CHROMOSOMES AND THEIR

ABNORMALITIES

A.M.R.Taylor
Institute of Cancer & Genomic Sciences
 DNA is tightly packaged in the cell
nucleus
3x109 bp, ~2m
long

3x109 bp, ~0.2mm

long
Figures refer to a single
(haploid) chromosome
set
NORMAL HUMAN CHROMOSOMES
Human Karyotype - 46 chromosomes

46XY or 46XX

22 pairs of autosomes plus 2 sex chromosomes

For chromosome preparations

Blood lymphocytes
Bone marrow cells
Skin fibroblasts

Amniotic fluid cells

Chorionic villus
Fetal blood

Giemsa banding
 G- banded chromosomes

1. At the level of overall size, chromosome pairs look

identical in terms of their banding pattern.

2. At this level of resolution they can also show some

differences

a. Size of heterochromatic blocks at the centromere

b. Satellite regions - variable size.

c. Variable size of the Y chromosome

 Normal female karyotype

22 pairs of autosomes (numbered 1 – 22)

Normal male karyotype

1 pair of sex chromosomes –

X and Y
CHROMOSOMAL
TRANSMISSION OF GENES

Mitosis and meiosis

What happens normally and what

happens when mistakes occur.
What is the purpose of mitosis?

Cell division -
Products genetically identical-
retain full complement of DNA

Normal growth of organism-

(wound healing, tumour growth)
Mitosis
05_17_cell cycle.jpg
02_07.jpg
 Metaphase – spindle gathers chromosomes to equator
Tension on kinetochores at centromeres facing opposite directions

Drugs that target the microtubule

proteins M-phase checkpoint!
Meiosis
• Function
reduction division (23 chromosomes per gamete)
reassortment of genes:
- independent segregation of chromosomes
- crossing-over
• Mechanism
Each homologue replicates to give two chromatids
Homologues pair
Exchange of material between non-sister chromatids
crossing-over, recombination
Chiasmata (visible cytologically) are the physical
manifestations of crossing-over
 Meiosis

Gives rise to the egg and sperm

Variation in the individual comes from:

1. Free assortment of maternal and paternal

chromosomes.

2. Presence of crossing over exchanges between

homologous chromosomes - recombination).
 What is the basis for the normal variation we
see between ourselves?

 A lot of the normal variation is a result of the

combinations in which we can inherit genes
from our parents (random assortment of
genes).

 Recombination
 02_10.jpg

Independent assortment of maternal and paternal

homologues at meiosis I generates a possible
8.4 million different combinations
- five are shown!
Male meiosis
Chiasmata – hold paternal and maternal
homologues together; stabilise them on
metaphase plate
There may be several chiasmata
Bivalent between non-sister chromatids per
bivalent (increasing reassortment of
genes)

Chromatid
Chromatids held together by synaptonemal
complex for recombination to occur
Female Gametogenesis
In females, the total number of eggs ever to be produced are
present in the newborn female.

1. In females, all eggs are arrested at an early stage of the first

meiotic division as a primary oocyte. Following puberty, during
each menstrual cycle, pituitary gonadotrophin stimulates
completion of meiosis 1 the day before ovulation.

2. In meosis 1, a diploid cell becomes 2 haploid daughter cells.

One cell becomes the secondary oocyte the other the first polar
body.

3. The secondary oocyte then undergoes meiosis 2 which

arrests at metaphase and will not continue without fertilization.

Ovulation releases this oocyte from the ovary.

Normal female
meiosis
 Sex differences in meiosis

1. In males all the cell division products develop into

mature sperm

In females one division product gives the ovum. The

remainder are lost as polar bodies.

2. In the male, meiosis, follows a long series of mitotic

divisions which is completed when the spermatids
develop into sperm.

In the female, meiosis starts very early in

development- it is then arrested- and finishes only
after fertilisation
CHROMOSOMES AND
THEIR ABNORMALITIES
 Chromosomal non-disjunction

• Results from a chromosome pair failing to

separate

• Non-disjunction of sex chromosomes

Non-disjunction of sex chromosomes at
1st meiotic division
Non- disjunction at 1st meiotic division

Non- disjunction at 2nd meiotic division

Klinefelter Outwardly normal
47XXY male Infertile
Great majority have a
normal IQ

Turner Syndrome Female - short

45X0 stature, webbed neck
Infertile (gonadal
dysgenesis

47XXX Outwardly normal

female; some patients
fertile

47XYY Tall or very tall male,

relatively infertile
NON-DISJUNCTION OF AN AUTOSOME
 Trisomy 21-Down Syndrome

47XX+21
or
47XY+21
Extra chromosome 21 results from:

1. Non-disjunction at meiosis
or
2. Mitotic non-disjunction

In 80% of cases the extra 21 is maternal in origin.

In 20% cases it is paternal in origin.

In <1% of cases it is mitotic

Most cases of Down syndrome result from non-

disjunctions in the 1st meiotic division
Association of Down Syndrome with
Maternal age
Translocation Down Syndrome
The remarkable point about sex chromosome
abnormalities (e.g. addition of an extra X
chromosome) is that individuals can appear
normal.

Compare with Down Syndrome patients who

have an additional chromosome 21- the smallest chromosome -
severe learning difficulties.

Why are trisomy X individuals normal, intellectually, but not

trisomy 21 patients?
Explanation

X chromosome inactivation.

In early embryonic development one X chromosome in

normal XX female is inactivated.

In females the second X chromosome remains active.

In females the progeny of each cell have the same X
chromosome active.

Gives a mosaic effect with respect to the two X chromosomes.

Where there is more than two X chromosomes (Eg triple X

female), rule is all X chromosomes except one is inactivated.
E.g. in cats
In tortoise shell cat, coat colour is determined
by a gene on the X chromosome. One X
carries an allele for ginger colour and the
other X carries the allele for black.

Random X inactivation of the X in these

females gives rise to the tortoise shell colour
effect.

Therefore in, say 47XXX, all the X

chromosomes except one are inactivated.
Same is true for 48XXXX etc. Only one X is
functional
Abnormalities of chromosome number

Triploidy - 69 chromosomes
A few triploid fetuses have been born but
survival is brief.

Aneuploidy
This is mainly:

1. Loss of one autosome - monosomy

(monosomy for a single autosome is lethal)

2. Gain of one chromosome - trisomy

E.g. Down syndrome.

 Other chromosome abnormalities
Deletions

Deletion of a small segment of a chromosome. Leads to

monosomy for that segment
Eg. Prader-Willi syndrome, chromosome 15;
Cri-du-chat syndrome, chromosome 5.

Chromosome translocations
Breakage of two chromosomes and exchange between them.

Can occur in the germline.

Can occur in somatic cells and there they are important in the
pathogenesis of cancer.

Fragile X associated mental retardation

An apparently normal chromosome complement
may be pathogenic if they have the wrong
parental origin.

Some genes are imprinted with their parental

origin and are expressed differentially according
to their origin (maternal or paternal)

E.g. a hydatidiform mole is an abnormal

conceptus, 46XX, where all the chromosomes are
of paternal origin

Ovarian teratoma - disorganised embryonic

tissue, 46XX, exclusively of maternal origin.
Chromosome breakage disorders
Bloom Syndrome
Fanconi anaemia cells following exposure to DNA cross linking agent
mitomycin C

Unusual sensitivity to DNA crosslinking agents

Ionizing radiation induced chromosome damage in a lymphocyte from a patient with
Ataxia telangiectasia

Broken triradial chromosome

Chromatid type gap

Triradial chromosome

Chromatid type gap

Unusual sensitivity to IR

Shapes of normal chromosome

CHROMOSOMES AND CANCER
Philadelphia chromosome in CML
 Colon Cancer: Morphological and Genetic changes

Chromosome 5 Ras gene Chromosome 18 Chromosome 17

Gene alteration mutation allele loss allele loss

Adenoma class Adenoma class Adenoma class

Normal Hyperproliferative I II III
CARCINOMA
Epithelium Epithelium Small adenoma Large adenoma Large adenoma +
(<1.0cm) (>1.0cm) foci of carcinoma

Other chromosome
loss
METASTASIS
 Main biological subtypes of chromosome abnormalities in childhood leukaemia

Subtype Cell type Chromosome Molec. Freq. (%) Product

involved Abnormality Lesion

Acute lymphoblastic B cell 11q23 MLL-AF4 85% of infant ALL Modified

leukaemia progenitor- translocations MLL-ENL 5% of all ALL transcrp. factor
(ALL) (infants) + others

B cell precursor Hyperdiploidy inc. gene dose 35% of - precur. ?

t(12: 21) (q13;q22) TEL-AML 20% of B-precur. Chim. Transcr fact.

fusion

t(1;19)(q23;p13) E2A-PBX1 5% of B-precur. Chim. Transc. fact

fusion

t(9;22)(q34;q11) BCR-ABL 5% of B-precur. Activated kinase

T cell precursor 1q deletion SIL-SCL 25% of T-precur. Dysreg. Transc fact

t(1;14)(p32;q11) fusion

Acute myeloid In infants 11q23 MLL-AF6, AF9, 50% infant AML Mod. Transc. fact
Leukaemia translocations AF10 or other

t(8;21)(q22;q22) AML1-ETO 15% of total `AML Chim. Trans. fact

fusion