Multi-omics analysis identifies a CYP9K1 haplotype conferring pyrethroid resistance in the malaria vector Anopheles funestus in East Africa.
Multi-omics analysis identifies a CYP9K1 haplotype conferring pyrethroid resistance in the malaria vector Anopheles funestus in East Africa.
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多组学分析确定了东非疟疾媒介按蚊中具有拟除虫菊酯抗性的CYP9K1单倍型。
DOI：
10.1111/mec.16497
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发表时间：
2022-07
影响因子：
4.9
通讯作者：
Wondji CS
中科院分区：
文献类型：
--
作者：
Hearn J;Djoko Tagne CS;Ibrahim SS;Tene-Fossog B;Mugenzi LMJ;Irving H;Riveron JM;Weedall GD;Wondji CS
对拟除虫菊酯的代谢性耐药性对疟疾病媒控制的持续有效性构成威胁。它的分子基础很复杂，在非洲各地的地理位置也各不相同。在这里，我们使用了多组学方法，随后进行了功能验证，以证明细胞色素P450的定向选择单倍型CYP9K1是funestus按蚊抗性的主要驱动因素。PoolSeq GWAS使用了来自马拉维和喀麦隆暴露氯菊酯后的活蚊和死蚊，检测到了候选基因组区域，但在重复中缺乏一致性。候选抗性基因的靶向测序检测到与已知拟除虫菊酯抗性qtl相关的几个snp。最显著的snp位于细胞色素P450 CYP304B1（喀麦隆）、CYP315A1（乌干达）和ABC转运基因ABCG4（马拉维）。然而，当将田间抗性蚊子与实验室易感蚊子进行比较时，除乌干达P450 CYP9K1的snp显著外，拟除虫菊酯类杀虫剂抗性位点rp1和ABC转运体ABCG4周围的snp均显著。重组CYP9K1体外异源代谢试验显示，它代谢II型拟除虫菊酯（溴氰菊酯，消耗64%），但不代谢I型（氯菊酯，0%），而适度代谢DDT（17%）。CYP9K1在乌干达表现出遗传多样性的降低，这是广泛选择性扫描的基础。此外，乌干达蚊子CYP9K1中甘氨酸到丙氨酸（G454A）氨基酸的变化是固定的，而在其他非洲蚊子中没有。funestus人群。这项研究进一步揭示了一种主要疟疾媒介代谢耐药性的进化，它暗示了更多的基因和变异，这些基因和变异可用于设计适用于田间的标记，以更好地跟踪全非洲的耐药性。
Metabolic resistance to pyrethroids is a menace to the continued effectiveness of malaria vector controls. Its molecular basis is complex and varies geographically across Africa. Here, we used a multi‐omics approach, followed‐up with functional validation to show that a directionally selected haplotype of a cytochrome P450, CYP9K1 is a major driver of resistance in Anopheles funestus. A PoolSeq GWAS using mosquitoes alive and dead after permethrin exposure, from Malawi and Cameroon, detected candidate genomic regions, but lacked consistency across replicates. Targeted sequencing of candidate resistance genes detected several SNPs associated with known pyrethroid resistance QTLs. The most significant SNPs were in the cytochrome P450 CYP304B1 (Cameroon), CYP315A1 (Uganda) and the ABC transporter gene ABCG4 (Malawi). However, when comparing field resistant mosquitoes to laboratory susceptible, the pyrethroid resistance locus rp1 and SNPs around the ABC transporter ABCG4 were consistently significant, except for Uganda where SNPs in the P450 CYP9K1 was markedly significant. In vitro heterologous metabolism assays with recombinant CYP9K1 revealed that it metabolises type II pyrethroid (deltamethrin; 64% depletion) but not type I (permethrin; 0%), while moderately metabolising DDT (17%). CYP9K1 exhibited reduced genetic diversity in Uganda underlying an extensive selective sweep. Furthermore, a glycine to alanine (G454A) amino acid change in CYP9K1 was fixed in Ugandan mosquitoes but not in other An. funestus populations. This study sheds further light on the evolution of metabolic resistance in a major malaria vector by implicating more genes and variants that can be used to design field‐applicable markers to better track resistance Africa‐wide.
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影响因子：
3
作者：
Antonio-Nkondjio C;Tene Fossog B;Kopya E;Poumachu Y;Menze Djantio B;Ndo C;Tchuinkam T;Awono-Ambene P;Wondji CS
通讯作者：
Wondji CS
影响因子：
3.7
作者：
Gregory R;Darby AC;Irving H;Coulibaly MB;Hughes M;Koekemoer LL;Coetzee M;Ranson H;Hemingway J;Hall N;Wondji CS
通讯作者：
Wondji CS
影响因子：
1.9
作者：
Hunt, RH;Brooke, BD;Coetzee, M
通讯作者：
Coetzee, M
影响因子：
7
作者：
Faucon F;Dusfour I;Gaude T;Navratil V;Boyer F;Chandre F;Sirisopa P;Thanispong K;Juntarajumnong W;Poupardin R;Chareonviriyaphap T;Girod R;Corbel V;Reynaud S;David JP
通讯作者：
David JP
影响因子：
9.2
作者：
Ghurye, Jay;Koren, Sergey;Besansky, Nora J.
通讯作者：
Besansky, Nora J.