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Identification of a rapidly-spreading triple mutant for high-level metabolic insecticide resistance in Anopheles gambiae provides a real-time molecular diagnostic for anti-malarial intervention deployment.
  • +18
  • Harun Njoroge,
  • Arjen van't Hof,
  • Ambrose Oruni,
  • Dimitra Pipini,
  • Sanjay C Nagi,
  • Amy Lynd,
  • Eric Lucas,
  • Sean Tomlinson,
  • Xavier Grau-Bové,
  • Daniel McDermott,
  • Francis t Wat'senga,
  • Emile Z Manzambi,
  • Fiacre R Agossa,
  • Arlette Mokuba,
  • Seth Irish,
  • Bilali Kabula,
  • Charles Mbogo,
  • Joel Bargul,
  • Mark JI Paine,
  • David Weetman,
  • Martin Donnelly
Harun Njoroge
Liverpool School of Tropical Medicine

Corresponding Author:harunnjoroge1@yahoo.com

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Arjen van't Hof
Liverpool School of Tropical Medicine
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Ambrose Oruni
Liverpool School of Tropical Medicine
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Dimitra Pipini
Liverpool School of Tropical Medicine
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Sanjay C Nagi
Liverpool School of Tropical Medicine
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Amy Lynd
Liverpool School of Tropical Medicine
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Eric Lucas
Liverpool School of Tropical Medicine
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Sean Tomlinson
Liverpool School of Tropical Medicine
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Xavier Grau-Bové
Liverpool School of Tropical Medicine
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Daniel McDermott
Liverpool School of Tropical Medicine
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Francis t Wat'senga
Institut National de Recherche Biomédicale
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Emile Z Manzambi
Institut National de Recherche Biomédicale
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Fiacre R Agossa
USAID President’s Malaria Initiative
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Arlette Mokuba
USAID President’s Malaria Initiative,
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Seth Irish
CDC
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Bilali Kabula
National Institute for Medical Research Amani Centre
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Charles Mbogo
Kenya Medical Research Institute
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Joel Bargul
Jomo Kenyatta University of Agriculture and Technology
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Mark JI Paine
Liverpool School of Tropical Medicine
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David Weetman
Liverpool School of Tropical Medicine
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Martin Donnelly
Liverpool School of Tropical Medicine
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Abstract

Insecticide resistance provides both a pressing threat to the control of vector-borne diseases and insights into the remarkable capacity of natural populations to show rapid evolutionary responses. Malaria control remains heavily dependent on deployment of insecticides, primarily in long lasting insecticide treated nets (LLINs), but resistance in the major malaria vectors has increased over the last 15 years. Identifying genetic mechanisms causing high-level resistance in mosquitoes, which may almost entirely overcome pyrethroid efficacy, is crucial for the development and deployment of potentially resistance-breaking tools. Using the Anopheles gambiae 1000 genomes data we identified a very recent selective sweep in Ugandan mosquitoes which localized to a cluster of cytochrome P450 genes. Further interrogation revealed a haplotype involving a trio of mutations, a point mutation in Cyp6p4, an insertion of a partial Zanzibar 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 region, with stepwise replacement of the double-mutant (Zanzibar TE and Cyp6p4-236M) 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 metabolise pyrethroids; is strongly predictive of resistance to pyrethroids but importantly, appears less effective against LLINs co-treated with the synergist piperonyl butoxide (PBO). Frequencies of the triple-mutant haplotype remain spatially variable even within countries, suggesting an effective marker system to guide deployment decisions for limited supplies of PBO-pyrethroid co-treated LLINs across African countries.
03 Feb 2022Submitted to Molecular Ecology
07 Feb 2022Submission Checks Completed
07 Feb 2022Assigned to Editor
15 Feb 2022Reviewer(s) Assigned
18 Apr 2022Review(s) Completed, Editorial Evaluation Pending
26 May 2022Editorial Decision: Revise Minor
07 Jun 2022Review(s) Completed, Editorial Evaluation Pending
07 Jun 20221st Revision Received
27 Jun 2022Editorial Decision: Accept
Jul 2022Published in Molecular Ecology. 10.1111/mec.16591