TAGUM DOCTOR’S COLLEGE INC.

CHROMOSOMA
L INHERITANCE
Mary Stephanie P. Chong, RMT, MD
Boveri - Sutton Chromosome Theory

THEODOR WALTER
BOVERI SUTTON
 Individual genes are found at specific
locations on particular chromosomes,
and that the behavior of chromosomes
during meiosis can explain why genes
are inherited according to Mendel’s laws
Chromosomes come in matched pairs. One member comes from the
father & the other member from the mother
The members of
a homologous
pair separate in
meiosis, so each
sperm or egg
receives just one
member
The members of different chromosome pairs are sorted into
gametes independently of one another in meiosis
Structural Chromosome Abnormalities
Aneuploidy
If an error occurs in meiosis or mitosis and a cell acquires a
chromosome complement that is not an exact multiple of 23.

Most commonly caused by:

1. Nondisjunction
Trisomy (2n+1)
Monosomy (2n-1)
2. Anaphase lag
1 normal cell
1 monosomic cell
Structural Chromosome Abnormalities
Mosaicism
Mitotic errors in early development give rise to two or more
populations of cells with different chromosomal complement in
the same individual

Can result from mitotic errors during the cleavage of the fertilized
ovum or in somatic cells

Autosomal mosaicism seems to be much less common than that

involving the sex chromosomes.
Structural Chromosome Abnormalitie
Deletions
Refers to loss of a portion of a chromosome.
Interstitial deletions occur when there are two breaks within a
chromosome arm, followed by loss of the chromosomal material
between the breaks and fusion of the broken ends.

Terminal deletions result from a single break in a chromosome

arm, producing a fragment with no centromere, which is then
lost at the next cell division.
Structural Chromosome Abnormalitie
Ring Chromosomes
A special form of deletion.
It is produced when a break occurs at both ends of a
chromosome with fusion of the damaged ends

Do not behave normally in meiosis or mitosis and usually result in

serious consequences.
Structural Chromosome Abnormalitie
Inversions
Refers to a rearrangement that involves two breaks within a single
chromosome with reincorporation of the inverted, intervening
segment

Paracentric:inversion involving only one arm of the

chromosome

Pericentric: breaks are on opposite sides of the centromere

Structural Chromosome Abnormalitie
Inversions
Structural Chromosome Abnormalitie
Isochromosome formation
Results when one arm of a
chromosome is lost and the
remaining arm is duplicated,
resulting in a chromosome
consisting of two short arms
only or of two long arms
Most common isochromosome
in livebirths: i(X)(q10)
Structural Chromosome Abnormalitie
Translocations
Segment of one chromosome is transferred to another

balanced reciprocal translocation

there are single breaks in each of two chromosomes,
with exchange of material
Robertsonian translocation
translocation between two acrocentric chromosomes.
Typically the breaks occur close to the centromeres of
each chromosome
Structural Chromosome Abnormalitie
Translocations
Diseases & Syndromes:

Down Syndrome
Edward Syndrome
Patau Syndrome
Hermaphrodism & Pseudohermaphrodism
Klinefelter Syndrome
Turner Syndrome
Cri-du-chat Syndrome
Di George’s Syndrome
Prader-Willi & Angelman Syndrome
Indications for Analysis of
Inherited Genetic
Alterations
Cell Culture
To obtain metaphase cells for chromosomes analysis, cells from
patients must be cultured in vitro.

Specimens:
Any nucleated cell sample
Heparinized peripheral blood
Bone Marrow Samples
Fibroblast Cultures
Amniotic Fluid (16-18 weeks of gestation)
Chorionic Villous Sampling (10-14 weeks AOG)
Cordocentesis/Percutaneous blood sampling (>20 weeks AOG)
Cell Culture
Transport:
Room Temperature
blood, bone marrow, amniotic fluid, chorionic villi
Wet ice
solid tissues

Techniques:
Suspension (Floating)
blood (lymphocytes: 3-4 days), bone marrow (24-48 hrs)
Mitotic inhibitor - colcemid

Monolayer (Fixed to a surface)

Cell Culture
Staining:
G-banding (Giemsa-banding)
Mild trypsinization of the chromosomes before staining apparently weakens
the DNA–protein interactions, yielding a defined pattern of alternating light
and dark regions after the stain is applied.
Q-banding
for rapid identification of Y chromosome; most useful in ambiguous genitalia
cases
C-banding (Constitutive/Centromere banding)
used to evaluate constitutive heterochromatin or to determine whether a
chromosome has two centromeres (dicentric)
R-banding (Reverse banding)
results in chromosomes with the same banding pattern as that seen in
G-banding, but the light and dark bands are reversed
Molecular Genetic
Diagnostics
Karyotype Analysis
A typical clinical study requires analysis of 15–20 cells
In cases of mosaicism or for other special situations,
10–30 additional cells may be evaluated.
Basis for Identifying Chromosomes:
overall size of each chromosomes
position of centromere
banding pattern

representative metaphase cells are captured and karyo-

grams are prepared (p arm up, q arm down)
Molecular Genetic
Diagnostics
Computer-Assisted Imaging
an image of a metaphase cell is captured using a
standard frame grabber, digitized, and displayed on the
computer monitor.

At this point, the software allows the image to be

modified by lightening, darkening, or changing the
contrast, and a variety of manipulations of the
chromosomes are possible, including straightening and
importing chromosomes from other fields
Molecular Genetic
Diagnostics
Fluorescence In Situ Hybridization
Uses a molecular probe (i.e., a fragment of DNA),
instead of a dye to bind to the chromosome

A quicker, more specific tool, and allows the use of

multiple probes in a single hybridization procedure

the most common goal of FISH is to determine whether

a gene, a specific mutation, or a particular
chromosomal rearrangement is present, so the
molecular probes used must be well characterized and
specific to the locus in question
Molecular Genetic
Diagnostics
Fluorescence In Situ Hybridization
Probe types:
chromosome painting probe
actually a cocktail of many unique DNA fragments from along the
entire length of a chromosome, such that, following hybridization, the
entire chromosome fluoresces; most useful in identifying complex
rearrangements or marker chromosomes

repeat sequence probe

centromere probe - usually used in chromosome enumeration

telomere probe - confirm the presence or absence of the

telomeric regions

unique sequence probe

usually isolated from cloned DNA of a disease-causing gene or a
fragment of DNA. used to identify the presence or absence of the gene,
gene region, or chromosomal rearrangement of interest
Molecular Genetic
Diagnostics
Fluorescence In Situ Hybridization
Uses metaphase or
interphase cells

Process:
denaturation
addition of fluorescent
annealing &
hybridization
staining (fluorochrome)
Techniques:
Results:
Molecular Genetic
Diagnostics
Microarray Technique
Used to screen the genome for copy number variation (CNV)

Three levels of Microarrays:

Bacterial Artificial Chromosomes Arrays
provide a general overview to the human genome and are usually
targeted to regions of known association with genetic disease

Oligonucleotide Arrays
generally also target known disease genes, but add in background
sequences so these arrays have an overall coverage of the genome with probes
spaced 50 to 100 KB

SNP Arrays
provide significantly more detailed coverage with probes on average
every 100 to 1000 base pairs
Molecular Genetic
Diagnostics
Polymerase Chain Reaction

involves synthesis of
relatively short DNA
fragments from a
DNA template, has
been a mainstay of
molecular
diagnostics for the
last few decades
Polymerase Chain Reaction
Polymerase Chain Reaction
Polymerase Chain Reaction
Results are visualized using Gel Electrophoresis
DOWN SYNDROME / TRISOMY 21
EDWARDS SYNDROME / TRISOMY 18
Make a table containing the following:
CHROMOSOMAL CHROMOSOMES
DISEASE ABNORMALITY CHROMOSOMAL AFFECTED KARYOTYPE CLINICAL DIAGNOSTIC
(STRUCTURAL OR ABNORMALITY (AUTOSOME/SEX FEATURES TOOL & RESULT
NUMERICAL) CHROMOSOME)

Down Aneuploidy Intellectual Karyotype,

Syndrome (Nondis-junct disability, FISH
(Trisomy 21) Numerical ion) Autosome 47, XX, +21 simian (include
crease, pic)
median
age at 47
Edward
Syndrome
(Trisomy 18)
TRUE HERMAPHRODITISM
TURNER SYNDROME / 45,
X
KLINEFELTER SYNDROME / 47,
XXY
CRI-DU-CHAT SYNDROME
DiGEORGE SYNDROME
PRADER-WILLI SYNDROME
ANGELMAN SYNDROME
studying sucks less
than failing