Degeneracy and complexity in biological systems Gerald - PDF document

DegeneracyandcomplexityinbiologicalsystemsGeraldM.Edelman*andJosephA.GallyTheNeurosciencesInstitute,LaJolla,CA92121ContributedbyGeraldM.Edelman,September21,2001Degeneracy,theabilityofelementsthatarestructurallydifferenttoperformthesamefunctionoryieldthesameoutput,isawellknowncharacteristicofthegeneticcodeandimmunesystems.Here,wepointoutthatdegeneracyisaubiquitousbiologicalpropertyandarguethatitisafeatureofcomplexityatgenetic,cellular,system,andpopulationlevels.Furthermore,itisbothnecessaryfor,andaninevitableoutcomeof,naturalselection.hereisnoevidencetosupporttheviewthatevolutionguaranteesprogress.Butfewwouldarguewiththenotionthatoverlargetractsoftime,thecomplexityofbiologicalsystemshas,ingeneral,increased.Whichpropertiesoflivingsystemsundergoingnaturalselectioncanaccountforthisfact? *Towhomreprintrequestsshouldbeaddressed.E-mail:edelman@nsi.edu.Thepublicationcostsofthisarticleweredefrayedinpartbypagechargepayment.Thisarticlemustthereforebeherebymarked“”inaccordancewith18U.S.C.§1734solelytoindicatethisfact.pnas.231499798PNASNovember20,2001vol.98no.24 vironmentcanleadtostrongselection,oftenthereisnofixedassignmentofexclusiveresponsibilityforagivenfunction,and,unliketheengineeringcase,interactionsbecomeincreasinglycomplex.Atheoreticalanalysis(1)suggeststhatthisincreaseincomplexityresultsnotonlyfromselectioninrichenvironments(whichincludeotherspecies)butalsofromtheprevalenceofdegeneracy.Forallofthereasonsmentionedabove,wesuggestthatinmanycasesthetermdegeneracyismoreaptthanredundancy.Thetermhasbeenusedcorrectlyinbiologytorefertothethirdpositionofcodewordsinthegeneticcodeandtotheabilityofstructurallydifferentantibodiestobindequallywelltothesameantigen(10).And,ofcourse,inquantummechanics,ithasbeenusedtodesignatedifferentbutequallycorrectsolutionsofthewaveequationastheyapplytosystemstakingonseveraldistinctenergylevelsorstates.DegeneracyinCellularSystemsThegeneticcoderelatingsequencesofpolypeptidesandpolynucleotidesisdegeneratebecausetherearemanymoretripletcodonsthanencodedaminoacidresidues.Consequently,anenormousnumberofstructurallydistinctmRNAspeciescouldbetranslatedtogeneratetheaminoacidsequenceofanyparticularprotein.Thisdegreeofstructuralvariationcanbeconsideredtobemerelythetipoftheiceberg,particularlyifwebroadenourdefinitionofdegeneracytoincludevariationsinpolynucleotidesequencesthatresultinfunctionallyequivalentgeneproducts.Forexample,itisnowclearthatatmanysitesalongthepolypeptidechain,substitutionofoneaminoacidresidueforanotherhaslittleeffectonoverallproteinconfor-mationorfunction.Byinference,wecanassumethatanastronomicalnumberofdifferentaminoacidsequencescouldcontributeequallytothesurvivalofthespecies.Itisbecomingincreasinglyevident,however,thatthisview,basedoncodingofthedegreeofpossibledegeneracyinbio-logicalstructures,isrelativelynarrow.Moreandmore,ithasbecomeevidentthatmanybiologicalfunctionscannotbeas-signedtocellularcomponentsinaone-to-onemanner.Instead,multiplegeneproductscontributetoalmostanyobservedbe-haviororfunction,andeverygenehasthepotentialforpleio-tropiceffects.Degeneracycanbefoundateverylevelandinmostprocessesfoundinlivingcells(seeTable1forsomeexamples).Agene,totakeoneexample,can,ingeneral,nolongerbethoughtofashavingonlyasinglesequencewithfixedendsandlength.Inmanycases,transcriptioncanbeginatanumberofdifferent5startsites(11),oritmayterminateatoneofseveral3sites(12,13);moreover,thetranscribedproductmayundergodifferentpat-ternsofRNAsplicingtoyieldadegeneratesetofisoforms(14).Theexactpatternofisoformsproducedisregulatedbyintra-genicsegmentscalledsplicingenhancers;suchelementsinageneforcardiactroponinhavebeenreportedtodemonstratefunctionalredundancy(15).TheRNApolymeraseholoenzymethatcatalyzesRNAsynthesisitselfappearsnottobeasingle,welldefinedentitybut,rather,isadegeneratepopulationofcom-plexeswithdifferentpolypeptidechaincompositions(16).Often,adegeneratesetofDNAsequenceelementsthatdeterminestherateofgenetranscriptionislocatedupstream,ordownstream,orincodingornoncodingsegmentsofaparticulareukaryoticgene.Numerous,distinctpolynucleotidemotifscom-monlyarefoundwithinthesepromoterandenhancerelements,andinsomeinstancestheyhavebeensaidtobe21).Innumerousexperimentalsystems,theproteintranscriptionfactorsthatbindtothesesequencesalsohavebeenfoundtoactdegeneratelyi.e.,individualregulatoryfactorsappeartohavefunctionallyoverlappingroles(2224).Inananalogousfashion,degeneratesetsofspecificintramolecularmotifshavebeenshowntostabilizemRNA(25)aswellastolocalizeitsproductstotheappropriatecellularcompartments28).TheintracellularlocalizationoftheproteinmoleculessynthesizedbyusingthesemRNAsalsohasbeenshowntobedeterminedbydegeneratesignals,which,inthesecases,arecontainedwithintheirpolypeptidechains(29,30).Theverycomplexityofthesedegeneratestructuresandthemechanismsoperatingtoensurethattheproductsofaparticulargeneareexpressedinspecifiedamountswithinspecifiedcom-partmentsofcertaincellsofanorganismwouldseemtosupportthepresuppositionthatthegeneinquestionmustplayacrucialroleinthesurvivaloftheorganismorspecies.Thatsuchageneoftencanbeinactivatedcompletelywithoutsignificanteffectonthephenotypeoftheorganismthereforeinitiallywasquitesurprising.Onereasonforthisalreadyhasbeenmentioned:certaingeneproductsthemselvesformadegeneratesetwithoverlappingfunctions.Evenproteinshavingnoapparentstruc-tural,physiologic,orevolutionaryrelationshipcantogetherTable1.Degeneracyatdifferentlevelsofbiologicalorganization 1.Geneticcode(manydifferentnucleotidesequencesencodea2.Proteinfold(differentpolypeptidescanfoldtobestructurallyandfunctionallyequivalent)3.Unitsoftranscription(degenerateinitiation,termination,andsplicingsitesgiverisetofunctionallyequivalentmRNAmolecules)4.Genes(functionallyequivalentalleles,duplications,paralogs,etc.,allexist)5.Generegulatorysequences(therearedegenerategeneelementsinpromoters,enhancers,silencers,etc.)6.Genecontrolelements(degeneratesetsoftranscriptionfactorscangeneratesimilarpatternsofgeneexpression)7.Posttranscriptionalprocessing(degeneratemechanismsoccurinmRNAprocessing,translocation,translation,anddegradation)8.Proteinfunctions(overlappingbindingfunctionsandsimilarcatalyticspeciÞcitiesareseen,andÔÔmoonlightingÕÕoccurs)9.Metabolism(multiple,parallelbiosyntheticandcatabolicpathwaysexist)10.Foodsourcesandendproducts(anenormousvarietyofdietsarenutritionallyequivalent)11.Subcellularlocalization(degeneratemechanismstransportcellconstituentsandanchorthemtoappropriatecompartments)12.Subcellularorganelles(thereisaheterogeneouspopulationofmitochondria,ribosomes,andotherorganellesineverycell)13.Cellswithintissues(noindividualdifferentiatedcellisuniquely14.Intra-andintercellularsignaling(parallelandconvergingpathwaysofvarioushormones,growthfactors,secondmessengers,etc.,transmitdegeneratesignals)15.Pathwaysoforganismaldevelopment(developmentoftencanoccurnormallyintheabsenceofusualcells,substrates,orsignalingmolecules)16.Immuneresponses(populationsofantibodiesandotherantigen-recognitionmoleculesaredegenerate)17.Connectivityinneuralnetworks(thereisenormousdegeneracyinlocalcircuitry,long-rangeconnections,andneuraldynamics)18.Mechanismsofsynapticplasticity(changesinanatomy,presynaptic,orpostsynapticproperties,etc.,arealldegenerate)19.Sensorymodalities(informationobtainedbyanyonemodalityoftenoverlapsthatobtainedbyothers)20.Bodymovements(manydifferentpatternsofmusclecontractionyieldequivalentoutcomes)21.Behavioralrepertoires(manystepsinstereotypicfeeding,mating,orothersocialbehaviorsareeitherdispensableorsubstitutable)22.Interanimalcommunication(therearelargeandsometimesnearlyinÞnitenumbersofwaystotransmitthesamemessage,asituationmostobviousinlanguage)EdelmanandGally performdegenerateroles.Forexample,fasciclin,acell-adhesionproteinfoundonthesurfaceofneurons,hasnoobviousstructuralorfunctionalsimilaritytothecytoplasmicAbelsontyrosinekinasemadeinthesameanimals.Acompletedeletionofthegeneforeitherofthesetwoproteinsresultsinnogrossabnormalitiesinnervoussystemdevelopment,whereastheabsenceofbothproteinsleadstomajordefects(31).DegeneracyinMulticellularSystemsThespatiotemporalpatternofgeneregulationwithinameta-zoanisorchestratedbyanetworkofintra-andintercellularsignalstofulfillthehigher-orderphysiologicfunctionsandneedsoftheorganismasawhole.Variousdifferentcomponentsofsignalingpathwaysinthisnetworkprovidemultipleexamplesofdegeneracy.Growthfactorsthatfunctionatnumeroussitesduringanimaldevelopmenthavebeenshown,forexample,tocompriseadegeneratesetinsomeexperimentalsystems(32,33).Theyexerttheireffectsbybindingtoapopulationofcell-surfacereceptorsthatisalsodegenerate(34).Commonly,theserecep-tors,inturn,initiateintracellularsignalsbycatalyzingthephosphorylationoftyrosineresiduesinanumberofdifferentintracellularsubstrates.Thisphosphorylationhasbeenshowntoactivateanumberofparallel,intracellularsignalingpathwaysthatareeitherindependentorconnectedinnetworks.Byselectivelyinactivatingindividualpathways,ithasbeenfoundthatsuchnetworksoftenactinadegeneratefashion(35,36).Moreover,componentsofnetworksofsignalingpathwayscom-monlybindtoandaffectthefunctionalpropertiesofmorethanonedownstreamtarget.Suchbranchedsignalingpathwaysandcross-talkamongthemcontributetobiologicaldegen-eracy(37).Genesthathaveevolvedtofacilitateintercellularorsystemicfunctionsinmulticellularorganismsdemonstratetheemergentpropertiesinherentindegeneracyaswellas,orbetterthan,geneswhosefunctionsarelimitedtosinglecells.Theimmunesystemsofvertebrates,forexample,provideprotectiononlybecauseanimalshaveevolvedtheabilitytogeneratetheverylarge,degeneratepopulationofantigen-recognitionsitesrequiredfortheclonalselectiontheorytooperate.Thedegeneracyoftheimmunoglobulinsmadebyananimalensuresthattheanimalpossessestheabilitytomakeantibodiesthatprotectagainstessentiallyanyforeign,infectiousagent(10).Similarly,itseemsasifananimalsabilitytodistinguishamongalmostanytwoolfactorycuesdependsonitspossessingadegeneraterepertoireofolfactoryreceptors(38).Theroleofdegeneracyinthedevelopmentandfunctionofnervoussystemsisasfundamentalasitisinimmunesystemsand,indeed,providesoneoftherichestexamplesforexploration.Weshallthereforefocusonithere.Thefunctionalpropertiesofthenervoussystemofananimaldependlargelyonthepatternsofstructuralandfunctionalconnectivityamongtheneuronsinthesystem.But,withthepossibleexceptionofanimalshavingexceptionallysimplebodyplans,theexactpatternofconnectivityisnotgeneticallyprespecifiedwithgreatprecision.Instead,thepatternarisesduringdevelopmentinpartbyaprocessinvolvingexcessneuronproduction,exuberantextensionofneuronalprocessesthatcompetefortargetsinanactivity-dependentfashion,variantcellmigration,andmassivecelldeath.Despitetheverylargenumberofneuronswithinanyvertebratenervoussystem,itisalmostcertainthatnotwoneuralcellswithinananimalareidenticalinoverallshape.Similarly,notwoneuronstakenfromtwodifferentvertebrateindividualshaveexactlythesamemorphology,eveniftheanimalsaregeneticallyidentical.Typically,neuronsinthebrainreceivesynapticinputfrommanythousandsofotherneuronssothatinhumans,forexample,thereareapproximatelyonebillionsyn-apsesineachcubicmillimeterofbraingraymatter.Thepatternofconnectivitycreatedbysomanysynapseswithinsuchatinyvolumeoftissueinoneanimalcouldnotbegeneticallypre-specifiedand,thus,mustbeuniquetoeachindividual.Indeed,thedegreeofdegeneracyinneuralconnectivityprobablydwarfsthatofanyothersystemdiscussedinthisreview.Thisdegeneracyofconnectivityatthemicroscopicscalecomplementsthehighdegreeofintraspecificvariationobservedinthegrossanatomyofanimalbrains.Astrikingexampleisprovidedbypeoplewhodonotformthemajorfibertractinterconnectingthetwocerebralhemispheres(thecorpuscal-losum).SeveralsuchpersonshavebeendiscoveredtopossessthisabnormalityonlyafterMRIscans.Theseindividualsmaybequiteasymptomaticduringdailypursuits,althoughsubtleab-normalitiescanbedetectedupondetailedpsychologicaltesting(39).Although,inthepast,variationsinthegrossshapeofthebrainwerestudiedcarefullyineffortstofindcorrelationsbetweenanatomicalfeaturesandmentalabilitiesorpropensi-ties,itnowisacceptedthattheseeffortsarelargelyfruitless.Instead,itisrecognizedthatmanydifferentpatternsofneuralarchitecturearefunctionallyequivalent,i.e.,functionalneuro-anatomyishighlydegenerate.Evenwithinthebrainofasingleindividual,thedetailedpatternofconnectivityisnotfixed,becauseneuralactivitywithinthenervoussystematonetimecanaffecttheefficacyofintercellularcommunicationatalatertime.Mostofthesalientchangesarethoughttooccuratsynapses,sitesatwhichneuro-transmittersarereleasedtosubsequentlybindtoreceptorsonthepostsynapticcells.Manydistinctformsofsynapticplasticityhavebeenstudied.Ithasbeenshownthatintercellularcommu-nicationcanbeeitherpotentiatedordepressed.Moreover,synapticchangesmaylastonlyashorttime(measuredinsecondsorless),ortheymaypersistforaslongasagivenmeasurementcanbemade.Becauseitisplausiblethatthesechangesunderlieananimalsabilitytolearn,remember,orforget,theirmecha-nismhasbeenthesubjectofintenseandextensiveexperimentalscrutiny(40).Ithasbecomeincreasinglyapparentfromsuchstudiesthatanumberofdegeneratemechanismscontributetotheoverallchangesinsynapticefficacywhethertheyaretestedbiochemi-cally,neurophysiologically,orbehaviorally.Forexample,afterstimulation,changeshavebeenreportedintheanatomicshapeofbothpresynapticandpostsynapticcellularstructures.Presyn-aptically,plasticityhasbeencorrelatedwiththenumberofsynapticvesiclesdockedatreleasesites,withtheconcentrationofneurotransmitterpervesicle,andwiththeprobabilityofreleasewhenthecellfires.Thepostsynapticresponsecanbemodulatedbychangesinthenumbers,kinds,andphosphoryla-tionstatesoftheneurotransmitterreceptorsandbythetrans-membranepotentialacrossthepostsynapticcellmembrane.Thisresponse,inturn,ismodulatedbythenature,number,anddistributionofvariousionchannelsandpumpswithinthismembraneaswellasbythepreviouspatternofsynapticinputsonthecell,thepatternofgeneexpressioninthecellnucleus,andthetransportandturnoverofproteinswithinthedendriticarbors.Thecomplexityofthesystemincludesmanysitesatwhichavarietyofchangescanmodulatesynapticefficacyinasimilarmanner.Wheneverevidenceforeachofthesechangeshasbeensoughtexperimentally,ithasbeenfound.Thus,synapticplas-ticityexemplifiesdegeneracyinfullmeasure.Toprovidecoordinatedoutputsinmammalianbrains,link-agesofdegeneratenetworksareachievedthroughaprocesscalledreentry.Reentryisadynamicprocessofongoingspatio-temporalcorrelationoccurringbetweenfunctionallysegregatedneuralareasthatismediatedbysignalingthroughmassivelyparallel,reciprocalfibers(41).Thisprocessensureslinkageandintegrationofcomplexfunctionsandbehaviors,evenintheabsenceoflogicandprogramming.Reentryhasbeenmodeledsuccessfully(42)andevenhasbeendemonstratedtooccurinhumanbrainsduringconsciousattention(43).ThefunctioningEdelmanandGallyNovember20,2001vol.98no.24 ofseveralneuralmodelsexploredsofar(see,forexample,ref.42)dependsonthepresenceofalargenumberofdifferent,alternativereentrantcircuitsthatdynamicallyyieldasimilaroutput,i.e.,suchcircuitsaredegenerate.Themajoroutcomesofneuralactivitythatultimatelycon-tributetoanimalsurvivalarethosemanifestedwhenmotorneuronactivityinitiatesorinhibitsmuscularcontractions.Theselectiveadvantageofaflexible,multiplyjointedbodyplaninvariousspeciesisobvious,but,hereagain,theevolutionofsuchasystembothrequiresandgeneratesdegeneracy.Considerthearmmovementofamonkeythatwishestobrushawayaflythathaslandedonitsnose.Howmanydifferentpatternsofmusclecontractionsmightitusetoaccomplishthattask?Therearesomanydifferentdegeneratepatternsofneuromuscularactivitythatcouldaccomplishthatsametaskthatspecifyinghowanyparticularpatternisselectedisasignificantchallengetotheoriesofmotorcontrol(44).Alloftheobservationswehavereviewedhere,andthosesummarizedinTable1,pointtoacentralquestion:whataccountsfortheomnipresenceofdegeneracyatsomanylevelsofbiologicalorganizationinavarietyofspecies?Clearly,anyattempttoanswerthisquestionmustbeginbyconsideringtheevolutionarypathsthatgiverisetodegeneracy.DegeneracyandEvolutionDegeneracyisaprerequisiteofnaturalselectionbecausenaturalselectioncanonlyoperateamongapopulationofgeneticallydissimilarorganisms.Thisimpliesthatmultiplegenescontributeinanoverlappingfashiontotheconstructionofeachphenotypicfeatureundergoingselection.Moreover,because,ingeneral,severaldifferentgenenetworkscontributetotheexpressionofeachfeature,andbecauseselectionhasnowayofassigningresponsibilityforanyphenotypicparametertoparticulargeneloci,degeneratesystemswillbemaintainedandfavored.More-over,someofthemostgenerallyusedmechanismsforgeneratinggeneticdiversityovertimeoftenfacilitateanincreaseindegen-eracy.Examplesincludegeneorchromosomalduplicationsandtheutilizationofgeneproductsinnovelcontextstocreatenovelstructures.Adetailedinvestigationastowhyloss-of-functionmutationsinyeastsocommonlyhavelittleornodetectablephenotypiceffectconcludedthatinteractionsamonganetworkofunrelatedgenescouldbetteraccountforthisobservedrobustnessthantheexistenceofduplicatedgeneswithsimilar,merelyredundantfunctions(45).Computersimulationsofchangesingenefrequenciesinpopulationsoforganismshaveprovidedmodelsbywhichtwogenesperformingapparentlyinterchangeablefunctionscanbeevolutionarilystable(46).Althoughtwodistinct,degeneratestructuresormechanismsmayfunctionequallywellinanorganismtoachieveagoalsetbynaturalselection,thiseffectdoesnotimplythatthesemecha-nismsarefullyequivalent,asmightbesuggestedifthetermredundancywereapplied.Despiteaconvergenceoffunction,eachvariantconfersitsownnovelpropertiesontheorganismandoffersauniquetargetforevolutionarymolding.Forexam-ple,thedegeneracyofthegeneticcodepermitsdifferentgenestorespondverydifferentlytoselectivepressures,eventhoughtheygiverisetoidenticalpolypeptidechains.Thisoccursbecauseoftheirdifferentsusceptibilitytoprocesses,suchasgenecon-versionorviralinsertion,thataredependentonspecificpolynu-cleotidesequences.Furthermore,familiesofhomologouspro-teinshavingdistinctphysiologicfunctionscanarisebyaprocessofgeneduplicationanddivergence,andthisentailssomedegreeoffunctionalversatilityineachnovelgeneproductasitisTheprocessofsexualreproductionprovidesstrikingexamplesofkeyprinciplesrelatedtodegeneracyandredundancy.Thesurvivalofaspeciescriticallydependsonindividualorganismsproducingagreatnumberofgametes,farmorethanpossiblycouldbeusedtogenerateviableoffspring.Althoughthislargeoversupplycouldbesaidtoillustratetheuseofredundancytoensureagainstrandomlossorfailure,itmustalsoberecognizedthatnonumberofgametescouldensurethesurvivalofthespeciesiftheyallcontainedidenticalgeneticmaterial.Contin-uedexistenceofthespeciesinthefaceofavariableenvironmentrequiresthatgametepopulationsnotonlymustbelargebutalsogeneticallydiverse.Onlythisprovidesthenecessarydegreeofdegeneracyneededtoadaptoverevolutionarytime.Geneticvariantsnotonlycreatenewopportunitiesforevo-lutionarychange,buttheexistenceofanunfilledornovelnicheintheenvironmentalsofavorstheselectionofadegeneratesetofgenes.Consider,forexample,anenvironmentalchangethatincreasesthereproductiveadvantageoflargerorganismsofaspecies.Thismightselectforanimalswithmorecells,orlargercells,oranimalshavingmoreextracellularmaterial.Multitudi-nouscomplementarymechanismscouldcontributetoeachofthesechanges,includingincreasingratesofsynthesisoraccu-mulationofchemicalcompounds,decreasedratesofbreakdown,increasedcellproliferation,anddecreasedcelldeath,etc.Alargenumberoffactorscancontributetodeterminingtheratesofeachoftheseprocesses.Uponwhichwillnaturalselectionoperate?Theobviousandinescapableansweristhatnobiolog-icalfactoriscompletelyexemptfromselection,and,therefore,wecanexpectadjustmentsinmanyorevenallofthesefactorsasanorganismadaptstoanewenvironment.Althoughincreas-ingthesizeofcellsorthenumberofcellsmayyieldeffectivedegenerateresponsestoaparticularselectiveforceand,thus,resultinequivalentfitness,suchchangesclearlyareneitherstrictlyequivalentnorredundant.Eachgeneticvarianthasauniquepotentialforgoodorill,andeachcombinationofvariantscontributestoanovelphenotypetobesubjectedovertimetoevolutionarywinnowing.Whatistrueregardingtheresponseofspeciestoselectionforsizewould,ofcourse,applyequallyforselectiononthebasisofshape,appearance,behavior,fecundity,longevity,diseaseresis-tance,andallotherglobalpropertiesoftheorganism.Whenconsideredinthislight,oneappreciatesmoreclearlythefallacyofspeakingofageneorgenesforsize,shape,intelligence,etc.Allobservablepropertiesofanorganismaredeterminedbytheworkingsofadegeneratenetworkofmanygenes.Wehaveemphasizedthattheprocessesofevolutionandnaturalselectionnecessarilyareaccompaniedbydegeneracy.Indeed,intheabsenceofdegeneracy,itislikelythatmostmutationseventuallywouldresultinlethality,forthentherewouldbenotradeoffbetweenindividualgeneactionandgenenetworkinteraction.Tradeoffisfoundinothercontexts.Insomaticselectionalsystemssuchastheimmunesystem,forexample,thereisatradeoffbetweenthespecificityandtherangeofbindingofantibodiestoforeignantigens(10).Thistradeoffisareflectionofdegeneracy,and,again,withoutit,themereincreaseintherepertoireofdifferentantibodiescouldnotleadtoarobustandbroad-rangingimmuneresponse.Giventheexistenceofdegeneracy,differentantibodieseveninidenticaltwinscangivesimilaroveralloutputresponses.Thephenomenonofevolutionaryconvergencemayreflect,inpart,theabilityofdegeneratesystemsacrossdifferentlevelsoforganizationtoyieldsimilarfunctionalresults.Itisclearinthiscase,asitisinthecaseofknockoutanimals,thatdegeneracyisAnycompensationthatoccursisastatisticalresultofthetradeoffbetweenspecificityandrangethatfollowsincomplexsystemshavingdegeneracy.Itisstrikinghowuni-versalthispropertyis,rangingasitdoesoveralllevelsofbiologicalorganization(seeTable1).Wesurmisethatthisfar-ranging,across-levelspropertyresultsfromevolutionaryselectionofthoseindividualshavingsufficientfitness,regardlessofthevariationsandaccumulatedmutationsthatoccurwithinandacrosstheirmanylevelsoforganization.Bythesemeans,EdelmanandGally evolutionbringsaboutdegeneracyatvariouscombinationsoflevels,withoutnecessarilyselectingforchangesateachlevel.RelatingDegeneracyandComplexityAseriesofformalanalyseshasbeencarriedouttoprovideandrelatemeasuresofdegeneracyandcomplexity(1,47,48).Theseanalysesusemeasuresusedinstatisticalinformationtheory,suchasentropyandmutualinformation,buttheydonotrelyonassumptionsrelatedtomessages,codes,ornoisychannels.Wepresenthereabriefverbaldescriptionofresultsobtaineduponapplyingthesemeasures,mainlytogivethereadertheflavoroftheanalyses.Formathematicaldetails,wesuggestconsultationoftheoriginalpublications.Inbiologicalsystems,degeneracyisalmostinvariablyaccom-paniedbycomplexity.Acomplexsystemmaybeconsideredasoneinwhichsmallerpartsarefunctionallysegregatedordif-ferentiatedacrossadiversityoffunctionsbutalsoasonethatshowsincreasingdegreesofintegrationwhenmoreandmoreofitspartsinteract.Putotherwise,acomplexsystemmaybeviewedasonethatrevealsaninterplaybetweenfunctionalspecializationandfunctionalintegration.Intuitively,itiseasytoseethat,belowacertainlevelofcomplexity,therewillbeveryfewwaysinwhichstructurallydifferentpartscaninteracttoyieldthesameoutputorfunctionalresult.Accordingly,atlowlevelsofcomplexity,degeneracywillbelowornonexistent.Foradefinedfunction,however,redundancycanstillexisteveninrelativelysimpleApplyingsuitablequantitativemeasures(1),wehavefoundthatdegeneracyishighinsystemsinwhichverymanystructur-allydifferentsetsofelementscanaffectagivenoutputinasimilarway.Insuchsystems,however,degeneracyalsocanleadtodifferentoutputs.Unlikeredundantelements,degenerateelementscanproducenewanddifferentoutputsunderdifferentconstraints.Adegeneratesystem,whichhasmanywaystogeneratethesameoutputinagivencontext,isthusextremelyadaptableinresponsetounpredictablechangesincontextandoutputrequirements.Therelevancetonaturalselectionisobvious.Inourlimitedexperiencesofar,wehavefoundthatsystemsselectedforhighdegeneracywithrespecttoanygivensetofoutputsalsoshowhighcomplexity(1,47,48).Althoughageneralfunctionaldependenceofdegeneracyoncomplexityhasnotyetbeenformallyderived,itisaninterestingconjecturethatthetwopropertiesgohandinhand.IssuesandApplicationsWebeganthisreviewbycomparingthefailuretorecognizethegeneralityoftheconceptofdegeneracywithPoespurloinedinplainview,butcrumpledandsubjecttofalseclues.PerhapsabetterliteraryanalogymightbetoMolieresMonsieurJourdain,whowaspleasedtolearnhehadbeenspeakingproseallhislife.Certainly,thecasefortheubiquitousnessofdegen-eracyinbiologyneedsnofurtherreinforcement.However,wemayusefullyconsiderafewmorespeculativeissuesrelatedtohumanactivities.Thefirstconcernshumancommunication,specificallylanguageandspeech.Itiswellknownthatspeechisredundant,butitislessexplicitlyappreciatedthatittoocarriesoutdegeneratefunctions.Theveryexistenceofmetaphor,anaphor,andpolysemyattesttothepowerfulroleofequivalentbutnonidenticalstructuresinconveyingmeaning.Ambiguity,whichoftenreflectsdegeneracy,canalsofunctioninapositivefashion,atleastinpoetryaswellasinanycreativeendeavorwithheuristicorassociativeneeds.Wehavementionedthat,inmoderntechnology,engineersbuildseparatemodulesfordesignedfunctionsandusuallykeepinteractionsbetweenthemtoanecessaryminimum.Thispow-erfulpolicygenerallymeetsbotheconomicanddesigncon-straints.Butwiththedevelopmentofnanotechnologyandthereducedcostofelectronicchipsandmemories,itisconceivablethatengineerswillturntothedeliberateconstructionofcomplexdegeneratesystems.Likebiologicalsystems,suchsystemsnec-essarilywillbeselectiveratherthaninstructive.Clearly,therewillbeusesforsuchsystems,particularlyinareasinwhichcomputationandlogicfail.Onesuchexampleisinunpredictableenvironmentalsituationsinwhichtherecognitionofnoveltyisimportantandprogrammedplanningisnotpossible.Thefurtherunderstandingofhowdegeneratesystemsbecomelinkedandsynchronizedacrosslevelsisamajorchallengeinmodernevolutionarybiology.Itisnotyetevidentwhethercoordinativelinkagessimilartoreentrantconnectionsinthenervoussystemarenecessarytocorrelatedifferentlevelsoforganizationinother,morewide-ranging,biologicalsystemsduringevolutionanddevelopment.Wesuspectthattheywillbefound.Whetherornotsuchlinkagesarefrequent,degeneracyremainsanecessaryconsequenceofnaturalselection.Itsfurtheranalysiswillbeparticularlyimportantinanyattempttodeepenourunderstandingofbiologicalcomplexity.WearegratefulforfundingfromtheNeurosciencesResearchFounda-tion,whichsupportstheworkoftheNeurosciencesInstitute.1.Tononi,G.,Sporns,O.&Edelman,G.M.(1999)Proc.Natl.Acad.Sci.USA2.Melton,D.W.(1994)3.Garry,D.J.,Ordway,G.A.,Lorenz,J.N.,Radford,N.B.,Chin,E.R.,Grange,R.W.,Bassel-Duby,R.&Williams,R.S.(1998)Nature(London)4.Saga,Y.,Yagi,T.,Ikawa,Y.,Sakakura,T.&Aizawa,S.(1992)GenesDev.5.Colucci-Guyon,E.,Portier,M.M.,Dunia,I.,Paulin,D.,Pournin,S.&Babinet,C.(1994)6.Witke,W.,Sharpe,A.H.,Hartwig,J.H.,Azuma,T.,Stossel,T.P.&Kwiatkowski,D.J.(1995)7.Elder,G.A.,Friedrich,V.L.,Jr.,Bosco,P.,Kang,C.,Gourov,A.,Tu,P.H.,Lee,V.M.&Lazzarini,R.A.(1998)J.CellBiol.8.Winzeler,E.A.,Shoemaker,D.D.,Astromoff,A.,Liang,H.,Anderson,K.,Andre,B.,Bangham,R.,B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