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dc.contributor.authorMitchell, Sara N.en_US
dc.contributor.authorRigden, Daniel J.en_US
dc.contributor.authorDowd, Andrew J.en_US
dc.contributor.authorLu, Fangen_US
dc.contributor.authorWilding, Craig S.en_US
dc.contributor.authorWeetman, Daviden_US
dc.contributor.authorDadzie, Samuelen_US
dc.contributor.authorJenkins, Adam M.en_US
dc.contributor.authorRegna, Kimberlyen_US
dc.contributor.authorBoko, Pelagieen_US
dc.contributor.authorDjogbenou, Lucen_US
dc.contributor.authorMuskavitch, Marc A. T.en_US
dc.contributor.authorRanson, Hilaryen_US
dc.contributor.authorPaine, Mark J. I.en_US
dc.contributor.authorMayans, Olgaen_US
dc.contributor.authorDonnelly, Martin J.en_US
dc.date.accessioned2014-05-06T16:16:48Z
dc.date.issued2014en_US
dc.identifier.citationMitchell, S. N., D. J. Rigden, A. J. Dowd, F. Lu, C. S. Wilding, D. Weetman, S. Dadzie, et al. 2014. “Metabolic and Target-Site Mechanisms Combine to Confer Strong DDT Resistance in Anopheles gambiae.” PLoS ONE 9 (3): e92662. doi:10.1371/journal.pone.0092662. http://dx.doi.org/10.1371/journal.pone.0092662.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:12152876
dc.description.abstractThe development of resistance to insecticides has become a classic exemplar of evolution occurring within human time scales. In this study we demonstrate how resistance to DDT in the major African malaria vector Anopheles gambiae is a result of both target-site resistance mechanisms that have introgressed between incipient species (the M- and S-molecular forms) and allelic variants in a DDT-detoxifying enzyme. Sequencing of the detoxification enzyme, Gste2, from DDT resistant and susceptible strains of An. gambiae, revealed a non-synonymous polymorphism (I114T), proximal to the DDT binding domain, which segregated with strain phenotype. Recombinant protein expression and DDT metabolism analysis revealed that the proteins from the susceptible strain lost activity at higher DDT concentrations, characteristic of substrate inhibition. The effect of I114T on GSTE2 protein structure was explored through X-ray crystallography. The amino acid exchange in the DDT-resistant strain introduced a hydroxyl group nearby the hydrophobic DDT-binding region. The exchange does not result in structural alterations but is predicted to facilitate local dynamics and enzyme activity. Expression of both wild-type and 114T alleles the allele in Drosophila conferred an increase in DDT tolerance. The 114T mutation was significantly associated with DDT resistance in wild caught M-form populations and acts in concert with target-site mutations in the voltage gated sodium channel (Vgsc-1575Y and Vgsc-1014F) to confer extreme levels of DDT resistance in wild caught An. gambiae.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0092662en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968025/pdf/en
dash.licenseLAAen_US
dc.subjectBiology and Life Sciencesen
dc.subjectAgricultureen
dc.subjectPest Controlen
dc.subjectEvolutionary Biologyen
dc.subjectEvolutionary Geneticsen
dc.subjectPopulation Geneticsen
dc.subjectGeneticsen
dc.subjectGene Identification and Analysisen
dc.subjectGenetics of Diseaseen
dc.subjectMolecular Geneticsen
dc.subjectOrganismsen
dc.subjectAnimalsen
dc.subjectInvertebratesen
dc.subjectArthropodaen
dc.subjectInsectsen
dc.subjectMosquitoesen
dc.subjectToxicologyen
dc.subjectToxicokineticsen
dc.subjectZoologyen
dc.subjectEntomologyen
dc.subjectMedicine and Health Sciencesen
dc.subjectEpidemiologyen
dc.subjectDisease Vectorsen
dc.subjectVector Biologyen
dc.titleMetabolic and Target-Site Mechanisms Combine to Confer Strong DDT Resistance in Anopheles gambiaeen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorMuskavitch, Marc A. T.en_US
dc.date.available2014-05-06T16:16:48Z
dc.identifier.doi10.1371/journal.pone.0092662*
dash.authorsorderedfalse
dash.contributor.affiliatedMuskavitch, Marc


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