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.

中文翻译：

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非洲疟疾媒介冈比亚按蚊和科鲁兹按蚊靶位点对拟除虫菊酯杀虫剂抗性的遗传结构

对拟除虫菊酯杀虫剂的抗性是疟疾媒介控制的一个主要问题。拟除虫菊酯针对的是电压门控钠通道（VGSC），这是蚊子神经系统的重要组成部分。氨基酸序列的取代可以诱导抗性表型。我们使用冈比亚按蚊1000 个基因组计划 (Ag1000G)第二阶段的全基因组序列数据来全面描述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之外，我们还以明显的群体频率描述了 20 种其他非同义核苷酸取代，并将这些变体映射到蛋白质模型上，以研究拟除虫菊酯抗性表型的可能性。发现这些新等位基因中的 13 个几乎只出现在携带已知 L995F kdr（敲低抗性）等位基因的单倍型上，并且可能增强或补偿 L995F 抗性基因型。一个新的突变 I1527T 与预测的拟除虫菊酯结合位点相邻，被发现与 V402L 取代紧密连锁，类似于与其他昆虫物种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最近经历了正选择，并描述了携带已知kdr等位基因的十个不同的单倍型组。其中五个群体分布在多个国家，其中一个群体相隔 3000 多公里，这提供了有关耐药性地理传播潜力的新信息。我们的研究结果表明，疟疾载体中拟除虫菊酯靶点抗性的分子基础比之前认识的更为复杂，并为开发用于杀虫剂抗性管理的新遗传工具奠定了基础。