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. Author summary Control of mosquito populations via insecticidal tools or interventions is a mainstay of campaigns to reduce malaria transmission. However, especially in sub-Saharan Africa, continued insecticidal selection pressure on the most important species of Anopheles malaria mosquitoes has favoured the evolutionary selection of increasingly effective resistance mechanisms. We investigate the genetic basis of resistance to the organophosphate pirimiphos-methyl, the dominant insecticide now used for indoor residual spraying campaigns in Africa. Genome-wide association analysis of a population from Cote d’Ivoire showed that resistant specimens share a unique combination of mutations in one gene, the acetylcholinesterase enzyme, which constitute the prime cause of pirimiphos-methyl resistance. Further testing of these mutations in diagnostic assays involving two major malaria vectors, A . coluzzii and A . gambiae , validate their use as informative predictors of pirimiphos-methyl resistance. Using data from a large collection of whole genome sequenced specimens from a broader range of locations (Burkina-Faso, Côte d’Ivoire, Ghana, and Guinea), our evolutionary analyses demonstrate that these mutations emerged in A . gambiae and transferred into A . coluzzii by inter-specific hybridisation. Our results show how resistance mechanisms in key malaria vectors have developed and spread, and provide validated tools for molecular surveillance to inform public health campaigns.
【초록키워드】 public health, Mutation, Variation, Genetic, diagnostic, Intervention, Transmission, Population, Predictive value, malaria, Replication, Spread, Surveillance, sub-Saharan Africa, vector, African, Effectiveness, Control, selection pressure, genomes, predictor, molecular, genomic, Haplotype, association, Carbamate, Combination, Analysis, Non-synonymous, ACE1, resistance mechanism, copy number, insecticide, insecticides, Predictive, resistance mechanisms, enzyme, complex, specimen, West, phenotypic, whole genome, duplications, Anopheles gambiae, vectors, organophosphate, pirimiphos-methyl, duplication, dominant, approach, acetylcholinesterase, populations, Prevent, effective, highlight, sequenced, provide, occur, unique, overcome, reduce, driven by, malaria vector, increasingly, Anophele, insecticidal, transferred, 【제목키워드】 resistance, African, locus, West, duplication, Anophele,