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Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes:...

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Human Chromosomes: Human Chromosomes: Genotype/Phenotype Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Muhammad Faiyaz-Ul-Haque, PhD, FRCPath
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Page 1: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Human Chromosomes:Human Chromosomes:Genotype/PhenotypeGenotype/Phenotype

Muhammad Faiyaz-Ul-Haque, PhD, FRCPathMuhammad Faiyaz-Ul-Haque, PhD, FRCPath

Human Chromosomes:Human Chromosomes:Genotype/PhenotypeGenotype/Phenotype

Muhammad Faiyaz-Ul-Haque, PhD, FRCPathMuhammad Faiyaz-Ul-Haque, PhD, FRCPath

Page 2: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

By the end of this lecture, the students should be able to:

Describe the number, structure, and classification of human chromosomes.

Explain what a Karyotype is and how it is obtained. Describe chromosomal banding and explain its

use. Describe the process of in situ hybridization and

the information it provides.

Lecture Objectives:Lecture Objectives:Lecture Objectives:Lecture Objectives:

Page 3: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

G T A C T A

Chromosome

The order of bases in DNA is a code for making proteins. The code is read in groups of three

DNAGene

Cell machinery copies the code making an mRNA molecule. This moves into the cytoplasm.

Ribosomes read the code and accurately join Amino acids together to make a protein

AUG AGU AAA GGA GAA GAA CUU UUC ACU GGA UAG

M S E E LK G TF G

The protein folds to form its working shape

M

S EK G

E L TF G

M

S

E

K

GE L TF G

M

S

E

K

G

EL

TF

G

M

S

E

K

G

EL

TF

G

M

S

E

K

G

EL

T F

G

CELL

NUCLEUSM

S

E

K

G

EL

T F

G

T

G

M

S

E

K

G

EL

F

T

G

M

E

K

G

EL

FSGene ExpressionGene ExpressionGene ExpressionGene Expression

Page 4: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

DNA->RNA->ProteinDNA->RNA->Protein

Nucleus

DNA bases

mRNA

DNA

Protein

Ribosome

Cell membrane

Gene

Chain of amino acids

Page 5: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Eukaryotic cellEukaryotic cellEukaryotic cellEukaryotic cell

Page 6: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

■ Cytogenetics:

The study of the structure and function of chromosomes and chromosome behaviour during somatic and germline division

■ Molecular genetics:

The study of the structure and function of genes at a molecular level and how the genes are transferred from generation to generation.

GENETICS :GENETICS :GENETICS :GENETICS :

Page 7: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Cytogenetics: Cytogenetics: Cytogenetics: Cytogenetics:

Human Cytogenetics involves the study of human chromosomes in health and disease.

Chromosome studies are an important laboratory diagnostic procedure in1)prenatal diagnosis2)certain patients with mental retardation and multiple birth defects3)patients with abnormal sexual development4)some cases of infertility or multiple miscarriages5)in the study and treatment of patients with malignancies & hematologic disorders.

New techniques allow for increased resolution.

Page 8: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Spectral KaryotypeSpectral KaryotypeSpectral KaryotypeSpectral Karyotype

Page 9: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Human ChromosomesHuman Chromosomes

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16

17 18 19 20 21 22 X Y

Page 10: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Cytogenetics:■ Non-Banded Karyotype■ Banded Karyotype■ High resolution Karyotype

Molecular cytogenetics:■ Fluorescent in situ hybridization (FISH).

Page 11: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

10-12 hrs.

6-8 hrs.

2-4 hrs.

Mitotic cell cycleMitotic cell cycleMitotic cell cycleMitotic cell cycle

Page 12: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Centromere

Telomere

Metacentric Submetacentric Acrocentric

Telomere

Arm

Longarm (q)

Shortarm (p)

Chromosome MorphologyChromosome Morphology

Page 13: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

p

q

Arm Region Band Subband

2

1

1

2

21

1

12

3

4

3212154321

12

312312, 34123

17q11.2

Chromosome 17

Defining Chromosomal LocationDefining Chromosomal Location

Page 14: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Metaphase chromosomes: Metaphase chromosomes:

■ Each chromosome has a centromere (CEN), region which contains the kinetochore,

■ The 2 sister-chromatids are principally held together at the centromeric region.

■ CEN divides the chromosome into two arms: the short arm (p arm) and the long arm (q arm).

■ Each arm terminates in a telomere.

A single complete set of chromosomes. (N=23 for humans)

Page 15: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Centromeric position and arm length:Centromeric position and arm length:Centromeric position and arm length:Centromeric position and arm length:

The ratio of the lengths of the two arms is constant for each chromosome.

This ratio is an important parameter for chromosome identification and allows classification of chromosomes into several basic morphologic types: i-metacentric ii-sub-metacentric iii-acrocentric

In the human karyotype chromosome pairs 13, 14, 15, 21, 22 are acrocentric

Page 16: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Translocation Deletion

Insertion

Inversion Isochromosome

Ringchromosome

Derivativechromosome

Chromosome Structure Chromosome Structure AbnormalitiesAbnormalities

Page 17: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

-22 pairs of autosomes, numbered from 1 to 22 by order of decreasing length

-1 pair of sex chromosomes: XX in the female, XY in the male.

Chromosomal classificationChromosomal classificationChromosomal classificationChromosomal classification

Page 18: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

KaryotypingKaryotypingKaryotypingKaryotyping

Based on:1.the length2.the position of the centromere3.the presence or absence of satellites

A B

C

D E

G XF

Page 19: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

46, XY 46, XX

■ Normal Karyotypes

Items in the Description Of Karyotype:Items in the Description Of Karyotype:Items in the Description Of Karyotype:Items in the Description Of Karyotype:

47, XY, + 21

45, XO,

■ Abnormal Karyotypes

Turner Syndrome

Down Syndrome

Page 20: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Visualizing Metaphase Visualizing Metaphase Chromosomes (Banding)Chromosomes (Banding)

• Giemsa-, reverse- or centromere-stained metaphase chromosomes

G-Bands R-Bands C-Bands

Page 21: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

46, XY, t (9;22)(q34;q11)

Page 22: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Fluorescence In-Situ Hybridization Fluorescence In-Situ Hybridization (FISH)(FISH)

Fluorescence In-Situ Hybridization Fluorescence In-Situ Hybridization (FISH)(FISH)

Page 23: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Probe

Interphase or metaphasecells on slide (in situ)

Microscopicsignal (interphase)

Fluorescent Fluorescent in situin situ Hybridization (FISH)Hybridization (FISH)

Hybridization of complementary gene- or region-specific fluorescent probes to chromosomes.

Page 24: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

FISH of interphase nuclei with a chromosome 21 centromeric

probe showing 3 signals consistent with trisomy 21

FISH of metaphase with a probe for telomere showing signals at

the end of each chromatid

Fluorescence In-Situ Hybridization Fluorescence In-Situ Hybridization (FISH)(FISH)

Fluorescence In-Situ Hybridization Fluorescence In-Situ Hybridization (FISH)(FISH)

Page 25: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

Growth is a Complex ProcessGrowth is a Complex Process

FGFs (fibroblast growth factors) - instruct cells to differentiate into cartilage, not divide patterningDominant mutation in FGF receptor 3 is linked to achondroplasia(~95% of all dwarfs)

Page 26: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

The packaging of DNA into chromosomes involves several orders of DNA coiling and folding.

The normal human karyotype is made up of 46 chromosomes consisting of 22 pairs of autosomes and a pair of sex chromosomes, XX in the female, and XY in the male.

Each chromosome consists of a short (p) and a long (q) arm joined at the centromere.

Molecular cytogenetic techniques (e.g. FISH) are based on the ability of DNA probes to attach with its complementary target sequence. They can be used to study chromosmes in metaphase or interphase.

Take Home MessageTake Home MessageTake Home MessageTake Home Message

Page 27: Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath Human Chromosomes: Genotype/Phenotype Muhammad Faiyaz-Ul-Haque, PhD, FRCPath.

THANK YOU THANK YOU


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