At a Glance Introduction 1 PartI.Fundamentals 23 Prologue 24 MolecularBasisofGenetics 30 ProkaryoticCellsandViruses 94 EukaryoticCells 110 MitochondrialGenetics 130 FormalGenetics 138 Chromosomes 176 RegulationofGeneFunction 208 EpigeneticModifications 228 PartII.Genomics 237 PartIII.GeneticsandMedicine 269 Cell-to-CellInteractions 270 SensoryPerception 286 GenesinEmbryonicDevelopment 298 ImmuneSystem 308 OriginsofCancer 324 Hemoglobin 342 LysosomesandPeroxisomes 356 CholesterolMetabolism 364 Homeostasis 372 MaintainingCellandTissueShape 386 SexDeterminationandDifferentiation 398 AtypicalPatternsofGeneticTransmission 406 Karyotype–PhenotypeRelationship 412 ABriefGuidetoGeneticDiagnosis 418 MorbidAnatomyoftheHumanGenome 422 ChromosomalLocation—AlphabeticalList 428 Appendix—SupplementaryData 433 Glossary 447 Index 469 II ToJamesLafayetteGermanIII,MD NewYork Physician—HumanBiologist—Musician, MentorandFriend III Color Atlas of Genetics EberhardPassarge,MD ProfessorofHumanGenetics FormerDirector InstituteofHumanGenetics UniversityHospitalEssen Essen,Germany Thirdedition,revisedandupdated With202colorplatesprepared byJürgenWirth Thieme Stuttgart·NewYork IV LibraryofCongressCataloging-in-Publication ImportantNote:Medicineisanever-changing Data scienceundergoingcontinualdevelopment.Re- searchandclinicalexperiencearecontinually Passarge,Eberhard expanding our knowledge, in particular our [TaschenatlasderGenetik.English] knowledgeofpropertreatmentanddrugther- ColorAtlasofgenetics/EberhardPassarge; apy.Insofarasthisbookmentionsanydosageor with202colorplatespreparedbyJürgen application,readersmayrestassuredthatthe Wirth.–3rded.,rev.andupdated. authors, editors, and publishers have made p.;cm. everyefforttoensurethatsuchreferencesare Includesbibliographicalreferencesand inaccordancewiththestateofknowledgeatthe index. timeofproductionofthebook. ISBN-13:978-3-13-100363-8 (GTV:alk.paper) ISBN-10:3-13-100363-4(GTV:alk.paper) ISBN-13:978-1-58890-336-5 1stGermanedition1994 (TNY:alk.paper) 1stEnglishedition1995 ISBN-10:1-58890-336-2(TNY:alk.paper) 1stFrenchedition1995 1.Genetics–Atlases.2.Medicalgenetics– 1stJapaneseedition1996 Atlases.I.Tile. 1stChineseedition1998 [DNLM:1.Genetics,Medical–Atlases, 1stItalianedition1999 2.Genetics,Medical–Handbooks, 1stTurkishedition2000 QZ17P286t2006a] 2ndEnglishedition2001 QH436.P37132006 2ndFrenchedition2003 576.5022'2–dc22 2ndGermanedition2004 2006023813 1stPolishedition2004 1stPortugueseedition2004 1stSpanishedition2004 1stGreekedition2005 2007GeorgThiemeVerlagKG Someoftheproductnames,patents,andregis- Rüdigerstraße14,D-70469Stuttgart,Germany tereddesignsreferredtointhisbookareinfact http://www.thieme.de registered trademarks or proprietary names ThiemeNewYork,333SeventhAvenue, eventhoughspecificreferencetothisfactisnot NewYork,NY10001USA alwaysmadeinthetext.Therefore,theappear- http://www.thieme.com ance of a name without designation as pro- prietaryisnottobeconstruedasarepresenta- ColorplatespreparedbyJürgenWirth,Profes- tion by the publisher that it is in the public sorofVisualCommunication,Dreieich,Ger- domain. many Thisbook,includingallpartsthereof,islegally protectedbycopyright.Anyuse,exploitation,or TypesettingbyDruckhausGötzGmbH, commercialization outside the narrow limits D-71636Ludwigsburg setbycopyrightlegislation,withoutthepub- PrintedinGermanybyApplAprintaDruck, lisher’sconsent,isillegalandliabletoprosecu- Wemding tion.Thisappliesinparticulartophotostatre- production,copying,mimeographingordupli- ISBN10:3-13-100363-4(GTV) cationofanykind,translating,preparationof ISBN13:978-3-13-100363-8(GTV) microfilms,andelectronicdataprocessingand ISBN10:1-58890-336-2(TNY) storage. ISBN13:978-1-58890-336-5(TNY) 1 2 3 4 5 6 V Preface Theaimofthisbookistogiveanaccountofthe munication,signalingandmetabolicpathways, scientificfieldofgeneticsbasedonvisualdis- epigenetic modifications, apoptosis (pro- playsofselectedconceptsandrelatedfacts.Ad- grammedcelldeath),RNAinterference,studies ditionalinformationispresentedintheintro- in genomics, origins of cancer, principles of duction,withachronologicallistofimportant genetherapy,andothertopics. discoveries and advances in the history of Asingle-authorbookofthissizecannotprovide genetics,inanappendixwithsupplementary allthedetailsonwhichspecializedscientific dataintables,inanextensiveglossaryexplain- knowledgeisbased.However,itcanpresentan inggeneticterms,andinreferences,including individualperspectivesuitableasanintroduc- websitesforfurtherin-depthstudies.Thisbook tion.Thishopefullywillstimulatefurtherinter- iswrittenfortwokindsofreaders:forstudents est.Ihaveselectedmanytopicstoemphasize of biology and medicine, as an introductory the intersection of theoretical fundamentals overview,andfortheirmentors,asateaching andthemedicalapplicationsofgenetics.Dis- aid. Other interested individuals will also be eases are included as examples representing abletogaininformationaboutcurrentdevelop- geneticprinciples,butwithoutthemanydetails mentsandachievementsinthisrapidlygrow- requiredinpractice. ingfield. ThroughoutthebookIhaveemphasizedtheim- GerhardusKremer(1512–1594),themathema- portanceofevolutioninunderstandinggenet- tician and cartographer known as Mercator, ics.AsnotedbythegreatgeneticistTheodosius firstusedthetermatlasin1594forabookcon- Dobzhansky,“Nothinginbiologymakessense taining a collection of 107 maps. The fron- exceptinthelightofevolution.”Indeed,genet- tispieceshowsafigureoftheTitanAtlashold- icsandthescienceofevolutionareintimately ingtheglobeonhisshoulders.Whenthebook connected. For the many young readers nat- was published a year after Kremer’s death, urallyinterestedinthefuture,Ihaveincludeda many regions were still unmapped. Genetic historicalperspective.Wheneverpossibleand mapsarealeitmotifingeneticsandarecurrent appropriate,Ihavereferredtothefirstdescrip- themeinthisbook.Establishinggeneticmapsis tionofadiscovery.Thisisareminderthatthe anactivitynotunlikemappingnew,unknown platformofknowledgetodayrestsonprevious territories500yearsago. advances. Thisthirdeditionhasbeenextensivelyrewrit- Allcolorplateswerepreparedforpublication ten, updated, and expanded. Every sentence by Jürgen Wirth, Professor of Visual Com- andillustrationwasvisitedandmanychanged municationattheFacultyofDesign,University toimproveclarity.Thegeneralstructureofthe ofAppliedSciences,Darmstadt,Germany1986– previouseditions,whichhaveappearedin11 2005.Hecreatedalltheillustrationsfromcom- languages,hasbeenmaintained: puterdrawings,handsketches,orphotographs PartI,Fundamentals;PartII,Genomics;PartIII, assembledforeachplatebytheauthor.Iam GeneticsandMedicine. deeplyindebtedtoProfessorJürgenWirthfor Eachcolorplateisaccompaniedbyanexplana- themostpleasantcooperation.Hismostskillful tory text on the opposite page. Each double workisafundamentofthisbook.Ithankmy pageconstitutesasmall,self-containedchap- wife,MaryFetterPassarge,MD,forhercareful ter.Thelimitedspacenecessitatesaconcentra- editingofthemanuscriptandforhernumerous tiononthemostimportantthreadsofinforma- helpful suggestions. At Thieme International, tion at the expense of related details not in- Stuttgart, I was guided and supported by cluded.Therefore,thisbookisasupplementto, StephanKonnry.IalsowishtothankStefanie ratherthanasubstitutefor,classictextbooks. LangnerandElisabethKurzoftheProduction Newtopicsinthisthirdedition,representedby Departmentforthepleasantcooperation. newplates,includeoverviewsofthetaxonomy of living organisms (“tree of life”), cell com- EberhardPassarge VI Acknowledgements Inpreparingthisthirdeditionmanycolleagues ler(Bielefeld),HelgaRehder(Marburg),André fromdifferentcountriesagainkindlyprovided Reis(Erlangen),DavidL.Rimoin(LosAngeles), illustrations,valuablecomments,orusefulin- MichaelRoggendorf(Essen),HansHilgerRopers formation.Iamgratefultothemandtoanyone (Berlin),GerdScherer(Freiburg),AxelSchneider whosuggestspossibleimprovementsforfuture (Essen),EvelinSchröck(Dresden),EricSchulze- editions. Bahr (Münster), Peter Steinbach (Ulm), Gesa IwishtoexpressmygratitudetoAlirezaBarad- SchwanitzandHeredithSchüler(Bonn),Michael aran (Mashhad, Iran), John Barranger (Pitts- Speicher (Graz, formerly München), Manfred burgh),ClausR.Bartram(Heidelberg),LauraCar- Stuhrmann-Spangenberg (Hannover), Gerd rel (Hershey, Pennsylvania), Thomas Cremer Utermann(Innsbruck),ThomasVoit(Essen),Mi- (München),NicoleM.Cutright(Creighton,Penn- chael Weis (Cleveland), Johannes Zschocke sylvania),AndreasGal(Hamburg),RobinEdison (Heidelberg). (NIH,Bethesda,Maryland),EvanE.Eichler(Seat- In addition, the following colleagues at our tle),WolfgangEngel(Göttingen),GebhardFlatz Department of Human Genetics, Universi- (Bonn, formerly Hannover), James L. German täsklinikum Essen, made helpful suggestions: (NewYork),DorotheaHaas(Heidelberg),Cor- Karin Buiting, Hermann-Josef Lüdecke, Bern- nelia Hardt (Essen), Reiner Johannisson (Lü- hardHorsthemke,DietmarLohmann,BeateAl- beck),RichardI.Kelley(Baltimore),KiyoshiKita brecht, Michael Zeschnigk, Stefan Böhringer, (Tokyo),ChristianKubisch(Köln),NicoleMcNeil Dagmar Wieczorek, and Sven Fischer. In sec- and Thomas Ried (NIH, Bethesda, Maryland), retarial matters I was supported by Liselotte Roger Miesfeld (Tucson, Arizona), Clemens Freimann-Gansert and Astrid Maria Noll. Müller-Reible(Würzburg),MaximilianMuenke FigureswereprovidedbyBeateAlbrecht,Karin (NIH,Bethesda,Maryland),StefanMundlos(Ber- Buiting, Gabriele Gillessen-Kaesbach (now lin), Shigezuku Nagata (Osaka), Daniel Nigro Lübeck), Bernhard Horsthemke, Elke Jürgens, (LongBeachCityCollege,California),AlfredPüh- andDietmarLohmann. VII AbouttheAuthor beforeworkingasaresearchfellowinhuman geneticswithJamesGermanattheCornellMe- dicalCenterNewYorkfrom1966–1968.There- after he established cytogenetics and clinical geneticsattheDepartmentofHumanGenetics, UniversityofHamburg(1968–1976).In1976he becameFoundingChairmanoftheDepartment ofHumanGenetics,UniversityofEssen,Ger- many.Heretiredfromthechairin2001,butre- mainsactiveinteachinghumangenetics.The author’s field of research covers the genetics andclinicaldelineationofhereditarydisorders, inparticularHirschsprungdiseaseandBloom syndrome, and associated congenital malfor- mations, and includes chromosomal and molecular studies documented in more than 230peer-reviewedresearcharticlesandintext- books.HeisformerPresidentoftheGerman SocietyofHumanGenetics(1990–1996),Sec- retary-General of the European Society of HumanGenetics(1989–1992),andamemberof various scientific societies in Europe and the USA. The practice of medical genetics and teachingofhumangeneticsareofparticularin- teresttotheauthor.HereceivedtheHufeland Prize in 1978 and the Mendel Medal of the The author is a medical scientist in human CzechoslovakianBiologicalSocietyin1986.He geneticsattheMedicalFacultyoftheUniversity isanhonorarymemberoftheCzechoslovakian of Duisburg–Essen, Germany. He graduated SocietyforMedicalGeneticsandthePurkyne fromtheUniversityofFreiburgin1960withan SocietyPrague,correspondinghonorarymem- MD degree and received training in different ber of the Romanian Academy of Medical fieldsofmedicineinHamburg,Germany,and Sciences, and corresponding member of the Worcester, Massachusetts/USA, between 1961 American College of Medical Genetics. He and1963,inpartwithastipendfromtheVent- servedasViceRectoroftheUniversityofEssen nor Foundation. During a residency in pedi- from 1983–1988, as Chairman of the Ethics atricsattheUniversityofCincinnati,Children’s CommitteeMedicalFacultyEssenfrom1981– MedicalCenter,heworkedinhumangenetics 2001, and on the editorial board of several asastudentofJosefWarkanyfrom1963–1966 scientificjournalsinhumangenetics. VIII TableofContents Introduction ...................... 1 TrinucleotideRepeatExpansion ..... 88 DNARepair ........................ 90 Chronology ........................... 17 XerodermaPigmentosum ........... 92 ImportantAdvancesthatContributed ProkaryoticCellsandViruses ........... 94 totheDevelopmentofGenetics ..... 17 BacteriaintheStudyofGenetics .... 94 RecombinationinBacteria .......... 96 PartI.Fundamentals ............ 23 Bacteriophages .................... 98 DNATransferbetweenCells ........ 100 Prologue .............................. 24 ClassificationofViruses ............ 102 TaxonomyofLivingOrganisms: ReplicationofViruses .............. 104 TheTreeofLife .................... 24 Retroviruses ....................... 106 HumanEvolution .................. 26 RetrovirusIntegrationand TheCellandItsComponents ........ 28 Transcription ...................... 108 MolecularBasisofGenetics ............ 30 EukaryoticCells ....................... 110 SomeTypesofChemicalBonds ..... 30 CellCommunication ............... 110 Carbohydrates ..................... 32 Yeast:EukaryoticCellswithaDiploid Lipids(Fats) ....................... 34 andaHaploidPhase ................ 112 NucleotidesandNucleicAcids ...... 36 MatingTypeDeterminationin AminoAcids ....................... 38 YeastCellsandYeastTwo-Hybrid Proteins ........................... 40 System ............................ 114 DNAasaCarrierofGenetic CellDivision:Mitosis ............... 116 Information ....................... 42 MeiosisinGermCells .............. 118 DNAandItsComponents ........... 44 MeiosisProphaseI ................. 120 DNAStructure ..................... 46 FormationofGametes .............. 122 AlternativeDNAStructures ......... 48 CellCycleControl .................. 124 DNAReplication ................... 50 ProgrammedCellDeath ............ 126 TheFlowofGeneticInformation: CellCulture ........................ 128 TranscriptionandTranslation ....... 52 MitochondrialGenetics ................ 130 GenesandMutation ................ 54 Mitochondria:EnergyConversion ... 130 GeneticCode ...................... 56 ChloroplastsandMitochondria ...... 132 ProcessingofRNA .................. 58 TheMitochondrialGenome DNAAmplificationbyPolymerase ofMan ............................ 134 ChainReaction(PCR) ............... 60 MitochondrialDiseases ............. 136 DNASequencing ................... 62 FormalGenetics ....................... 138 AutomatedDNASequencing ........ 64 TheMendelianTraits ............... 138 RestrictionMapping ................ 66 SegregationofMendelianTraits ..... 140 DNACloning ....................... 68 IndependentDistributionofTwo cDNACloning ...................... 70 DifferentTraits .................... 142 DNALibraries ...................... 72 PhenotypeandGenotype ........... 144 SouthernBlotHybridization ........ 74 SegregationofParentalGenotypes .. 146 DetectionofMutations MonogenicInheritance ............. 148 withoutSequencing ................ 76 LinkageandRecombination ......... 150 DNAPolymorphism ................ 78 EstimatingGeneticDistance ........ 152 Mutations ......................... 80 SegregationAnalysiswithLinked MutationsDuetoDifferentBase GeneticMarkers ................... 154 Modifications ...................... 82 LinkageAnalysis ................... 156 Recombination .................... 84 QuantitativeDifferencesinGenetic Transposition ...................... 86 Traits ............................. 158 TableofContents IX NormalDistributionandPolygenic Structure .......................... 230 ThresholdModel ................... 160 GenomicImprinting ................ 232 DistributionofGenesina MammalianXChromosome Population ........................ 162 Inactivation ........................ 234 Hardy–WeinbergEquilibrium Principle .......................... 164 PartII.Genomics ................. 237 ConsanguinityandInbreeding ...... 166 Twins ............................. 168 Genomics,theStudyofthe Polymorphism ..................... 170 OrganizationofGenomes ........... 238 BiochemicalPolymorphism ......... 172 GeneIdentification ................. 240 DifferencesinGeographical IdentificationofExpressedDNA ..... 242 DistributionofSomeAlleles ........ 174 ApproachestoGenomeAnalysis .... 244 Chromosomes ......................... 176 GenomesofMicroorganisms ........ 246 ChromosomesinMetaphase ........ 176 TheCompleteSequenceofthe VisibleFunctionalStructures EscherichiacoliGenome ............ 248 ofChromosomes ................... 178 TheGenomeofaMultiresistant ChromosomeOrganization ......... 180 Plasmid ........................... 250 FunctionalElementsof ArchitectureoftheHumanGenome . 252 Chromosomes ..................... 182 TheHumanGenomeProject ........ 254 DNAandNucleosomes ............. 184 GenomicStructureoftheHumanX DNAinChromosomes .............. 186 andYChromosomes ............... 256 TheTelomere ...................... 188 GenomeAnalysiswithDNA TheBandingPatternsof Microarrays ....................... 258 HumanChromosomes .............. 190 GenomeScanandArrayCGH ....... 260 KaryotypesofManandMouse ...... 192 TheDynamicGenome:Mobile PreparationofMetaphase GeneticElements .................. 262 ChromosomesforAnalysis .......... 194 EvolutionofGenesandGenomes .... 264 FluorescenceIn-SituHybridization ComparativeGenomics ............. 266 (FISH) ............................. 196 Aneuploidy ........................ 198 PartIII.Geneticsand ChromosomeTranslocation ......... 200 StructuralChromosomal Medicine ........................... 269 Aberrations ........................ 202 Cell-to-CellInteractions ................ 270 MulticolorFISHIdentificationof IntracellularSignalTransduction .... 270 Chromosomes ..................... 204 SignalTransductionPathways ....... 272 ComparativeGenomic TGF-(cid:1)andWnt/(cid:1)-CateninSignaling Hybridization ..................... 206 Pathways .......................... 274 RegulationofGeneFunction ............ 208 TheHedgehogandTNF-αSignal RibosomesandProteinAssembly ... 208 TransductionPathways ............. 276 Transcription ...................... 210 TheNotch/DeltaSignalingPathway . 278 ProkaryoticRepressorandActivator: NeurotransmitterReceptorsandIon thelacOperon ..................... 212 Channels .......................... 280 GeneticControlbyAlternativeRNA GeneticDefectsinIonChannels: Structure .......................... 214 LQTSyndromes .................... 282 BasicMechanismsof ChlorideChannelDefects:Cystic GeneControl ...................... 216 Fibrosis ........................... 284 RegulationofGeneExpressionin SensoryPerception .................... 286 Eukaryotes ........................ 218 Rhodopsin,aPhotoreceptor ......... 286 DNA-BindingProteins,I ............ 220 MutationsinRhodopsin:Pigmentary DNA-BindingProteins,II ............ 222 RetinalDegeneration ............... 288 RNAInterference(RNAi) ............ 224 ColorVision ....................... 290 TargetedGeneDisruption .......... 226 AuditorySystem ................... 292 EpigeneticModifications ............... 228 DNAMethylation .................. 228 ReversibleChangesinChromatin