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).kdr | selective sweep | inactivation particle

Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed nets

“…S4). The N1575Y SNP is associated with increased pyrethroid resistance and is found only on a resistant genetic background of L1014F (22). A synonymous SNP located 4,974 bp upstream of the L1014F was detected in association mapping for pyrethroid resistance (21).…”

Phenotypic effects of concomitant insensitive acetylcholinesterase ( ace-1 R ) and knockdown resistance ( kdr R ) in Anopheles gambiae : a hindrance for insecticide resistance management for malaria vector control

“…kdr R resistance is caused by mutations in the sodium channel: leucine to phenylalanine substitution, originally observed in West Africa [31], and leucine to serine mutation in East Africa [32]. Recently, a new mutation in the sodium channel associated with kdr-west mutation conferring additional resistance to DDT and permethrin [33] was reported [34]. Experimental studies conducted in Southern Benin and in South Africa respectively with lambdacyhalothrin [33] on bednets and with deltamethrin [33] through indoor residual house spraying [35] suggested that PYRs resistance may have contributed to the failure of vector control endeavours in these areas [21,[35][36][37][38].…”

A Mutation in the Intracellular Loop III/IV of Mosquito Sodium Channel Synergizes the Effect of Mutations in Helix IIS6 on Pyrethroid Resistance

“…The N 1575 Y mutation is located in the intracellular cytoplasmic loop connecting domains III and IV (LIII/IV) (Fig. 1) F mutation (Jones et al, 2012). However, whether the N 1575 Y mutation confers pyrethroid resistance has not been functionally confirmed yet.…”

“…Recently, a new sodium channel mutation N 1575 Y was reported in the malaria mosquito, An. gambiae, in Africa (Jones et al, 2012). The N 1575 Y mutation is located in the intracellular cytoplasmic loop connecting domains III and IV (LIII/IV) (Fig.…”

“…gambiae (Jones et al, 2012), the N 1575 Y change was also introduced into AaNa v 1-1 carrying the L 2i16(1014) F mutation, which was generated in a previous study , to create a double mutation construct L (Fig. 2).…”