I ColorAtlasofGenetics 2ndedition Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. II Tomywife,Mary Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. III Color Atlas of Genetics EberhardPassarge,M.D. ProfessorofHumanGenetics InstituteofHumanGenetics UniversityofEssen Essen,Germany Secondedition,enlargedandrevised With194colorplatesbyJürgenWirth Thieme Stuttgart·NewYork2001 Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. IV LibraryofCongressCataloging-in-Publication ImportantNote:Medicineisanever-changing Data scienceundergoingcontinualdevelopment.Re- Passarge,Eberhard. searchandclinicalexperiencearecontinually [TaschenatlasderGenetik.English] expanding our knowledge, in particular our Coloratlasofgenetics/EberhardPassarge,– knowledgeofpropertreatmentanddrugther- 2nded.,enl.,andrev. apy.Insofarasthisbookmentionsanydosageor p.;cm. application,readersmayrestassuredthatthe Includesbibliographicalreferencesand authors, editors, and publishers have made index. everyefforttoensurethatsuchreferencesare ISBN3131003626–ISBN0-86577-958-9 inaccordancewiththestateofknowledgeatthe 1.Genetics–Atlases. timeofproductionofthebook. 2.Medicalgenetics–Atlases.I.Title. [DNLM:1.Genetics,Medical–Atlases. 2.Genetics,Medical–Handbooks.QZ17 P286t2000a] QH436P37132000 576.5’022’2–dc21 00-048874 1stGermanedition1994 1stEnglishedition1995 1stFrenchedition1995 1stJapaneseedition1996 1stChineseedition1998 1stItalianedition1999 1stTurkishedition2000 !2001GeorgThiemeVerlag, Someoftheproductnames,patents,andregis- Rüdigerstraße14,D-70469Stuttgart,Germany tereddesignsreferredtointhisbookareinfact ThiemeNewYork,333SeventhAvenue, registered trademarks or proprietary names NewYork,N.Y.10001U.S.A. eventhoughspecificreferencetothisfactisnot alwaysmadeinthetext.Therefore,theappear- ColorplatesbyJürgenWirth,Professorof ance of a name without designation as pro- VisualCommunication,Fachhochschule prietaryisnottobeconstruedasarepresenta- Darmstadt tion by the publisher that it is in the public domain. TypesettingbyDruckhausGötzGmbH, Thisbook,includingallpartsthereof,islegally D-71636Ludwigsburg protectedbycopyright.Anyuse,exploitation,or (CCS-Textline[Linotronic630]) commercialization outside the narrow limits PrintedinGermanybyAppl,Wemding setbycopyrightlegislation,withoutthepub- lisher’sconsent,isillegalandliabletoprosecu- tion.Thisappliesinparticulartophotostatre- production,copying,mimeographingordupli- cationofanykind,translating,preparationof ISBN3-13-100362-6 (GTV) microfilms,andelectronicdataprocessingand ISBN0-86577-958-9 (TNY) 1 2 3 4 5 storage. Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. V Preface Knowledge about genes (genetics) and troduction,hopefullystimulatinginterestinan genomes (genomics) of different organisms excitingfieldofstudy. continuestoadvanceatabriskpace.Allmani- This second edition has been extensively re- festationsoflifearedeterminedbygenesand vised,rewritten,updated,andexpanded.Anew their interactions with the environment. A sectionongenomics(PartII)hasbeenadded. geneticcomponentcontributestothecauseof Twentynewplatesdealwithavarietyoftopics nearlyeveryhumandisease.Morethanathou- suchasthemolecularbasesofgenetics,regula- sanddiseasesresultfromalterationsinsingle tionandexpressionofgenes,genomicimprint- knowngenes. ing,mutations,chromosomes,genespredispos- Classical genetics, developed during the first ingtocancer,ionchanneldiseases,hearingand halfofthelastcentury,andmoleculargenetics, deafness, a brief guide to genetic diagnosis, developedduringthesecondhalf,havemerged human evolution, and many others. The intoafascinatingscientificendeavor.Thishas ChronologyofImportantAdvancesinGenetics providedbothatheoreticalfoundationanda andtheDefinitionsofGeneticTermshavebeen broadrepertoireofmethodstoexplorecellular updated.Asinthefirstedition,referencesare mechanisms and to understand normal includedforfurtherreading.Hereandinthelist processesanddiseasesatthemolecularlevel. ofgeneralreferences,thereaderwillfindaccess Decipheringthegenomesofmanydifferentor- tomoredetailedinformationthancanbepres- ganisms,includingbacteriaandplants,byde- entedinthelimitedspaceavailable.Websites terminingthesequenceoftheindividualbuild- forfurtherinformationareincluded. ing blocks—the nucleotide bases of deoxyri- A single-author book cannot provide all the bonucleicacid(DNA)—willaugmentourunder- detailsonwhichscientificknowledgeisbased. standing of normal and abnormal functions. However,itcanpresentanindividualperspec- Thenewknowledgeholdspromiseforthede- tivesuitableasanintroduction.Inmakingthe signofpharmaceuticalcompoundsaimedatin- difficultdecisionsaboutwhichmaterialtoin- dividualrequirements.Thiswillpavethewayto cludeandwhichtoleaveout,Ihavereliedon25 newapproachestotherapyandprevention.In- years’experienceofteachingmedicalstudents sightsaregainedintohoworganismsarere- at preclinical and clinical levels. I have at- latedbyevolution. tempted to emphasize the intersection of Students in biology and medicine face an theoretical fundaments and the medical enormoustaskwhenattemptingtoacquirethe aspectsofgenetics,takingabroadviewpoint newknowledgeandtointerpretitwithinacon- basedontheevolutionoflivingorganisms. ceptualframework.Manygoodtextbooksare Allthecolorplateswereproducedascomputer available(seeGeneralReferences,p.421).This graphicsbyJürgenWirth,ProfessorofVisual ColorAtlasdiffersfromstandardtextbooksby CommunicationattheFacultyofDesign,Uni- using a visual approach to convey important versity of Applied Sciences, Darmstadt. He conceptsandfactsingenetics.Itisbasedon created the plates from hand drawings, carefully designed color plates, each accom- sketches, photographs, and photocopies as- paniedbyacorrespondingexplanatorytexton sembledbytheauthor.Iamdeeplyindebtedto theoppositepage. ProfessorJürgenWirthforhismostskilfulwork, In1594Mercatorfirstusedtheterm“atlas”fora thepleasantcooperation,andhispatiencewith collectionofmaps.Althoughmapsofgenesare alloftheauthor’srequests.Withouthimthis highlyimportantingenetics,thetermatlasin bookwouldnothavebeenpossible. thecontextofthisbookreferstoillustrationsin general.Heretheyprovidethebasisforanin- Essen,November2000 E.Passarge Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. VI Acknowledgements Inupdating,revising,andrewritingthissecond Inaddition,thefollowingcolleaguesatourDe- edition,Ireceivedinvaluablehelpfrommany partment of Human Genetics, University of colleagueswhogenerouslyprovidedinforma- Essen Medical School, made helpful sugges- tion and advice, photographic material, and tions: Beate Albrecht, Karin Buiting, Gabriele otherusefulsuggestionsintheirareasofex- Gillessen-Kaesbach, Cornelia Hardt, Bernhard pertise:HansEsche,Essen;UlrichLangenbeck, Horsthemke, Frank Kaiser, Dietmar Lohmann, Frankfurt; Clemens Müller-Reible, Würzburg; Hermann-Josef Lüdecke, Eva-Christina Prott, MaximilianMuenke,Bethesda,Maryland;Ste- Maren Runte, Frank Tschentscher, Dagmar fan Mundlos, Berlin; Alfred Pühler, Bielefeld; Wieczorek,andMichaelZeschnigk. Gudrun Rappold, Heidelberg; Helga Rehder, Ithankmywife,Dr.MaryFetterPassarge,for Marburg; Hans Hilger Ropers, Berlin; Gerd hercarefulreadingandnumeroushelpfulsug- Scherer, Freiburg; Evelyn Schröck, Bethesda, gestions.LiselotteFreimann-GansertandAstrid Maryland;EricSchulze-Bahr,Münster;Michael MariaNolltranscribedthemanyversionsofthe Speicher,München;ManfredStuhrmann-Span- text. I am indebted to Dr. Clifford Bergman, genberg,Hannover;GerdUtermann,Innsbruck; MsGabrieleKuhn,MrGertKrüger,andtheir andDouglasCWallaceandMarieLott,Atlanta. co-workersatThiemeMedicalPublishersStutt- gartfortheirexcellentworkandcooperative spirit. AbouttheAuthor The author is a medical scientist in human DepartmentofHumanGenetics,Universityof geneticsattheUniversityofEssen,MedicalFac- Essen,fromwhichhewillretirein2001.The ulty,Germany.Hegraduatedin1960fromthe author’s special research interests are the UniversityofFreiburgwithanM.D.degree.He geneticsandtheclinicaldelineationofheredi- receivedtrainingindifferentfieldsofmedicine tary disorders, including chromosomal and inHamburg,Germany,andWorcester,Massa- molecular studies, documented in more than chusetts/USAbetween1961and1963.Duringa 200 peer-reviewed research articles. He is a residencyinpediatricsattheUniversityofCin- former president of the German Society of cinnati,Children’sMedicalCenter,heworkedin Human Genetics, secretary-general of the humangeneticsasastudentofJosefWarkany European Society of Human Genetics, and a (1963-66),followedbyaresearchfellowshipin memberofvariousscientificsocietiesinEurope humangeneticsattheCornellMedicalCenter andtheUSA.Heisacorrespondingmemberof New York with James German (1966-68). theAmericanCollegeofMedicalGenetics.The Thereafter he established cytogenetics and practice of medical genetics and teaching of clinicalgeneticsattheDepartmentofHuman humangeneticsareareasoftheauthor’spartic- Genetics,UniversityofHamburg(1968–1976). ularinterests. In1976hebecamefoundingchairmanofthe Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. VII TableofContents(Overview) Indroduction ........................ 1 ImmuneSystem ....................... 300 ChronologyofImportant OriginofTumors ...................... 316 OxygenandElectronTransport ......... 336 AdvancesinGenetics ............... 13 LysosomesandLDLReceptor ........... 352 Homeostasis .......................... 362 PartI.Fundamentals ............ 19 MaintainingCellandTissueShape ...... 374 MammalianSexDeterminationand MolecularBasisofGenetics ............ 20 Differentiation ........................ 386 ProkaryoticCellsandViruses ........... 84 AtypicalInheritancePattern ............ 394 EukaryoticCells ....................... 104 Karyotype/PhenotypeCorrelation ....... 400 MitochondrialGenetics ................ 124 ABriefGuidetoGeneticDiagnosis ...... 406 FormalGenetics ....................... 132 Chromosomes ......................... 170 ChromosomalLocationof RegulationandExpressionofGenes ..... 204 MonogenicDiseases ................ 410 GeneralReferences ................. 421 PartII.Genomics ................. 233 Glossary ............................. 423 PartIII.Geneticsand Index ................................ 442 Medicine ........................... 263 Cell-to-Cell-Interactions ............... 264 GenesinEmbryonicDevelopment ...... 290 Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. 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VIII TableofContentsinDetail Introduction ...................... 1 DNARepair ........................... 80 XerodermaPigmentosum .............. 82 Chronology ......................... 13 ProkaryoticCellsandViruses ...... 84 AdvancesthatContributedtothe DevelopmentofGenetics .............. 13 ProkaryoticCells ...................... 84 IsolationofMutantBacteria ........ 84 RecombinationinBacteria .......... 86 Part1.Fundamentals ............ 19 Bacteriophages .................... 88 DNATransferbetweenCells ........ 90 MolecularBasisofGenetics ........ 20 Viruses ............................... 92 TheCellandItsComponents ........... 20 ReplicationCycleofViruses ......... 94 SomeTypesofChemicalBonds ..... 22 RNAViruses:Genome,Replication, Carbohydrates ..................... 24 Translation ........................ 96 Lipids(Fats) ....................... 26 DNAViruses ....................... 98 NucleotidesandNucleicAcids ...... 28 Retroviruses ....................... 100 AminoAcids ...................... 30 RetrovirusIntegrationand Proteins ........................... 32 Transcription ...................... 102 DNAasCarrierofGeneticInformation .. 34 EukaryoticCells ..................... 104 DNAandItsComponents ........... 36 DNAStructure ..................... 38 Yeast:EukaryoticCellswithaDiploid AlternativeDNAStructures ......... 40 andaHaploidPhase ................... 104 DNAReplication ................... 42 MatingTypeDeterminationinYeastCells Genes ................................ 44 andYeastTwo-HybridSystem .......... 106 TheFlowofGeneticInformation: FunctionalElementsinYeast TranscriptionandTranslation ....... 44 Chromosomes ......................... 108 GenesandMutation ................ 46 ArtificialChromosomesforAnalyzing GeneticCode ...................... 48 ComplexGenomes ..................... 110 TheStructureofEukaryoticGenes ... 50 CellCycleControl ...................... 112 RecombinantDNA ..................... 52 CellDivision:Mitosis .................. 114 DNASequencing ................... 52 MaturationDivision(Meiosis) .......... 116 AutomatedDNASequencing ........ 54 Crossing-OverinProphaseI ............ 118 DNACloning ....................... 56 FormationofGametes ................. 120 cDNACloning ...................... 58 CellCulture ........................... 122 DNALibraries ...................... 60 MitochondrialGenetics ............ 124 RestrictionAnalysisbySouthernBlot Analysis ........................... 62 GeneticallyControlledEnergy-Delivering RestrictionMapping ................ 64 ProcessesinMitochondria ............. 124 DNAAmplificationbyPolymerase TheGenomeinChloroplastsand ChainReaction(PCR) ............... 66 Mitochondria ......................... 126 ChangesinDNA ....................... 68 TheMitochondrialGenomeofMan ..... 128 MutationduetoBaseModifications . 70 MitochondrialDiseases ................ 130 DNAPolymorphism ................ 72 FormalGenetics .................... 132 Recombination .................... 74 Transposition ...................... 76 TheMendelianTraits .................. 132 TrinucleotideRepeatExpansion ..... 78 SegregationofMendelianTraits ........ 134 Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. 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TableofContentsinDetail IX IndependentDistributionofTwo ControlofTranscription ................ 212 DifferentTraits ........................ 136 TranscriptionControlinEukaryotes ..... 214 PhenotypeandGenotype .............. 138 RegulationofGeneExpressionin SegregationofParentalGenotypes ...... 140 Eukaryotes ............................ 216 MonogenicInheritance ................ 142 DNA-BindingProteins .................. 218 LinkageandRecombination ............ 144 OtherTranscriptionActivators .......... 220 GeneticDistancebetweenTwoGeneLoci . 146 InhibitorsofTranscriptionand AnalysiswithGeneticMarkers ......... 148 Translation ............................ 222 LinkageAnalysis ....................... 150 DNAMethylation ...................... 224 QuantitativeGeneticTraits ............. 152 GenomicImprinting ................... 226 NormalDistributionandPolygenic X-ChromosomeInactivation ............ 228 ThresholdModel ...................... 154 TargetedGeneDisruptioninTransgenic DistributionofGenesinaPopulation ... 156 Mice .................................. 230 Hardy-WeinbergEquilibrium ........... 158 ConsanguinityandInbreeding .......... 160 PartII.Genomics ................. 233 Twins ................................ 162 Polymorphism ........................ 164 Genomics,theStudyoftheOrganization BiochemicalPolymorphism ............ 166 ofGenomes ........................... 234 GeographicalDistributionofGenes ..... 168 TheCompleteSequenceofthe EscherichiacoliGenome ................ 236 Chromosomes ...................... 170 GenomeofaPlasmidfroma Nucleosomes .......................... 170 MultiresistantCorynebacterium ......... 238 DNAinChromosomes .................. 172 GenomeMaps ......................... 240 PolyteneChromosomes ............... 174 ApproachtoGenomeAnalysis .......... 242 DNAinLampbrushChromosomes ...... 176 OrganizationofEukaryoticGenomes .... 244 CorrelationofStructureandFunctionin GeneIdentification .................... 246 Chromosomes ........................ 178 TheHumanGenomeProject ............ 248 SpecialStructureattheEndsofa IdentificationofaCodingDNASegment . 250 Chromosome:theTelomere ............ 180 TheDynamicGenome: MetaphaseChromosomes .............. 182 MobileGeneticElements ............... 252 Karyotype ............................. 184 EvolutionofGenesandGenomes ....... 254 TheG-andR-BandingPatternsofthe ComparativeGenomics ................ 256 HumanMetaphaseChromosomes ...... 186 HumanEvolution ...................... 258 DesignationofChromosomal GenomeAnalysisbyDNAMicroarrays ... 260 Aberrations ........................... 188 PreparationofMetaphaseChromosomes . 190 PartIII.Geneticsand InSituHybridization ................... 192 SpecificMetaphaseChromosome Medicine ........................... 263 Identification ......................... 194 NumericalChromosomeAberrations .... 196 Cell-to-CellInteractions ............ 264 Translocation ......................... 198 IntracellularSignalTransduction StructuralChromosomalAberrations ... 200 Systems .............................. 264 DetectionofStructuralChromosomal TypesofCellSurfaceReceptors ......... 266 AberrationsbyMolecularMethods ..... 202 GProtein-coupledReceptors ........... 268 TransmembraneSignalTransmitters .... 270 RegulationandExpressionof ReceptorsofNeurotransmitters ......... 272 Genes ............................... 204 GeneticDefectsinIonChannels ........ 274 TheCellNucleusandRibosomalRNA ... 204 ChlorideChannelDefects: Transcription .......................... 206 CysticFibrosis ......................... 276 ControlofGeneExpressioninBacteriaby Rhodopsin,aPhotoreceptor ............ 278 Induction ............................. 208 MutationsinRhodopsin ................ 280 ControlofGeneExpressioninBacteriaby ColorVision ........................... 282 Repression ............................ 210 HearingandDeafness .................. 284 Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. 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