title: Identification and validation of a gene causing cross-resistance between insecticide classes in Anopheles gambiae from Ghana.
abstract: In the last decade there have been marked reductions in malaria incidence in sub-Saharan Africa. Sustaining these reductions will rely upon insecticides to control the mosquito malaria vectors. We report that in the primary African malaria vector, Anopheles gambiae sensu stricto, a single enzyme, CYP6M2, confers resistance to two classes of insecticide. This is unique evidence in a disease vector of cross-resistance associated with a single metabolic gene that simultaneously reduces the efficacy of two of the four classes of insecticide routinely used for malaria control. The gene-expression profile of a highly DDT-resistant population of A. gambiae s.s. from Ghana was characterized using a unique whole-genome microarray. A number of genes were significantly overexpressed compared with two susceptible West African colonies, including genes from metabolic families previously linked to insecticide resistance. One of the most significantly overexpressed probe groups (false-discovery rate-adjusted P < 0.0001) belonged to the cytochrome P450 gene CYP6M2. This gene is associated with pyrethroid resistance in wild A. gambiae s.s. populations) and can metabolize both type I and type II pyrethroids in recombinant protein assays. Using in vitro assays we show that recombinant CYP6M2 is also capable of metabolizing the organochlorine insecticide DDT in the presence of solubilizing factor sodium cholate.
authors.affiliation: Vector Group,  Liverpool School of Tropical Medicine, Liverpool L35QA,  United Kingdom.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Mitchell
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Stevenson
authors.forename: Pie
authors.initials: P
authors.lastname: Müller
authors.forename: Craig S
authors.initials: CS
authors.lastname: Wilding
authors.forename: Alexander
authors.initials: A
authors.lastname: Egyir-Yawson
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Field
authors.forename: Janet
authors.initials: J
authors.lastname: Hemingway
authors.forename: Mark J I
authors.initials: MJ
authors.lastname: Paine
authors.forename: Hilary
authors.initials: H
authors.lastname: Ranson
authors.forename: Martin James
authors.initials: MJ
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics* / Q000254:growth & development; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003634:DDT / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005869:Ghana; D006801:Humans; D019476:Insect Proteins / Q000235:genetics* / Q000378:metabolism; D007303:Insect Vectors / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D007305:Insecticide Resistance / Q000235:genetics*; D007306:Insecticides / Q000145:classification / Q000378:metabolism / Q000494:pharmacology; D008288:Malaria / Q000517:prevention & control; D009032:Mosquito Control / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D011722:Pyrethrins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019476:Insect Proteins; D007306:Insecticides; D011722:Pyrethrins; D003577:Cytochrome P-450 Enzyme System; D003634:DDT