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1、Medical Genetics末代沙皇尼古拉二世的公主斯塔西娅安娜-安德森1956电影”真假公主”Medical Genetics10 人类染色体畸变 chromosome aberration Medical GeneticsAnytypeofchangeinthechromosomestructure ornumber (deficiencies,duplications,translocations,inversions,etc.).Medical GeneticsAlthoughitcanbeamechanismforenhancinggeneticdiversity,suchalt
2、erationsareusuallyfatalorill-adaptive,especiallyinanimals.Medical Genetics1.factorsinducingchromosomeaberration1.factorsinducingchromosomeaberrationA. Ionizing radiation Ionizingradiationproducesrearrangementsofthegenome.Medical GeneticsMedical GeneticsWhenirradiationoccursduringtheG0/G1phaseofthece
3、llcycle,large-scalerearrangementsappearasexchange-typechromosomeaberrationsatthenextmitosis.Suchaberrationscanaltercellularphenotypes,andareimportantinvariousareasofbiology:Medical GeneticsAnalyzingchromosomeaberrationshelpscharacterizerepair/misrepairpathwaysinvolvedintheprocessingofDNAdamage.Ioniz
4、ingradiationhassomeuniquefeaturesasaprobeofsuchpathways.Comparedtoothergenotoxicagents,itproducescopiousquantitiesofDNAdoublestrandbreaks(DSBs),anditstimingcanbecontrolledmoreaccurately.Medical GeneticsMoreover,initialradiationdamagehasadiscrete,stochasticcharacterthatcanbemodulatedbyusingdifferentk
5、indsofradiation(e.g.a-particlesversusx-rays)havingdifferentionizationdensities.Medical GeneticsThespectrumofdifferentradiation-inducedchromosomeaberrationsisinformativeaboutthegeometryofchromosomesduringinterphase,andviceversa.Medical GeneticsB. chemical mutagen Akindofsubstances,suchasdrugsortoxins
6、,thatcauseschromosomalaberrationsoflivingorganisms,orincreasetherateofmutation.Medical GeneticsDrugantitumordrug（抗肿瘤药物）环磷酰胺、氮芥、白硝安（马利兰）、甲氨喋呤、阿糖胞苷等抗癌药物Tocolysis（子宫收缩抑制剂）drugwhichpreventpregnancyreaction(预防妊娠反应的药物)anti-epileptic苯妥英钠可引起人淋巴细胞多倍体细胞数增高Medical GeneticsagriculturalchemicalsSomeagriculturalc
7、hemicalscaninducechromosomeaberration,likephosphatepesticide.Medical GeneticsIndustrialpoisons苯、甲苯、铝、砷、二硫化碳、氯丁二稀、氯乙烯单体Medical GeneticsFoodadditivePreservative(防腐剂),pigment(色素),AF-2(硝基呋喃基糖酰胺),benzosulfimide(环己基糖精)。Medical GeneticsC biological mutagentoxoidsterigmatocystin(杂色曲霉素),Flavacin(黄曲霉素),clavac
8、in(棒曲霉素)等virusGermanmeaslesvirus(风疹病毒),(hepatovirus)乙肝病毒,Measlesvirus(麻疹病毒),cytomegalovirus(巨细胞病毒)Medical GeneticsDMaternalage DownDown综合征与母亲年龄综合征与母亲年龄Medical Genetics2.chromosomalaberrationsA.chromosome numerical aberrationNumericalaberrationisachangeinthenumberofchromosomesfromthenormalnumberchara
9、cteristicofthehumanbeings.Medical Genetics euploidchromosome numerical aberrationaneupliod Medical Genetics(1) Euploidy is the condition of having a normal number of structurally normal chromosomes.Euploidhumanfemaleshave46chromosomes(44autosomesandtwoXchromosomes).Medical GeneticsPolyploidyisamulti
10、pleofthehaploidchromosomenumber(n)otherthanthediploidnumber(i.e.,3n,4nandsoon).Medical GeneticsTriploidy Atriploidindividualhasthreeofeverychromosome,thatis,threehaploidsetsofchromosomes.Atriploidhumanwouldhave69chromosomes(3haploidsetsof23).Medical GeneticsProduction of triploidsseemstoberelatively
11、commonandcanoccurby,forexample,fertilizationbytwosperm.Medical Genetics双雄受精和双雌受精双雄受精和双雌受精双雄受精和双雌受精双雄受精和双雌受精Medical GeneticsDigyny(双雌受精)Dispermy(双雄受精)Endoreduplication（核内复制）Endomitosis（核内有丝分裂）Medical GeneticsMedical Genetics(2) Aneuploidy is the condition of having less than or more than the normal d
12、iploid number of chromosomes, and is the most frequently observed type of cytogenetic abnormality.Inotherwords,itisanydeviationfromeuploidy,althoughmanyauthorsrestrictuseofthistermtoconditionsinwhichonlyasmallnumberofchromosomesaremissingoradded.Medical GeneticsGenerally,aneuploidyisrecognizedasasma
13、lldeviationfromeuploidyforthesimplereasonthatmajordeviationsarerarelycompatiblewithsurvival,andsuchindividualsusuallydieprenatally.Medical Genetics The two most commonly observed forms of aneuploidy are monosomy and trisomy.Medical Genetics Monosomy is lack of one of a pair of chromosomes.Anindividu
14、alhavingonlyonechromosome6issaidtohavemonosomy6.AcommonmonosomyseeninmanyspeciesisXchromosomemonosomy,alsoknownasTurnerssyndrome.Monosomyismostcommonlylethalduringprenataldevelopment.Medical Genetics Trisomy is having three chromosomes of a particular type.AcommonautosomaltrisomyinhumansinDownsyndro
15、me,ortrisomy21,inwhichapersonhasthreeinsteadofthenormaltwochromosome21s.Trisomyisaspecificinstanceofpolysomy,amoregeneraltermthatindicateshavingmorethantwoofanygivenchromosome.Medical GeneticsHowever,birthofalivetriploidisextraordinarilyrareandsuchindividualsarequiteabnormal.Theraretriploidthatsurvi
16、vesformorethanafewhoursafterbirthisalmostcertainlyamosaic,havingalargeproportionofdiploidcells.Medical Genetics(3) Chromosome non-disjunctionThefailureofapairofhomologouschromosomestoseparateproperlyduringmeiosis.Thefailureofhomologues(atmeiosis)orsisterchromatids(atmitosis)toseparateproperlytooppos
17、itepoles,thatistwochromosomesorchromatidsgotoonepoleandnonetotheother.Medical GeneticsNon-disjunctioncanoccurduringmeiosisIormeiosisII.Medical GeneticsInmeiosisI,theerroroccurswhenthehomologouspairsbothtravelintothesamedaughtercell.Theresultistwodaughtercellsthathavetwocopiesofthechromosome(calleddi
18、somiccells)andtwocellsthataremissingthatchromosome(callednullisomiccells).Medical GeneticsNon-disjunctioninMeiosisI:Medical GeneticsInmeiosisII,theerroroccurswhenthesisterchromatidswillnotseparateandthustravelintothesamedaughtercell. 单体型单体型45,x45,xMedical GeneticsNon-disjunctioninMeiosisII:Medical G
19、eneticsFertilizationfollowingMeiosisIerror:Medical GeneticsFertilizationfollowingMeiosisIIerror:Medical GeneticsMedical Genetics三体型三体型2121三体三体Medical GeneticsNon-disjunctionoccursduringearlyperiodofmerogenesis,theresultismosaicMedical GeneticsChromosomelossMedical GeneticsB. Chromosome Structural Ab
20、errationStructuralaberrationisachangeinchromosomestructuredetectablebymicroscopicexaminationofthemetaphasestageofcelldivision,observedasdeletionsandfragments,intrachangesorinterchanges.Medical Genetics(1) A chromosome deletion occurs when the chromosome breaks and a piece is lost.Thisofcourseinvolve
21、slossofgeneticinformationandresultsinwhatcouldbeconsideredpartialmonosomyforthatchromosome.Medical GeneticsMedical GeneticsMedical GeneticsMedical Genetics缺失缺失缺失缺失a a a a：末端缺失；：末端缺失；：末端缺失；：末端缺失；b b b b：中间缺失：中间缺失：中间缺失：中间缺失46,XX(XY),del(1)(q21)/46,XX(XY),del(1)(pterq21)46,XX(XY),del(3)(q21q31)/46,XX(X
22、Y),del(3)(pterq21:q31q31)Medical Genetics(2) A related abnormality is a chromosome inversion.Inthiscase,abreakorbreaksoccurandthatfragmentofchromosomeisinvertedandrejoinedratherthanbeinglost.Inversionsarethusrearrangementsthatdonotinvolvelossofgeneticmaterialand,unlessthebreakpointsdisruptanimportan
23、tgene,individualscarryinginversionshaveanormalphenotype.Medical GeneticsMedical GeneticsMedical GeneticsMedical GeneticsMedical Genetics倒位倒位倒位倒位a a a a：臂内倒位染色体图解；：臂内倒位染色体图解；：臂内倒位染色体图解；：臂内倒位染色体图解；b b b b：臂间倒位染色体图解：臂间倒位染色体图解：臂间倒位染色体图解：臂间倒位染色体图解46XX(XY),inv(1)(p22p34)/46XX(XY),inv(1)(pterp34:p22p34:p22
24、qter)46XX(XY),inv(2)(p15q21)/46XX(XY),inv(2)(pterq15:q21p15:q21qter)Medical Genetics(3)ChromosomeDuplicationisjustthat,aduplicationofasectionofachromosome.Aduplicationissometimesreferredtoasapartialtrisomy.Trisomyreferstothree.Thereforeifaduplicationexists,thatindividualhasthreecopiesofthatareainste
25、adoftwo.Thismeansthereareextrainstructions(genes)presentthatcancauseanincreasedriskforbirthdefectsordevelopmentalproblems.Medical GeneticsMedical GeneticsMedical Genetics(4)Aringchromosomecanhappenintwoways.Oneisdemonstratedinthepicture;theendofthepandqarmbreaksoffandthensticktoeachother.Thebluepart
26、sofeacharelostthusresultinginlossofinformation.Second,theendsofthepandqarmsticktogether(fusion),usuallywithoutlossofmaterial.Howevertheringcancauseproblemswhenthecelldividesandcancauseproblemsfortheindividual.Medical GeneticsMedical GeneticsMedical Genetics环状染色体环状染色体环状染色体环状染色体46,XX(XY),r(2)(p21p31)/
27、46,XX(XY),r(2)(p21p31)Medical Genetics(5)Translocations are chromosomal abnormalities whichoccurwhenchromosomesbreakandthefragmentsrejointootherchromosomes.Medical GeneticsTherearemanystructurallydifferenttypesoftranslocations.Aswithinversions,thereisnolossofgeneticmaterial,althoughthebreakpointcanc
28、ausedisruptionofacriticalgeneorjuxtaposepiecesoftwogenestocreateafusiongenethatinducescancer.Medical GeneticsReciprocal translocations Inareciprocaltranslocation,twonon-homologouschromosomesbreakandexchangefragments.Medical GeneticsMedical GeneticsMedical Genetics Individualscarryingsuchabnormalitie
29、sstillhaveabalancedcomplementofchromosomesandgenerallyhaveanormalphenotype,butwithvaryingdegreesofsubnormalfertility.Medical Genetics46,XX(XY),t(2;5)(q21:q31)/46,XX(XY),t(2;5)(2pter2q21:5q315qter;5pter5q31:2q212qter)Medical GeneticsMedical Genetics Translocationsarethusheritableandcanbeperpetuatedin
30、populations.Medical GeneticsCentric Fusions Acentricfusionisatranslocationinwhichthecentromeresoftwoacrocentricchromosomesfusetogenerateonelargemetacentricchromosome.TheyarealsooftencalledRobertsonian translocations,althoughthattermisusedbypuriststodesignateaverysimilarbutdistincttranslocationinwhic
31、honeofthetwocentromeresislost.Medical GeneticsThekaryotypeofanindividualcarryingacentricfusionhasonelessthanthenormaldiploidnumberofchromosomes.Medical Genetics.Medical GeneticsMedical Genetics Ingeneral,centricfusionsappeartocauseamildreductioninfertility(5-15%),muchlessseverethaninthecaseofreciprocaltranslocations.Medical Genetics(6)isochromosomeMedical GeneticsMedical Genetics(7) Chromosome breakage and re-union StructuralaberrationsarealmostformedbyChromosomebreakageandre-union.Medical GeneticsMedical GeneticsMedical Genetics
