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chapter5DNA.WhilewethinkofgenomicDNAasastablegeneticblueprint,thelymphocytecelllineagedoesnotretainanin-tactcopyofthisblueprint.Genomicrearrangementisanes-sentialfeatureoflymphocytedifferentiation,andnoothervertebratecelltypehasbeenshowntoundergothisprocess.Thischapterfirstdescribesthedetailedorganizationoftheimmunoglobulingenes,theprocessofIg-generearrange-ment,andthemechanismsbywhichthedynamicim-munoglobulingeneticsystemgeneratesmorethan108differentantigenicspecificities.Thenitdescribesthemecha-nismofclassswitching,theroleofdifferentialRNAprocess-ingintheexpressionofimmunoglobulingenes,andtheregulationofIg-genetranscription.ThechapterconcludeswiththeapplicationofourknowledgeofthemolecularVκJκJκ3′CκVJCκPolyadenylationRNAsplicing(A)n5′LLIGeneticModelCompatiblewithIgStructureIMultigeneOrganizationofIgGenesIVariable-RegionGeneRearrangementsIMechanismofVariable-RegionDNARearrangementsIGenerationofAntibodyDiversityIClassSwitchingamongConstant-RegionGenesIExpressionofIgGenesISynthesis,Assembly,andSecretionofImmunoglobulinsIRegulationofIg-GeneTranscriptionIAntibodyGenesandAntibodyEngineeringOrganizationandExpressionofImmunoglobulinGenesOthevertebrateimmunesystemisitsabilitytorespondtoanapparentlylimitlessarrayoffor-eignantigens.Asimmunoglobulin(Ig)sequencedataaccu-mulated,virtuallyeveryantibodymoleculestudiedwasfoundtocontainauniqueaminoacidsequenceinitsvari-ableregionbutonlyoneofalimitednumberofinvariantse-quencesinitsconstantregion.Thegeneticbasisforthiscombinationofconstancyandtremendousvariationinasingleproteinmoleculeliesintheorganizationoftheim-munoglobulingenes.Ingerm-lineDNA,multiplegenesegmentsencodepor-tionsofasingleimmunoglobulinheavyorlightchain.Thesegenesegmentsarecarriedinthegermcellsbutcannotbetranscribedandtranslatedintocompletechainsuntiltheyarerearrangedintofunctionalgenes.DuringB-cellmatura-tioninthebonemarrow,certainofthesegenesegmentsarerandomlyshuffledbyadynamicgeneticsystemcapab...