染色體畸變結(jié)構(gòu)改變

1、Chromosomal Abnormalities(染色體畸變),Cytogenetics (細(xì)胞遺傳學(xué)) is the field of study involving examination of the genetic material of the cells.The genetic material (DNA) is contained in chromosomes. Each organism has a ch

2、aracteristic number and arrangement of chromosomes.,Introduction,A karyotype （核型） is a photograph of the chromosomes at metaphase, when they are most easily seen.In a karyotype, the chromosomes are arranged by pairs: a

3、lterations in chromosome size (structure) or number are seen here.,Normal Human Karyotype,A normal human cell contains 46 chromosomes: 22 pairs of autosomes（常染色體）, and two sex chromosomes.,Chromosomal Abnormalities,Chrom

4、osomal abnormalities can be of two types. (1) Structural(結(jié)構(gòu)) abnormalities are caused by breaks in the chromosome being incorrectly repaired. “Ends” of broken chromosomes are very unstable in a cell. (2

5、) Numerical(數(shù)目) abnormalities are caused by gain or loss of chromosomes.,Common Structural Abnormalities,(1) Deletions (缺失)：loss of genetic material(2) Inversions (倒位): no change in the amount of genetic material,Commo

6、n Structural Abnormalities,(3) Duplications(重復(fù)): gain of genetic material(4) Translocation(易位): no change in the amount of genetic material (if balanced),(一) Deletions,①頂端缺失(Terminal Deletions )：指缺失的區(qū)段位于染色體某臂的外端。 ②中間缺

7、失(Interstitial Deletions )：指缺失的區(qū)段位于染色體某臂的中間。,(1)無著絲粒斷片：最初發(fā)生缺失的細(xì)胞在分裂時(shí)可見落后染色體——無著絲粒斷片，(2)頂端缺失 有絲分裂出現(xiàn)因斷裂—融合→雙著絲粒染色體——后期染色體橋。 減數(shù)分裂聯(lián)會時(shí)，有未配對的游離區(qū)段。(3)中間缺失 減數(shù)分裂染色體聯(lián)會時(shí)形成缺失環(huán)。注意：較小的缺失往往并不表現(xiàn)出明顯的細(xì)胞學(xué)特征；缺失純合體減數(shù)分裂過程也無明顯的細(xì)胞學(xué)特征

8、。,缺失的細(xì)胞學(xué)鑒定,,缺失的細(xì)胞學(xué)特征,斷裂(breakage)—融合(fusion)—橋(bridge),頂端缺失的形成(斷裂)復(fù)制姊妹染色單體頂端斷頭連接(融合)有絲分裂后期橋(橋)新的斷裂,,玉米缺失雜合體粗線期缺失環(huán),果蠅唾腺染色體的缺失環(huán),,,(1)缺失的后果 打破了基因的連鎖平衡，破壞了基因間的互作關(guān)系，基因所控制的生物功能或性狀可能喪失或異常。(2)缺失的危害程度 取決于缺失區(qū)段的大小、缺失

9、區(qū)段所含基因的多少、缺失基因的重要程度、染色體倍性水平。 缺失純合體——致死或半致死 缺失雜合體——缺失區(qū)段較長時(shí)，生活力差、配子(尤其是花粉)敗育或育性降低；缺失區(qū)段較小時(shí)，可能會造成假顯性現(xiàn)象或其它異?，F(xiàn)象(貓叫綜合癥)。,缺失的遺傳學(xué)效應(yīng),缺失雜合體的假顯性現(xiàn)象,,Micro Deletions（教材下冊p8 ）,Some genetic syndromes are caused by very small deletio

10、ns in the chromosome in human.These syndromes have been useful in locating genes involved in specific processes.“Cri du Chat” (cry of the cat) is caused by a small deletion at the tip of chromosome 5 in human.,1 in 5

11、0000 newborns,5p－ Syndrome (Cat Cry syndrome),Characteristics,Round, moon-shaped face“Cry of the cat”Varying degrees of mental retardationLow set ears,Cri du chat syndrome,(二)Duplication的細(xì)胞學(xué)特征,,,,重復(fù)的遺傳學(xué)效應(yīng),,重復(fù)對基因平衡的影響：

12、擾亂了生物體本身基因固有的平衡體系，影響了個體的生活力。有害程度：取決于重復(fù)區(qū)段基因數(shù)量的多少及其重要性，與缺失相比，有害性相對較小，但若重復(fù)區(qū)段過長，往往使個體致死。對育性的影響：重復(fù)雜合體一般敗育，重復(fù)純合體會產(chǎn)生“劑量效應(yīng)(dosage effect)”。,果蠅復(fù)眼的小眼組成數(shù)目的劑量效應(yīng),,,,Duplication may be caused by unequal crossover in meiosis.,（三）In

13、version,(1)臂內(nèi)倒位(Paracentric inversion)：指倒位發(fā)生在染色體的某一臂內(nèi)，又稱為一側(cè)倒位。 (2)臂間倒位(Pericentic inversion)：指倒位發(fā)生在兩臂之間（含著絲粒），又稱為兩側(cè)倒位。,Inversion Loop,Inversions do not change the genetic content of a cell, however they have consequenc

14、es for meiotic products (gametes)Top: diagram of inversion loopBottom: EM micrograph of inversion loop during meiosis in a mouse cell,Inversion Loop （倒位環(huán)）,Chromosomes with inverted regions can form “inversion loops” wh

15、en pairing occurs during meiosis.,Paracentric Inversion Crossover,A crossover involving a paracentric inversion (when the centromere is not in the inverted region) produces altered chromosomes. One product has no centro

16、mere (acentric), one has two centromeres (dicentric).,Pericentric Inversion Crossover,A crossover involving a pericentric inversion (when the centromere is in the inverted region) produces altered chromosomes. One produ

17、ct has gained genetic material (a duplication), one has lost genetic material (a deletion).,Dicentric Chromosomes are Unstable,Dicentric chromosomes can be formed from crossovers involving inversions, or in mitotic cells

18、 by “healing” of broken ends.Dicentrics undergo a cyclic “breakage-fusion-bridge” during repeated cell divisions.,倒位的細(xì)胞學(xué)鑒定,細(xì)胞學(xué)特征 同源染色體聯(lián)會時(shí)： 倒位區(qū)段過長——倒過來，其余游離 倒位區(qū)段較短——正常部分配對，其余不配對 倒位區(qū)段適中——形成倒位環(huán)注意:區(qū)分倒位環(huán)與缺失、重復(fù)環(huán)

19、的結(jié)構(gòu)差異, 倒位純合體無明顯細(xì)胞學(xué)特征,,倒位的遺傳效應(yīng),,（1）對基因關(guān)系的影響：倒位改變了基因間的連鎖關(guān)系；因不能正常配對而降低了連鎖基因間的重組率。有害程度：取決于倒位區(qū)段的長短，倒位區(qū)段過長往往致死。,倒位的遺傳效應(yīng),,（2）對育性的影響：倒位雜合體倒位環(huán)內(nèi)發(fā)生交換后，產(chǎn)生的交換型配子(50%)含重復(fù)缺失染色單體，這類配子不育。所以倒位雜合體部分不育。倒位純合的同源染色體聯(lián)會完全正常，但會產(chǎn)生“位置效應(yīng)”。倒

20、位雜合體通過自交（自群繁育），可能產(chǎn)生倒位純合體后代，這些倒位純合體后代與其原來的物種不能受精，形成生殖隔離，產(chǎn)生新的變種，促進(jìn)了生物進(jìn)化.自學(xué)）,(四)Translocation,(1)簡單易位(Simple translocation)(單向)：指一個染色體上的某一區(qū)段轉(zhuǎn)移到了另一非同源染色體上的現(xiàn)象，故又稱為轉(zhuǎn)移。(2)相互易位(reciprocal translocation)：指兩個非同源染色體都被折斷，兩個斷片交換重接到

21、兩條被折斷的非同源染色體上的現(xiàn)象。,When a part of one chromosome is relocated to another chromosome, the result is called a translocationIf parts of two chromosomes “trade places” so no genetic material is lost, it is called a reciproc

22、al (or balanced) translocation,相互易位的細(xì)胞學(xué)鑒定,(1)相互易位雜合體 同源染色體聯(lián)會時(shí)粗線期呈十字形配對終變期呈四體環(huán)（十字形配對結(jié)構(gòu)發(fā)生交叉端化后所形成的大環(huán)結(jié)構(gòu)，用○4表示)或四體鏈（十字形配對結(jié)構(gòu)發(fā)生交叉端化后所形成的鏈狀結(jié)構(gòu)用C4表示)中期I呈8字形或圓環(huán)形（十字形配對結(jié)構(gòu)的交替式分離和相鄰式分離） 交替式分離:產(chǎn)生不育配子。相鄰式分離：產(chǎn)生可育配子(2)相互易位純合體：同源

23、染色體聯(lián)會一切正常。,Balanced Translocations Pair “Oddly” during Meiosis,The translocated portion of the chromosome pairs with its normal homologue in meiotic tetradsAltered segregation affects the gametes: this can be a cause

24、of reduced fertility,Depending on the segregation pattern in a single meiotic division, all of the gametes may have normal DNA content (but half have the translocation), or all of the gametes may be defective (have dupli

25、cation and deletion),Balanced Translocations can Yield Altered Genetic Content in Gametes,易位雜合體的聯(lián)會和分離,果蠅巨染色體易位圖,易位的遺傳學(xué)效應(yīng),（1）降低了連鎖基因間的重組率——易位改變了基因間的連鎖關(guān)系，抑制了正常連鎖群的重組；聯(lián)會的緊密程度降低。（2）易位雜合體半不育出現(xiàn)假連鎖現(xiàn)象——因易位改變了基因間的連鎖關(guān)系，使本應(yīng)獨(dú)立遺傳的

26、基因出現(xiàn)連鎖——假連鎖。,,1960年，Nowell ——慢性粒細(xì)胞白血病(CML),核型：有“標(biāo)記性染色體”,Ph染色體,血液學(xué)特征,Ph染色體,1960年，首先在美國費(fèi)城的CML患者骨髓和外周血淋巴細(xì)胞中，發(fā)現(xiàn)一個很小的異常的近端著絲粒染色體，小于G組染色體(21、22、Y),T(9;22) (22pter→22q11::9q34→9qter) 1973年，Rowley 采用顯帶技術(shù)證實(shí),Ph染色體,der(22)(9; 22)

27、 (q34; q11.2),理論意義：首次證實(shí)了一種染色體畸變與一種特異性腫瘤的關(guān)系，為Boveri提出的“腫瘤染色體理論”提供了實(shí)驗(yàn)證據(jù), 是腫瘤遺傳學(xué)研究的里程碑。,Ph染色體發(fā)現(xiàn)的意義：,臨床意義：①診斷依據(jù)， 大約95%的CML患者的細(xì)胞中有Ph染色體 ②鑒別診斷依據(jù) ③預(yù)后診斷依據(jù),Philadelphia Chromosome and Cancer,Besides meiotic problems, translo

28、cations can produce more specific concernsIn this 9:22 translocation, a specific pair of genes become fusedThe fused gene product (protein) is involved in causing a certain cancer (CML or Chronic Myelogenous Leukemia)

29、The fused protein is called “BCR-ABL”(假連鎖)Newer molecular genetic techniques (such as PCR) are able to detect specific known abnormalities,分子水平：“BCR-ABL”( 稱“假連鎖”，融合基因)經(jīng)過轉(zhuǎn)錄、翻譯產(chǎn)生一個融合蛋白，叫P210，P210具有增強(qiáng)酪氨酸激酶的活性，改變了細(xì)胞多種蛋白質(zhì)酪