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Contemporary evolution of resistance at the major insecticide target site geneAce-1by mutation and copy number variation in the malaria mosquito Anopheles gambiae

Weetman, David ORCID:, Mitchell, Sara N., Wilding, Craig S., Birks, Daniel P., Yawson, Alexander E., Essandoh, John, Mawejje, Henry D., Djogbenou, Luc S., Steen, Keith ORCID:, Rippon, Emily, Clarkson, Christopher S., Field, Stuart G., Rigden, Daniel J. and Donnelly, Martin ORCID: (2015) 'Contemporary evolution of resistance at the major insecticide target site geneAce-1by mutation and copy number variation in the malaria mosquito Anopheles gambiae'. Molecular Ecology, Vol 24, Issue 11, pp. 21656-2672.

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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 Anopheles 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. Multicopy 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.

Item Type: Article
Subjects: QU Biochemistry > Genetics > QU 460 Genomics. Proteomics
QX Parasitology > Insects. Other Parasites > QX 515 Anopheles
QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):
Depositing User: Carmel Bates
Date Deposited: 19 May 2015 10:52
Last Modified: 16 Sep 2019 09:17


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