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Chapter 8. Chromosomal Structure and Chromosomal Mutations. Objectives. Define mutations and polymorphisms. Distinguish the three types of DNA mutations: genome, chromosomal, and gene. Diagram a human chromosome and label the centromere, q arm, p arm, and telomere.

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chapter 8

Chapter 8

Chromosomal Structure and Chromosomal Mutations

objectives
Objectives
  • Define mutations and polymorphisms.
  • Distinguish the three types of DNA mutations: genome, chromosomal, and gene.
  • Diagram a human chromosome and label the centromere, q arm, p arm, and telomere.
  • Illustrate the different types of structural mutations that occur in chromosomes.
  • Show how karyotypes reveal chromosomal abnormalities.
  • Describe interphase and metaphase FISH analyses.
slide3

Mutations and Polymorphisms

  • Mutation: a permanent transmissable change in the genetic material, usually in a single gene
  • Polymorphism:two or more genetically determined, proportionally represented phenotypes in the same population
types of mutations
Types of Mutations
  • Genomic: abnormal chromosome number (monosomy, polysomy, aneuploidy)
  • Chromosomal: abnormal chromosome structure
  • Gene: DNA sequence changes in specific genes
chromosome morphology
Chromosome Morphology
  • Telomere: chromosome ends
  • Centromere: site of spindle attachment
    • Constriction of the metaphase chromosome at the centromere defines two arms
  • Nucleosome: DNA double helix wrapped around histone proteins
chromosome morphology6
Chromosome Morphology

Telomere

Short

arm (p)

Arm

Centromere

Long

arm (q)

Telomere

Metacentric Submetacentric Acrocentric

defining chromosomal location

Arm

Region

Band

Subband

3

2

2

1

2

2

1

p

1

5

1

4

1

3

2

1

1

17

q

1

1

.

2

2

1

1

3

1

2

2

q

3

1

3

2, 3

4

1

2

2

4

Chromosome 17

3

Defining Chromosomal Location
chromosome morphology changes during the cell division cycle
Chromosome Morphology Changes During the Cell Division Cycle.
  • DNA double helix: 2nm diameter Interphase (G1, S, G2)
  • Chromatin “beads on a string:” 11nm
  • Chromatin in nucleosomes: 30nmMetaphase (Mitosis)
  • Extended metaphase chromosomes: 300 nm
  • Condensed metaphase chromosomes: 700 nm
cell division cycle
Cell Division Cycle

Metaphase

(300–700 nm fibers)

Interphase

(11–30 nm fibers)

G1

S

G2

M

Mitosis:

Prophase

Anaphase

Metaphase

Telophase

visualizing metaphase chromosomes
Visualizing Metaphase Chromosomes
  • Patient cells are incubated and divide in tissue culture.
  • Phytohemagglutinin (PHA): stimulates cell division
  • Colcemid: arrests cells in metaphase
  • 3:1 Methanol:Acetic Acid: fixes metaphase chromosomes for staining
karyotype
Karyotype
  • International System for Human Cytogenetic Nomenclature (ISCN)
    • 46, XX – normal female
    • 46, XY – normal male
  • G-banded chromosomes are identified by band pattern.
chromosome structure abnormalities

Deletion

Translocation

Inversion

Isochromosome

Insertion

Ring

chromosome

Derivative

chromosome

Chromosome Structure Abnormalities
fluorescent in situ hybridization fish
Fluorescent in situ Hybridization (FISH)
  • Hybridization of complementary gene- or region-specific fluorescent probes to chromosomes.

Interphase or metaphase

cells on slide (in situ)

Probe

Microscopic

signal (interphase)

fluorescent in situ hybridization fish20
Fluorescent in situ Hybridization (FISH)
  • Metaphase FISH
    • Chromosome painting
    • Spectral karyotyping
  • Interphase FISH
uses of fluorescent in situ hybridization fish
Uses of Fluorescent in situ Hybridization (FISH)
  • Identification and characterization of numerical and structural chromosome abnormalities.
  • Detection of microscopically invisible deletions.
  • Detection of sub-telomeric aberrations.
  • Prenatal diagnosis of the common aneuploidies (interphase FISH).
fish probes
FISH Probes
  • Chromosome-specific centromere probes (CEP)
    • Hybridize to centromere region
    • Detect aneuploidy in interphase and metaphase
  • Chromosome painting probes (WCP)
    • Hybridize to whole chromosomes or regions
    • Characterize chromosomal structural changes in metaphase cells
  • Unique DNA sequence probes (LSI)
    • Hybridize to unique DNA sequences
    • Detect gene rearrangements, deletions, and amplifications
fish probes23
FISH Probes
  • Telomere-specific probes (TEL)
    • Hybridize to subtelomeric regions
    • Detect subtelomeric deletions and rearrangements

Probe binding site

Telomere

100–200 kb 3–20 kb

Unique sequences

Telomere associated repeats

(TTAGGG)n

genetic abnormalities by interphase fish lsi probe
Genetic Abnormalities by Interphase FISH LSI Probe
  • Greater or less than two signals per nucleus is considered abnormal.

Cell

nucleus

Normal diploid signal

Trisomy or insertion

Monosomy or deletion

summary
Summary
  • Mutations are heritable changes in DNA.
  • Mutations include changes in chromosome number, structure, and gene mutations.
  • Chromosomes are analyzed by Giemsa staining and karyotyping.
  • Karyotyping detects changes in chromosome number and large structural changes.
  • Structural changes include translocation, duplication, and deletion of chromosomal regions.
  • More subtle chromosomal changes can be detected by metaphase or interphase FISH.