Association Mapping of Insecticide Resistance in Wild Anopheles gambiae Populations Major Variants Identified in a Low-Linkage Disequilbrium Genome 英文参考文献.docVIP

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Association Mapping of Insecticide Resistance in Wild Anopheles gambiae Populations Major Variants Identified in a Low-Linkage Disequilbrium Genome 英文参考文献.doc

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Association Mapping of Insecticide Resistance in Wild Anopheles gambiae Populations Major Variants Identified in a Low-Linkage Disequilbrium Genome 英文参考文献

AssociationMappingofInsecticideResistanceinWild AnophelesgambiaePopulations:MajorVariants IdentifiedinaLow-LinkageDisequilbriumGenome DavidWeetman1.*,CraigS.Wilding1.,KeithSteen1,JohnC.Morgan1,Fre′de′ricSimard2,MartinJ. Donnelly1 1VectorGroup,LiverpoolSchoolofTropicalMedicine,PembrokePlace,Liverpool,UnitedKingdom,2LaboratoiredeLuttecontrelesInsectesNuisibles(LIN),Institutde RecherchepourleDe′veloppement(IRD),UR016,Montpellier,France Abstract Background:Associationstudiesareapromisingwaytouncoverthegeneticbasisofcomplextraitsinwildpopulations. Dataonpopulationstratification,linkagedisequilibriumanddistributionofvarianteffect-sizesfordifferenttrait-typesare requiredtopredictstudysuccessbutarelackingformosttaxa.Wequantifiedandinvestigatedtheimpactsofthesekey variablesinalarge-scaleassociationstudyofastronglyselectedtraitofmedicalimportance:pyrethroidresistanceinthe AfricanmalariavectorAnophelesgambiae. Methodology/Principal Findings: We genotyped 1500 resistance-phenotyped wild mosquitoes from Ghana and Cameroonusinga1536-SNParrayenrichedforcandidateinsecticideresistancegeneSNPs.Threefactorsgreatlyimpacted studypower.(1)Populationstratification,whichwasattributabletoco-occurrenceofmolecularforms(MandS),andcryptic within-formstratificationnecessitatingbothapartitionedanalysisandgenomiccontrol.(2)AllSNPsofsubstantialeffect (oddsratio,OR.2)wererare(minorallelefrequency,MAF,0.05).(3)Linkagedisequilibrium(LD)wasverylowthroughout mostofthegenome.Nevertheless,locallyhighLD,consistentwitharecentselectivesweep,anduniformlyhighORsineach subsample facilitated significant direct and indirect detection of the known insecticide target site mutation kdr L1014F (OR6;P,1026),butwithresistancelevelmodifiedbylocalhaplotypicbackground. Conclusion:Primarilyasaresult ofverylowLDinwild A.Gambiae, LD-basedassociationmappingischallenging,butis feasible at least for major effect variants, especially where LD is enhanced by selective sweeps. Such variants will be of greatestimportancefor