With the completion of the human genome project, followed by the rise in high-throughput technologies like the various microarray and now high throughput genomic sequencing platforms,weexperiencedthebirthofSystemsBiologyafteritslonggestation. Thisrevolutionis markedbyachangeintheresearchparadigmfromthesinglesmall-scaleexperiment,i. e. ,following thechangeofacomponentinamulticomponentsystem,toonethatattemptstosimultaneousl y monitorthechangeoftensofthousandsofmoleculeswithinthisbody. Thisclearlynecessitatesthe unparalleleduseofproject-specificinformatictools,which,todate,requiresanunpre cedentedlevel ofdevelopmenttocollect,manageandminethedataforinterestingassociations. Tobegintounderstandthisinformationwenowrelyonstatisticalanalysistoaidinoursel ection ofthefruitfromthetree. However,thisoftentakesusonajourneyintoanewfieldforwhichweare notyetprepared. SamuelJohnson(1709-1784)foreshadowedthedilemmawewouldfaceand characterizeditasfollows:"Knowledgeisoftwokinds. Weknowasubjectourselves,orweknow wherewecanfindinformationonit. "Itisforthelatterthatweroutinelyturntotheliterature. The rateofgrowthoftheliteratureparallelsthatofsequencingdataandthearraydataplacin gan almostimpossibletaskbeforeeachinvestigator. Topartiallyeasethisburdenweareagainturning towardsdevelopinginformaticaidsthatminetheliteratureanddatatodevelopsummaries and associationstodirectlyaddressthequestionsposedandthenewhypothesesthataretobet ested. Althoughmoreclearlyarticulated,weagainfacesimilarchallengesasthosetackledduri ngthe courseofthehumangenomeproject. Itisessentialthatthetrainingofthebiologistandcomput- scientistoccurinaninterdisciplinaryenvironmentofcross-fertilization. Withthisgoalinmindthe textbook"BioinformaticsforSystemsBiology"wasundertaken. WebeginthisexplorationwithPartI,toprovidethecomputerscientistwithanintroducti ontothe underlyingprinciplesofcellbiology. ThisisfollowedbyabriefintroductioninPartIIasameansfor thebiologisttobecomefamiliarwithconceptsandthestatisticalanalysisoflargedatas ets. PartIII thendescribes,todate,thebestcharacterizeduseofthemicroarrayplatformthatisnowm oving towardswholegenomeanalysis. Withallofthisdata,howdowebeginanalysisforcommonelements guidingtheunderlyingprinciples ThisisdiscussedinPartIVwhichleadstoPartVandPar tVIto test,insilico,therelationshipsonawidescaleinordertoassesstheirapplicability. Upondeveloping theassociations,PartVIIaskshowdoesthisinformationrelatetowhatwasmeasured Asth esebasic principlesaredevelopedfroman"omics"drivenbiologicalsystemsapproach,theyareapp liedin PartVIIItotranslationalmedicine. Anexcellentexampleisthenewterm"personalizedmedicine" thatisbeginningtoreverberateinclinicalcare. ItistheculminationoftheSystemsBiologyrevolution wheretechnologicaladvancesandcross-fertilizationhavedriventhefieldtomaturetot hepoint whereitisbeingincorporatedinatruebench-to-bedsidemanner. Asyoureadthechapters,youwillfindthattheycanstandalone,yetcanbecombinedto emphasizetheintegralroleofinformaticsinSystemsBiology. Mostofthefiguresandtablesarein greyscale. IwouldencourageyoutoviewthosethatbenefitfromcolorontheaccompanyingCD. ThematerialcontainedontheCDprovidesanexcellentsourceofslidesforyourlecturesan d presentations. v vi Preface Thechapter-relatedGlossaryandAbbreviationssectionwillassistinfamiliarizingyou withthe terms. Youwillalsofindtheliteratureandsuggestedreadingsections,includingkeyreference s, veryusefulasyoudelveintothesubjectmatter. Technology,byitsverymeaningimpliesrefinement and change. The informatics approaches used in systems biology are continually subject to refinement. Withthisreality,youareencouragedtoutilizethewebsiteinformationprovidedin variouschapterstohelpaccessthemostcurrentinformationandresourcesavailable. AsSystems Biologydevelopsweareabletowitnessgrowingpainsandmilestones. Withcontinuedinformatic andbiologicalcross-fertilization,advancementsinSystemsBiologywillrevolutioniz epersonalized medicineansweringquestionsbyintegratinginformationinunexpectedways. Contents PartI LifeofaCellandItsAnalysis...1 1 StructureandFunctionoftheNucleusandCellOrganelles...3 JonHolyandEdPerkins 2 TranscriptionandtheControlofGeneExpression...33 NadineWiper-BergeronandIlonaS. Skerjanc 3 RNAProcessingandTranslation...51 ChristinaKaramboulas,NadineWiper-Bergeron,andIlonaS. Skerjanc 4 DNAReplication,Recombination,andRepair...67 LindaB. Bloom 5 CellSignaling...89 DanielA. RappoleeandD. RandallArmant 6 EpigeneticsofSpermiogenesis-drivenbiologicalsystemsapproach,theyareappliedin PartVIIItotranslationalmedicine. Anexcellentexampleisthenewterm"personalizedmedicine" thatisbeginningtoreverberateinclinicalcare. ItistheculminationoftheSystemsBiologyrevolution wheretechnologicaladvancesandcross-fertilizationhavedriventhefieldtomaturetot hepoint whereitisbeingincorporatedinatruebench-to-bedsidemanner. Asyoureadthechapters,youwillfindthattheycanstandalone,yetcanbecombinedto emphasizetheintegralroleofinformaticsinSystemsBiology. Mostofthefiguresandtablesarein greyscale. IwouldencourageyoutoviewthosethatbenefitfromcolorontheaccompanyingCD. ThematerialcontainedontheCDprovidesanexcellentsourceofslidesforyourlecturesan d presentations. v vi Preface Thechapter-relatedGlossaryandAbbreviationssectionwillassistinfamiliarizingyou withthe terms. Youwillalsofindtheliteratureandsuggestedreadingsections,includingkeyreference s, veryusefulasyoudelveintothesubjectmatter. Technology,byitsverymeaningimpliesrefinement and change. The informatics approaches used in systems biology are continually subject to refinement. Withthisreality,youareencouragedtoutilizethewebsiteinformationprovidedin variouschapterstohelpaccessthemostcurrentinformationandresourcesavailable. AsSystems Biologydevelopsweareabletowitnessgrowingpainsandmilestones. Withcontinuedinformatic andbiologicalcross-fertilization,advancementsinSystemsBiologywillrevolutioniz epersonalized medicineansweringquestionsbyintegratinginformationinunexpectedways. Contents PartI LifeofaCellandItsAnalysis...1 1 StructureandFunctionoftheNucleusandCellOrganelles...3 JonHolyandEdPerkins 2 TranscriptionandtheControlofGeneExpression...33 NadineWiper-BergeronandIlonaS. Skerjanc 3 RNAProcessingandTranslation...51 ChristinaKaramboulas,NadineWiper-Bergeron,andIlonaS. Skerjanc 4 DNAReplication,Recombination,andRepair...67 LindaB. Bloom 5 CellSignaling...89 DanielA. RappoleeandD. RandallArmant 6 EpigeneticsofSpermiogenesis-CombiningInSilicoandProteomicApproaches intheMouseModel...105 SophieRousseauxandMyriamFerro 7 GenomicToolsforAnalyzingTranscriptionalRegulatoryNetworks...119 JohnJ. Wyrick PartII StatisticalToolsandTheirApplication...137 8 ProbabilityandHypothesisTesting...139 MichaelL. Kruger 9 StochasticModelsforBiologicalPatterns...151 GautamB. Singh 10 PopulationGenetics...163 JillS. Barnholtz-SloanandHemantK. Tiwari 11 StatisticalToolsforGeneExpressionAnalysisandSystemsBiology andRelatedWebResources...1 81 ChiaraRomualdiandGerolamoLanfranchi vii viii Contents PartIII TranscriptomeAnalysis...207 12 WhatGoesinisWhatComesOut:HowtoDesignandImplementaSuccessful MicroarrayExperiment...209 JeffreyA. LoebandThomasL. Beaumont 13 ToolsandApproachesforanEnd-to-EndExpressionArrayAnalysis...227 AdrianE. PlattsandStephenA. Krawetz 14 AnalysisofAlternativeSplicingwithMicroarrays...267 JingyiHui,ShivendraKishore,AmitKhanna,andStefanStamm PartIV StructuralandFunctionalSequenceAnalysis...281 15 AnIntroductiontoMultipleSequenceAlignment-andtheT-CoffeeShop. BeyondJust AligningSequences:HowGoodcanyouMakeyourAlignment,andsoWhat ...283 StevenM. Thompson 16 ASpectrumofPhylogenetic-BasedApproachesforPredictingProtein FunctionalSites...315 DukkaBahadurK. C. andDennisR. Livesay 17 TheRoleofTranscriptionFactorBindingSitesinPromotersandTheir InSilicoDetection...339 ThomasWerner 18 InSilicoDiscoveryofDNARegulatorySitesandModules...353 PanayiotisV. Benos PartV LiteratureMiningforAssociationandMeaning...367 19 MiningtheResearchLiteratureinSystemsBiology...369 KeirT. Reavie 20 GoPubMed:ExploringPubMedwithOntologicalBackgroundKnowledge...385 HeikoDietze,DimitraAlexopoulou,MichaelR.
