Transcript What are chromosomes?

Chromosomes
Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of Tehran University
What are chromosomes?
Chromosomes are the structures that hold our
genes
 Genes are the individual instructions that tell our
bodies how to develop and function
They govern our physical and medical
characteristics, such as hair color, blood type and
susceptability to disease.
 Each chromosome has a p and q arm; p is the
shorter arm and q is the longer arm.
 The arms are separated by a pinched region
known as the centromere
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How many chromosomes do humans
have?
The typical number of chromosomes in
a human cell is 46 - two pairs of 22
+ XX/XY
 Holding an estimated 30,000 to
35,000 genes.
 One set of 23 chromosomes is
inherited from the biological mother
(from the egg), and the other set is
inherited from the biological father
(from the sperm).
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study of the chromosomes
with a microscope , then Stainning
 The chromosomes look like strings with
light and dark "bands"
 A picture, or chromosome map, of all
46 chromosomes is called a karyotype
 The karyotype : identify chromosome
abnormalities: that are evident in either
the structure or the number of
chromosomes.
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study of the chromosomes
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The pairs have been numbered from 1 to
22, with the 23rd pair labeled "X" and "Y."
In addition, each chromosome arm is
defined further by numbering the bands
that appear after staining
The higher the number, the further that
area is from the centromere.
Study of the chromosomes
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The first 22 pairs of chromosomes are
called "autosomes"
Final pair is called the "sex chromosomes."
The sex chromosomes an individual has
determines that person's gender; females
have two X chromosomes (XX), and males
have an X and a Y chromosome (XY)
Karyotype )46, Xy)
How Chromosome
Abnormalities Happen?
Meiosis
Mitosis
Maternal Age
Environment
Meiosis
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Chromosome abnormalities :
happen as a result of an error in cell
division.
“Meiosis” : the cell division that the
egg and sperm go through when they
are developing.
Normally, meiosis causes a halving of
chromosome material, so that each
parent gives 23 chromosomes to a
pregnancy
Meiosis
Meiosis
Chromosome abnormalities
 Abnormality
of chromosome
number or structure:
 Numerical
Abnormalities
 Structural
Abnormalities
Numerical Abnormalities
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When an individual is missing either a
chromosome from a pair (monosomy) or has more
than two chromosomes of a pair (trisomy).
An example: Down Syndrome, also known as
Trisomy 21 (an individual with Down Syndrome
has three copies of chromosome 21, rather than
two).
Turner Syndrome is an example of monosomy the
individual is born with only one sex chromosome,
an X.
Kleinfelter Syndrome is an example of trisomy
the individual is born with three sex
chromosome, XXY.
Down Syndrome (Trisomy 21(
Trisomy 2(
Down Syndrome
(Trisomy 21(
Down syndrom )Trisomy 21, 46)
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critical region:
A region on the long (q) arm of
chromosome 21
Down syndrome causes mental
retardation, a characteristic facial
appearance, and multiple malformations
Associated with a major risk for heart
malformations a small but still significant
risk of acute leukemia .
3 copies of chromosome number 21
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incidence of 1 in 660 and is by far the
most common chromosomal abnormality
Slight flattening of the face
A low bridge of the nose (lower than the
usually flat nasal bridge of the normal
newborn)
An epicanthal fold (a fold of skin over top
of the inner corner of the eye, which can
also be seen less frequently in normal
babies)
A ring of tiny harmless white spots around
the iris
mental retardation
Trisomy 18, 47 Ch.
Trisomy 18, 47 Ch.
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incidence of about 1 in 3,000
There is a 3:1 preponderance of females to
males
Thirty percent of affected newborns die
within the first month
50% by two months
and 90% by one year.
severe mental retardation
microcephaly
overlapping fingers, and rocker bottom feet
Neurologically they are hypertonic
Other common malformations include
congenital heart, kidney, .... abnormalities.
Trisomy 18, 47 Ch.
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Trisomy 13 (XX/XY, 47 Ch)
has an incidence of 1 in 5,000
Forty-four percent of affected newborns
succumb in the first month of life
and 69% by six months
Only 18% of the babies born with trisomy 13
survive the first year
microcephaly
microophthalmia (small eyes)
cleft lip or cleft palate
polydactyly (extra fingers)
congenital heart defects
urogenital defects
brain malformations
severe mental retardation.
Turner Syndrome (45 , X)
45, X
Turner Syndrome
(45, X)
Turner syndrome
• Only females
• One X chromosome
• Or has two X chromosomes but one is
damaged
• Short stature
• Delayed growth of the skeleton
• Sometimes heart abnormalities
• Usually infertile due to ovarian failure
• Diagnosis is by blood test (karyotype)
• 1 out of every 2,500 female live births
worldwide
• Short neck with a webbed appearance
Kleinefelter
XXY
Kleinefelter47/XXY
Klinefelter syndrome (47, XXY)
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In boys and men
47 chromosomes with XXY sex
chromosomes
XXY is one of the most common
chromosomal abnormalities
1 in 500 male births
the most common genetic cause of male
infertility
Often : undiagnosed : variation in clinical
presentation
Small testes , insufficient production of
testosterone , and infertility
Klinefelter syndrome (47, XXY)
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Breast enlargement, lack of facial and
body hair, a rounded body type , to
be overweight , and be taller than
their fathers and brothers
Learning and/or behavioral problems
Testosterone replacement corrects
the symptoms of androgen deficiency
Sex chromosome and autosomal
chromosome abnormalities is higher in
spermatozoa from patients with
Klinefelter syndrome than in those
from normal men.
Fragile X Syndrome
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1 in 3,600 males and 1 in 4,000 to
6,000 females with the full mutation
worldwide
It is estimated that 1 in 250 females
and 1 in 700 males are carriers of
the premutation.
It is second only to Down Syndrome
as a cause of mental retardation
Fragile X syndrome appears in
children of all ethnic, racial and
socio-economic backgrounds
Fragile X Syndrome
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most common inherited form of familial
mental retardation
(CGG)n trinucleotide expansion in the FMR1
gene leading to the typical Martin-Bell
phenotype
Clinical features vary depending on age and
seX
Expansion of a (CCG)n repeat in the FMR2
gene corresponds to the FRAXE fragile site
which lies distal to FRAXA and is also
associated with mental retardation, but it
is less frequent and lacks a consistent
phenotype
Fragile X Syndrome
Fragile X
Syndrome
Chromosome abnormalities
 Abnormality
of chromosome
number or structure:
 Numerical
Abnormalities
 Structural
Abnormalities
Structural Abnormalities
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Deletions: A portion of the
chromosome is missing or deleted
(>5 Mb).
 Paraderwilli
Syndrome (Ch 15)
 Angleman Syndrome (Ch 15)
 Imprinting
effect
DELETIONS
 Deletion
refers to the loss of a
segment of a chromosome
 This can be terminal (close to
the end of the chromosome on
the long arm or the short arm)
 or it can be interstitial (within)
 eg.DGS
II
DELETIONS
Structural Abnormalities
• Duplications: A portion of the
chromosome is duplicated,
resulting in extra genetic
material.
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Oncogenes (c-onc, c-fos, c-myc)
DUPLICATIONS
refers to an extra chromosomal
segment within the same
homologous chromosome or an
extra chromosomal segment on
another nonhomologous
chromosome.
 Again, the clinical findings are
highly variable depending upon the
chromosomal segments involved.
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 Gene
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expantion:
Huntington Disease/ Fragile X, ….
DUPLICATIONS
Structural Abnormalities
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Translocations: When a portion of
one chromosome is transferred to
another chromosome.
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There are two main types of
translocations.
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In a reciprocal translocation,
segments from two different
chromosomes have been exchanged.
In a Robertsonian translocation, an
entire chromosome has attached to
another at the centromere.
TRANSLOCATIONS
Translocation involves two
nonhomologous chromosomes (e.g.,
chromosome 2 and chromosome 6)
 Following a break in each of the
chromosomes, and subsequent
reunion
 a segment of chromosome 2
becomes attached to chromosome
6
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TRANSLOCATIONS
Balanced reciprocal translocation
Balanced reciprocal translocation
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Robertsonian translocation
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The reciprocal transfer of the long
arms of two of the acrocentric
chromosomes: 13, 14, 15, 21 or 22
On rare occasions, other nonacrocentric chromosomes undergo
Robertsonian translocation
a reciprocal transfer of the whole long
or short arms close to the centromere
A relatively common Robertsonian
translocation is between chromosome
14 and chromosome 21
In meiosis, a trivalent is formed.
Robertsonian translocation
Structural Abnormalities
 Inversions:
A portion of the
chromosome has broken off,
turned upside down and
reattached, therefore the
genetic material is inverted.
 eg
Ch9 inv in Iran
Inversions
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involve only one chromosome
the intervening segment is rejoined in an
inverted or opposite manner.
Since there is no loss nor gain of chromosomal
material, inversion carriers are normal
Paracentric: does not include the centromere
pericentric:inverted segment contains the
centromere
In meiosis, the normal chromosome and the
inverted chromosome will form a loop to allow
pairing of specific DNA sequences
that occur within the inversion loop result in
gametes with both deletions and duplications
inversion carriers have a relatively low risk of
having abnormal offspring.
Inversions
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Rings: A portion of a chromosome has
broken off and formed a circle or
ring. This can happen with or without
loss of genetic material.
Ring
Oncology
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Chronic Myelogenous Leukemia (CML)
a clonal expansion of transformed hematopoietic
progenitor cells:
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Myeloid
Monocytic
Erythroid
Megakaryocytic
lymphoid lineages
Molecular level
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CML: characterized by the bcr-abl fusion
gene
reciprocal translocation t(9;22)(q34;q11)
creating the Philadelphia (Ph) chromosome
survival time of patients : to 5 to 7 years
Hematology
Bone marrow
Chronic myelogenous leukemia
(CML)
15% to 20% of leukemias in adults
incidence of 1 to 2 cases per 100,000
population
 myeloproliferative disorder:
 results from neoplastic transformation
of hematopoietic progenitor cells
 affects myeloid, monocytic, erythroid,
megakaryocytic, and lymphoid lineages
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Chronic myelogenous leukemia
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occurs more frequently in males than in
females (ratio of 1.3 to 1)
Incidence: increases with age
the median age at presentation is between
45 and 55 years
Up to 30% of patients with CML are 60
years or older
which is an important consideration for the
selection of therapeutic strategies
 stem-cell transplantation
 treatment with interferon-alfa (Intron A,
Roferon-A)
The Philadelphia Chromosome
a reciprocal translocation between the long
arms of chromosome 9 and chromosome
22
 the large segment of the c-abl gene from
chromosome 9q34
 to the part of the bcr gene on chromosome
22q11 in a head-to-tail fashion
 creating a hybrid bcr-abl gene that is
transcribed into a chimeric bcr-abl mRNA
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Role of the bcr-abl Fusion Gene in
CML Pathogenesis
Ch 9: c-abl gene :a proto-oncogene
 Encodes: a nonreceptor tyrosine kinase
 with a molecular mass of 145 kd (p145cabl)
 It is localized in both cytoplasm and
nucleus
 It consists of 11 exons
 230 kilobases (kb)
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Role of the bcr-abl Fusion Gene in
CML Pathogenesis
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c-abl gene : Exon 1 has two alternative forms
 1a and 1b
In most cases
the breakpoint in the abl gene occurs in the 5¢
part of abl exon a1/2
within the segment between exons 1a and 1b
Abl exons a2 to a11:are transposed into a region
of the bcr gene between exons 12 and 16 (also
referred to as b1 to b5) on chromosome 22
creating a bcr-abl fusion mRNA of 8.5 kb
The fusion mRNAs are translated into a 210-kd
chimeric protein called p210bcr-abl
Detection of bcr-abl
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Cytogenetic analysis
Ph chromosome in 90% of patients with CML
Such analysis is tedious and time-consuming
allows the examination of only 20 to 25
metaphases per bone marrow sample
misses the 5% of patients who are Ph-negative
but bcr-abl-positive
Despite these shortcomings, cytogenetic
analysis is the gold standard in the diagnosis of
CML.
Molecular tools
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important for detecting the molecular
abnormalities associated with Ph
for monitoring the course of disease during
treatment
These include polymerase chain reaction
(PCR)
as well as Southern blot
Western blot analyses
RT-PCR
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Quantitative reverse transcriptase–
polymerase chain reaction
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following patients with CML after stem-cell
transplantation
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Its use for monitoring patients receiving
interferon-alpha is not well-defined
FISH
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Fluorescence in situ hybridization
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allows for the analysis of metaphase
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and nondividing interphase cells
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Results of FISH studies are easily
quantifiable
fluorescence in situ hybridization (FISH)
fluorescence in situ hybridization
(FISH)
FISH
Bcr
Abl
AblBcr
Abl-Bcr