Fifth lecture

Chromosomes and their variation

in structure and number
 How do Scientists Read
Chromosomes?
To "read" a set of chromosomes, scientists
use three key features to identify their
similarities and differences:
1.Size. This is the easiest way to tell
chromosomes apart.
2. Banding pattern. The size and location
of Giemsa bands make each chromosome
unique.
3.Centromere position. Centromeres
appear as a constriction. They have a role
in the separation of chromosomes into
daughter cells during cell division (mitosis
and meiosis)
 Telomers and centromere
A chromosome consists primarily of DNA and proteins with a small amount
of RNA. Chromosomes are duplicated and transmitted, via cell division
(mitosis or meiosis), to the next cell generation. The different chromosome
types have long been described and distinguished by size and shape, using
stains and dyes to contrast dark heterochromatin with the lighter
euchromatin. Heterochromatin consists mostly of highly repetitive DNA
sequences, whereas euchromatin has many protein-encoding sequences.).
The essential parts of a chromosome are:
■ Telomeres.
■ Origin of replication sites, where replication forks begin to form; and
■ The centromere.
Centromere positions
 Telomers and centromere
Telomeres are chromosome tips. In humans, each telomere repeats the
sequence TTAGGG. In most cell types, telomeres shorten with each
mitotic cell division. The centromere is where spindle fibers attach when
the cell divides. A chromosome without a centromere is no longer a
chromosome. Centromeres, like chromosomes, consist mostly of DNA and
protein. Many of the hundreds of thousands of DNA bases that form the
centromere are copies of a specific 171-base DNA sequence. The size and
number of repeats are similar in many species, although the sequence
differs. The similarity among species suggests that these repeats have a
structural role in maintaining chromosomes rather than an informational
one from their sequence. Certain centromere-associated proteins are
synthesized only when mitosis is about to start, forming a structure called
a kinetochore that contacts the spindle fibers, enabling the cell to divide.
 Telomer features in cell types
• White blood cells and other cell types with the capacity to divide very
frequently have a special enzyme that prevents their chromosomes from losing
their telomeres. Because they retain their telomeres, such cells generally live
longer than other cells.
• Telomeres also play a role in cancer. The chromosomes of malignant cells
usually do not lose their telomeres, helping to fuel the uncontrolled growth that
makes cancer so devastating.
• In many types of cells, telomeres lose a bit of their DNA every time a cell
divides. Eventually, when all of the telomere DNA is gone, the cell cannot
replicate and dies.
 Karyotypes Chart Chromosomes
A karyotype displays chromosomes in pairs by size and by physical
landmarks that appear during mitotic metaphase. Figure in slide below
shows a karyotype with one extra chromosome, which is called a trisomy.
The 24 human chromosome types are numbered from largest to smallest-
1 to 22. The other two chromosomes are the X and the Y. Early attempts
to size-order chromosomes resulted in generalized groupings because
many of the chromosomes are of similar size. Use of dyes and stains
made it easier to distinguish chromosomes by creating patterns of bands.
A chromosome is metacentric if the centromere divides it into two arms of
approximately equal length. It is submetacentric if the centromere
establishes one long arm and one short arm, and acrocentric if it pinches
off only a small amount of material toward one end. Some species have
telocentric chromosomes that have only one arm, but humans do not.
Karyotyping
Features of normal chromosomes
 karyotyping usage
Karyotypes are useful at several levels. When a baby is born with the
distinctive facial features of Down syndrome, a karyotype confirms the
clinical diagnosis. Within families, karyotypes are used to identify relatives
with a particular chromosome aberration that can affect health. In one
family, several adults died from a rare form of kidney cancer. Karyotypes
revealed that the affected individuals all had an exchange of genetic
material between chromosomes 3 and 8. When karyotypes showed that
two healthy young family members had the unusual chromosomes,
physicians examined and monitored their kidneys. Cancer was found very
early and successfully treated. Karyotypes of individuals from different
populations can reveal the effects of environmental toxins, if
abnormalities appear only in a group exposed to a contaminant. Because
chemicals and radiation that can cause cancer and birth defects often
 Detecting Chromosomes
Laboratory tests to detect or analyze chromosomes can be done
on cells sampled at any stage of prenatal development or at any
age. Many such tests are conducted on cells from a fetus or the
structures that support it. Direct methods of prenatal testing
collect cells and separate the chromosomes, then add a stain or
a DNA probe (a labeled piece of DNA that binds its complement)
to distinguish the different chromosomes, or collect small pieces
of DNA from the maternal bloodstream that are from the
placenta and sequence it. Indirect methods detect changes in
levels of biochemicals or rely on clinical findings (such as
symptoms or ultrasound scans) associated with a particular
chromosomal condition.
 Causes of chromosomal variations
and detecting
1)Some medicines 2)Street drugs 3)Alcohol 4)Tobacco 5)Toxic
chemicals
6)Some viruses and bacteria 7)Some kinds of radiation
8)Certain health conditions, such as uncontrolled diabetes
Chromosomal abnormality may occur accidentally during:
1- The formation of the egg or the sperm.
2- The early developmental stages of the fetus.
3- Certain environmental factors may play a role in the occurrence of genetic errors.
How do we can predict chromosomal disorders?
1- There are unexpected phenotypes.
2- Low percentage of fertility and increase abortion
3- Change in linkage relationships.
 Numerical chromosome aberrations

A gain or loss of one or more whole chromosome(s) (whether an

autosome or a sex chromosome) or a whole set of
chromosomes. The normal chromosome count is 46 (i.e. 2n =
46) as it is arranged in two sets of chromosomes. The numerical
abnormalities, when one or more chromosomes are in excess or
missing, ultimately modify the entire genome size, so they can
be considered genome mutations as well.
Nondisjunction- Mistake in cell division where chromosomes do
not separate properly in anaphase. Usually in meiosis, although
in mitosis occasionally. In meiosis, can occur in anaphase I or II.
 Variation in chromosomes number
1. Aneuploidy: missing one copy or have an extra copy of a single chromosome.
a. Hyperploidy:
Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part
of a third copy of chromosome 21. Although the non-disjunction of chromosome 21 is not the only
cause of Down syndrome -a smaller proportion of the cases is due to either centric fusion or
translocation - it is the most common type. Despite the fact that trisomy 21 fetuses die in utero the
average population frequency of Down syndrome is 1:650, but this value increases dramatically with
maternal age, at 45 years of age it is more than 1:100. Most trisomies and monosomies are lethal
before birth in humans.
Also, there are: Patau syndrome(trisomy 13) , Edward syndrome(trisomy 18)
b. Hypoploidy:
Turner syndrome also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or
completely missing an X chromosome.
2. Polyploidy
Triploid syndrome: is a chromosomal disorder in which a fetus has three copies of every chromosome
Variations in chromosomal
number
Names of chromosomal
variations in number
.
.
.•
Types of variation in chromosomal structure
 Genetic diseases due to Chromosomal abnormalities

A chromosome disorder results from a change in the number or structure of

chromosomes. Any deviation from the normal karyotype is known as a
chromosome abnormality. While some chromosome abnormalities are harmless,
some are associated with clinical disorders. The majority of human chromosomal
abnormalities occur in autosomes. There are three trisomies that results in baby
which can survive for time after birth; the other are too devastating and baby
usually dies in utero.
A. Structural abnormalities
This is when large sections of DNA are missing from or are added to a
chromosome.
 Deletion
The Loss of Genetic Material in a Deletion Tends to Be Detrimental to an Organism.
Loss of chromosome segment, together with genes contained in it. A chromosomal
deletion occurs when a chromosome breaks in one or more places and a fragment
of the chromosome is lost. In Figure 8.3a , a normal chromosome has broken into
two separate pieces. The piece without the centromere is lost and degraded. This
event produces a chromosome with a terminal deletion. In Figure 8.3b, a
chromosome has broken in two places to produce three chromosomal fragments.
The central fragment is lost, and the two outer pieces reattach to each other. This
process has created a chromosome with an interstitial deletion. Deletions can also
be created when recombination takes place at incorrect locations between two
homologous chromosomes. The products of this type of aberrant recombination
event are one chromosome with a deletion and another chromosome with a
duplication.
 Deletion
The phenotypic consequences of a chromosomal deletion depend on the size of
the deletion and whether it includes genes or portions of genes that are vital to the
development of the organism. When deletions have a phenotypic effect, they are
usually detrimental. Larger deletions tend to be more harmful because more genes
are missing. Many examples are known in which deletions have significant
phenotypic influences.
For example,
1- A human genetic disease known as cri-du-chat, or Lejeune, syndrome is caused
by a deletion in a segment of the short arm of human chromosome 5, which is
written 5p-.
2- Prader-Willi syndrome( feel of hungry) /Angelman syndrome
Microdeletion from short arm of chromosome 15
3- Granulocytic leukemia –deletion of long arm of chromosome 21.
Deletions in human chromosome 1
 2- Duplication
Duplications result in extra genetic material or doubling
chromosome segment. The extra set of genes is generally called
“repeat”. They are usually caused by abnormal events during
recombination. Under normal circumstances, crossing over
occurs at properly aligned sites between homologous
chromosomes. On rare occasions, a crossover may occur at
misaligned sites on the homologs. Duplications are more likely
to have phenotypic effects if they involve a large piece of the
chromosome. In general, small duplications are less likely to
have harmful effects than are deletions of comparable size. This
observation suggests that having only one copy of a gene is
more harmful than having three copies.
 2- Duplication
In humans, relatively few well-defined syndromes are caused by
small chromosomal duplications. An example is Charcot-Marie-
Tooth disease (type 1A), a peripheral neuropathy characterized
by numbness in the hands and feet that is caused by a small
duplication on the short arm of chromosome 17. Why is it
advantageous to have a family of globin genes? Although all
globin polypeptides are subunits of proteins that play a role in
oxygen binding, the accumulation of different mutations in the
various family members has produced globins that are more
specialized in their function.
 2- Duplication
For example, myoglobin is better at binding and storing oxygen in muscle
cells, and the hemoglobins are better at binding and transporting oxygen
via the red blood cells. Also, different globin genes are expressed during
different stages of human development. The ε- and ζ-globin genes are
expressed very early in embryonic life, whereas the α-globin and γ-globin
genes are expressed during the second and third trimesters of gestation.
Following birth, the α-globin gene remains turned on, but the γ-globin
genes are turned off and the β-globin gene is turned on. These differences
in the expression of the globin genes reflect the differences in the oxygen
transport needs of humans during the embryonic, fetal, and postpartum
stages of life.
Pallister-Killian syndrome
Due to part of the 12 chromosome is duplicated.
.
.
 3-Inversion
A chromosome with an inversion contains a segment that has been flipped to the
opposite direction. Geneticists classify inversions according to the location of the
centromere. If the centromere lies within the inverted region of the chromosome,
the inverted region is known as a pericentric inversion. Alternatively, if the
centromere is found outside the inverted region, the inverted region is called a
paracentric inversion.
When a chromosome contains an inversion, the total amount of genetic material
remains the same as in a normal chromosome. Therefore, the great majority of
inversions do not have any phenotypic consequences. In rare cases, however, an
inversion can alter the phenotype of an individual. When an inversion occurs, the
chromosome is broken in two places, and the center piece flips around to produce
the inversion. If either breakpoint occurs within a vital gene, the function of the gene
is expected to be disrupted, possibly producing a phenotypic effect. For example,
some people with hemophilia (type A) have inherited an X-linked inversion in which a
breakpoint has inactivated the gene for factor VIII, a blood-clotting protein.
 3-Inversion and rings

Inv(9)(p12q13): This the most common inversion on chromosome 9 is

generally considered to have no harmful effects, but there is some
evidence it leads to an increased risk for miscarriage for about 30% of
affected couples.
Rings:
Ring chromosome 14 syndrome: Is a condition characterized by seizures
and intellectual disability. Recurrent seizures (epilepsy) develop in
infancy or early childhood. In many cases, the seizures are resistant to
treatment with anti-epileptic drugs. Most people with ring chromosome
14 syndrome also have some degree of intellectual disability or learning
problems. Development may be delayed, particularly the development
of speech and of motor skills such as sitting, standing, and walking.
Ring chromosome 14
 4-Translocation
There are two main types of translocations:
i. Reciprocal : Caused by exchange of material between non-homologous
chromosomes. Two detached fragments of two different chromosomes are
switched.
Chronic Myelogenous Leukemia (chronic granulocytic leukemia (CGL)):
Characterized by the increased and unregulated growth of predominantly myeloid
cells in the bone marrow and the accumulation of these cells in the blood.
ii. Nonreciprocal : Occurs when two non-homologous chromosomes get attached,
meaning that given two healthy pairs of chromosomes, one of each pair "sticks"
and blends together homogeneously. Translocation in Down’s syndrome: The
extra chromosome 21 or part of it may be attached to chromosome 14,
sometimes to 13, 15, or
22. In some cases, two chromosomes 21 can be attached to each other.
 4-Translocation
The globin genes encode polypeptides that are subunits of proteins
that function in oxygen binding. For example, hemoglobin is a
protein found in red blood cells; its function is to carry oxygen
throughout the body. The globin gene family is composed of 14
paralogs that were originally derived from a single ancestral globin
gene. According to an evolutionary analysis, the ancestral globin
gene first duplicated about 500 million years ago and became
separate genes encoding myoglobin and the hemoglobin group of
genes. The primordial hemoglobin gene duplicated into an α-chain
gene and a β-chain gene, which subsequently duplicated to produce
several genes located on chromosomes 16 and 11, respectively.
Currently, 14 globin genes are found on three different human
chromosomes.
 Chromosome disorders of sex chromosome
• Turner syndrome: previously explained
• XXY male (Klinefelter syndrome)
Klinefelter syndrome (KS) is a genetic condition where there’s an extra X chromosome
present in a male’s genetic code. Instead of having a total of 46 chromosomes, they
have 47 — with two copies of the X chromosome and one copy of the Y chromosome
(47,XXY).
• XYY male (XYY syndrome) "superman" or Jacobs syndrome
In this case normal, slightly taller than the average males have 47,XYY karyotype. The
birth rate is 1:1000. They derived only from paternal second meiotic non-disjunction. In
contrast to all meiotic non-disjunctions, the formation is not affected by age.
• XXX female (triple X syndrome)
Triple X syndrome can also be referred to as trisomy X syndrome or 47,XXX. Triple X
syndrome happens when a female is born with an extra X chromosome, and therefore
has a total of 47 chromosomes.