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apythonEnvironmentforTreeExplorationReviewedbyJaimeHuerta-Cepas,correspondingauthor1JoaquínDopazo,2andToniGabaldóncorrespondingauthor1AbstractManybioinformaticsanalyses,rangingfromgeneclusteringtophylogenetics,producehierarchicaltreesastheirmainresult.Theseareusedtorepresenttherelationshipsamongdifferentbiologicalentities,thusfacilitatingtheiranalysisandinterpretation.Anumberofstandaloneprogramsareavailablethatfocusontreevisualizationorthatperformspecificanalysesonthem.However,suchapplicationsarerarelysuitableforlarge-scalesurveys,inwhichahigherlevelofautomationisrequired.Currently,manygenome-wideanalysesrelyontree-likedatarepresentationandhencethereisagrowingneedforscalabletoolstohandletreestructuresatlargescale.Keywords:Python,spikingneurons,simulation,integrateandfire,teaching,neuralnetworks,computationalneuroscience,softwareBackgroundHerewepresenttheEnvironmentforTreeExploration(ETE),apythonprogrammingtoolkitthatassistsintheautomatedmanipulation,analysisandvisualizationofhierarchicaltrees.ETElibrariesprovideabroadsetoftreehandlingoptionsaswellasspecificmethodstoanalyzephylogeneticandclusteringtrees.Amongotherfeatures,ETEallowsfortheindependentanalysisoftreepartitions,hassupportfortheextendednewickformat,providesanintegratednodeannotationsystemandpermitstolinktreestoexternaldatasuchasmultiplesequencealignmentsornumericalarrays.Inaddition,ETEimplementsanumberofbuilt-inanalyticaltools,includingphylogeny-basedorthologypredictionandclustervalidationtechniques.Finally,ETE'sprogrammabletreedrawingenginecanbeusedtoautomatethegraphicalrenderingoftreeswithcustomizednode-specificvisualizations.ConclusionsETEprovidesacompletesetofmethodstomanipulatetreedatastructuresthatextendscurrentfunctionalityinotherbioinformatictoolkitsofamoregeneralpurpose.ETEisfreesoftwareandcanbedownloadedfrom(OTU)andinternalnodesastheircorrespondingancestors.Insuchphylogenetictrees,branchlengthsareusuallyproportionaltotheevolutionarydistanceamongsequences.Otherapplications,suchastheanalysisofgeneexpression,usehierarchicalclusteringanalysistogroupgenesorexperimentalconditionsaccordingtothesimilarityoftheirexpressionpatterns.Likewise,treesareusedbymanyproteinclassificationmethodsandfortheanalysisofphylogeneticprofiles.Thus,theanalysisoftreedatastructuresisacommontaskinmanyareasofbioinformaticsandthereisaneedforanalyticalandvisualizationtools.Inthisrespect,anumberofbioinformaticprogramsdoexistthatassistintheexplorationofhierarchicaltrees.Mostofthem,however,consistofstandaloneapplicationsthatarefocusedonvisualizationand,occasionally,onperformingspecifictests.SomewellknownexamplesareTreeView[1],awidelyusedprogramforinspectingphylogenetictrees;ClusterTreeview[2],anapplicationforvisualizingmicroarrayclusteringresults;ATV[3],ajavaprogramusedtoexplorephylogenieswhichprovidesalsosomeeditingoptions;MEGA[4],anevolutionarygeneticsanalysissuitethatincludesabuilt-intreeviewer;andmanyotherrecentapplications[5-8].Whilealltheseprogramsareveryusefultomanagesingletrees,theycanhardlybeautomatizedoradaptedtospecificneeds.Thus,whentheanalysisofhundredsorthousandsoftreesisrequired,theuseofstandaloneprogramsbecomesrestrictive,becauseamuchhigherlevelofautomationisrequired.Insuchcases,programmingtoolkitsrepresentamoreadequateframework,sincetheyprovidetoolsandmethodstohandledataatalowerlevel.Usingtoolkits,bioinformaticianscaneasilycreatetheirownanalysispipelinesandprogramcustomtasksoverlargecollectionsofdata[9].Severalgenericbioinformatictoolkitsdoexistthatcoverawiderangeofprogramminglanguagesandscopes,withBioPerl[10]andBioPython[11]beingthemostextensivelydeveloped.Togetherwithabroadrangeofotherfeatures,thesetoolkitsallowcertainlevelofinteractionwithtreedatastructures.However,onlybasicactionsarecurrentlysupported.Alternatively,thePyCogent[12]andP4~pf/p4.htmlpythontoolkitscanbeusedtoextendthisfunctionality,althoughtheyaremostlyfocusedonphylogeneticreconstruction.R[13],ageneralpurposestatisticalframework,doesincludeseveralpackagestoperformstatisticaltestsonclusteringandphylogenetictrees.Nevertheless,thesepackagesarefocusedonperformingspecificanalysesratherthaninprovidingtreehandlingandmanipulationfeatures.Finally,incontrasttothegreatnumberofstandalonetreeviewers,programmingtoolkitsofferfew,ifany,graphicalrenderingpossibilities.AnintermediatealternativebetweenstandaloneviewersandprogrammatictreerenderingisthatoftheTre
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