- 2.1 Introduction
- 2.2 Types of Chromosomal Aberrations
- 2.2.1 Numerical Aberrations
- 2.2.2 Structural Aberrations
- 2.3 Aneuploidy Changes in Humans
- 2.3.1 Autosomal Trisomies
- 2.3.2 Autosomal Monosomies
- 2.3.3 Allosomal Aberrations
- 2.3.4 Mosaicism and Chimerism
- 2.4 Structural Chromosomal Aberrations
- 2.4.1 Deletions
- 2.4.2 Duplications
- 2.4.3 Robertsonian Translocation
- 2.4.4 Reciprocal Translocation
- 2.4.5 Inversions
- 2.4.6 Isochromosomes and Ring Chromosomes
- 2.5 Causes of Chromosomal Aberrations
- 2.5.1 Non-disjunction
- 2.5.2 Robertsonian Translocation
- 2.5.3 Reciprocal Translocation
- 2.5.4 Inversions
2.1 INTRODUCTION
In this unit we shall discuss genetic changes at the level of the chromosomes and their effects in humans. Almost all individuals of a species contain the same number of chromosomes specific for that species. For example, you and I contain, within each of our cells, a total of 46 chromosomes which is specific for Homo sapiens. However, there are individuals who show variations from this normal complement. These variations could be changes in number of chromosomes or structural changes within and among chromosomes – together such changes are called chromosomal aberrations.
The genetic component of an organism regulates its development and interaction with the environment. Thus, any change in this genetic component leads tovariation in phenotypic characters. Depending on the extent of the aberration, these effects can range from being lethal to being harmless variations. We shall discuss the different types of aberrations, their phenotypic effects, the causes of such aberrations, and their roles in human disorders.
2.2 TYPES OF CHROMOSOMAL ABERRATIONS
Chromosomal aberrations are broadly classified as numerical or structural aberrations. They are f2.2.1 Numerical Aberrations Numerical aberrations are those that cause a change (addition or deletion) in the number of chromosomes. They are further classified as euploidy changes or aneuploidy changes.
• Euploidy is the condition when an organism gains or losses one or more complete set of chromosomes, thus causing change in the ploidy number. For example, triploid (3n), tetraploid (4n) etc. (Table 2.1).
• Aneuploidy is the condition when an organism gains or losses one or more chromosomes and not the entire set. For example, trisomy (2n + 1), monosomy (2n – 1) (Table 2.1).
In humans, euploidy conditions do not exist because the extent of abnormality is too large to sustain life. Aneuploidy conditions, however, are more common and are manifested in disorders such as Down syndrome, Klinefelter syndrome and Turner syndrome. We shall discuss these changes in detail later in the unit.urther classified as shown in Figure 2.1
2.2.2 Structural Aberrations
Structural aberrations are those that involve a change in the chromosome structure. These include deletions, duplications and rearrangements (inversions and translocations). Structural changes occur when chromosomes break and later rejoin in combinations that are different from the original. When there is a net loss or gain or chromosomal segments, the change is called an unbalanced structural change. When there is no net loss or gain of chromosomal segments, instead there is only a rearrangement; it is called a balanced structural change (Figure 2.2). Thus, balanced changes usually do not show any abnormal phenotypes, which unbalanced changes do. You should keep in mind that these changes are not mutations in genes; they only cause the number and order of genes to be changed.
As with aneuploidy changes, structural changes are also seen in humans, and manifest in disorders such as Cri-du-chat syndrome, Wolf-Hirschhorn syndrome, Prader-Willi syndrome and Angelman syndrome. We shall discuss each of these changes and their effects later in the unit.
2.3 ANEUPLOIDY CHANGES IN HUMANS
As was discussed previously, aneuploidy conditions are non-lethal and result in abnormal phenotypes described as syndromes. The effects of aneuploidy changes differ significantly depending on the type of chromosome involved. For example, changes in chromosomes involved in sex determination (allosomes) results in changes in the primary and secondary sexual characters of that individual, whereas changes in other chromosomes (autosomes) do not. As you can see, there are various factors that affect the phenotypic manifestations of chromosomal disorders. We shall now look at the different aneuploidy conditions in humans and their clinical manifestations.
2.3.1 Autosomal Trisomies
Trisomy is the condition where there is an additional copy of one chromosome. It is represented as 2n+1. Individuals, who are trisomics, thus show three copies of the chromosome rather than the normal two. It is usually observed that trisomies of the smaller chromosomes are more tolerated than trisomies of the larger chromosomes. This is expected, because additional copies of larger chromosomes contribute to larger genetic imbalance than additional small chromosomes. You will find it no surprise that the most common trisomy is of the shortest chromosome in human – chromosome 21. The other trisomies that have been reported include trisomy 13 (Patau syndrome) and trisomy 18 (Edward syndrome).
Down Syndrome
Down syndrome was one of the first reported chromosomal abnormalities in humans. It was described as Mongolian Idiocy by John Langdon Down in 1866. It wasn’t until 1959 that it was shown to be caused by the presence of an extra chromosome 21, resulting in an increase of number of chromosomes to 47 (karyotype 47, XX / XY, +21). Thus, this disorder is also known as trisomy 21 or Down syndrome. Figure 2.3 shows the karyotype of an individual with 3 copies of chromosome 21, or trisomy 21. With an incidence of 1 in 800 live births, this is one of the common trisomies seen in humans. This incidence increases to 1 in 350 when the woman conceives beyond 35 years of age and to 1 in 25 when she conceives beyond 45 years. Down syndrome is caused by trisomy 21 in almost 90% of the cases. 6% of the cases are also shown to be caused by a translocation rather than a numerical change (see Section 2.5.2) and the other 4 % are known to be caused by mosaicism (see Section 2.3.4).
There are many phenotypic manifestations that are typical in patients of this syndrome. However, as in other syndromes, not all affected individuals show all the symptoms. Any single individual usually expresses only a subset of the manifestations. Some of the most common are:
• Flat face, round head, and typical epicanthic fold of the eyes
• Short, broad hands
• Mental retardation
• Hypotonia – poor muscle tone
• Short stature
• Protruding furrowed tongue
• Mild to moderate developmental disabilities
• Typical dermatoglyphic patterns (palm and fingerprint patterns)
The most common cause of this trisomy is the non-disjunction (see Section 2.5.1) or the failure of separation of the chromosomes during meiotic division. Due to this one of the gametes undergoing fertilization contains two copies of chromosome 21 instead of the normal one copy (gametes are haploid containing one copy of each chromosome). This non-disjunction can occur at either meiosis I or II. Chromosomal analysis has shown that 75% of the cases are due to nondisjunction occurring at meiosis I. When such a gamete is fertilized by a normal gamete, it results in trisomy 21.
2.3.2 Autosomal Monosomies
Autosomal monosomies have not been reported beyond birth in humans. Even the loss of the smallest chromosome is not compatible with life. Most known cases, therefore, are stillbirths and spontaneously aborted fetuses. It seems that loss of whole chromosomes cause too much genetic imbalance, which cannot support life. However, partial monosomies have been reported and welldocumented. Partial monosomy refers to the loss of a part of a chromosome while the rest of the chromosome is retained. Since such a partial monosomy is a chromosomal deletion, strictly speaking, we shall discuss it under Section 2.4.1.
2.3.3 Allosomal Aberrations
Changes in number of allosomes (X and Y chromosomes in humans) are termed allosomal aberrations. The gain or loss of these chromosomes alters the phenotype leading to syndromes. For example, the loss of one X chromosome in females leads to turner syndrome (XO) and the excess of one X chromosome in males leads to Klinefelter syndrome (XXY). As mentioned earlier changes in allosomes cause changes in the primary and secondary sexual characters along with other manifestations. We shall look at the consequences of two such changes and thecontrasting variation they produce.
Turner Syndrome
This syndrome is characterized by the partial or complete absence of one of the X chromosomes in females (Fig. 2.4). This results in a reduction of the total number of chromosomes to 45 (karyotype – 45, X). Thus, this syndrome is also called Monosomy X. Its first description as a syndrome was by Henry Turner in 1938. Later, in 1954, the absence of barr body (inactivated X-chromosome seen in buccal cells) and presence of only one X chromosome was noted. As we saw in Down syndrome, monosomy of X is not the only cause of this syndrome. Mosaicism, deletions and isochromosome (see Sections 2.3.4 and 2.4.6) have also been shown to cause this condition.
It is well known that, of the two X chromosomes in females, one is inactivated throughout her lifetime. If normal females have only one active X chromosome, then why should the loss of one X chromosome cause abnormal phenotype? The answer lies in the fact that although we speak of inactivated X chromosome, not all genes on that chromosome are being inactivated. There is a small subset of genes on the X chromosomes that are required to be expressed by both chromosomes for normal female development. Thus, individuals who lack one X chromosome fail to develop normal female character.
Some of the commonly seen manifestations of Turner syndrome are:
• Primary hypogonadism – poor ovary development
• Short stature
• Minimal breast development
• Broad shield-like chest with widely spaced nipples
• Absence of menstrual periods
• Absence of secondary sexual characteristics
• Horseshoe-shaped kidney
• Inability to produce gametes – sterility
Klinefelter Syndrome
The presence of an additional X chromosome in males causes abnormal sexual development and is described as Klinefelter syndrome. This set of characteristics was first described by Harry Klinefelter in 1942. In 1959 it was shown to be due to the presence of an additional X chromosome in males by the presence of barr bodies in these males (normal males do not show barr body). The additional X chromosome results in an increase in the total number of chromosomes to 47 (karyotype 47, XXY). It has an overall incidence of 1 in 1000 live male births. While most patients show the XXY condition, individuals showing variations like XXXY or XXYY have also been reported (Fig. 2.5).
The additional X chromosome arises due to non-disjunction (see Section 2.5.1) during meiosis. Due to this, the gamete contains two X chromosomes rather than one. When such an egg containing XX is fertilized by sperm containing Y, an XXY zygote is formed that develops into a Klinefelter male. The extra X chromosome may be either of maternal or paternal origin, but it is more often to be of maternal origin.
Individuals with this syndrome show hypogonadism and reduced fertility. These males do no develop masculine secondary sexual characteristics and show femaletype characteristics. Some of the clinical manifestations include:
• Primary male hypogonadism
• Reduced facial, body and pubic hair
• Small and soft testes
• Slight learning difficulties
• Increased breast tissue – gynacomastia
• Long limb bones and lanky body
• Azoospermia – absence of sperm production leading to infertility
2.3.4 Mosaicism and Chimerism
So far we have seen how changes in chromosome number can affect an individual. We also saw that the extent of these effects vary between individuals. Some individuals show very mild conditions. These individuals provided examples of a phenomenon known as mosaicism. This is defined as the presence of more than one cell line in an individual derived from a single zygote. These cell lines can differ in their chromosome constitution, with a percentage of the individual’s cells showing numerical changes. Karyotype analysis from these individuals show that some cells have the normal number of chromosome while other have either losses or gains.
A classic example of this mosaicism is Down syndrome. These individuals show milder symptoms of the syndrome because only a portion of their body cells have the associated abnormality. Other numerical abnormalities also include mosaic individuals such as for Turner syndrome and Klinefelter syndrome. The severity of symptoms in these individuals is dependent on two things: what percentage of their cells shows the abnormality and which of their cells show the abnormality. For example, because the ovaries are the most affected organs, a Turner syndrome female whose ovary cells are from the normal cell line would show much milder symptoms than a Turner syndrome female whose ovary cells have the monosomy.
Like aneuploidy, mosaicism too can result from non-disjunction of chromosomes. But here the non-disjunction occurs in one of the early mitotic divisions of the zygote. This gives rise to three cell lines – normal, trisomic and monosomic (fig 2.6). The monosomic line usually does not survive; the normal and trisomic lines do. Thus, the embryo is formed of normal and abnormal cells.
Chimerism is similar to mosaicism in that the individual possesses cell lines of more than one type. The difference is that, while in mosaicism the cell lines are derived from the same zygote, in chimerism the cell lines are derived from different zygotes. A temporary chimeric condition is developed when a person undergoes blood transfusion. For a few days after the transfusion, the individual will have his own cells and the donor’s cells circulating in his body. Since the donor cells in his body are not of his own origin he is said to be chimeric.
A more permanent form of chimerism can develop if cells from a different zygote get incorporated into the developing embryo. There is an increased risk of this during in-vitro fertilization methods. Chimeric individuals often do not show any abnormal phenotypes, but their fertility and type of offspring would depend on which cell line gave rise to the reproductive organs. Especially, ambiguous genitalia (genitalia that look neither completely like male nor female), hermaphroditism, and intersexuality can result if one cell line is genetically female (XX) and the other is genetically male (XY).
2.4 STRUCTURAL CHROMOSOMAL ABERRATIONS
So far, we have described the types and effects of numerical chromosomal changes. We also saw that these syndromes can also be caused by certain types of structural changes. In this section you will learn the different structural changes and their consequences.
2.4.1 Deletions
A deletion refers to the loss of a segment of a chromosome. This leads to the loss of the genes present in the missing region. A single break in the chromosome leads to the loss of the terminal segment and is called terminal deletion (see Figure 2.2). Intercalary deletion, however, involves two breaks in the chromosome, loss of the segment, and rejoining of the two chromosomal parts. Very large deletions are usually lethal because the monosomic condition of the large number of genes of the missing fragment reaches the level of genetic imbalance that cannot sustain life. Usually any deletion resulting in loss of more than 2% of the genome has a lethal outcome. Microdeletions, however, are reported and documented for specific disorders.
Cri-du-chat Syndrome
This syndrome results from a deletion on the short arm of chromosome 5. It is also known by other names such as 5p deletion syndrome and Lejeune’s syndrome. The disorder gets its name from the characteristic cat-like cry of affected infants.
Described first by Jérôme Lejeune in 1963, this disorder has an incidence of 1 in 25,000 live births. This disorder, being autosomal, should affect males and females in equal frequencies; but incidence is seen to be more in females by a ratio of 4:3 of females: males affected.
The deletion occurring on the short (p arm) arm of chromosome 5 varies in different affected individuals. The phenotypic effects are also shown to vary between individuals. Most cases show deletion of 30 to 60% of the terminal region of the short arm. Studies show that larger deletions tend to result in more severe intellectual disability and developmental delay than smaller deletions. Figure 2.7 shows the chromosome 5 pair from a karyotype of an individual with this syndrome. You can see that one of the chromosomes (left) has the normal length of the short arm while the other (right) has significantly reduced short arm. More specifically, a dark band is prominently seen in the normal chromosome, which is missing in the deletion chromosome.
Affected individuals characteristically show a distinctive, high-pitched, catlike cry in infancy with growth failure, microcephaly, facial abnormalities, and mental retardation throughout life. Some common clinical manifestations are:
- Cry that is high-pitched and sounds like a cat
- Downward slant to the eyes
- Low birth weight and slow growth
- Low-set or abnormally shaped ears
- Mental retardation (intellectual disability)
- Partial webbing or fusing of fingers or toes
- Slow or incomplete development of motor skills
- Small head (microcephaly)
- Small jaw (micrognathia)
- Wide-set eyes
2.4.2 Duplications
Duplications, like deletions, can cause abnormal phenotypic effects. They usually arise by errors in homologous recombination (unequal crossing-over). Duplications have their importance not only in medical genetics, but also in evolutionary genetics. The presence of an extra copy of the gene virtually makes it free of selection pressure. Thus, it contributes to diversification of protein functions resulting in families of proteins. Proteins of such families have related functions differing in the task they are specialized for. A classic example is that of the globin genes. Different globin proteins express during different times of development, each of which is specialized to transport oxygen under thoseconditions. These differences arose by gene duplications. Without digressing too much we shall now look at the clinical significance of duplications exemplified by Charcot–Marie–Tooth disorder.
Charcot–Marie–Tooth (CMT) Disorder
This disorder results from duplication in the short arm of chromosome 17 in the region 17p12. It is a hereditary motor and sensory neuropathy that affects the nerve cells of the individual. Affected individuals typically show loss of touch sensation and muscle tissue. The chromosomal basis of this disorder is varied, with 17p12 duplication being one of the causes. The severity and symptoms shown differ depending on the region affected, and the presence of other chromosomal abnormalities associated with the duplication. In CMT type 1A, the duplication causes more of the protein to be produced from the genes in that region. This causes the structure and function of the myelin sheath around nerve fibres to be abnormal, causing various clinical manifestations such as:
- Weak feet and lower leg muscles
- Foot deformities (eg: high arch)
- Difficulty with fine motor skills due to muscle atrophy
- Mild to severe pain as age progresses
- May lead to respiratory muscle weakness
2.4.3 Robertsonian Translocation
Translocations generally do not result in loss of genetic material. Robertsonian translocations, however, result in the loss of small parts of the chromosomes involved. The fusion of two acrocentric chromosomes with the subsequent loss of the two short arms is termed Robertsonian translocation or centric fusion (Figure 2.8). Although this translocation causes loss of the short arms, it is maintained as a balanced translocation. This is explained by the fact that the genes on the short arms are most rRNA genes that are present in many copies on other chromosomes; thus deletion of these copies doesn’t have much phenotypic manifestation as you might expect.
One of the commonly seen such translocation is between chromosome 14 and 21, that gives rise to individuals showing characteristics of Down syndrome. Since this translocation is functionally a balanced translocation, individuals with this aberration usually do not show any abnormal phenotype. Their effects are only seen in the next generation due to production of abnormal gametes. Balanced changes cause disturbances during the meiotic segregation. Due to this, the resulting gametes end up with loss of chromosome, or gain chromosome. How they cause such aberrations will bediscussed in Section 2.5.2.
2.4.4 Reciprocal Translocation
Reciprocal translocation involves breaks in two chromosomes and the subsequent exchange of segments between the two chromosomes (Figure 2.9). Reciprocal translocation do not change the number of chromosomes. However, they may change the size and type of chromosome if the segments being exchanges are differing in size (Figure 2.9-b). For reasons not yet clear, reciprocal translocations involving chromosomes 11 and 22 are fairly common in the population.
Reciprocal translocations can give rise to deletion-duplication conditions and can cause disorders associated with such conditions. However, as in the case of Robertsonian translocation, an individual possessing the translocation himself would not show any abnormal phenotype. Due to disturbances during meiotic segregation of these translocated products, individual of the next generation have a possibility of showing abnormal phenotype. This is discussed in Section 2.5.3.
2.4.5 Inversions
An inversion is a condition wherein a segment of a chromosome is inverted. This is caused by two breaks in the chromosome and the subsequent rejoining in a reverse manner. This changes the order of genes on that chromosome and does not cause any changes in the chromosome number (Figure 2.11). Depending on the involvement of the centromere, inversion are of two types – pericentric and paracentric.
- Pericentric inversions occur when the inverted segment that includes the centromere. The product after inversion can differ significantly in the arm length and thus change the type of chromosome (eg: sub-metacentric to metacentric as shown in Figure 2.11-a).
- Paracentric inversions occur when the inverted segment does not include the centromere. The product after inversion remains the same type as the original except for a change in the order of genes (Figure 2.11-b)
Pericentric and paracentric inversion are both balanced rearrangements because they do not cause any net loss or gain of genes. Except in the very rare cases that the break points in the chromosome is within a gene (which gets disrupted), individuals with inversions do not show any abnormal phenotype. As you may expect, their effects are seen as deletion-duplication only in the next generation. Hence we shall discuss it under the causes of aberrations in Section 2.5.4.
2.4.6 Isochromosomes and Ring chromosomes
Isochromosomes
An isochromosome is an abnormal chromosome with two identical arms – either having two short (p) arms or two long (q) arms. An isochromosome, thus, has an entire arm deleted along with the duplication of the other arm. This type of aberration is caused due to the transverse separation of the centromere during cell division instead of the normal lateral separation (Figure 2.12).
Isochromosomes, due to their deletion-duplication nature, cause abnormal phenotypes in individuals possessing them. The most common isochromosome is that of the X chromosome. This condition leads to the individual showing phenotypic charactertictics of Turner syndrome. The missing genes on the missing arm contributes to the development of Turner syndrome in these females. Such X-isochromosomes account for as much as 15% of Turner syndrome cases.
Ring chromosomes
Ring chromosomes are formed when a chromosome losses its telomere regions and joins back on itself end-to-end. Breaks at the terminal regions cause the chromosome to have “sticky ends” because of loss of telomere region. These end, thus, join with each other causing the chromosome to become circular or ‘ring-like’ (Figure 2.13). Since the two terminal fragments are lost, loss of genes in those regions can have an effect on the phenotype. If these regions have important genes, their consequences can be serious abnormality in the phenotype.
Disorders caused by ring chromosomes are not due to the ring formation itself, but due to the deletion of the genes in terminal regions. Also, ring chromosome are unstable during mitosis, hence the daughter cells may have lost the chromosome altogether. This results essentially in a monosomy. As much as 5% of Turner syndrome cases are shown to be due to ring chromosome-X. Some of the other disorders include ring chromosome 20 syndrome where a ring formed by one copy of chromosome 20 is associated with epilepsy; ring chromosome 14 and ring chromosome 13 syndromes are associated with mental retardation and dysmorphic (malformation) facial features; ring chromosome 15 is associated with mental retardation, dwarfism and microcephaly (small head).
2.5 CAUSES OF CHROMOSOMAL ABERRATIONS
In the preceding sections we looked at the different types of numerical and structural aberrations, and their effects on phenotypes. We briefed through the causes and origins of these aberrations. In this section we will discuss them in detail.
Table 2.2 gives an overview of the types of aberrations and the origin of their causes. It is evident that the abnormality can occur not only during gamete formation, but also in the previous generation as well as after fertilization. Since the time of occurrence would lead to different consequences, it is important to analyze existing aberrations and offer effective methods for those who are at risk. Some of these methods are explained in the following unit. If an abnormal child is born into a family, it is strongly advised that the family should undergo genetic counseling. Finding the cause of the abnormality and taking steps to reduce future abnormalities is just as important as learning to deal with an affected child.
2.5.1 Non-disjunction
Non-disjunction is the failure of separation of the chromosomes during mitosis or meiosis. Normal division involves the separation of the two arms (mitosis and meiosis-II) of the chromosomes or separation of the two chromosomes (meiosis-I) during the anaphase stage. This ensure that one copy of each is moved to each pole and consequently each daughter cell receives one copy. When this separation fails, both copies will move to one pole. Hence, one of the daughter cells will now have two copies while the other has no copies of that chromosome. Simply put, this is the basis of aneuploidy changes where there is one extra copy present or one copy missing in the cells. Figure 2.15 shows the normal meiotic and mitotic division and the consequences of non-disjunction at meiosis-I, meiosis-II and mitosis anaphase stages.
The occurrence of non-disjunction is itself dependent on many factors. Some of these factors are:
- Advanced maternal age has been well correlated with an increase in the chances of non-disjunction. This is well illustrated in the fact that incidence of Down syndrome increases drastically as the maternal age increases. Figure 2.16 shows a graph correlating maternal age and incidence of Down syndrome (here Down syndrome is indicative of non-disjunction). This increase is attributed to the aging of the primary oocyte as age progresses and a reduction of the maternal competence to identify and abort abnormal fetuses.
- Increase in the time between ovulation and fertilization is well documented in animals to increase the rate of non-disjunction. As the frequency of copulations reduces there is an increased chance that there is a delay between ovulation and fertilization.
- Exposure to mutagens in general increases the chances of non-disjunction. Especially those who are constantly exposed to radiations have a high risk of non-disjunction.
- Genetic control of non-disjunction has been shown in a few species of Drosophila (fruit fly). These findings accounts for those few families that have shown to be prone to recurrent non-disjunction.
2.5.2 Robertsonian Translocation
As discussed before, Robertsonian translocation or centric fusion, causes a balanced rearrangement in the individual without any phenotypic abnormalities; however, due to improper meiotic segregation they give rise to trisomy-like and monosomy-like conditions in the offspring of such individuals.
A normal chromosomal complement in humans consists of two copies each of the 22 chromosomes and XY (for males) or XX (for females) – total of 46. Let us consider an individual who has a Robertsonian translocation between chromosomes 14 and 22. This person has a total of only 45 chromosomes. He has two copies of all the other chromosomes except 14 and 21. For this pair of chromosomes he has one chromosome 14, one chromosome 21 and one translocation 14/21 chromosome (Figure 2.17).
In a normal individual, during meiosis, one copy of each of these chromosome moves to each pole. This results in daughter cells each containing one copy of 14 and one of 21. In a translocation individual, however, because there are three chromosomes instead of four two of them move to one pole and one moves to another pole. This causes abnormal chromosomal constituents in the daughter cells (gametes). There are different possible ways of these three chromosomes segregating as shown in Figure 2.18. It is clear that only a small portion of gametes produced by individuals with such balanced translocations can produce normal offspring. Thus, a Robertsonian translocation can give rise to monosomies and trisomies of different chromosomes and their associated syndromes.
You should note that although these abnormalities do not cause true trisomies or monosomies, they give rise to conditions that are akin to true trisomies and monosomies. This is because, as stated before, the long arms of these chromosomes contain the bulk of the genes for that chromosome; presence of extra copies of the long arm has the same effect as having an extra copy of the entire chromosome.
2.5.3 Reciprocal Translocation
Translocations not only cause trisomy-like and monosomy-like conditions, they also produce deletion-duplication conditions. A deletion-duplicaion is a condition where one segment of the chromosome is missing (deletion) and another is present in an extra copy (duplication). Figure 2.19 shows an example of a deletionduplication condition.
Reciprocal translocations, wherein there is a mutual exchange of segments between two chromosomes, cause abnormal meiotic segregation. This abnormality is due to the formation of a quadrivalent of the four chromosomes during pairing (Figure 2.20). This structure is formed because the chromosomal segments always pair with their homologous regions. When such a complex structure is formed, separation of the chromosomes can happen in different ways depending on their orientation in the spindle. Figure 2.20 shows the different possibilities of segregation of a quadrivalent formed from reciprocally translocated chromosomes.
By analyzing the segregation products you should be able to predict the condition of the offspring from such a gamete. The first two segregation patterns produced phenotypically normal offspring. The next two segregation patterns may produce surviving offspring, but they will show abnormal phenotype due to the deletionduplication condition. Depending on the size of the del-dup segment the severity may vary. The last two segregation patterns are usually lethal. This is due to the del-dup segments being very large in these cases. If you recall, deletions of over 2% of the genome is incompatible with survival.
Hence, translocations by themselves do not cause deletions or duplications; it is only in the next generation that their effects are seen. It cannot be emphasized enough that a balanced translocation carrier will most probably have normal phenotype, unless the breakpoint disrupts some gene. As with all balanced rearrangements, we shall see that inversions, too, cause deletions and duplications because of abnormalities in meiotic division.
2.5.4 Inversions
Inversions are balanced genetic rearrangements that invert segments within the chromosome. Depending on the involvement of the centromere they are either paracentric or pericentric (see Section 2.4.5). It is important to distinguish between these two types because the crossover products after meiosis is different for each.
In Section 2.5.3 you saw how a reciprocal translocation gives rise to an abnormal complex during meiotic pairing. By the same logic, inversions too cause the formation of “inversion loops” during meiotic pairing. Because one of the two homologous chromosomes contains the inversion, it folds back into a loop to allow for maximum homologous pairing (Figures 2.21 and 2.22). Crossing over is a unique event in meiosis that causes recombination between the homologous pair of chromosomes. When crossing over occurs in a region within an inversion loop, it gives rise to recombinant products that contain deletion and duplication.
Look at Figures 2.21 and 2.22. You can see that the formation of the inversion loop produces maximum homologous regions to be paired up. In pericentric inversions the inversion loop contains the centromere and in paracentric inversion the centromere is outside the inversion loop. Crossing over outside the inversion loop will give rise to normal chromosomes and inversion chromosomes. A crossover within the inversion loop, however, produces two non-recombinants (one normal and one inverted) and two recombinants (that contain deletion and duplication). These recombinants will contain duplication of certain genes along with deletion of other genes.
In pericentric inversions the deleted and duplicated segments do not involve the centromere; hence four types of gametes will be produced. Two of these will contain the aberrations; depending on the extent of the aberration it may or may not be compatible with survival. In paracentric inversions the deleted and duplicated segments involve the centromere, hence we get one dicentric (containing two centromeres) and one acentric (containing no centromere) chromosome as recombinants. The dicentric chromosome forms a dicentric bridge during anaphase and thus arrests cell division (does not produce a gamete). The acentric chromosome is lost during division and thus doesn’t produce any viable gamete. Hence, only two types of gametes are produced from such individuals – one normal and one containing the inversion. These offspring will have normal phenotype because the inversion itself is a balanced rearrangement. Hence, the inversion itself will tend to persist in the population.
Sample Questions
- 1) What are the structural chromosomal aberrations, give a note with examples?
- 2) Give an account of common genetic syndromes caused by aneuploidy.
- 3) Describe the phenomenon of Genetic Imprinting
- 4) Write short notes on Non-disjunction and translocations?