Abstract
BackgroundThe emergence of insecticide resistance is a major threat to malaria control programmes in Africa, with many different factors contributing to insecticide resistance in its vectors, Anopheles mosquitoes. CYP6M2 has previously been recognized as an important candidate in cytochrome P450-mediated detoxification in Anopheles. As it has been implicated in resistance against pyrethroids, organochlorines and carbamates, its broad metabolic activity makes it a potential agent in insecticide cross-resistance. Currently, allelic variation within the Cyp6m2 gene remains unknown.MethodsHere, Illumina whole-genome sequence data from Phase 2 of the Anopheles gambiae 1000 Genomes Project (Ag1000G) was used to examine genetic variation in the Cyp6m2 gene across 16 populations in 13 countries comprising Anopheles gambiae and Anopheles coluzzii mosquitoes. To identify whether these alleles show evidence of selection either through potentially modified enzymatic function or by being linked to variants that change the transcriptional profile of the gene, hierarchical clustering of haplotypes, linkage disequilibrium, median joining networks and extended haplotype homozygosity analyses were performed.ResultsFifteen missense biallelic substitutions at high frequency (defined as > 5% frequency in one or more populations) are found, which fall into five distinct haplotype groups that carry the main high frequency variants: A13T, D65A, E328Q, Y347F, I359V and A468S. Despite consistent reports of Cyp6m2 upregulation and metabolic activity in insecticide resistant Anophelines, no evidence of directional selection is found occurring on these variants or on the haplotype clusters in which they are found.ConclusionThese results imply that emerging resistance associated with Cyp6m2 is potentially driven by distant regulatory loci such as transcriptional factors rather than by its missense variants, or that other genes are playing a more significant role in conferring metabolic resistance.
Highlights
The emergence of insecticide resistance is a major threat to malaria control programmes in Africa, with many different factors contributing to insecticide resistance in its vectors, Anopheles mosquitoes
Despite consistent reports of Cyp6m2 upregulation and metabolic activity in insecticide resistant Anophelines, no evidence of directional selection is found occurring on these variants or on the haplotype clusters in which they are found
Focus is placed on SNPs that change the amino acid sequence of the CYP6M2 enzyme as they have a potential to alter gene function in Cyp6m2-associated insecticide resistance (n = 193) (Additional file 2)
Summary
The emergence of insecticide resistance is a major threat to malaria control programmes in Africa, with many different factors contributing to insecticide resistance in its vectors, Anopheles mosquitoes. (2021) 20:234 progress has stagnated and case numbers are stable or on the rise in many countries in Africa [1,2,3] This is due to multiple factors, including the emergence of insecticide resistance, which threaten the effectiveness of vector control interventions [4]. Mutations that diminish the binding capacity of insecticides to their targets confer target-site resistance [5], those that lead to a reduction in the insecticide absorption rate confer penetration resistance [6], those that lead to behavioural modification to circumvent the lethal effects of insecticides confer behavioural resistance [7], and those that increase insecticide detoxification and elimination rates confer metabolic resistance [8] These mechanisms of insecticide resistance may occur concurrently within a single population or even within a single mosquito [9, 10]. They have led to increasing resistance to all four common insecticide classes—pyrethroids, organochlorines, carbamates and organophosphates—in all major malaria vectors across
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