Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum 英文参考文献.docVIP

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Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum 英文参考文献.doc

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Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum 英文参考文献

FitnessTrade-OffsintheEvolutionofDihydrofolate ReductaseandDrugResistanceinPlasmodium falciparum MarnaS.Costanzo*,KyleM.Brown,DanielL.Hartl DepartmentofOrganismicandEvolutionaryBiology,HarvardUniversity,Cambridge,Massachusetts,UnitedStatesofAmerica Abstract Background: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodiumfalciparum,theparasitethatcausesthemostseriousformofmalaria,antifolatedrugsinhibitthefunctionof essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolatereductase,conferdrugresistance.Understandinghowevolutionproceedsfromdrugsusceptibilitytodrug resistanceiscriticalifnewantifolatetreatmentsaretohavesustainedusefulness. Methodology/PrincipalFindings:Weuseatransgenicyeastexpressionsystemtobuildonpreviousstudiesthatdescribed theadaptivelandscapefortheantifolatedrugpyrimethamine,andwedescribethemostlikelyevolutionarytrajectoriesfor theevolutionofdrugresistancetotheantifolatechlorcycloguanil.Wefindthattheadaptivelandscapeforchlorcycloguanil ismulti-peaked,notallhighlyresistantallelesareequallyaccessiblebyevolution,andtherearebothcommonalitiesand differencesinadaptivelandscapesforchlorcycloguanilandpyrimethamine. Conclusions/Significance:Ourfindingssuggestthatcross-resistancebetweendrugstargetingthesameenzymereflectthe fitnesslandscapesassociatedwitheachparticulardrugandthepositionofthegenotypeonbothlandscapes.Thepossible publichealthimplicationsofthesefindingsarediscussed. Citation: Costanzo MS, Brown KM, Hartl DL (2011) Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum.PLoSONE6(5):e19636.doi:10.1371/journal.pone.0019636 Editor:LorenzvonSeidlein,MenziesSchoolofHealthResearch,Australia ReceivedDecember1,2010;AcceptedApril10,2011;PublishedMay23,2011 Copyright: ? 2011 Costanzo et al. This is an open-access article distributed under the terms of the Creative Commons Attri