-19. -Mousa Salah. -Shahd Alqudah. -Dr Belal
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1 التزام -19 -Mousa Salah -Shahd Alqudah -Dr Belal 1 P a g e
2 In the previous lecture we talked about the numerical chromosomal abnormalities, they are either autosomal or sex, and we said that the chromosomal abnormalities can be also structural for example when deleting the P arm in chromosome 5 which leads to cri du chat syndrome. Chronic myelogenous leukemia (CML) Another example about the structural abnormality is the translocations of chromosomes which leads to stem cell transformation into chronic myelogenous leukemia (CML). Leukemia is divided into two major groups: - 1- Lymphoblastic: if the lymphoid cells are damaged, the leukemia is lymphoblastic, it is either acute or chronic. 2- Myelogenous: if the myeloid cells are damaged, the leukemia is myelogenous, it is either acute or chronic. So, we have four types of leukemia: - 1- Acute lymphoblastic leukemia: caused by abnormalities in the lymphoid, more common in children. 2- Chronic lymphoblastic leukemia: more common in adults (55+ years old). 3- Acute myelogenous leukemia: caused by abnormalities in the myeloid, more common in adult and children. 4- Chronic myelogenous leukemia: more common in adults. 1 P a g e
3 Chronic myelogenous leukemia (CML) is caused by the translocation (exchange of genetic material between nonhomologous chromosomes) in chromosomes 9 and 22. Note: The centromere specifies the chromosome even if a part of it is translocated. So, if a translocation happened between chromosomes 9 and 22, we can locate chromosome 22 by its centromere and we call it translocated 22, the same with chromosome 9 which is called after the translocation, translocated 9. Why CML is caused by this translocation? As you remember, the gene consists of exons and introns and it is transcribed into pre-mrna, then we remove the introns to get the mature mrna, this process is done by the RNA polymerase with the help of the transcription factors, so the RNA polymerase locates the promoter region in the gene and start the transcription process with the help of the transcription factors. We have a region in chromosome 9 we call it ABL region (promoter + coding region ), also we have in chromosome 22 the BCR region. When the translocation happens between chromosome 9 and 22, the cut in chromosome 9 is done after the promoter and before the coding region of ABL, the same is happening in BCR in chromosome 22. By that the promotor of ABL stays on chromosome 9 and the promotor of BCR stays on chromosome 22. As we know, the promoter regulates how much mrna is needed to be expressed and determine what type of cells can express a certain gene. For example, a gene named crystalline exists in the lens of the eye, the expression of this gene can happen only in the lens of the eye because the promoter of this gene determines the location of the expression of this gene. 2 P a g e
4 All the cells in our body have the same DNA, but the cardiac cells for example are different from the neurons, this is due to the differential expression which means every cell chooses to express certain genes according to its nature and its need for certain proteins or RNA. So in this translocation, each part that has been cut from each chromosome goes to the other chromosome, the part that came from chromosome 9 (ABL) will connect with chromosome 22 on the promoter of BCR. Once the translocation is done, the coding region (exons and introns) of ABL finds itself suddenly under the promoter of BCR, which is the promoter of another gene. This is a serious problem that cause chronic myelogenous leukemia (CML). Note : ABL gene expresses a membrane associated protein, a tyrosine kinase, which induces the cell cycle. It has a neutral effect as long as it is under its normal promoter. But when translocation took place, the ABL coding region will be located under a very active promoter (BCR promoter) which will increase the number of tyrosine kinases in that cell. In addition, the product of the transcription will be a mutant tyrosine kinase encoded by the BCR-ABL transcript results in a protein that is always on. These changes will result in unregulated cell division and cell transformation into cancer cell. 3 P a g e
5 Not every translocation causes a disease, if the translocation happens in regions that don t have crucial genes ( ~99% of our genome) (heterochromatin or repeats) or the cuttings don t cause disruptions, there will be no clinical consequences. As we know the translocation is the exchange of genetic material between nonhomologous chromosomes, we have two scenarios for the translocation: - For example, we have in the figure chromosome 1 and 4. As you see, the cuts happened where the arrows are placed. The first scenario is that the two small parts will exchange between the two chromosomes, this cell will be stable in mitosis, which will give us identical daughter cells because every chromosome has its own centromere that the spindle fibers can attach to. In the second scenario, we have the same cuts as in scenario one but the long parts and the small parts will connect to each other, this cell will be unstable in mitosis because: - 1. There will be no identical daughter cells after mitosis. 2. The chromosome that produced from the small parts doesn t have centromere which will be lost in mitosis because the spindle fiber can t attach to it. 3. The chromosome that produced from the long parts has two centromeres, so the spindle fibers will attach to two centromeres for the same chromosome, which will cause instability in the number of chromosomes in the daughter cells. Reciprocal translocation (main type of translocation) 4 P a g e
6 As we said the translocation can happen between chromosome 9 and 22 and this will cause CML because there will be disruption in BCR-ABL gene, and as we said also the cut might be in a nonimportant region (heterochromatin or repeats) so there will be no clinical outcomes from exchanging the genetic material. For example, lets assume that a translocation happened between chromosome 5 and 6, this translocation will not necessarily cause a clinical outcome in this individual, we call this individual balanced carrier because there is no net loss or gain in the DNA after the translocation, the DNA only got rearranged. So there will be no clinical outcomes from this translocation, but there will be a problem in meiosis. As we said before, after meiosis we will have daughter cells, one daughter cell will have 23 chromosomes and the other daughter cell will have the other 23 homolog chromosomes. When meiosis happens in the balanced carrier, every chromosome and its homolog will be in different daughter cells including the chromosomes that have been translocated, the rearrangement of the chromosomes in the daughter cells is random according to Mendel s second law (the law of independent assortment), so there will be a lot of scenarios to the distribution of chromosomes in the daughter cells. But there will be two scenarios for the translocated chromosomes. In one scenario, a daughter cell will have all the chromosomes not translocated but the other daughter cell will have both of the translocated chromosomes, so the first daughter cell will have normal chromosomes and the other will have balanced translocated chromosomes. In the other scenario, a daughter cell will have the first translocated chromosome and the other daughter cell will have the other translocated chromosome as in the 5 P a g e
7 figure, the first daughter cell has the long chromosome normal and the short is translocated, the other daughter cell has the long chromosome translocated while the short is normal. So, in meiosis to a balanced carrier, there is only four possible cases for the gametes: one normal gamete, one has both of the translocated chromosomes and two gametes each one has different translocated chromosome. After meiosis, one of the four possible gametes (egg) will be produced and will be fertilized by a normal gamete, we have 4 possible cases for the produced zygote: - 1. Normal zygote: normal gamete fertilized by a normal gamete (normal complement of chromosomes). 2. Balanced carrier zygote: gamete has both of the translocated chromosomes fertilized by normal gamete, this zygote has a translocation but it is balanced because there is no net loss or gain of DNA (only rearrangement). 3. Zygote has partial trisomy or partial monosomy: look at the figure, we have two long yellow chromosomes and an extra yellow part in the short chromosome (partial trisomy), on the other hand we have one normal short chromosome and the other one has a missing part (partial monosomy). 4. Zygote has partial monosomy or partial trisomy: look at the figure, we have two short purple chromosomes and an extra purple part in the long chromosome (partial trisomy), on the other hand we have one normal long chromosome and the other one has a missing part (partial monosomy). 6 P a g e
8 *Which of these cases can cause abnormalities? Case 3 and 4. Robertsonian translocation If you remember we talked before about the acrocentric chromosomes (13, 14, 15, 21 and 22), they have the same P arm which is the ribosomal DNA with the satellite, and we know that if a deletion happened in one of these chromosomes in the P arm there will be no clinical consequence. robertsonian translocation happens only between the acrocentric chromosomes, so sometimes in a translocation, the cuts will be in the P arm above the centromere in two acrocentric chromosomes, the P arms of both chromosomes connect to each other and the Q arms with the centromeres connect to each other as well (Q arm + centromere + centromere + Q arm), the P arms in mitosis will be lost because they don t have centromere, so the daughter cells will not have the P arms. For example, if an individual had a robertsonian translocation in chromosomes 14 and 21. This individual will be normal or abnormal? He will be normal, because the Q arms of both chromosomes didn t get lost. How much chromosomes this individual will have after the translocation? 7 P a g e
9 He will have 45 chromosomes, because the Q arms and the centromeres of both chromosomes are connected to each other, the P arms will not be counted as a chromosome because they don t have a centromere. So if we do karyotyping for this individual chromosomes, he will have 45 chromosomes, but he is at the same time clinically normal. This individual will have a problem when producing gametes, so in metaphase 1 in meiosis, when the pairs of homologous chromosomes align together, for example chromosome 1 pairs with its chromosome 1 homolog and so on until the alignment reaches chromosomes 14 and 21, there will be confusion, sometimes chromosome 14 pairs with the translocated chromosome, and sometimes chromosome 21 pairs with it, so we have six different scenarios for the produced daughter cells: - - The first possible division: 1. Normal daughter cell: normal chromosomes aligned together (without translocated chromosome). 8 P a g e
10 2. Daughter cell with only the translocated chromosome (14/21). -The second possible division (in metaphase 1 the translocated chromosome paired with chromosome 21, chromosome 14 didn't have a homolog) : 3. Daughter cell with the translocated chromosome (14/21)[ which was the homologous chromosome of 21] and chromosome Daughter cell have chromosome 21. Chromosome 14 is absent. - The third possible division (in metaphase 1 the translocated chromosome paired with chromosome 14, chromosome 21 didn't have a homolog): 5. Daughter cell with translocated chromosome (14/21) )[ which was the homologous chromosome of 14]and chromosome Daughter cell have chromosome 14. Chromosome 21 is absent. After meiosis, one of the six possible daughter cells will be produced and will be fertilized by a normal gamete, we have 6 possible cases for the produced zygote: - 1. Normal zygote: normal daughter cell got fertilized by a normal gamete. 2. Balanced carrier zygote: a daughter cell with only the translocated chromosome got fertilized by normal gamete (no loss or gain in DNA) 3. Trisomy 14 zygote: Daughter cell with the translocated chromosome (14/21) and chromosome 14 got fertilized by a normal gamete. There will be two normal chromosomes 14 plus 9 P a g e
11 the extra chromosome 14 that came from the translocated chromosome (three chromosomes 14), also this zygote will have the normal number of chromosome 21 (normal chromosome 21 plus the one from the translocated chromosome), that s why its called trisomy Monosomy 14 zygote: Daughter cell have chromosome 14 got fertilized with normal gamete, so there will be one chromosome 14 missing. 5. Trisomy 21 zygote: the same as in trisomy 14 but the extra chromosome is chromosome 21 instead of chromosome Monosomy 21 zygote: the same as in monosomy 14 but the missing chromosome is chromosome 21 instead of chromosome 14. So the probability for every case to happen is 1/6, and the probability for the new born baby to be normal is 2/6, so we have a chance of 1/3 to have a zygote that can develop normally, in monosomy 14 and monosomy 21 the fetus will eventually die because the only viable monosomy is turner syndrome, also trisomy 14 will die because the only viable trisomies are 13, 18 and 21 (Patau, Edward and Down), trisomy 21 (Down syndrome) will live but will not be normal. The following is extra, the doctor said it is just for better understanding. So it is read only 10 P a g e
12 Three years ago, a woman had delivered a twin (not identical, a boy and a girl), the father found out that there is something wrong in the girl, when doctor Bilal checked the girl, she had low-set ears in comparison with the boy, when they did karyotyping to her chromosomes, she had 46 chromosomes but chromosome 18 part of it is duplicated so two chromosome 18 but one is bigger in size, this case is called partial Edward syndrome, the usual Edward has three chromosomes 18. Now the girl is 4 years old, the features of Edward is clear but it milder that trisomy 18. This is partial duplication for the chromosomes and it is not included in our course. When we think if an individual has a robertsonian translocation? For example, sometimes a couple come to a doctor with a baby has down syndrome, after a while they come with another baby with down syndrome, so the doctor starts to doubt that the parents are balanced carriers. So it is possible that the father have 45 chromosome with translocated chromosome that have two Q arms of chromosome 21, when he produces a sperm there will be 50% chance the sperm doesn t have chromosome 21 at all, and 50% that the sperm has a translocated chromosome (Q arm Q arm 21), so when the sperm that has the translocated chromosome fertilizes an egg with normal chromosomes, the baby will have down syndrome, in fact all the children of this couple will have down syndrome. So in this scenario the doctor will think of the translocations because this rare disease (1/800) happened to their two children which is unusual. BEST OF LUCK 11 P a g e
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