Professor A. Cuschieri

Department of Anatomy

University of Malta




By the end of this session the student should be able to:

* Explain how DNA is organised in chromosomes

* Distinguish between mitosis and meiosis

* State where mitosis and meiosis occur in the human

* List the events that occur during mitosis and meiosis

* Explain the significance of chromosome recombination

* Name the main features by which chromosomes are identified

* Give examples of  aneuploidies and explain how they arise

*  Classify main types of chromosome abnormalities

* Distinguish between balanced and unbalanced chromosome rearrangements

* Deduce how unbalanced chromosome anomalies may occur in the offspring of carriers of balanced rearrangements



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Fig. 6.1 Nuclei consist of chromatin strands as tightly packed heterochromatin or loosely packed euchromatin. 

In living cells DNA is always associated with proteins and is organised to form chromatin strands and chromosomes.  In interphase nuclei, i.e. nuclei of non-dividing cells, there are 46 extremely long chromatin strands, one for each chromosome.  In places, the strands are loosely arranged to form euchromatin and in others they are densely packed heterochromatin.  Everyone knows how thread becomes hopelessly tangled unless it is kept neatly organised on reels or balls. It is most remarkable how these extremely long, thin threads of chromatin do not become tangled and can sort themselves out and become neatly wound to form the chromosomes.  Chromosomes are neat ways of packaging the DNA during mitosis and meiosis for easy distribution to daughter cells.




The DNA in nuclei and chromosomes is associated with histone proteins to form chromatin strands (Fig. 6.1).   Eight histone protein molecules, consisting of four pairs of histones H2A, H2B, H3 and H4 are organised into a histone core.  A length of DNA consisting of about 140 base pairs makes two turns around the histone core thus forming a nucleosome.  The DNA extending between two nucleosomes is called linker DNA and is associated with histone 1.

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Fig 6.2.  Nucleosomes consist of two turns of DNA around a core of histones H2A, H2B, H3 and H4, and are joined together by a piece of linker DNA surrounded by H1 histone.




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Fig 6.3 A chromatin strand is a coiled coil of nucleosomes 

The beaded chain of nucleosomes is wound into a spiral containing six nucleosomes per turn. H1 histone is responsible for the secondary coiling.  The coiled coil filaments are the chromatin strands. These are further folded in complex ways to form tightly packed chromosomes in dividing cells or loosely packed chromatin in interphase nuclei.  Non-histone chromosome proteins regulate the unfolding of the chromatin so that transcription can take place.





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Fig 6.4 A chromosome consists of two complexly coiled chromatin strands

Chromosomes become evident as discrete structures only during cell division, whether mitosis or meiosis.  In both processes the chromatin strands replicate to form two identical strands and then coil up or condense to form chromosomes. Each chromosome is thus a duplicate structure consisting of two chromatids attached to one another at the centromere.







Mitosis is the process of cell division in which two identical daughter cells are formed. The cells replicate the genetic material so as to make two identical copies of DNA, which are then distributed to the daughter cells.  In a population of dividing cells the changes undergone by a cell are referred to as the cell cycle (Fig. 6.5).


Each cell cycle starts with a newly formed daughter cell at the end of a mitotic division and involves the following stages:

1.  Gap 1 phase (G1) during which the cell performs its normal functions

2.  Synthesis phase (S) during which replication (synthesis) of DNA occurs.

3.  Gap 2 phase (G2) during which the cell cytoplasm increases in bulk and forms new organelles in preparation for cell division

4. Mitosis (M), the actual process of cell division, which consists of a number of stages:

a. prophase: the chromosomes condense and become distinct

b. metaphase: the chromosomes collect at the equator of the cell and a mitotic spindle is formed.  The spindle is formed of microtubules which attach to the centromeres of the chromosomes

c.  anaphase: the chromosomes split at the centromere and the two chromatids move to opposite poles of the cell

d.  telophase: the chromosomes at opposite poles de-condenseand become enclosed in a nuclear envelope forming the two daughter nuclei.

Mitosis occurs in all cells during embryonic and foetal development.  In postnatal life it occurs in growing tissues.  In adults it is restricted to certain sites, namely:    

*  bone marrow for haemopoiesis;

*  epidermis of skin, nails and hairs;

*  epithelium lining the intestinal tract;

*  connective tissue and bone during repair following injury.

 In other tissues e.g. muscle, liver and most internal organs mitosis occurs at a very slow rate. In some tissues, notably the central nervous system, the cells lose their ability to divide in postnatal life.





Meiosis occurs only in the germ cells i.e. the cells that form the spermatozoa in males and the oocytes (ova) in females. Whereas somatic cells have a diploid number of chromosomes, i.e. the chromosomes are in pairs, the spermatozoa and oocytes have a haploid set of chromosomes, i.e. only one of each pair of chromosomes.   In man, the diploid number of chromosomes is 46.  The haploid set found in the germ cells consists of 23 chromosomes.  Meiosis is the process of reduction division in which the chromosome number is halved from diploid to haploid. This is necessary because fertilisation involves the fusion of a male and a female gamete to form a zygote thus restoring the normal chromosome number.  However, meiosis serves a second extremely important function - genetic recombination. 



In all diploid cells, the chromosomes occur in homologous pairs, derived one from the mother and one from the father.  During meiosis, homologous chromosome pairs associate with one another and exchange segments of DNA. This is referred to as crossing over. When the chromosomes separate, each chromosome is a mixture of the original maternal and paternal chromosomes.  This causes a reshuffling or recombination of genes. Recombination is an important means of ensuring genetic variation among the offspring.  Crossing over involves breakage and re-union of the chromatin strands.  


Cells undergoing meiosis pass through G1, S and G2 phases.  During S phase chromosome replication occurs.  The process of meiosis consists of  two consecutive divisions known as Meiosis 1 and Meiosis 2. 


a.      Meiosis 1.  Recombination occurs during the prophase of meiosis 1.  Pairing and crossing-over of segments occurs between homologous chromosome pairs. This is accompanied by condensation of chromosomes.  Metaphase of meiosis 1 results in separation of homologous chromosomes. Note that this is different from mitosis in which chromatids separate. The two daughter cells contain a haploid set of chromosomes (only one of each pair).

b.     Meiosis 2.   This occurs immediately after meiosis 1, when the chromosomes are still condensed.  Therefore there is no prophase. Metaphase of meiosis 2 results in the separation of chromatids.  4 germ cells are formed each containing a haploid set of chromatin strands.

These stages are summarised in Fig 6.7


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Note that there is no prophase preceding meiosis 2.   The chromosomes are already duplicated and condensed at the end of meiosis 1 and so proceed immediately to meiosis 2.



*  Meiosis results in four germ cells each receiving a haploid set of chromosomes

* The chromosomes in each germ cell are homologous but not identical to one another.

* The germ cells contain one set of genes

* As the sites of crossing over are random, the patterns of recombination of genes and chromosomes are almost infinite.



Chromosomes are visible as discrete structures only during cell division.  Chromosome analysis requires a source of dividing cells, usually obtained from  blood lymphocytes, which have been  stimulated to enter mitosis. Chromosomes are examined in cells in metaphase.


Chromosomes are classified as:

a.      Metacentric (centromere close to the centre) – chromosomes 1, 3, 16, 19 and 20 are metacentric of different size.

b.     Submetacentric  (centromere some distance away from the centre).

c.      Acrocentric (centromere close to one end) –chromosomes 13, 14 and 15 (large acrocentric) and chromosomes 21 and 22 (small acrocentrics).  All the acrocentric chromosomes have a very small short arm and a pair of "satellites" attached by a narrow stalk. The satellites consist of repeated copies of the same genes that form r-RNA and are known as the nucleolus organisers because they associate together within the nucleus to form the nucleolus. 

d.       Sex chromosomes – the X and Y chromosomes are unequal in size.  Females have XX  and males have XY sex chromosomes.

Note that the short arm of a chromosome is designated as "p" and the long arm as "q".

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These are classified into aneuploidy (numerical abnormalities) and structural chromosome abnormalities. 


Aneuploidy is an abnormality in chromosome number and involves the loss or gain of chromosomes. The most common aneuploidies are:

1. Trisomy

Trisomy affects one particular chromosome and occurs if there are three instead of a pair of homologous chromosomes. The karyotype has 47 chromosomes. Trisomy involves a large number of extra genes. This causes congenital anomalies that are recognisable as characteristic clinical syndromes.  The most common examples are:

Trisomy 21 - Down's Syndrome occurs in about 1 in 600 births. 

Trisomy 13 - Patau's Syndrome occurs in about 1 in 5,000 nirths

Trisomy 18 - Edward's Syndrome occurs in about 1 in 8,000births

Trisomies involving the sex chromosomes are much more frequent; they include XXY (Klinefelter Syndrome), XXX and XYY. 

Aneuploidies involving other chromosomes are rare as they are often incompatible with life and end as spontaneous miscarriages. 

2. Monosomy

Monosomy involves the loss of a chromosome.  The karyotype contains 45 chromosomes.  Monosomy involves the loss of a large number of genes. Most monosomies are incompatible with life and are seen only in spontaneous abortions.  The example that occurs quite commonly and is compatible with life is monosomy X (Turner Syndrome).

3. Other aneuploidies

These include tetrasomies and pentasomies (4 or 5 homologous chromosomes instead of a pair).  They are very rare and are found only involving the sex chromosomes.

Aneuploidy usually arises as a result of an error in meiosis when a pair of homologous chromosomes fails to separate.  The phenomenon is termed non-disjunction.  It is often a defect of the mitotic spindle, which fails to attach to one of the chromosomes.  Non-disjunction may occur in either the maternal or the paternal germ cells. Trisomy 21 arises more commonly in maternal than in paternal meiosis. Increasing maternal age is a contributory factor in causing non-disjunction.

4. Mosaicism

Mosaicism is the condition in which an individual has cells with different chromosome complements. Mosaicism usually results from non-disjunction during mitosis in the zygote. Consider a zygote with a normal chromosome complement of 46.  If non-disjunction affecting one chromosome pair occurs in the first mitotic division, one of the daughter cells would have 47 chromosomes and the other 45. If non-disjunction occurs in the second or subsequent mitosis, there will be three cell lines including the original 46, as well as 47 and 45 chromosomes.   During subsequent mitosis certain cell lines, especially monosomies are often eliminated or much reduced. 

Certain aneuploidies exist only in mosaic form e.g. trisomy 8 , trisomy 9 and trisomy 22

5. Polyploidy

Normally, somatic cells are diploid containing pairs of chromosomes. In polyploidy there are sets of three or four chromosomes. In triploidy there are 23 x 3 = 69 chromosomes and in tetraploidy there are 23 x 4 = 92 chromosomes. Triploidy is very rare and is invariably fatal at or shortly after birth; it is found more commonly among abortuses and stillbirths.   Triploidy may results from a complete failure of formation of the mitotic spindle or of cell division during meiosis.



The more common types are:

1. Deletions

A single chromosome break occurs in one of the chromosomes and the broken fragment is lost.  This results in the loss of a number of genes. Fig. 6.10 shows a deletion of the short arm of chromosome 5 resulting in the cri-du-chat syndrome.  The karyotype would be 46,XX 5p- or 46,XY 5p-.

2. Translocations

These are usually classified into two types:

a. Reciprocal translocations

Part of a chromosome breaks off and becomes attached to another chromosome.  Usually, there is a reciprocal translocation between two chromosomes where parts of two chromosomes break off and become attached to the other chromosomes. Fig.6.11 illustrates a reciprocal translocation between chromosomes 2 and 9.  Two abnormal translocation chromosomes are thus formed. The karyotype would be 46,XX t(2;9).

Note that the broken end of a chromosome cannot reattach to the intact end of a chromosome, as this would be stable. It can only attach to another broken site. If there is only one break point, a rearrangement cannot be formed and the acentric fragment would be lost as occurs in a deletion.

b. Robertsonian translocations

A Robertsonian translocation occurs between two acrocentric chromosomes, which appear to be attached to one another end to end. Fig.6.12 shows a Robertsonian translocation between chromosomes 14 and 21. However, this is not really an “end to end" translocation but a reciprocal translocation in which the long arms of the two chromosomes fuse. The short arms of both chromosomes also fuse to form a minute fragment, which is usually lost.  The loss of these short arms does not cause any abnormal effects since they contain the nucleolus organisers of which there are many other copies on the other acrocentric chromosomes.  The karyotype would be 45,XX t(914;21) or 45,XY t(2;9).


c. Unbalanced translocations

Translocations, as described above, are balanced. They do not involve any loss or gain of genes. Individuals who carry a balanced translocation are phenotypically normal.  However, problems may arise during pairing of homologous chromosomes in meiosis and may cause unbalanced translocations in the offspring. The following examples illustrates how unbalanced rearrangements may arise from balanced translocations in the parents:


Example 1.  Marika  is a carrier of a translocation between chromosomes 14 and 21.  What would be  the possible outcome for her offspring?

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In this case Marika has 45 chromosomes. There is only one each of normal chromosomes 14 and 21 and a translocation chromosome 14/21.  Pairing of homologous chromosomes during meiosis cannot occur in the normal fashion. The three chromosomes associate together as shown in Fig. 6.13 so that there is still point-to-point pairing of corresponding chromosome regions.  When the three chromosomes separate, two chromosomes go to one gamete while the remaining chromosome moves to the other gamete.  There are six possible ways in which these chromosomes can be sorted as shown in Fig.6.13.


The zygote receives a set of chromosomes 14 and 21 from the normal parent.  The possible outcomes in the zygote are (a) normal – 46,XX or XY;  (b) translocation carrier 45, XX or XY; (c)  trisomy 14 – karyotype 46,XX /XY, -21 + t(14;21); (d)  monosomy 14 – karyotype 45,XX /XY, -14; (e) trisomy 21 – 46,XX/XY, -14 + t(14;21); (f)  monosomy 21 – karyotype 45,XX /XY, -21. 

Monosomy 14, monosomy 21 and most cases of trisomy 14 would be lethal in early pregnancy and would result in spontaneous abortion.  Therefore, 1 out of 3 babies born at term would be expected to have translocation trisomy 21 (translocation Down Syndrome), 1 out of 3 would be a translocation carrier and 1 out of 3 will be normal.  These are theoretical risks.  In practice it is found that the actual or empiric risk for a carrier parent having a baby with Down syndrome is less than 1 in 3.  The reason for this is not understood.


Example 2: Raymond has a reciprocal translocation between the short arms of chromosomes 2 and 9.  What are his chances of having a normal child?  

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In this case, the short arm of chromosomes 2 (2p) has been translocated to the long arm of chromosome 9 (9q), while the short arm of chromosome 9 (9p) has been translocated to the long arm of chromosome 2 (2q).  This gave rise to two derivative chromosomes, which are designated in a simplified way as der(2q;9p) and der(9q;2p).  Here again chromosome pairing during meiosis will be very complex.  In fact, the four chromosomes associate together in a cross-like manner so that there is point to point correspondence of chromosome and crossing over is still possible (Fig.6.14).


When the four chromosomes separate, two will go to one gamete while the other two go to the other gamete.  This gives rise to six possible combinations as shown in Fig.6.14. The outcomes would be partial trisomies and partial monosomies of the translocated segments of chromosomes 2 and 9. All of these would be incompatible with life. Two out of three pregnancies would end in spontaneous abortions, while 1 in 3 would result in normal children, or ones who are carriers like their parent. Such individual are often discovered because of recurrent miscarriages, but others may remain unnoticed.   In cases of translocation involving very small segments of chromosomes, there could be partial trisomies and partial monosomies in which affected babies could survive till birth, although they would have congenital  malformations. 



Inversions occur when there are two breaks within the same chromosome. The middle segment is inverted and re-fusion of the broken ends occurs (Fig 6.15). 

A peri-centric inversion occurs around the centromere and, as a result, the relative lengths of the sort and long arms may change. 

A para-centric inversion does not involve the centromere. It may occurs in either the long arm or the short arm., whose lengths are not affected. 

In both types, the sequence of genes in the inverted segment will be altered. This will cause problems in pairing during meiosis and may give rise to unbalanced rearrangements in the offspring including duplications and deletions of the inverted segment.  

Some pericentric inversions do not cause unbalanced rearrangements.  An example is pericentric inversion of chromosome 9, which occurs as an inherited variant.

4. Partial monosomies and partial trisomies

Partial monosomy is the same as a deletion and means that a segment of chromosome has been lost. There is a single copy of genes in that segment, instead of a pair.  Partial trisomy occurs if there is an extra copy of a segment of chromosome in addition to the usual pair.  The genes in that segment are present in triplicate.  Partial monosomies and partial trisomies often occur together.  They may be the result of a balanced translocation or inversion in one of the parents.  In some cases they arise de novo, meaning that the unbalanced rearrangement arose in that particular individual. 

Text Box:  5.  Isochromosomes

Isochromosomes arise if the centromere splits transversely instead of longitudinally (Fig.6.16).  As a result the daughter chromosomes consist of either two long arms (isochromosome q) or of two short arms (isochromosome p).  Isochromosomes are rare.  They usually affect the X chromosome. In a female with isoXp  (isochromosome of the short arm of the X chromosome) there is monosomy of the long arm and trisomy of the short arm. In  isoXq there is monosmy of the short arm and trisomy of the long arm .




6. Ring chromosome

A ring chromosome forms when the tips of the long and short arms fuse together to form a ring (Fig. 6.17).  Usually there are small deletions of the tips of both arms.







Chromosome aneuploidies and unbalanced chromosome rearrangements are associated with well-defined clinical syndromes.  A syndrome is a group of clinical features that are characteristic for a particular anomaly.  Chromosome syndromes have been described for all chromosomes.  Only a few of the commonest syndromes are outlined here. 

Trisomy 21 - Down's Syndrome

Karyotype:   47,XX+21 or 47,XY+21  /  translocation  trisomy 21 e.g. 46,XX -14 + t(14;21)

Frequency : 1 in 600 births

Clinical features:

* Mental retardation       

* Hypotonia

* Flat occiput (brachycephaly)

* Round flat face

* Slanting palpebral fissure

* Broad nose

* Protruding tongue

* Short fingers (brachydactyly)

* Increased frequency of congenital heart disease

Trisomy 18 - Edwards Syndrome

Karyotype:   47,XX+18 or 47,XY+18

Frequency: 1 in 8,000 births;  Predominance of females 4F:1M

Clinical features:

* Growth retardation

* Small mouth

* Micrognathia (small chin)

* Flat, pointed ears

* Short neck

* Clenched hands with overlapping fingers

* Rocker-bottom feet

* Cleft lip, congenital heart disease and diaphragmatic hernia are common.


Trisomy 13 - Patau Syndrome

Karyotype 47,XX+13 or 47,XY+13

Frequency of Trisomy 13: 1 in 10,000 births

Clinical features:

* Microphthalmia

* Cleft lip and palate (often bilateral)

* Polydactyly of hands and feet

* Microcephaly

* Scalp defect

* Early death

5p monosomy (deletion) - Cri-du-chat syndrome 

Karyotype: 46,XX5p-  or 46,XY5p-

Frequency : 1 in 50,000 births

Clinical features:

* characteristic cat-like cry (due to underdeveloped larynx)

* microcephaly

* round "moon-like" face

* micrognathia

* hypertelorism

Klinefelter Syndrome - 47,XXY

Frequency: 1 in 1,000 males  (occurs only in males)

Clinical features:

* Testicular atrophy and azoospermia

* Gynaecomastia

* Usually tall stature

Turner Syndrome - 45,X

Frequency: 1 in 2,500 females (occurs only in females)

Clinical features:

* short stature

* lack of pubertal development

* amenorrhoea

* ovarian dysgenesis

* low posterior hair line

* webbed neck






1.  How does the chromatin in interphase nuclei differ from that in chromosomes?


2.  What is the importance of histone proteins in interphase nuclei and chromosomes?  What would happen if the H1 histones were to be removed by chemical treatment?  What would happen if all histone proteins were to be removed?


3. How does genetic recombination occur?  What is its importance?


4. In the following table indicate whether each statement is true (+) or false (-) regarding mitosis, meiosis I and meiosis II.





Is preceded by DNA replication




Separation of chromatids occurs




Division of the centromere




Crossing over between homologous chromosomes occurs




Results in a haploid set of chromosomes




Daughter cells are genetically identical




A spindle is formed





5. A baby girl is born with clinical features of Down syndrome.  Her mother is has a balanced translocation between chromosomes 21 and 15.  What would be the karyotype of the child and of her mother?


6. If a person is a carrier of a Robertsonian translocation between chromosomes 15 and 21, what are the possible chromosome outcomes in the offspring?  Indicate diagrammatically the chromosomes in the parent, the gametes and the offspring.


7.  If a person is a carrier of a Robertsonian translocation between the two chromosomes 21, what are the possible outcomes in the offspring?  Indicate diagrammatically the chromosomes in the parent, the gametes and the offspring.


8. Explain how Turner syndrome and Klinefelter syndrome are likely to arise. Can these abnormalities arise from a defect in meiosis in the father or in the mother?