Abstract
Vector population control using insecticides is a key element of current strategies to prevent malaria transmission in Africa. The introduction of effective insecticides, such as the organophosphate pirimiphos-methyl, is essential to overcome the recurrent emergence of resistance driven by the highly diverse Anopheles genomes. Here, we use a population genomic approach to investigate the basis of pirimiphos-methyl resistance in the major malaria vectors Anopheles gambiae and A. coluzzii. A combination of copy number variation and a single non-synonymous substitution in the acetylcholinesterase gene, Ace1, provides the key resistance diagnostic in an A. coluzzii population from Côte d’Ivoire that we used for sequence-based association mapping, with replication in other West African populations. The Ace1 substitution and duplications occur on a unique resistance haplotype that evolved in A. gambiae and introgressed into A. coluzzii, and is now common in West Africa primarily due to selection imposed by other organophosphate or carbamate insecticides. Our findings highlight the predictive value of this complex resistance haplotype for phenotypic resistance and clarify its evolutionary history, providing tools to for molecular surveillance of the current and future effectiveness of pirimiphos-methyl based interventions.
Highlights
Pirimiphos-methyl is an organophosphate insecticide that is widely used in control interventions against populations of the malaria vector Anopheles, especially in Africa [1,2]
In this study we provide an in-depth investigation of the relationship between Ace1 mutations and pirimiphos-methyl resistance in A. gambiae and A. coluzzii using whole-genome sequenced samples from the Anopheles gambiae 1000 Genomes project [32,33], and a wider testing of phenotyped specimens from across West Africa
We examined the frequency and distribution of the two Ace1 mutations that have been associated with organophosphate and carbamate resistance in A. gambiae and A. coluzzii: the G280S non-synonymous single nucleotide polymorphism (SNP), and copy number variation (CNV) polymorphisms of Ace1 and the surrounding genomic region
Summary
Pirimiphos-methyl is an organophosphate insecticide that is widely used in control interventions against populations of the malaria vector Anopheles, especially in Africa [1,2]. Since 2013, the World Health Organization (WHO) has recommended the use of pirimiphos-methyl for indoor residual spraying (IRS) interventions, the major anti-vector strategy in malaria control after treated bednet distribution [1,3]. The increase in pyrethroid resistance in Anopheles populations [7] has led to a progressive replacement with acetylcholinesterase-targeting insecticide classes, first the carbamate bendiocarb, and, latterly, the organophosphate pirimiphos-methyl [1]. Pirimiphos-methyl is the active ingredient in the most widely used insecticide for IRS in Africa, the spray formulation Actellic, which is highly effective and has strong residual performance [2,5,8,9]. Resistance has recently been reported in several populations of African Anopheles s.l. [10,11], and though control failures have yet to be reported, it represents a clear threat to the efficacy of IRS strategies
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