Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, UK.
Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
Mol Ecol. 2022 Aug;31(16):4307-4318. doi: 10.1111/mec.16591. Epub 2022 Jul 12.
Studies of insecticide resistance provide insights into the capacity of populations to show rapid evolutionary responses to contemporary selection. Malaria control remains heavily dependent on pyrethroid insecticides, primarily in long lasting insecticidal nets (LLINs). Resistance in the major malaria vectors has increased in concert with the expansion of LLIN distributions. Identifying genetic mechanisms underlying high-level resistance is crucial for the development and deployment of resistance-breaking tools. Using the Anopheles gambiae 1000 genomes (Ag1000g) data we identified a very recent selective sweep in mosquitoes from Uganda which localized to a cluster of cytochrome P450 genes. Further interrogation revealed a haplotype involving a trio of mutations, a nonsynonymous point mutation in Cyp6p4 (I236M), an upstream insertion of a partial Zanzibar-like transposable element (TE) and a duplication of the Cyp6aa1 gene. The mutations appear to have originated recently in An. gambiae from the Kenya-Uganda border, with stepwise replacement of the double-mutant (Zanzibar-like TE and Cyp6p4-236 M) with the triple-mutant haplotype (including Cyp6aa1 duplication), which has spread into the Democratic Republic of Congo and Tanzania. The triple-mutant haplotype is strongly associated with increased expression of genes able to metabolize pyrethroids and is strongly predictive of resistance to pyrethroids most notably deltamethrin. Importantly, there was increased mortality in mosquitoes carrying the triple-mutation when exposed to nets cotreated with the synergist piperonyl butoxide (PBO). Frequencies of the triple-mutant haplotype remain spatially variable within countries, suggesting an effective marker system to guide deployment decisions for limited supplies of PBO-pyrethroid cotreated LLINs across African countries.
研究杀虫剂抗性为了解种群对当代选择表现出快速进化反应的能力提供了线索。疟疾控制仍然严重依赖拟除虫菊酯杀虫剂，主要是在长效驱虫蚊帐（LLIN）中。主要疟疾传播媒介的抗性随着 LLIN 分布的扩大而增加。确定高水平抗性的遗传机制对于开发和部署抗药性工具至关重要。利用冈比亚按蚊 1000 基因组（Ag1000g）数据，我们在来自乌干达的蚊子中发现了一个非常近期的选择清除，该清除定位于一组细胞色素 P450 基因。进一步的询问揭示了一个涉及三个突变的单倍型，Cyp6p4 中的非同义点突变（I236M），一个 Zanzibar 样转座元件（TE）的部分插入和 Cyp6aa1 基因的重复。这些突变似乎是最近在肯尼亚-乌干达边境的冈比亚按蚊中起源的，具有双突变（Zanzibar 样 TE 和 Cyp6p4-236M）的逐步取代，与三重突变单倍型（包括 Cyp6aa1 重复），该单倍型已传播到刚果民主共和国和坦桑尼亚。三重突变单倍型与能够代谢拟除虫菊酯的基因的表达增加强烈相关，并且强烈预测对拟除虫菊酯（尤其是溴氰菊酯）的抗性。重要的是，当携带三重突变的蚊子暴露在增效剂增效醚（PBO）处理过的网中时，死亡率增加。三重突变单倍型的频率在国家内仍然存在空间变异性，这表明这是一种有效的标记系统，可以指导在非洲国家有限的 PBO-拟除虫菊酯处理过的 LLIN 供应下进行部署决策。
