In addition to known resistance alleles, we describe 20 other non‐synonymous nucleotide substitutions at appreciable population frequency and map these variants onto a protein model to investigate the likelihood of pyrethroid resistance phenotypes. Thirteen of these novel alleles were found to occur almost exclusively on haplotypes carrying the known L995F kdr (knock‐down resistance) allele and may enhance or compensate for the L995F resistance genotype. A novel mutation I1527T, adjacent to a predicted pyrethroid‐binding site, was found in tight linkage with V402L substitutions, similar to allele combinations associated with resistance in other insect species. We also analysed genetic backgrounds carrying resistance alleles, to determine which alleles have experienced recent positive selection, and describe ten distinct haplotype groups carrying known kdr alleles. Five of these groups are observed in more than one country, in one case separated by over 3000 km, providing new information about the potential for the geographical spread of resistance. Our results demonstrate that the molecular basis of target‐site pyrethroid resistance in malaria vectors is more complex than previously appreciated, and provide a foundation for the development of new genetic tools for insecticide resistance management.
Highlights
Pyrethroid insecticides have been the cornerstone of malaria prevention in Africa for almost two decades (Bhatt et al, 2015)
Pyrethroids are currently used in all insecticide-treated bed-nets (ITNs) and are used in indoor residual spraying (IRS) as well as in agriculture. Resistance to these insecticides is widespread in malaria vector populations across Africa (Hemingway et al, 2016)
The World Health Organization (WHO) has published plans for insecticide resistance management (IRM) that emphasize the need for improvements in both our knowledge of the molecular mechanisms of resistance and our ability to monitor them in natural populations (World Health Organization, 2012; World Health Organization et al, 2017)
Summary
Pyrethroid insecticides have been the cornerstone of malaria prevention in Africa for almost two decades (Bhatt et al, 2015). No studies in malaria vectors have analysed genetic variation across the full Vgsc coding sequence, and the molecular basis of pyrethroid target-site resistance has not been fully explored. Occurs on several different genetic backgrounds, suggesting multiple independent outbreaks of resistance driven by this allele (Etang et al, 2009; Lynd et al, 2010; Pinto et al, 2007; Santolamazza et al, 2015) These studies analysed only small gene regions in a limited number of mosquito populations and had limited resolution to make inferences about relationships between haplotypes carrying this allele. We use haplotype data from the chromosomal region spanning the Vgsc gene to study the genetic backgrounds carrying resistance alleles, investigate the geographical spread of resistance between mosquito populations and provide evidence for recent positive selection. We explore ways in which variation data from Ag1000G can be used to design high- throughput, low-cost genetic assays for surveillance of pyrethroid resistance, with the capability to differentiate and track resistance outbreaks
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