title: Footprints of positive selection associated with a mutation (N1575Y) in the voltage-gated sodium channel of Anopheles gambiae.
abstract: Insecticide resistance is an ideal model to study the emergence and spread of adaptative variants. In the African malaria mosquito, Anopheles gambiae, this is complemented by a strong public health rationale. In this insect, resistance to pyrethroid and DDT insecticides is strongly associated with the mutations L1014F and L1014S within the para voltage-gated sodium channel (VGSC). Across much of West Africa, 1014F frequency approaches fixation. Here, we document the emergence of a mutation, N1575Y, within the linker between domains III-IV of the VGSC. In data extending over 40 kbp of the VGSC 1575Y occurs on only a single long-range haplotype, also bearing 1014F. The 1014F-1575Y haplotype was found in both M and S molecular forms of An. gambiae in West/Central African sample sites separated by up to 2,000 km. In Burkina Faso M form, 1575Y allele frequency rose significantly from 0.053 to 0.172 between 2008 and 2010. Extended haplotype homozygosity analysis of the wild-type 1575N allele showed rapid decay of linkage disequilibrium (LD), in sharp contrast to the extended LD exhibited by 1575Y. A haplotype with long-range LD and high/increasing frequency is a classical sign of strong positive selection acting on a recent mutant. 1575Y occurs ubiquitously on a 1014F haplotypic background, suggesting that the N1575Y mutation compensates for deleterious fitness effects of 1014F and/or confers additional resistance to insecticides. Haplotypic tests of association suggest the latter: The 1014F-1575Y haplotype confers a significant additive benefit above 1014F-1575N for survival to DDT (M form P = 0.03) and permethrin (S form P = 0.003).
authors.affiliation: Vector Group,  Liverpool School of Tropical Medicine, Liverpool L3 5QA,  United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jones
authors.forename: Milindu
authors.initials: M
authors.lastname: Liyanapathirana
authors.forename: Fiacre R
authors.initials: FR
authors.lastname: Agossa
authors.forename: David
authors.initials: D
authors.lastname: Weetman
authors.forename: Hilary
authors.initials: H
authors.lastname: Ranson
authors.forename: Martin James
authors.initials: MJ
authors.lastname: Donnelly
authors.forename: Craig S
authors.initials: CS
authors.lastname: Wilding
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D007305:Insecticide Resistance; D015640:Ion Channel Gating; D009154:Mutation; D012641:Selection, Genetic; D015222:Sodium Channels / Q000502:physiology*
chemical_list: D015222:Sodium Channels