Wellcome Sanger Institute, Cambridge, UK.
Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Mol Ecol. 2021 Nov;30(21):5303-5317. doi: 10.1111/mec.15845. Epub 2021 Mar 8.
Resistance to pyrethroid insecticides is a major concern for malaria vector control. Pyrethroids target the voltage-gated sodium channel (VGSC), an essential component of the mosquito nervous system. Substitutions in the amino acid sequence can induce a resistance phenotype. We use whole-genome sequence data from phase 2 of the Anopheles gambiae 1000 Genomes Project (Ag1000G) to provide a comprehensive account of genetic variation in the Vgsc gene across 13 African countries. In addition to known resistance alleles, we describe 20 other non-synonymous nucleotide substitutions at appreciable population frequency and map these variants onto a protein model to investigate the likelihood of pyrethroid resistance phenotypes. Thirteen of these novel alleles were found to occur almost exclusively on haplotypes carrying the known L995F kdr (knock-down resistance) allele and may enhance or compensate for the L995F resistance genotype. A novel mutation I1527T, adjacent to a predicted pyrethroid-binding site, was found in tight linkage with V402L substitutions, similar to allele combinations associated with resistance in other insect species. We also analysed genetic backgrounds carrying resistance alleles, to determine which alleles have experienced recent positive selection, and describe ten distinct haplotype groups carrying known kdr alleles. Five of these groups are observed in more than one country, in one case separated by over 3000 km, providing new information about the potential for the geographical spread of resistance. Our results demonstrate that the molecular basis of target-site pyrethroid resistance in malaria vectors is more complex than previously appreciated, and provide a foundation for the development of new genetic tools for insecticide resistance management.
对拟除虫菊酯类杀虫剂的抗性是疟疾媒介控制的主要关注点。拟除虫菊酯类杀虫剂靶向电压门控钠离子通道（VGSC），这是蚊子神经系统的一个重要组成部分。氨基酸序列的替换可以诱导抗性表型。我们利用来自 2 期冈比亚按蚊 1000 基因组计划（Ag1000G）的全基因组序列数据，全面描述了 13 个非洲国家 Vgsc 基因的遗传变异。除了已知的抗性等位基因外，我们还描述了 20 个其他非同义核苷酸替换，这些替换在相当大的种群频率中出现，并将这些变体映射到蛋白质模型上，以研究其产生拟除虫菊酯抗性表型的可能性。这 13 个新等位基因几乎只出现在携带已知 L995F kdr（击倒抗性）等位基因的单倍型上，可能增强或补偿 L995F 抗性基因型。我们发现一个新的突变 I1527T，位于一个预测的拟除虫菊酯结合位点附近，与 V402L 替换紧密连锁，类似于与其他昆虫物种的抗性相关的等位基因组合。我们还分析了携带抗性等位基因的遗传背景，以确定哪些等位基因经历了最近的正选择，并描述了携带已知 kdr 等位基因的十个不同的单倍型组。其中五个组在一个以上的国家中观察到，在一个案例中，它们之间的距离超过 3000 公里，这为抗性的地理传播潜力提供了新的信息。我们的研究结果表明，疟疾媒介中靶标位点拟除虫菊酯抗性的分子基础比以前所认识的更为复杂，并为新的遗传工具的开发提供了基础，以用于杀虫剂抗性管理。
