The argininosuccinate lyase gene exacerbates pyrethroid resistance in the major African vectors Anopheles funestus

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Abstract

Escalating pyrethroid resistance in malaria vectors is jeopardizing malaria control. Deciphering its complex evolutionary mechanisms is paramount to mitigate its impact. Here, we demonstrate that over-expression and allelic variation of the argininosuccinate lyase ( ASL) gene exacerbate pyrethroid resistance in Anopheles funestus . Multi-omics analyses revealed that ASL is upregulated Africa-wide and detected a strong signal of genetic differentiation around ASL in resistant populations exhibiting copy number variation (CNV). A predominant resistant haplotype harboring the R125H and T-277A mutations was detected in resistant mosquitoes. Transgenic expression of ASL and RNAi confirm its ability to confer pyrethroid resistance. A DNA-based assay confirmed its association with super-resistance, revealing a marked temporal increase in Uganda (2010–2023) but with a drastic reduction observed in 2024 after deployment of chlorfenapyr-based bed nets. This study elucidates a novel resistance pathway driven by ASL and introduces a new DNA-based diagnostic tool to monitor its spread and impact in Africa.

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