醫(yī)學(xué)遺傳學(xué)-10人類染色體畸變-課件

10人類染色體畸變

chromosomeaberration

Anytypeofchangeinthechromosomestructureornumber(deficiencies,duplications,translocations,inversions,etc.).Althoughitcanbeamechanismforenhancinggeneticdiversity,suchalterationsareusuallyfatalorill-adaptive,especiallyinanimals.1.factorsinducingchromosomeaberration

A.Ionizingradiation

Ionizingradiationproducesrearrangementsofthegenome.WhenirradiationoccursduringtheG0/G1phaseofthecellcycle,large-scalerearrangementsappearasexchange-typechromosomeaberrationsatthenextmitosis.Suchaberrationscanaltercellularphenotypes,andareimportantinvariousareasofbiology:Medicalandpublic-healthapplicationsincludeperinataldiagnosticscharacterizationofspecificcancertypes,carcinogenesisriskestimation,radiationbiodosimetryandradiotherapeutictreatmentplanning.Analyzingchromosomeaberrationshelpscharacterizerepair/misrepairpathwaysinvolvedintheprocessingofDNAdamage.Ionizingradiationhassomeuniquefeaturesasaprobeofsuchpathways.Comparedtoothergenotoxicagents,itproducescopiousquantitiesofDNAdoublestrandbreaks(DSBs),anditstimingcanbecontrolledmoreaccurately.Moreover,initialradiationdamagehasadiscrete,stochasticcharacterthatcanbemodulatedbyusingdifferentkindsofradiation(e.g.a-particlesversusx-rays)havingdifferentionizationdensities.Thespectrumofdifferentradiation-inducedchromosomeaberrationsisinformativeaboutthegeometryofchromosomesduringinterphase,andviceversa.Chromosomalinstability,inwhichnewaberrations(thoughoftennotofthetypecharacteristicofG0/G1damage)continuetoarisemanygenerationsafterirradiation,representsaformofgenomicinstability,andgenomicinstabilityisprominentduringneoplasticprogression.B.chemicalmutagen

Akindofsubstances,suchasdrugsortoxins,thatcauseschromosomalaberrationsoflivingorganisms,orincreasetherateofmutation.

2.chromosomalaberrationsA.

chromosomenumericalaberrationNumericalaberrationisachangeinthenumberofchromosomesfromthenormalnumbercharacteristicofthehumanbeings.(1)Euploidyistheconditionofhavinganormalnumberofstructurallynormalchromosomes.

Euploidhumanfemaleshave46chromosomes(44autosomesandtwoXchromosomes).

Polyploidyisamultipleofthehaploidchromosomenumber(n)otherthanthediploidnumber(i.e.,3n,4nandsoon).(2)

Aneuploidyistheconditionofhavinglessthanormorethanthenormaldiploidnumberofchromosomes,andisthemostfrequentlyobservedtypeofcytogeneticabnormality.

Inotherwords,itisanydeviationfromeuploidy,althoughmanyauthorsrestrictuseofthistermtoconditionsinwhichonlyasmallnumberofchromosomesaremissingoradded.Generally,aneuploidyisrecognizedasasmalldeviationfromeuploidyforthesimplereasonthatmajordeviationsarerarelycompatiblewithsurvival,andsuchindividualsusuallydieprenatally.Thetwomostcommonlyobservedformsofaneuploidyaremonosomyandtrisomy.

Monosomyislackofoneofapairofchromosomes.Anindividualhavingonlyonechromosome6issaidtohavemonosomy6.AcommonmonosomyseeninmanyspeciesisXchromosomemonosomy,alsoknownasTurner'ssyndrome.Monosomyismostcommonlylethalduringprenataldevelopment.

Trisomyishavingthreechromosomesofaparticulartype.Acommonautosomal

trisomyinhumansin

Downsyndrome,ortrisomy21,inwhichapersonhasthreeinsteadofthenormaltwochromosome21s.Trisomyisaspecificinstanceofpolysomy,amoregeneraltermthatindicateshavingmorethantwoofanygivenchromosome.Anothertypeofaneuploidyistriploidy.Atriploidindividualhasthreeofeverychromosome,thatis,threehaploidsetsofchromosomes.Atriploidhumanwouldhave69chromosomes(3haploidsetsof23).Productionoftriploidsseemstoberelativelycommonandcanoccurby,forexample,fertilizationbytwosperm.However,birthofalivetriploidisextraordinarilyrareandsuchindividualsarequiteabnormal.Theraretriploidthatsurvivesformorethanafewhoursafterbirthisalmostcertainlyamosaic,havingalargeproportionofdiploidcells.(3)Chromosomenon-disjunction

Thefailureofapairofhomologouschromosomestoseparateproperlyduringmeiosis.Thefailureofhomologues(atmeiosis)orsisterchromatids(atmitosis)toseparateproperlytooppositepoles,thatistwochromosomesorchromatidsgotoonepoleandnonetotheother.Non-disjunctioncanoccurduringmeiosisIormeiosisII.

AnerrorinthepropersegregationofthechromosomesduringbothmeiosisIandIIarepicturedbelow.

InmeiosisI,theerroroccurswhenthehomologouspairsbothtravelintothesamedaughtercell.

Theresultistwodaughtercellsthathavetwocopiesofthechromosome(calleddisomiccells)andtwocellsthataremissingthatchromosome(callednullisomic

cells).

Non-disjunctioninMeiosisI:

InmeiosisII,theerroroccurswhenthesisterchromatidswillnotseparateandthustravelintothesamedaughtercell.

Non-disjunctioninMeiosisII:FertilizationfollowingMeiosisIerror:

FertilizationfollowingMeiosisIIerror:B.ChromosomeStructuralAberration

Structuralaberrationisachangeinchromosomestructuredetectablebymicroscopicexaminationofthemetaphasestageofcelldivision,observedasdeletionsandfragments,intrachangesorinterchanges.(1)

Achromosomedeletionoccurswhenthechromosomebreaksandapieceislost.Thisofcourseinvolveslossofgeneticinformationandresultsinwhatcouldbeconsidered"partialmonosomy"forthatchromosome.(2)Arelatedabnormalityisachromosomeinversion.

Inthiscase,abreakorbreaksoccurandthatfragmentofchromosomeisinvertedandrejoinedratherthanbeinglost.Inversionsarethusrearrangementsthatdonotinvolvelossofgeneticmaterialand,unlessthebreakpointsdisruptanimportantgene,individualscarryinginversionshaveanormalphenotype.(3)ChromosomeDuplicationisjustthat,aduplicationofasectionofachromosome.

Aduplicationissometimesreferredtoasa'partialtrisomy'.Trisomyreferstothree.Thereforeifaduplicationexists,thatindividualhasthreecopiesofthatareainsteadoftwo.Thismeansthereareextrainstructions(genes)presentthatcancauseanincreasedriskforbirthdefectsordevelopmentalproblems.(4)Aringchromosomecanhappenintwoways.Oneisdemonstratedinthepicture;theendofthepandqarmbreaksoffandthensticktoeachother.Thebluepartsofeacharelostthusresultinginlossofinformation.Second,theendsofthepandqarmsticktogether(fusion),usuallywithoutlossofmaterial.Howevertheringcancauseproblemswhenthecelldividesandcancauseproblemsfortheindividual.(5)

Translocationsarechromosomalabnormalitieswhichoccurwhenchromosomesbreakandthefragmentsrejointootherchromosomes.Therearemanystructurallydifferenttypesoftranslocations.Aswithinversions,thereisnolossofgeneticmaterial,althoughthebreakpointcancausedisruptionofacriticalgeneorjuxtaposepiecesoftwogenestocreateafusiongenethatinducescancer.

Ingeneralhowever,theproblemwithtranslocationsoccursduringmeiosisandismanifestasreductionsinfertility.Reciprocaltranslocations

Inareciprocaltranslocation,twonon-homologouschromosomesbreakandexchangefragments.

Individualscarryingsuchabnormalitiesstillhaveabalancedcomplementofchromosomesandgenerallyhaveanormalphenotype,butwithvaryingdegreesofsubnormalfertility.

Translocationsarethusheritableandcanbeperpetuatedinpopulations.CentricFusions

Acentricfusionisatranslocationinwhicht