染色体的结构张成岗二所十一室2011.09.20~2nm~11nm~30nm~300nm~700nm~1400nmEachDNAmoleculeispackagedintoachromosome50,000Xshorterthanitsextendedlength染色体:碱性(组)蛋白+酸性核酸ProteinMolecularweightMajorAminoacidH121Lys++H2a13.8LysH2b13.8LysH315.4ArgH415.4Arghistonecluster1,H1b[Homosapiens]IEPofNP_005313.1from1to226IsoelectricPoint=11.6925histonecluster2,H2ab[Homosapiens]IEPofNP_778235.1from1to130IsoelectricPoint=11.5282GenBank:humanhistone153条记录•gi|4504291|ref|NP_003525.1|H3histonefamily,memberH[Homosapiens]•gi|4504271|ref|NP_003516.1|histonecluster1,H2bi[Homosapiens]•gi|4504285|ref|NP_003522.1|histonecluster1,H3c[Homosapiens]•gi|4504293|ref|NP_003526.1|histonecluster1,H3j[Homosapiens]•gi|4504297|ref|NP_003528.1|histonecluster1,H3b[Homosapiens]•gi|4504301|ref|NP_003529.1|histonecluster1,H4a[Homosapiens]•gi|4504303|ref|NP_003530.1|histonecluster1,H4d[Homosapiens]•......•gi|4885379|ref|NP_005312.1|histonecluster1,H1e[Homosapiens]•gi|4758496|ref|NP_004884.1|H2Ahistonefamily,memberYisoform2[Homosapiens]•gi|13128862|ref|NP_003874.2|histonedeacetylase3[Homosapiens]•gi|28195394|ref|NP_778235.1|histonecluster2,H2ab[Homosapiens]CoreparticleApproximately1.8turnsofDNA(consistingof146bp)woundaroundtheoutsideofthehistoneoctamer.HistonedepletedmetaphasechromosomesHE染色的原理人类染色体ChromosomenumberDNAofagenomeisdividedintochromosomes(variablesizeandnumber)毛冠鹿Chromosomenumber分析的意义•哪一种结构更加合理?–染色体数量:多vs少?–多乎哉,不多也•可能的答案:–基因剂量(Genedosage)是关键GenomeComparisonOrganism~Size~#Genes~GeneDensityHuman3000million30-35K1/100,000Mouse3000million30,0001/100,000FruitFly135million13,0611/13,781Arabidopsis100million25,0001/4,000C.elegans97million19,0991/5,079Yeast12.1million6,0341/2,005Bacteria(E.coli)4.67million3,2371/1,443ChromosomestructureGenesinclude:•Exons-codingregions•Introns-non-codingregionsinterspersedbetweenexons•Regulatorysequences基因的结构、组成Inadditiontogenes,chromosomeshavelotsof“non-coding”sequenceX400ChromosomestructureStructuralfeatures•Replicationorigin•Centromere•TelomeresRepetitiousDNA•LINESandSINES•DNAonlytransposons•Segmentalduplicationsandsimplesequencerepeats•LINE–长散置元(longinterspersedelements)•SINE–短散置元(shortinterspersedelements)Chromosomestructure2~3%vs97~98%||已知vs未知?Specializedregionsofchromosomes•Originsofreplication–Eukaryoticchromosomeshavemanyorigins•Centromere(1per)–Attacheschromosometothemitoticspindleapparatus•Telomere(2per)–Linearendofthechromosome命名:区、带、亚带染色体带命名的国际规则(ISCN)•命名方法:1.染色体的名称2.染色体臂的名称3.区号4.带号•注意:1.离着丝粒最近的区为1区,其次2区;2.在一个区内,离着丝粒最近的带为1带,其次2带3.带、亚带:与带之间用“.”隔开。1.如:1p36.1(3区6带1亚带)染色体的带型细胞遗传学问题思考•染色体是静态的还是动态的?–地球深部的奥秘[地震、火山是地心活动的不同表现形式]…–染色体呢?–病毒会攻击染色体吗?•逆转录病毒向染色体的整合问题思考•变与不变的关系–变是进化之源、不变是进化之果–没有变化就没有进化–变化是否会失控:•分子进化问题:中性突变理论问题思考•核小体在染色体上的分布是等间距吗?–Ifyes:细胞如何处理转录因子和组蛋白的关系?–Ifno:那么会是何种分布形式?–注意:细胞通常不会处于线性状态。–染色体重塑:Chromosomeremodeling染色体结构的稳定性•性命攸关–生死相关(肿瘤、转归)•染色体结构的稳定性与衰老–DNA解旋酶与早老症有关•染色体结构的稳定性与肿瘤–Translocation等Chromosomenumbervariation•Euploidy(整倍体)•Aneuploidy(非整倍体)EuploidytypesymbolSetofchromosomemonoploidnABCDiploid2nAABBCCPolyploidTriploid3nAAABBBCCCTetraploid4nAAAABBBBCCCCPentaploid5nAAAAABBBBBCCCCCAneuploidtypesymbolNumberofchromosomeDisomic2nAABBCCmonosomic2n-1AABBCNullisomic2n-2AABBPolysomicTrisomic2n+1AABBCCCDoubletrisomic2n+1+1AABBBCCCTetrasomic2n+2AABBCCCCPentasomic2n+3AABBCCCCC染色体结构的变化基因复制是基因家族产生之源(已有信息的再利用在进化上比较经济)示例:基因家族定位具有成簇化(Clustering)倾向•黑色素瘤抗原编码基因家族(MAGE)•人MAGE-D1的染色体定位已经报道(Xp11.21-p11.23)•人MAGE-D也位于Xp11.21-p11.23(据PAC克隆及Lucas等的结果)•人KIAA1114定位于Xp11.21-p11.23(据PAC克隆AL049732)•人MAGE-D1的染色体定位已经被报道位于Xp11.23从而,MAGE-D亚家族的所有人类基因成员均定位于Xp11.21-p11.23,形成了一个典型的位于X染色体上的基因簇(cluster)ABCD0.1hsKIAA1114hsMAGE-DhsMAGE-D1mmDLXIN-1rnSNERG-1hsNECDINmmNECDINhsMAGE-B3hsMAGE-B2hsMAGE-B1hsMAGE-B4hsMAGE-C1hsMAGE-C2hsMAGE-A10hsMAGE-A11hsMAGE-A1hsMAGE-A4hsMAGE-A5hsMAGE-A12hsMAGE-A2hsMAGE-A3hsMAGE-A6hsMAGE-A9hsMAGE-A8ADEBCAlterationsofchromosomestructureChangesinChromosomeStructure•Deletion–Chromosome7:Williamssyndrome•Duplication–Chromosome15:invdup15•Translocation–Chromosomes21&14:Downssyndrome–Chromosomes2&20:Alagillesyndrome•Inversion染色体的不稳定性与癌症Instability•已知在所有癌细胞中都发生了染色体的增加或删减。•但这种异常的遗传不稳定性和癌症之间的关系一直未能确定。•NazneenRahman等对八个MVA(mosaicvariegatedaneupoidy)家族的DNA进行筛选。•MVA是一种遗传性的疾病,病人25%的细胞发生了染色体的非整倍性,而且这种病人发生儿童癌症的几率比正常情况下要高。•结果发现5个儿童的BUB1B基因的两个拷贝都发生了突变。这5个孩子的非整倍性细胞的百分比很高,而且有两个人已经患上了癌症。•BUB1B基因编码一种特殊的能够协助保持染色体数量在细胞间的传递过程中正确无误的蛋白(Nature,2004)。染色体结构研究技术•染色体核型分析(Karyotypeanalysis)•荧光原位杂交技术(FISH)•比较基因组杂交(CGH)染色体核型分析及其应用价值•放射损伤相关。•遗传学分析:特别在人类优生优育方面应用广泛。–检查胎儿的染色体可用于胎儿早期遗传疾病的检查ChromosomeBanding/KaryotypingBandingpatternisduetodifferentialstainingofdifferentregionsofagivenchromosomeKaryotypeanalysis1.Getaphotoofchromosomes2.Cutoffeachchromosome3.Pairingthehomologouschromosome4.Drawabaselineinapieceofpaper5.Arrangethechromosomeaccordingtotherulesshowninpreviouspage6.Measureeacharmsofthechromosomepair7.Calculatethefractionofeacharminthetotalarms’length8.Gettheshort/longarmratioforeachpairofchromosome9.Doastatisticsforatleast30photos染色体核型分型(Karyotyping)•染色体核型分析是遗传学科学研究和辅助临床诊断的重要手段之一,是分析染色体异位和缺失,诊断各种遗传疾病的关键指标。•染色体计数•染色体边缘着色(便于分辨接触的染色体)•分割接触及重叠的染色体•选择G