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Chromosomal Disorders 张咸宁 [email protected] Tel:13105819271; 88208367 Office: A705, Research Building 2012/09 Chromosome Disorders Are A Major Category of Genetic Disease • Large proportion of: – Reproductive wastage (miscarriages) – Congenital malformations – Mental retardation • Significant role in pathogenesis of malignancy Chromosome Disorders Are A Major Category of Genetic Disease • Specific chromosomal abnormalities are: – Responsible for >100 identifiable syndromes – Collectively more common than all of the Mendelian single gene disorders together! Chromosome Disorders Are A Major Category of Genetic Disease – ~ 1% of live births – ~ 2% of prenatal diagnoses in women >35 yrs old – 50% of all first trimester spontaneous abortions What are the indications for ordering a chromosome analysis? • Growth and developmental abnormalities • Pregnancy with “advanced maternal age” (AMA) • Family history of chromosome abnormalities • Stillbirth/neonatal death • Infertility • Infertility/history of pregnancy loss • Neoplasia How is a karyotype(核型) prepared? • • • • • Sample: blood, skin, amnio, CVS Cells grown in culture Blocked in metaphase using colchicine Spread on slide and stained Abnormalities detected by number, morphology and banding pattern • • • • • Anatomy Centromere Chromosome placement p (short arm) q (long arm) Size Banding pattern (Giemsa stain) – Heterochromatin 异染色质 (inactive, condensed) - dark – Euchromatin 常染色质 (active, decondensed) - light Interphase & Metaphase Nuclei Giemsa Staining (G-banding) Normal Human Male Karyotype Individual Chromosomes Cut from Metaphase Spread Ideogram of Human Male G-banded Metaphase Chromosomes (400 bands per haploid karyotype) Abnormalities of Chromosome Number • Heteroploid(异倍体) – Any chromosome number other than 46 (1) Euploid (整倍体) – An exact multiple of the haploid chromosome number (n), where n = 23 (2) Aneuploid (非整倍体) – Any chromosome number that is not an exact multiple of the haploid number (n) Triploidy(三倍性) • Most often due to fertilization by two sperm (dispermy) or occasionally a diploid sperm or egg • Partial hydatidiform moles (remnants of placenta ± small atrophic fetus): triploid with extra paternal set – Mole: from the Latin mola, for false conception • Extra maternal set: early spontaneous abortions Molar pregnancies • Partial mole: remnants of fetal tissue (embryonic and/or extraembryonic) • Triploid, paternal • Complete mole: no fetal tissues • Risk for ovarian teratoma or choriocarcinoma • Diploid but all chromosomes are maternal or paternal, respectively Aneuploidy(非整倍性) • Trisomy(三体): three copies – 47,XY+21: Down syndrome • Monosomy (单体) : one copy – 45,X: Turner syndrome • Nondisjunction(不分离): failure of a pair of chromosomes to separate (to disjoin) normally in meiosis I or II Different Consequences to the Gamete of Nondisjunction at Meiosis I or Meiosis II both parental 21s present 2 copies of one parental 21 Abnormal Male Karyotype: 47,XY +21 Down syndrome • Most common trisomy 1:800 in new born • Most common sever mental retardation • Related with advanced maternal age Down syndrome Down syndrome Trisomy 18 (Edward syndrome) • 1:7500 in liveborn and more common in abortion and stillbirth • Severe mental retardation and multiple structural anomalies Trisomy 18 Trisomy 13 (Patau syndrome) • 1:20,000 in liveborn and more common in abortion and stillbirth • Severe structural anomalies lead to death in one month Trisomy 13 Trisomy 13 Monosomy • Almost all monosomy for an entire chromosome is lethal • Turner syndrome: 45,X, the only monosomy can be born and survive Turner syndrome XXY, Klinefelter syndrome • 1:1,000 in male liveborn • Hypogonadism • Infertility Abnormalities of Chromosome Structure • Balanced: nothing gained or lost • Unbalanced: material gained or lost Balanced Rearrangements (平衡性重排) • Individuals with balanced rearrangements appear normal • Therefore, they may not be detected until: – Birth of a child with an unbalanced rearrangement – Infertility evaluation (recurrent pregnancy loss) Balanced and Unbalanced Translocations (平衡易位、非平衡易位) Translocation • Reciprocal ~ (相互易位) Resulted from breakage of nonhomologous chromosomes, with reciprocal exchange of the broke-off segments Reciprocal Translocation (9;22) Robertsonian Translocation (罗氏易位) • Two acrocentric chromosomes fuse near the centromere region with loss of the short arms, which carry multiple copies of genes for rRNA. • Only 45 chromosomes with balanced karyotype and phenotype 45, XX, rob ( 13q14q) Balanced translocation in meiosis High Risk to produce unbalanced offspring Translocation Down Syndrome • 4% of all Down cases • One chromosome is a Robertsonian translocation • 21q + q of another acrocentric chromosome, usually 14 or 22 • 46,XX,rob(14;21),+21 or 46,XY,rob(14;21),+21 Down syndrome:21/21 t Offsprings Down syndrome: t Down syndrome: t The Tools: Cytogenetic Analysis Conventional Karyotyping SKY(spectral karyotyping) What is FISH? 13 12 p 11.2 11.1 11.1 11.2 12 11.2 13 12 13 14 15 21.1 21.2 21.3 22.1 22. 2 q 22.3 23 24 p q 25 26.1 26.2 26. 3 13 12 11.2 11.1 11.1 11.2 12 13 14 15 21.1 21.2 21.3 22.1 22. 2 22.3 23 24 25 26.1 26.2 26. 3 Norma l chromo some 15 Dupl ica tion ch romos ome 15 • Fluorescence in situ hybridization • Detects a specific position or gene on an intact chromosome • Can be used to detect numeric problems or rearrangements – Banding could not be detected < 4Mb Fluorescence In Situ Hybridization(FISH) Cs+ Probe Co-denature Anneal,hybridize • 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 Down syndrome----FISH Chromosome Painting Specific Cytogenetic Changes in Cancer • Association of cytogenetic changes with specific forms of cancer • Breakpoints may be associated with structural rearrangements of oncogenes • Cytogenetic changes in cancer are numerous and diverse – Many seen repeatedly in same type of tumor – Evaluate by FISH and chromosomal painting Philadelphia Chromosome in Chronic Myelogenous Leukemia Ph Chromosome FISH 嵌合体:Mosaic and chimera Aberration Mosaic Aberration Chimera Submicroscopic polymorphic chromosome region copy number variants are increasingly being detected by high-resolution techniques such as aCGH. Array Comparative Genomic Hybridization (aCGH) Suggested Readings Acknowledge(PPT特别鸣谢!) • UCLA David Geffen School of Medicine • www.medsch.ucla.edu/ANGEL/ • Prof. Grody WW (Divisions of Medical Genetics and Molecular Pathology), et al.