TEXT Introduction During evolutionary history of organisms, the genomes of organisms are continuously being rearranged and reshaped.

Transcription

1 TEXT Introduction During evolutionary history of organisms, the genomes of organisms are continuously being rearranged and reshaped. These rearrangements may change the position of a segment within a chromosome, or they may bring together segments from different chromosomes. In either case, the structure of the chromosome is changed, and the order of the genes is altered. These changes are, thus, called structural changes in chromosomes; which include gross chromosomal changes, involving larger chromosomal segments, viz. Deletions, Duplications, Inversions and Translocations. All these structural changes in chromosomes occur by breakage and reunion process as proposed by Stadler, Sax and Muller in 1930 s. Chromosome breakage occurs frequently in nature due to mechanical pressure, induction by physical and chemical agents etc. Generally these chromosomal breaks are repaired to their original position and are thus indistinguishable in the subsequent stages of meiosis, or in the phenotype of an organism. However, sometimes the broken segments may be lost or reunited in a different manner, leading to various types of structural changes in chromosomes. Translocations, also known as interchanges, are those structural changes in chromosomes in which a segment from one chromosome is detached and then reattached to a different non- homologous chromosome. In other words, genes from one chromosome are transferred to another and vice versa.translocations were first reported by Belling (1925) in Stizolobium

2 deeringianum and Blakeslee (1928) in Datura stramonium. Translocations occur naturally in some plants, such asoenothera lamarckiana, Tradescantia, Delphinium sp.and Rheo discolor,etc.

3 Fig. Translocation between two non homologous chromosomes(fig. downloaded from internet) Types of translocations Different types of translocations exist in nature, as given below: 1. Simple translocations In this case a single break occurs in a chromosome releasing a terminal acentric fragment. This is followed by transfer of this acentric fragment to the end of a nonhomologous chromosome. This type of translocation was first reported by Muller and Painter in It was, however, later revealed that the presence of telomeres on the ends of non-homologous chromosome will not allow

4 such fusion. Therefore, atleast two breaks must occur, one in each non-homologous chromosome, in order to facilitate the fusion or reunion of the translocated segment. Again, the one way translocation will create a chromosome (from which the segment was broken) which lacks telomere. Such a chromosome may not function properly without telomere. Therefore, simple translocations actually do not exist in nature. 2. Shifts or intercalary translocations This type of translocation is commonly found in nature and involves atleat three breaks two breaks in one chromosome releasing an acentric fragmnet and one break in another non-homologous chromosome. The released acentric fragment is then inserted at the intercalary position near the break produced in the nonhomologous chromosome. This type of translocation was first reported by Bridges in Both simple type and intercalary translocations are also called as non-reciprocal translocations. It can be either intrachromosomal type where the chromosomal segment from one chromosome is translocated to other position but in the same chromosome,or interchromosomal type where the chromosomal segment from one chromosome is translocated to the other nonhomologous chromosome.

5 Fig. Types of translocations (Drawn from Genetics by Strickberger) 3.Reciprocal translocations This is the most frequently found and best studied type of translocation. When chromosomal segments are exchanged between two non-homologous chromosomes without any net loss of genetic material, the event is referred to as a reciprocal translocation. In reciprocal translocation, atleast a single break occurs in each nonhomologous chromosome, releasing a terminal telomeric

6 fragment. This is followed by mutual exchange of these fragments between the two non-homologous chromosomes, e.g. a part of chromosome-1is detached and becomes attached to chromosome 2. At the same time, a part of chromosome 2 is detached and becomes attached to chromosome 1. Such translocations are also called interchanges. The net result of this translocation is that genes from one chromosome are transferred to the other, and vice-versa. Fig. Non-reciprocal or simple translocation and reciprocal translocation(fig. Downloaded from internet) Since reciprocal translocation is found more frequently in nature, only this type of translocation is discussed in detail. Translocation homozygote and heterozygote If the exchange of chromosomal segments takes place between two non homologous chromosomes, so that in each homologous pair one chromosome is normal

7 and the other contains exchanged part, the individual is called translocation heterozygote. But,if both the partners of a homologous pair exchange their chromosomal segments with other homologous pair, then it will give rise to a translocation homozygote. Translocation heterozygote is, however, more important and has evolutionary significance. Fig. Translocation homozygote and heterozygote (Drawn from Genetics by PK Gupta) Origin of translocations Since translocations originate by breakage and reunion process, any event that leads to breakage in chromosomes followed by reunion with non-homologous chromosomes results in translocations. Translocations can originate spontaneously in nature, and can also be induced. Different ways by which translocation occur include;

8 a). Mechanical shear: Breaks occur frequently due to mechanical shear because of chromosome entanglement at interphase or prophase. The broken chromosome segments then reunite with nonhomologous chromosome to produce translocations. b). Formation of interlocked bivalents: Interlocking takes place during prophase stage of meiosis when a non-homologous chromosome passes through a loop of two homologous chromosomes that are in the process of pairing. The interlocked bivalents subsequently separate at anaphase-i, but during this process breakage and reunion takes place. d). Physical and chemical agents: Some physical mutagens like X-rays, gamma rays and various chemical agents, have the ability to induce breaks in the chromosomes. If, two or more breaks occur simultaneously in the non-homologous chromosomes, this may result in translocations. Most of the naturally occuring translocations are due to these mutagenic agents because the organisms are continuously exposed to these agents, in the environment. d). Crossing over in homologous regions: Some times, some duplicated segments are found between non-homologous chromosomes. These duplicated segments are homologous to each other and crossing over between these segments may lead to translocations. Similarly, centromeric regions contain repetitive DNA elements which may be similar in nonhomologous chromosomes. Crossing over at such positions may also result intranslocations.

9 Fig. Origin of translocations due to breakage and crossing over ( Fig. downloaded from internet) Cytology of translocation heterozygotes Translocation homolozygotes show normal pairing and bivalent formation during meiosis. The segregation of chromosomes at anaphase is also normal. In case of translocation heterozygote, two homologous pairs are involved and one chromosome of each pair contains translocation, while the other one is normal. Due

10 to the exchange of chromosomal segments between two non-homologous chromosomes, the normal pairing into bivalents is not possible. In such a situation, the pairing takes place in such a way that a cross/plus (+) shaped figure, involving all the four chromosomes, is observed at pachytene stage. The position of centre of a cross will vary depending upon the position of breakpoints (i.e. the point where breakage has initially occurred, leading to translocation of the broken segments). Depending upon different combinations of crossing over in the four arms of this cross shaped figure, we get different configurations of this quadrivalent at metaphase-i, for example. a) A ring of four chromosomes (1 IV ), showing terminal chiasmata between the homologous chromosome arms, i.e. chiasmata are formed in each of the paired arms. b) A chain of four chromosomes (1 IV ), if any of the terminal chiasmata is broken, or if any of the paired arm fails to form the chiasmata. c) Two bivalents, if two terminal chiasmata are broken (2 II ) or if two arms fail to form chiasmata. d) A chain of three chromosomes and a univalent (1 III +1 I ). However, the most characteristic configuration is a ring of four chromosomes at Metaphase-I. Infact, translocation heterozygosity can be detected through cytological analysis where a cross (+) shaped figure at pachytene and a ring quadrivalent at Metaphase-I stage of meiosis is observed. Karyotypes prepared from mitotic chromosomes can also be used for detection of translocation. This is because translocations will bring

11 about changes in the lengths of individual chromosomes and the position of centromeres. Such karyotypes are compared with normal karyotype of the species to detect translocations. The ring quadrivalent is later arranged at the metaphase plate followed by attachment by spindle fibres. The fate of chromosome segregation at anaphase and subsequent gamete formation will depend on the orientation of this quadrivalent at Metaphase plate. The quadrivalent at Metaphase-1 can have one of the following three orientations: 1. Alternate: In this case, alternate chromosomes will be oriented towards the same pole, or the adjacent chromosomes will orient towards opposite poles. A characteristic eight (8) shaped figure is formed at metaphase. Due to alternate type of orientation, the translocated and non-translocated chromosomes enter into separate gametes. The net result is that two types of gametes are formed; one carrying normal chromosomes, and the other one carrying translocated chromosomes. However, both these types of gametes are normal as there are no deletions and duplications, i.e. no gene is lost or duplicated. 2. Adjacent-I: In this type of orientation adjacent chromosomes having non-homologous centromeres are oriented towards the same pole. The anaphase segregation and subsequent stages of meiosis will result in the formation of gametes, carrying translocated chromosomes with deletions and duplications. Therefore, all gametes will be non functional.

12 3. Adjacent-II: In this type of orientation, adjacent chromosomes with homologous centromeres will move towards the same pole at anaphase. The gametes produced will carry deletions and duplications, and are thus non functional. Fig. Meiotic behaviour of translocation heterozygote (Drawn from Genetics by PK Gupta) In short, the orientation of translocation ring at metaphase determines the nature of gametes produced. It is clearly seen that, only alternate disjunction will give

13 rise to functional gametes. Both Adjacent-I and Adjacent- II disjunctions will give non functional gametes. If the three types of orientations occur at random in th PMC s of translocation heteozygote, it is expected that approximately two thirds of the gametes produced will be non viable. Therefore, an individual having translocation in heterozygous condition will produce considerable amount of non functional or sterile gametes. A number of factors govern the formation of translocation ring and its orientation at metaphase, e.g. the chromosomes should be fairly long enough to permit chiasmata formation in each arm. If the chromosomes are too long, the chiasmata may be too numerous to permit complete terminalization, and the ring too flexible to orient properly on the spindle. Similarly, the exchanged chromosomal segments must be of sufficient length to permit regular chiasma formation. These exchanged chromosomal segments must also be equal in length to form symmetrical rings at metaphase plate. Asymmetrical rings have difficulty in orientation and segregation. A high degree of terminalization, or chiasma formation restricted to the ends of chromosome arms, is also essential for proper orientation and adjacent disjunction and segregation at anaphase. Crossing over in translocation heterozygote As shown above, the gametes formed due to adjacent disjunctions in a translocation ring carry deletions and duplications and are, therefore, nonfunctional. On the other hand, gametes produced by alternate disjnction are balanced and functional. However, such an inference did not take crossing over into consideration. Infact, in a translocation ring, crossing

14 over can take place at various positions, e.g. between the interchanged arms, between non interchangedarms and in the interstitial region, i.e. the region between cetromere and interchange breakpoint. The crossing over in interchanged and non interchanged arms will not influence the constitution of gametes produced. However, when crossing over takes place in interstitial region, the chromaid segments are exchanged and finally it leads to the production of gametes, 50% of which are sterile even when alernate disjunction is taking place. Similarly, if adjacent-i disjunction takes place in such a situation, 50% gametes produced will be fertile. The adjacent-ii segregation will be rare or altogether absent. Therefore, for an interchange heterozygote to be succesful in nature, not only there should be 100% alternate disjunction, but the intersitial segments should be very small and preferably heterochromatic, so that no crossing over takes place in this region. Breeding behaviour of translocation heterozygotes The presence of translocation heterozygosity can be detected by the presence of semisterility and low seed set. This can in turn be confirmed by cytological analysis, where a characteristic translocation ring is observed at diakinesis or metaphase stages of meiosis. We have already seen that only alternate disjunction results in the formation of functionl gametes. During selfing of a translocation heterozygote, two types of gametes are formed on male and female side, one carrying normal chromosomes, and the other type carrying translocated chromosomes. Random fertilization between these gametes will produce a progeny of normal, translocation

15 heterozygotes and translocation homozygotes in the ratio of 1:2:1, respectively. Fig. Breeding behaviour of translocation heterozygote (Drawn from Genetics by PK Gupta) Rarely, however, an interchange ring may undergo 3:1 disjunction at anaphase, resulting in the formation of n+1 and n-1 gametes. Although the deficient gamete is non functional, but the gamete with n+1 condition on fertilization with normal gamete will lead to the production of variety of trisomics. Robertsonian Translocation During translocations, generally small chromosomal segments carrying one or a few genes are involved. However, sometimes the entire chromosome arms are

16 exchanged. Such translocations are called Robertsonian tanslocations. These translocations are important because they may lead to a change in chromosome number of the concerned species. Robertsonian translocation can occur by the fusion of two acrocentric or telocentric chromosomes in to one metacentric chromosome or by fission or splitting of one metacentric chromosome into to telocentric chromosomes. In the former case a crossing over between two acrocentric chromosomes will result in the formation of a large metacentric chromosome, and a small dot like chromosome which is eventually lost.in the later case, a metacentric chromosome breaks in the centromeric region to produce two telocentric chromosomes. However, both these chromosomes will then lack telomere on one side. Therefore, some other mechanism may be involved in such a type of Robertsonian translocation.

17 Fig. Robertsonian translocaton between two telocentric chromosomes (Downloaded from internet) Fig. Crossing over between two acrocentric chromosomes. (Downloaded from internet) Genetic consequences of translocations Translocations result in the exchange of chromosomal segments between non-homologous chromosomes. The net result of this event is transfer of genes from one chromosome to the other, and the disturbed meiotic behaviour leading to the formation of unbalanced gametes. Depending upon the size of translocated segment, the number of genes are affected accordingly

18 and hence the phenotype. Some of the genetic consequences of translocations are as follows: 1. Formation of unbalanced gametes and sterility: In a translocation heterozygote, both adjacent-i and adjacent-ii disjunctions result in the formation of defective gametes, carrying deletions and duplications. The fertile gametes are produced only by alternate disjunction. The overall fertility and seed set in a translocation heterozygote is low. Infact semi-sterility of pollen and low seed set in an otherwise fertile plant are idications of translocation heterozygosity, which can then be confirmed through cytological analysis. 2. Position effect During translocations, the position of genes is changed from one chromosome to the other. The genes generally perform their normal functions at their fixed positions in the chromosome due to various allelic and non-allelic interactions existing there. Due to change in position of genes, all these interactions are affected, and hence the expression of the genes involved. Any phenotypic change due to change in position of genes is called position effect. Some times a highly transcribed gene is translocated to a region of inactive heterochromatin, or the breakage may occur within a regulatory part or internal sequence of a gene. All these events will make the translocated gene inactive and the phenotype is thus affected. Reciprocal translocations also change the linkage relationships of genes. 3. Change in chromosome number and karyotype evolution

19 One of the important evolutionary implications of translocations is the change in chromosome number, leading to the origin of different cytotypes / karyotypes within a species. It is believed that Robertsonian translocations have played importment role in the karyotype evolution, especially in mammals. The changes in chromosome number occur due to the fusion of two non-homologous acrocentric chromosomes (centric fusion) into a single metacentric chromosome, or separation of a metacentric chromosome (centric fission) into two telocentric chromosomes. The former event will decrease the chromosome number, while the latter one will increase the chromosome number. Besides, such translocations change the centromeric positions of the chromosomes by converting two acrocentrics into a single metacentric chromosome and vice-versa, e.g. Mouse, Drosophila, Bovoidea, Gibasis, etc. One species of Mouse Mus musculus (Hose mouse) has 2n=40 with all acrocentric chromosomes. The other species of mouse M. poschiavinus (Tobacco mouse) has 2n=26,with 14 metacentric chromosomes. This could be either due to fusion of some telocentric chromosomes to give a karyotype of metacentric chromosomes, or fission of some metacentric chromosomes to produce a karyotype of telocentric chromosomes. The former event will give rise to M. poschiavinus, while the latter one will give rise to the karyotype of Mus musculus. 4. Genetic disorders in humans In humans, translocations have been found to be responsible for certain genetic disorders, e.g. a deletion of chromosome 22 was first reported by P.C. Nowell and D.A. Hungerford and was called as the Philadelphia

20 chromosome (Ph / ) after the city in which the discovery was made. This deletion was accociated with Chronic Myelocytic Leukemia in the bone marrow of such individuals. Later it was found that this leukemia was actually due to the translocation of a part of long arm of chromosome 22 to chromosome 9 (46xx, 9q +, 22 - ). Another well known human disorder is Familial Down s Syndrome. In this case, a part of chromosome 21 is translocated to chromosome 14 (14 21 ). The individuals carrying this translocation have a normal chromosome 14 and 21, in addition to the translocated chromosome Such individuals will produce gametes bearing a normal chromosome 21 and the translocated chromosome Fertilization of this gamete with a normal gamete will result into an offspring with two normal chromosome 21 and a part of chromosome 21 attached to chromosome 14 (14 21 ). Thus, such individuals are tisomic for major part of chromosome 21which results into a Down s Syndrome.

21 Fig. Down s Syndrome due to Robertsonian Translocation (Downloaded from internet)

22 Fig. showin occuance of Downs Syndrome (Downloaded from internet) Conclusion: Translocations are a class of structural changes in chromosomes, which involves exchange of chromosomal segments. The net result is that genes from one chromosome are transferred to the other non homologous chromosome. The meiotic behaviour of translocation heterozygote is disturbed, leading to the formation of defective gametes. Due to the position effect, translocations result in various phenotypic disorders in humans. Robertsonian translocations have played important role in karyotype evolutions.

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