title: Restriction to gene flow is associated with changes in the molecular basis of pyrethroid resistance in the malaria vector Anopheles funestus.
abstract: Resistance to pyrethroids, the sole insecticide class recommended for treating bed nets, threatens the control of major malaria vectors, including Anopheles funestus Effective management of resistance requires an understanding of the dynamics and mechanisms driving resistance. Here, using genome-wide transcription and genetic diversity analyses, we show that a shift in the molecular basis of pyrethroid resistance in southern African populations of this species is associated with a restricted gene flow. Across the most highly endemic and densely populated regions in Malawi, An. funestus is resistant to pyrethroids, carbamates, and organochlorides. Genome-wide microarray-based transcription analysis identified overexpression of cytochrome P450 genes as the main mechanism driving this resistance. The most up-regulated genes include cytochrome P450s (CYP) CYP6P9a, CYP6P9b and CYP6M7. However, a significant shift in the overexpression profile of these genes was detected across a south/north transect, with CYP6P9a and CYP6P9b more highly overexpressed in the southern resistance front and CYP6M7 predominant in the northern front. A genome-wide genetic structure analysis of southern African populations of An. funestus from Zambia, Malawi, and Mozambique revealed a restriction of gene flow between populations, in line with the geographical variation observed in the transcriptomic analysis. Genetic polymorphism analysis of the three key resistance genes, CYP6P9a, CYP6P9b, and CYP6M7, support barriers to gene flow that are shaping the underlying molecular basis of pyrethroid resistance across southern Africa. This barrier to gene flow is likely to impact the design and implementation of resistance management strategies in the region.
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.|FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138.|Broad Institute, Cambridge, MA 02142.
authors.forename: Kayla G
authors.initials: KG
authors.lastname: Barnes
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Irving
authors.affiliation: Malaria Alert Centre, College of Medicine, University of Malawi, Blantyre 3, Malawi.
authors.forename: Martin
authors.initials: M
authors.lastname: Chiumia
authors.affiliation: Malaria Alert Centre, College of Medicine, University of Malawi, Blantyre 3, Malawi.
authors.forename: Themba
authors.initials: T
authors.lastname: Mzilahowa
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Coleman
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; janet.hemingway@lstmed.ac.uk charles.wondji@lstmed.ac.uk.
authors.forename: Janet
authors.initials: J
authors.lastname: Hemingway
authors.affiliation: Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; janet.hemingway@lstmed.ac.uk charles.wondji@lstmed.ac.uk.|LSTM/OCEAC Research Unit, Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, BP 288 Yaoundé, Cameroon.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Wondji
mesh_terms: D000353:Africa, Southern; D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000235:genetics*; D051456:Gene Flow / Q000235:genetics*; D016678:Genome / Q000235:genetics; D007303:Insect Vectors / Q000235:genetics*; D007305:Insecticide Resistance / Q000235:genetics*; D007306:Insecticides / Q000494:pharmacology; D008288:Malaria / Q000469:parasitology* / Q000635:transmission; D046228:Microarray Analysis / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics; D011722:Pyrethrins / Q000494:pharmacology*
chemical_list: D007306:Insecticides; D011722:Pyrethrins
keywords: Anopheles funestus; cytochrome P450; gene flow; malaria; pyrethroid resistance