Cytogentetics lecture

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Cytogenetics

2005

Cytogenetics
The study of chromosome and the related disease states caused by abnormal chromosome number and\or structure. Chromosomes : complex structures located in the cell nucleus, composed of DNA, histone and non-histone proteins, RNA, and polysacchairdes.

History of human cytogenetics
“Dark Ages’’ ( prior to 1952 )
no. of chromosomes = 48.

The “HypotonicEra” started in 1952
no. of chromosomes = 46.

The “Trisomy Period”. The “Banding Era”. The “Molecular Era”.

Cell Division – Meiosis I& II

Karyotype preparation

Chromosomes Banding
Type
Q-banding

Stain
Quinacrine

Area Stained
Chromosome arms; mostly repetitive AT-rich DNA

Effect
Under UV light, distinct fluorescent banded pattern for each chromosome. Distinct bandedpattern for each chromosome; same as Q-banding pattern except single additional band near centromere of chromosomes 1 and 16 Reverse banding pattern of that observed with Q- or Gbanding

G-banding

Giemsa

Chromosome arms; mostly repetitive AT-rich DNA

R-banding

Variety of techniques

Chromosome arms; mostly unique GC-rich DNA

C-banding

Variety of techniques

Centromere regionof each chromosome and distal portion of Y chromosome; highly repetitive, mostly AT-rich DNA

Largest bands usually on chromosomes 1, 9, 16, and Y; chromosomes 7, 10, and 15 have medium-sized bands; size of C-bands highly variable from person to person

NonNon-Banded Karyotype

G-Banding/chromosome morphology

Ideograms

Chromosome Morphology

Normal Karyotype

Low/HighResolutions Karyotype

18
7

Q-Banding

C-Banding

R-Banding

Changes in number, or sets, of chromosomes
(3n, 4n, etc) plants > animals. B) Aneuploidy – change in the no. of chromosomes nullisomy 2n-2 monosomy 2n-1 trisomy 2n+1 tetrasomy 2n+2 Gene dosage effect 1- Sex-chromosomal aneuploids . 2- Autosomal aneuploids .

A) Polypoidy – change in complete sets of chromosomes

Changesin structure of individual chromosome
A) Chromosome rearrangements: Effects Deletion. Duplication. Inversion – paracentric pericentric Translocation. B) Fragile-X Syndrome. C) Cancer/mutations.
pseudodominance dicentric chr. gene dosage positional positional new linkage rearrangement

Fragile-X-Syndrome

Advantages and Disadvantages of conventional technique

Advantages
1-Enable the entire genome to be viewed at one time. 2- Suitable when a specific anomaly is suspected ( e.g. Philadelphia in CML ) and as a general diagnostic tool to detect additional chr. Abnormalities commonly seen in disease progression of CML.

Disadvantages
1- Detect major structural abnormalities
( one band = 6mb of DNA ~ 150 genes ).

2- Labor intensive and highly dependent uponoperator experience and skills.

Fluorescence in situ hybridization (FISH)
Increased the sensitivity , specificity ,and resolution of chromosome analysis. Fluorescently labeled DNA probe ~40 kb.to detect or confirm gene or chromosome abnormalities that are beyond the resolution of routine cytogenetics. Metaphase FISH Interphase FISH

MetaphaseMetaphase- FISH

InterphaseInterphase-FISH Fluorescence in situ hybridization (FISH) I. Microdeletion Syndromes
Cri-du-chat (5p-). Miller-Dieker syndrome (7q11.23). Smith-Magenis syndrome (17p13.3). Steroid Sulfatase Deficiency (Xp22.3). DiGeorge/Velo-cardio-facial/CATCH-22/ Shprintzen Syndrome (22q11.2). Kallman Syndrome (Xp22.3). Williams Syndrome (7q11.23). Wolf-Hirsch horn (4p-). Prader-Willi/Angelman Syndrome (15q11.2-13). X-LinkedIcthyosis (xp22.3). Retinoblastoma (13q14).

DiDi-George Syndrome

II. Trisomy Detection and Sex Determination
Probes for chromosomes 13,18,21,X,Y and SRY.

III. Oncology
Single Gene Probes( deletion or amplification)
P58 CLK-1 Locus (1p36). D7S486 (7q31). Retinoblastoma (13q14). P53 (17p13.1). Her-2/ neu (17q11.2-q12).

OncologyOncology-cont.
Enumeration probes for all chromosomes...
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