遺傳往屆肽鏈從核蛋白體釋放后經(jīng)過細(xì)胞內(nèi)各種修飾處理成為有活性的成熟蛋

1、Post-Translation ProcessingPost-translational modifications:肽鏈從核蛋白體釋放后，經(jīng)過細(xì)胞內(nèi)各種修飾處理成為有活性的成熟蛋白質(zhì)的過程。Primary translation product is folded and bonded into a specific three-dimensional structure.Two or more polypeptide chains combine to form a single mature protein complex.Cleavage of the protein The pro

2、tein products may also be modified chemicallySTRUCTURE OF HUMAN CHROMOSOMES Composition of ChromatinDNAProteins (histones and nonhistone) The basic structure unit of chromatin: Nucleosome H1, (H2A, H2B, H3, H4)2(H2A,H2B,H3,H4)ORGANIZATION OF THE HUMAN GENOMESingle-copy or unique DNARepetitive DNASin

3、gle-Copy DNA SequencesOnce or a few times /a genomeShort stretches (several kb)Coding portion of genes: a small proportion of all the single-copy DNARepetitive DNA FamiliesDefinition Hundreds to millions of times in the genomeRole Maintain chromosome structureCategoryClustered repeated sequencesDisp

4、ersed repeated sequencesPrinciples of Clinical CytogeneticsYuxia YangDepartment of Medical Genetics, Peking University Health Science CenterKey Points Introduction Karyotype Classification of Human Chromosome Human Chromosome Identification Categories Definitions Mechanisms Chromosome AbnormalitiesI

5、ntroduction to CytogeneticsClinical indications for chromasome analysis Cytogenetics: the study of chromosomes and their abnormalities is called cytogenetics.The Human KaryotypeThe chromosomes are classified into 7 groups (A-G) Karyotype：是指一個體細(xì)胞中的全部染色體，按照大小、形態(tài)特征順序排列所構(gòu)成的圖像Centromere (primary constric

6、tion) 、p (short arm) 、 q (long arm) G bandingA chromosome at metaphase chromatid 染色單體 chromatid 1 chromosome p qTelomere（端粒）telomereCentromere（著絲粒）(primary constriction)topa,b: metacentric（中央著絲粒） c,d: submetacentric（亞中著絲粒） e: acrocentric（近端著絲粒） f: telocentric（端著絲粒）Classification of Human Chromosomes

7、A Normal male Karyotype: 46,XYChromosome Identification Identification of Human Chromosomes stained A uniform system of chromosome classification ISCN (An International System for Human Cytogenetic Nomenclature)Chromosome IdentificationG Banding: trypsin(胰蛋白酶) 、 Giemsa(姬姆薩)Q Banding: quinacrine must

8、ard(喹吖因氮芥) R Banding: special treatmemt (heating) 、 staining 、 the reverse of G or Q bandingG BandingQ BandingR bandingIdeogram showing G banding patterns for human chromosomes at metaphaseChromosome Identification Identification of Human Chromosomes stained A uniform system of chromosome classifica

9、tion ISCN (An International System for Human Cytogenetic Nomenclature)ISCN規(guī)定的界標(biāo)：著絲粒、端粒、明顯的帶Arm Region Band Sub-bandXq13Chromosome Identification C Banding: staining the centromeric region、 other constitutive heterochromatin regionsHigh-Resolution Banding: chromosomes stained at the stage of prophase

10、 or prometaphase, detecting a subtle structural abnormality(前中期、晚前期的單倍染色體帶紋數(shù)可達(dá)550-850條帶;典型中期染色體，一套單倍染色體帶紋數(shù)約320-400條帶 )C BandingHigh-Resolution Banding Fluorescence In Situ Hybridization (FISH:熒光原位雜交)Principles: Labeling probe with a fluorescent dye Denature of the probe and metaphase、prophase or int

11、erphase chromosomes Hybridization Visualizing the location of hybridization under a fluorescence microscopeChromosome Identification Probes: three typesgene-specific or locus-specific probes, repetitive DNA probes (satellite DNA probes) chromosome painting probes (probes for entire chromosomes or ch

12、romosome arms)one-color, two-color, three-color, multicolorA single-copy DNA probe specific for the factor VIII gene on the X chromosomeMetaphase：中期Interphase:間期A repetitive alpha satellite DNA probe specific for the centromere of chromosome 17MetaphaseInterphaseA whole chromosome “paint” probe spec

13、ific for the X chromosomeMetaphaseInterphaseSpectral karyotyping (SKY：光譜核型分析) Application: to examine the presence or absence of a particular DNA sequence to diagnose the existence of an abnormal chromosome number in clinical materialto detect chromosome rearrangements with combinations of FISH prob

14、eschromosome 18 aqua, X chromosome green, Y chromosome redchromosome 18 aqua, X chromosome greenchromosome 13 green, chromosome 21 redPrader-Willi syndromedemonstrating deletion of 15q11-q13 Green：alpha satellite DNA at the chromosome 15 centromereRed：SNRPN geneChromosome AbnormalitiesAbnormalities

15、of Chromosome NumberAbnormalities of Chromosome StructureAbnormalities of Chromosome Number Euploid Variation：以染色體組為單位發(fā)生的染色體成倍的增減。 Aneuploid Variation：細(xì)胞內(nèi)染色體數(shù)目增加或減少一條或幾條。Triploidy and Tetraploidy Triploid(三倍體) Definition: 3nReason: dispermy(雙受精) (most common)、 digyny(雙雌受精)Phenotypic expression: pate

16、rnal-abnormal placenta; maternal-abortionkaryotypes: 69,XXX; 69,XXY; 69,XYYdispermydigyny Tetraploid(四倍體)Definition: 4nReason: endoreduplication (核內(nèi)復(fù)制), endomitosis (核內(nèi)的有絲分裂) Karyotypes: 92,XXXX or 92,XXYYAneuploidy TrisomyDefinition: a trisomic cell involves a single extra chromosome; that is, the

17、cell has three copies of a particular chromosomes and two copies of other chromosomes. A trisomic cell is 2n+1Example: trisomy 21 (karyotype: 47,XX/XY,+21) MonosomyDefinition: a monosomic cell involves a loss of a single chromosome; that is, the cell is 2n-1.Example: Turner syndrome (Turner syndrome

18、 karyotype: 45, X)MechanismMeiotic(減數(shù)分裂)nondisjunction (most common): the failure of a pair of chromosomes to disjoin properly during one of the two meiotic divisions, usually during meiosis I. The propensity of a chromosome pair to nondisjunction has been strongly associated with aberrations in the

19、 frequency or placement, or both, of bination events in meiosis I.Premature separation of sister chromatids : in meiosis I in stead of meiosis II, the separated chromatids may by chance segregate to the oocyte(卵母細(xì)胞)or to the polar body, leading to an unbalanced gamete(配子).Mitotic (有絲分裂)nondisjunctio

20、n: nondisjunction can occur in a mitotic division after formation of the zygote (受精卵). If this happens at an early cleavage division, clinically significant mosaicism may result.46464646464745nondisjunctionmitotic nondisjunction-mosaicism醫(yī)學(xué)遺傳學(xué)實驗調(diào)課通知實驗課時間為第2，4，5周下午（醫(yī)實、臨床7班、臨床9班、預(yù)防、口腔-2班、醫(yī)檢）實驗課時間為第3，6

21、，7周下午（口腔-1班、臨床8班）注意：醫(yī)實、臨床7班、9班時間調(diào)整為周二下午13：30 醫(yī)檢調(diào)整為周五下午13：30 口腔-1班、臨床8班調(diào)整為周五下午13：30 地點(diǎn)：細(xì)胞樓三層，具體教室分配見三層宣傳欄 Abnormalities of Chromosome StructureMechanism: chromosome breakage 、 reconstitution in an abnormal combinationIncidence: 1 in 375 newborns Types of structure rearrangementsBalancedUnbalancedUnba

22、lanced RearrangementsDeletion (del)Definition: is a chromosomal mutation in which part of a chromosome is missingIncidence of autosomal deletions: 1/7000 live birthTypes: terminal, interstitialKaryotype: 46,XX,del(1)(q21) 46,XX,del(1)(pterq21:)Terminal deletionLoss常見染色體結(jié)構(gòu)畸變的描述方法：按國際規(guī)定的要求，依次先寫明染色體總數(shù)，

23、性染色體組成，然后用一個字母（如t）或三聯(lián)字符號（如del）說明重排染色體類型的名稱，其后在括號內(nèi)寫明有關(guān)的染色體號數(shù)，接著在另一括號內(nèi)注明區(qū)、帶號以表示斷裂點(diǎn)。簡式：只用其斷點(diǎn)來表示： 46, XX, del(1)(q21)；繁式：在最后括弧內(nèi)，描述染色體重排的帶的組成： 46, XX, del(1)(pterq21:)Karyotype: 46,XX(XY),del(3)(q21q31) 46,XX(XY),del(3)(pterq21:q31qter) LossInterstitial deletionReasons: Deletions may originate simply by

24、chromosome breakage and loss of the acentric segment. Unequal crossing over between misaligned homologous chromosomes or sister chromatids.Deletions can also be generated by abnormal segregation from a balanced translocation or inversionDuplication (dup)Definition: is a chromosomal mutation that res

25、ults in the doubling of a segment of a chromosome.正位重復(fù)反位重復(fù)Duplication (dup)Reasons: Can originate by unequal crossing overBy abnormal segregation from meiosis in a carrier of a translocation or inversion.Marker and Ring ChromosomesMarker Chromosome (mar)Definition: very small unidentified chromosome

26、s, called marker chromosomes, are also referred to as supernumerary chromosomes or extra structurally abnormal chromosomes (ESACs)Ring Chromosome (r)Definition: deletions sometimes occur at both tips of a chromosome. The remaining chromosome ends can then fuse, forming a ring chromosome.ring chromos

27、omelosslosslossIsochromosomes (i)Definition: is a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion.isochromosomereplicationafter replicationafter replicationisochromosomesIsochromosomes (i)Mechanisms: Misdivision through the centromere in meiosis II Exchange

28、involving one arm of a chromosome and its homolog (or sister chromatid) at the proximal edge of the arm, adjacent to the centromere.Isochromosomes (i)Common Isochromosomes: i(Xq) i(18p) i(12p) Dicentric(雙著絲粒 ) Chromosomes (dic)Definition: a dicentric is a rare type of abnormal chromosome in which tw

29、o chromosome segments (from different chromosomes or from the two chromatids of a single one), each with a centromere, fuse end to end, with loss of their acentric fragments.dicentric chromosomeBalanced RearrangementsInversions (inv)Definition: occurs when a single chromosome undergoes two breaks an

30、d is reconstituted with the segment between the breaks inverted.Types: Paracentric (not including centromere) Pericentric (including centromere)ParacentricKaryotypes: 46,XX,inv(1)(p22p34) 46,XX,inv(1)(pterp34:p22p34:p22qter)PericentricKaryotypes: 46,XX,inv(2)(p15q21) 46,XX,inv(2)(pterp15:q21p15:q21q

31、ter)Inversion carrier: a carrier of either type of inversion is at risk of producing abnormal gametes that may lead to unbalanced offspringABACDBCDThe risk that a carrier of a paracentric inversion will have a liveborn child with an abnormal karyotype is very low indeed.ABACDBCD臂間倒位攜帶者在形成生殖細(xì)胞的減數(shù)分裂過程

32、中，根據(jù)在配子形成中同源染色體節(jié)段相互配對的規(guī)律，它將形成倒位圈，并且，經(jīng)過在倒位圈內(nèi)的交換，形成4種不同的配子，一種為正常染色體，一種為倒位染色體，另外兩種均帶有部分重復(fù)及部分缺失的重排染色體。這兩種異常重排染色體各有一個著絲粒，屬于穩(wěn)定性畸變而可往后傳遞。因此其遺傳效應(yīng)主要決定于重復(fù)和缺失片段的長短及其所含基因的致死效應(yīng)。一般來說，其倒位片段越短，則重復(fù)和缺失部分越長，形成配子和合子正常發(fā)育的可能性越小，臨床表現(xiàn)為婚后不育、早期流產(chǎn)和死產(chǎn)的比例越高，娩出子女的可能性相對低；而倒位片段越長，則其重復(fù)和缺失部分越短，其配子和合子正常發(fā)育的可能性越大，娩出畸形胎兒的危險性相對較高Transloc

33、ations (t)Definition: involves the exchange of chromosome segments between two, usually nonhomologous chromosomesMain types: reciprocal, RobertsonianReciprocal Translocations (rcp)Definition: this type of rearrangement results from breakage of nonhomologous chromosomes, with reciprocal exchange of t

34、he broken-off segments.Karyotypes:46, XX, t(2;5)(q21;q31)46, XX, t(2;5)(2pter2q21:5q315qter;5pter5q31:2q212qter)reciprocal translocationCarriers of balanced reciprocal translocation: are associated with a high risk of unbalanced gametes and abnormal progenyFigure 9-12. A, Diagram of a balanced trans

35、location between chromosome 3 and chromosome11, t(3;11)(q12;p15.5)平衡易位攜帶者在形成生殖細(xì)胞的減數(shù)分裂的前期I時，易位染色體將在聯(lián)會時配對形成四射體。至后期I時，相關(guān)染色體可進(jìn)行對位分離和鄰位1和鄰位2分離以及3:1分離。其中，僅有一種配子是正常的，一種是平衡易位的，其余都是不平衡的。與正常配子受精后所形成的合子中，大部都形成單體或部分單體、三體或部分三體患胎而導(dǎo)致流產(chǎn)、死胎或畸形兒。Pairing at meiosisSegregationUnbalanced Unbalanced Normal balancedUnbala

36、nced Unbalanced(50%)(50%)(rare)(inviable)(inviable)(viable)Robertsonian Translocations (rob)Definition: this type of rearrangement involves two acrocentric chromosomes that fuse near the centromere region with loss of the short arms羅伯遜易位：又稱著絲粒融合。兩條近端著絲粒染色體在著絲粒部位或著絲粒附近部位發(fā)生斷裂后，兩者的長臂在著絲粒處結(jié)合在一起，形成一條由長臂構(gòu)成的衍生染色體，兩個短臂則構(gòu)成一個小染色體，小染色體往往在第二次細(xì)胞分裂時丟失，這可能是由于缺乏著絲?；蚱渫耆僧惾?/p>