Weetman, D, Mitchell, SN, Wilding, CS, Birks, DP, Yawson, AE, Essandoh, J, Mawejje, HD, Djogbenou, LS, Steen, K, Rippon, EJ, Clarkson, CS, Field, SG, Rigden, DJ and Donnelly, MJ (2015) Contemporary evolution of resistance at the major insecticide target site gene Ace-1 by mutation and copy number variation in the malaria mosquito Anopheles gambiae. Molecular Ecology. ISSN 0962-1083

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Abstract

Functionally-constrained genes are ideal insecticide targets because disruption is often fatal, and resistance mutations are typically costly. Synaptic acetylcholinesterase (AChE) is an essential neurotransmission enzyme targeted by insecticides used increasingly in malaria control. In Anopheles and Culex mosquitoes, a glycine-serine substitution at codon 119 of the Ace-1 gene confers both resistance and fitness costs, especially for 119S/S homozygotes. G119S in A. gambiae from Accra (Ghana) is strongly associated with resistance, and, despite expectations of cost, resistant 119S alleles are increasing significantly in frequency. Sequencing of Accra females detected only a single Ace-1 119S haplotype whereas 119G diversity was high overall but very low at non-synonymous sites; evidence of strong purifying selection driven by functional constraint. Flanking microsatellites showed reduced diversity, elevated linkage disequilibrium and high differentiation of 119S, relative to 119G homozygotes across up to two megabases of the genome. Yet these signals of selection were inconsistent and sometimes weak tens of kilobases from Ace-1. This unexpected finding is attributable to apparently ubiquitous amplification of 119S alleles as part of a large copy number variant (CNV) far exceeding the size of the Ace-1 gene, whereas 119G alleles were unduplicated. Ace-1 CNV was detectable in archived samples collected when the 119S allele was rare in Ghana. Multi-copy amplification of resistant alleles has not been observed previously and is likely to underpin the recent increase in 119S frequency. The large CNV compromised localization of the strong selective sweep around Ace-1, emphasizing the need to integrate CNV analysis into genome scans for selection. This article is protected by copyright. All rights reserved.

Item Type:	Article
Additional Information:	This is the accepted version of the following article from Molecular Biology: "Contemporary evolution of resistance at the major insecticide target site gene Ace-1 by mutation and copy number variation in the malaria mosquito Anopheles gambiae" / D. Weetman [et al.], which has been published in final form at http://dx.doi.org/10.1111/mec.13197.
Uncontrolled Keywords:	06 Biological Sciences
Subjects:	Q Science > QH Natural history > QH301 Biology
Divisions:	Natural Sciences & Psychology (closed 31 Aug 19)
Publisher:	Wiley
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed/25865270
Date Deposited:	15 Apr 2015 10:48
Last Modified:	04 Sep 2021 14:31
DOI or ID number:	10.1111/mec.13197
URI:	https://researchonline.ljmu.ac.uk/id/eprint/869

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