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Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering.doc

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Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering

Kuoetal.GenomeBiology2010,11:R77 /2010/11/7/R77 RESEARCH OpenAccess Evolutionarydivergenceinthefungalresponse tofluconazolerevealedbysoftclustering DwightKuo1?,KaiTan2?,GuyZinman3?,TimothyRavasi1,4,ZivBar-Joseph3*,TreyIdeker1* Abstract Background:Fungalinfectionsareanemerginghealthrisk,especiallythoseinvolvingyeastthatareresistantto antifungalagents.Tounderstandtherangeofmechanismsbywhichyeastscanrespondtoanti-fungals,we comparedgeneexpressionpatternsacrossthreeevolutionarilydistantspecies-Saccharomycescerevisiae,Candida glabrataandKluyveromyceslactis-overtimefollowingfluconazoleexposure. Results:Conservedanddivergedexpressionpatternswereidentifiedusinganovelsoftclusteringalgorithmthat concurrentlyclustersdatafromallspecieswhileincorporatingsequenceorthology.Theanalysissuggests complementarystrategiesforcopingwithergosteroldepletionbyazoles-Saccharomycesimportsexogenous ergosterol,Candidaexportsfluconazole,whileKluyveromycesdoesneither,leadingtoextremesensitivity.Insupport ofthishypothesiswefindthatonlySaccharomycesbecomesmoreazoleresistantinergosterol-supplemented media;thatthisdependsonsterolimportersAus1andPdr11;andthattransgenicexpressionofsterolimportersin Kluyveromycesalleviatesitsdrugsensitivity. Conclusions:Wehavecomparedthedynamictranscriptionalresponsesofthreediverseyeastspeciesto fluconazoletreatmentusinganovelclusteringalgorithm.Thisapproachrevealedsignificantdivergenceamong regulatoryprogramsassociatedwithfluconazolesensitivity.Infuture,suchapproachesmightbeusedtosurveya widerrangeofspecies,drugconcentrationsandstimulitorevealconservedanddivergentmolecularresponse pathways. Background The fungal response to azoles has been most often Mucosalandinvasivemycosesareamajorworldhealth studied in yeast [5,7,12-17], primarily through analysis problemleadingtomorbidity[1,2] andamortalityrate ofstandard laboratory strains of Candida[12,13,18] or of up to 70% in immunocompromised hosts [3]. The Saccharomyces [14,16,17] ortheir resistant clinical iso-