遗传学英文课件：Chromosome-12a

1、,Chapter Five Chromosome Disorders,Jin Fan, ,1. Chromatin and chromosome,Euchromatin: Slightly and evenly stained, non- or low-repetitive DNA regions Heterochromatin: Darkly and unevenly stained, highly repetitive DNA regions,Chromatin in nucleus,Chromatin composition,Double helix,Nucleosome fiber,S

2、olenoid,Interphase nucleus,Chromatin is the basic components in the cell nucleus Composed of DNA, histones and non-histone proteins,From Chromatin to Chromosome,Different mode of chromatin in metaphase Resulted from highly compaction of chromatin:,Cell Cycle,Chromosome Preparation,Cell culture: Peri

3、pheral blood: PHA stimulating Fibroblast from varous cells Bone marrow for leukemia Amniotic fluid cell for fetal diagnosis Colchicine arresting metaphase Harvest a great number of metaphases Hypotonic treatment Chromosome spread preparation Identify each chromosome,scaffold,Telomere,Long Arm,Short

4、Arm,Chromatid,Chromatids, two after S-phase Centromere Long arm and short arm Telomere,2. Chromosome identification,1. Morphology of chromosome Length RL: Relative length, Ch L / total L of a haploid set Position of centromere AI: Arm index, Long arm L( q ) / Short arm L ( p ) CI: Centromere index,

5、q / Ch L,Metacentric Ch. CI: 1/25/8,Submetacentric Ch. CI: 5/87/8,Acrocentric Ch. CI: 7/8,Satellite,Centromere,Metacentric Ch,Submetacentric Ch,Acrocentric Ch,Short Arm,Long Arm,Satellite arm,International System for Human Cytogenetic Nomenclature ISCN, Denver,1. Rl: from large to small Chromosome l

6、ength: from long to short 2. CI: from small to large Centromere position: from low to high 3. Variable heterochromatic region: 1qh, 9qh, 16qh, Yq Satellite and satellite arm of acrocentric chromosomes,2. Banding of chromosome,Q bands: Caspersson (1970) Quinacrine mustard Fluorescence microscopy Brig

7、ht and dim bands,Giemsa bands: Trypsin digestion Giemsa staining Permanent Dark and light bands,G Bands,Reversed bands: Heated, KOH Giemsa staining Permanent Dark and light bands reversed to G bands,R Banding,Heated, KOH Giemsa staining Heterochromatin in the centromeres, long arm of the Y and 1qh ,

8、 9qh and 16qh,C Bands,Nomenclature of human chromosome,Sister chromatids,Short Arm, p,Long Arm, q,Telomere,Zone,Band,Centromere,heterochromatin,Zones and bands of the chromosme,band,zone,arm,Ch,Chromosomes in different stages of phases of cell cycle More detailed analysis,High-resolution bands,Fluor

9、escence In Situ Hybridization （FISH）,Using DNA probe labeled with a certain marker Hybridizing with DNA in chromosomes and nuclei on slides Probes hybridized with the fragment in chromosome are detected by signals from the labeled markers,Ch.,+Probe,Co- (denature),(anneal),Rapid mapping of genes and

10、 sequences in chromosome Detecting small fragment in interphase. Detecting cryptic rearrangements or small deletions Banding could not be detected 4Mb,Fragile Sites,46, Y, fra(X)(q27-28) Non-staining gaps that occasionally observer at charcteristic sites on several chromosomes Depend on growth condi

11、tions Heritable variants,Lable test DNA with green,Hybrized onto male chromosomal preparation,1：1 mixed,Lable normal DNA with red,Comparative Genomic Hybridization (CGH),CGH,Compare the intensity of two fluorochromes along the chromosome set. Detection of duplication or deletion of chromosomal segme

12、nt.,Array CGH，aCGH,Euploid,46,XX,46,XY,arr (12)(pter-qter)1, -12,arr (9)(q12-qter)3, (15)(q12-qter)1, der t(12q;15q),3. Chromosome abnormalities,(1). Numerical chromosomal abnormalities Heteroploidy: A chromosome complement with chromosome number other than 46 Euploidy: A chromosome complement with

13、an exact multiple of the haploid chromosome number Aneuploidy: A chromosome complement with chro-mosome number other than an multiple of the haploid chromosome number,A. Euploidy:Monoploidy and Polyploidy,1N: Monoploidy 23X or 23Y: in parthenogenesis 3N: Triploidy 69, XXX or 69, XXY in partial mole,

14、 aborted fetus and liveborn who does not survive long 4N: Tetraploid 92, XXXX or 92, XXYY in aborted fetus,Triploidy,13-green, 21-red,Triploidy,parthenogenesis,Imprinting: The expression of the phenotype depends on whether the gene or genome inherited from the father or mother.,Loss or gain of chrom

15、osomes (not multiple of a haploidy) Monosomy 2n-1: one instead of a pair of homologous chromosomes Trisomy 2n+1: three instead of a pair of homologous chromosomes,(2). Aneuploidy,Monosomy,Resulted from nondisjunction of the homologous chromosomes (meiosis I) or sister chromatids (mitosis or meiosis

16、II).,Trisomy,a. Monosomy,Almost all monosomy for an entire chromosome is lethal Turners syndrome: 45,X, the only monosomy can be born and survive,45,X,Typical Turners syndrome,Short stature Gonadal dysgenesis: steak gonads Unusual faces, webbed neck, low posterior hairline, broad chest with widely s

17、paced nipples,b. Trisomy,Trisomy 21, Downs syndrome 47, XY, +21,Trisomy 21 Downs syndrome,Most common trisomy 1:800 in new born Most common sever mental retardation,Eyes with brushfield spot Flat nosal bridge Low set ear Open mouth with protruding tongue Short and broad hand with a single transverse

18、 palmar crease,Trisomy 21 Downs syndrome,Related with advanced maternal age,Trisomy 21 Downs syndrome,Trisomy 18 Edwards syndrome,1:7500 in liveborn and more common in abortion and stillbirth Sever mental retardation and multiple structural anomalies,18-green, X-aqua,Trisomy 18 Edwards syndrome,47,

19、XY, +18,Trisomy 13Pataus syndrome,1:20,000 in liveborn and more common in abortion and stillbirth Sever structural anomalies lead to death in one month,Trisomy 13Pataus syndrome,13-green, 21-orange,47, XY, +13,XXY, Klinefelters syndrome,1:1,000 in male liveborn Hypogonadism and Infertility: Tall sta

20、ture Long limbs Small genitalia Gynecomastia,XXY, Klinefelters syndrome,X-green, Y-red,47, XXY,47, XYY syndrome,1:1,000 in male live birth Normal intelligence and normal appearance but: Educational problem: language delays and spelling difficulties Behavioral problems: attention deficits, hyperactiv

21、ity and impulsiveness Fertility problem: increase risk of chromosomal abnormal child,47, XYY syndrome,47, XYY,47, XXX syndrome,1:1,000 in Female live birth Normal intelligence and normal appearance A significant deficit in performance on IQ tests 70 % with some learning problems Infertility: 50%,47,

22、 XXX syndrome,47, XXX,XXXXX Syndrome,Why? Autosome: only trisomy 21, 18 and 13 found in live-birth, no monsomy Sex chromosome in livebirth: XO, XXX, XXY, XYY, XXXX, XXXXX,50, XXXXX,X chromosome inactivation and XIST,Gene dosage compensation is achieved in all persons with two or more X chromosomes i

23、n their genetic constitution by partial inactivation of all X chromosomes except one. The process is controlled by XIST (X inactive specific transcripts) gene in Xq13.2, which encodes a large RNA that appears to coat the X chromosome and facilitate inactivation of genes on the X chromosome.,During t

24、he late blastocyst stage, all X chromosomes except one undergo heterochromatinization and form X chromatin bodies in each cell. The balance of gene dosage on X chromosome is achieved. The explanation of various kinds of X polysomies in live-birth.,Barr body,(3) Mosaic and chimera,Mosaic,Chimera,Aber

25、ration,Aberration,Mosaic and chimera,45,X/47,XXX,Resulted from chromosome breakage and reunion. Balanced structural abnormality With normal complement of chromosomal material Unbalanced structural abnormality With loss or gain of chromosomal material,(2). Abnormalities of chromosome structure,a. Unb

26、alanced structure abnormality,Deletion: Loss of a chromosome segment Resulted from breakage or unequal cross-over or segregation of balanced abnormality,Cri Du Chat (5p-) syndrome,Deletion: 5p15 Crying sounds like a newing cat Typical features: hypertelorism, epicanthus and retrognathia,Cri Du Chat

27、(5p-) syndrome,5-p-telomere -green,46,XY,5p-; 46, XY, del(5p15:) 46, XY, del(5)(p15:) 46, XY, del(5)(qter-cen-p15:),4p- syndrome,46, XX, del(4)(p16:),Deletion of 22q-, Mosaic,46, XY (40) / 46, XY, del(22)(q13:) (10),Duplication,Gain of a extract chromosome segment in the same chromosome Resulted fro

28、m unequal cross-over or segregation of balanced abnormality,18q23,46,XY,dup (18)(q23),46, XY, dup(18)(pter -cen-q23:q23:qter),46,X, dup(X)(q13q26) 46, X, dup(X)(pter-q26:q13q26:q26-qter),Insertion,Gain of a extract chromosome segment from the different chromosome Resulted from segregation of balance

29、d abnormality,Father 46, XY, t(3;11)(q27;q13), ins(11;3)(q13;p26p13),Son 46, XY, der(11) ins(11;3)(q13;p26p13),Isochromosomes,One arm is deleted and the other duplicated One arm is monosomy and other is trisomy The most common isochromosome is i(Xq),46, X, i(Xq),Ring chromosomes,Formed when a chromo

30、some undergoes two breaks and broken ends of the chromosome reunite in a ring structure,46, X, r(X),Ring chromosome, unstable,Summary of chromosome number abnormality,Deletion Duplication Insertion Ring chromosome Isochromosome,With normal complement of chromosomal material Usually have no phenotypi

31、c effects Repeated abortion, intrauterus fetal death, stillbirth and birth defects due to the abnormal segregation of involved chromosomes in meiosis,b. Balanced structure abnormality,(a) Inversions,A single chromosome undergoes two breaks and is reconstituted with the segment between the breaks inv

32、erted.,Inversion of Chromosome 1,46, XX, inv(1) 46, XY, inv(1),46, XX, inv(1)(q24q32),Pericentric: involving centromere Paracentric: not involving centromere Usually no abnormal phenotype A inversion loop is formed between the pair of chromosomes and may lead to produce unbalanced gametes or offspri

33、ng:,Inversions,Pericentric inversion,The products of meiosis,1/4：Normal 1/4：Inversion 1/2：Partial trisomy and partial monosomy,A inversion loop,Paracentric inversion,The products of meiosis,1/4：Normal 1/4： Bicentric ch. 1/4： Acentris frag. 1/4：Inversion,A inversion loop,Reciprocal Resulted from brea

34、kage of nonhomologous chromosomes, with reciprocal exchange of the broke-off segments,Translocation,Reciprocal Translocation (9;22),t(9;22)(q34;q12) t(9;22)(9pter-cen-9q34:22q21-22qter; 22pter-cen-22q21:9q34-9qter),Reciprocal translocation in meiosis 2:2 separation,High Risk to produce unbalanced of

35、fspring,2:2,Abortion, Fetal death, Birth defects,1/18 Normal, 1/18 carrier，8/9 various kinds of unbalanced,Possible offsprings of Reciprocal translocation,Abortion, Fetal death, Birth defects,Mother: 46, XX, t(11;22)(q24;q12),Normal phenotype,Son: 47, XX, +der(22) t(11;22)(q24;q12)mat,Mental retarda

36、tion Multiple structural abnormalities,Unbalanced derivated from reciprocal translocation of the parents,45,XY,-22,der(6)t(6;22)(p25.3;q11.2) 45,XY,-22,der(6)t(6;22)(6qter-cen-6p25.3:22q11.2-22qter),Robertsonian Translocation,Two acrocentric chromosomes fuse near the centromere region with loss of t

37、he short arms, which carry multiple copies of genes for rRNA.,Only 45 chromosomes with balanced karyotype and phenotype,45, XX, rob t ( 13q14q),t(14q21q) 14 21,Offspring of Rob. translocation,Limitation of resolution of microscopy: 4 Mb DNA Duplication or deletion 4 Mb DNA: Microdeletion Microduplic

38、ation Diagnosis with Fluorescent in-situ hybridization (FISH) with specific DNA probe or comparative genomic hybridization (CGH),(3) Chromosomal micro-abnormality,Parader-Willi Syndromes(PWS),Excessive eating and Obesity Small hands, feet and short stature Hypogonadism Mental retardation,Angelman Sy

39、ndromes(AS),Unusual facial appearance, Short stature Spasticity,Seizure S mental retardation,Similar deletion, Different origin, Associated with gene imprinting,DiGeorge (velo-cardio-facial, 22q11.2 deletion) syndrome,Congenital heart disease (particularly conotruncal malformations) Palatal abnormal

40、ities especially velopharyngeal insufficiency (VPI) Hypocalcemia Immune deficiency Learning difficulties,46, XX, del( 22q11.2),Williams syndrome,Characteristic dysmorphic facies, frequently referred to as elfin facies (100%) Supravalvular aortic stenosis (80%) Variable mental retardation (75%) Chara

41、cteristic cognitive/behavioral profile (90%),Williams syndromeDeletion of 7q11.23 or elastin gene,46, XY, del(7q11.23),Steroid Sulfatase Deficiency and X-Linked Ichthyosis,Deletion of Xp22.3 STS,46, X, del(Xp22.3),X-linked ichthyosis showing thick, large, polygonal, dark-brown scales involving the e

42、xtensor. Steroid sulfatase deficiency during pregnancy in carrier females: Leads to an overall decrease in the levels of estrogen,Steroid Sulfatase Deficiency and X-Linked Ichthyosis,Kallmanns syndromeDeletion of Xp22.3 KAL,Congenital reduced pituitary gonadotropic activity with resulting associatio

43、n of hypogonadism, eunuchoidism and anosmia.,46, Y, del(Xp22.3),Summary of Chromosome disorders,Duplication or deletion of the certain chromosomes or the certain chromosomal segments Number or structure abnormality 0.6 % in live birth and 50% in spontaneous abortions in first-trimester in microscopi

44、c observation,Summary of Chromosome disorders,Involving the changes of a groups of genes: complicated symptom Syndrome: Featured by serious mental retardation, structural abnormality of face, body and multiple organs,Hermaphroditism,Sex Differentiation,Genes, Chromosome Ovary and Tesitis Hormone: fe

45、male hormones, Male hormones Mallerian duct: uterus, fallopian tube Wolffian duct: epididymis. glandula seminalis Exterior genitalia Social, Brain,Sex Differentiation,Two intact and normally functioning X chromosomes, in the absence of a Y chromosome lead to the formation of an ovary Female sex diff

46、erentiation will occur in the presence of an ovary or streak gonads or if no gonad is present 8w: exterior genitalia in all fetus remains like females,Female sex differentiation,A Y chromosome or the presence of the testis-determining factor (SRY) will lead to testicular organogenesis Differentiation of the external genitalia along male lines depends on the action of testosterone and particularly dihydrotestosterone,Male sex differentiation,SRY F m m,1. True Hermaphroditism,Both