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Background |
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HOW DOES TRISOMY MOSAICISM OCCUR? | ||
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At fertilization, the egg and the sperm fuse to form a zygote with 46 chromosomes. The single-celled zygote then enters a stage of growth called cleavage. Cleavage produces a rapidly increasing number of cells which get progressively smaller and smaller in size. The zygote divides through a process called mitosis. During mitosis the 46 chromosomes make an identical copy of themselves and each pair of replicated chromosomes pull apart from each other into separate daughter cells. | ||
| The purpose of mitosis is to pass on a complete copy of genetic material to each daughter cell. The contents of the daughter cells are identical to the original cell. The diagram on the right illustrates typical mitosis.
In the earliest stages of growth and development the zygote divides successively to create a ball of cells, called the morula. During these early cleavages, each new cell is called a blastomere. Each blastomere contains the identical chromosome content to the precursor cell, usually 46 chromosomes. As the cells multiple, the morula begins to develop an inner hollow space and an inner cell mass. This is the blastocyst stage.
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| This diagram illustrates the first stages of cleavage and early cell division, from the single-celled zygote to the 64-celled blastocyst. | ||
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| Mistakes can happen... | ||
| Sometimes there is a mistake in the separation or segregation of the chromosomes during mitosis. Two sister chromatids may get "stuck together" and travel into the same daughter cell. Or, a malfunction in chromosome sorting may find two identical chromosomes in the same daughter cell. These errors in proper chromosome segregation are called non-disjunction. Previously we discussed non-disjunction during the development of the sperm and the egg, which is called meiotic non-disjunction. Non-disjunction in the zygote is called post-zygotic non-disjunction or mitotic non-disjunction. Anaphase lag is another mechanism where one chromosome simply fails to get incorporated into the nucleus of a daughter cell. Anaphase lag is probably the most common mechanism involved in trisomy mechanism.
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| Trisomy mosaicism can originate in two ways. | ||
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Mitotic non-disjunction in a cell of a fertilized egg with the typical 46 chromosomes, leads to a different cell line with an additional chromosome. Diagram A illustrates a somatic origin of the trisomy. The cell with three copies of the chromosome may continue to grow, however the cell with only one copy of the chromosome is more often severely disadvantaged and usually will not continue to reproduce (Gardner & Sutherland, 1996). The other mechanism, which involves loss of the extra chromosome, can occur through a process called anaphase lag in an abnormal fertilized egg with 47 chromosomes. In the process of anaphase lag, the extra chromosome fails to be included in the formation of the new cell and becomes isolated and eventually lost. Diagram B illustrates a meiotic origin of the trisomy.
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| A. Somatic origin | ||
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| B. Meiotic origin | ||
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| This "mistake" in an abnormal trisomic zygote can be seen as a "correction" and is called "trisomic rescue". If trisomic rescue occurs early in post-zygotic divisions and involves the cells destined to become the embryo, then the originally abnormal chromosome content of the fetus may be "rescued". In both situations A and B the timing of non-disjunction greatly impacts the outcome.
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| Two cells lines | ||
| If an error occurs in one of the cells after fertilization it is possible to see how a baby might develop with two "lines" of cells with different chromosomal content. In this illustration, the error in mitosis occurred in one of the cells at the 4 cell stage, represented in green. | ||
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There are two possible scenarios:
The effect on the health of the developing baby depends on the mosaic "pattern". The frequency of somatic origin versus meiotic origin of trisomy depends on the chromosome involved. Somatic errors are associated with lower levels of trisomy in the body. In general, meiotic origin is correlated with higher levels of trisomy in the body. The outcome is probably influenced by the viability of trisomic cells in the specific cell lineages (Robinson et al, 1997). It is important to consider that the baby is derived from only a few cells (1-5 cells) from the 64-celled blastocyst. The majority of cells at the blastocyst stage contributes to the placenta. So, when an error occurs in a cell at the blastocyst stage it is more likely to be a cell that is destined to be part of the placenta than one destined to become the baby.
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| The mosaic pattern depends on many factors. | ||
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1. Number of cells present at the time of the non-disjunction mistake A very early mistake, as diagramed above, will effect a greater proportion of the cells in the baby. Mosaicism originating from an early mistake, either in the first or second division of the fertilized egg, leads to generalized mosaicism, since most tissues of the baby are affected, often in a "patchy" way. A mistake which occurs at a later stage, for example at the 64-celled blastocyst stage, will effect a smaller proportion of the cells in the baby. "Later errors" may lead to an abnormal line of cells confined to a certain area or tissue in the developing individual. Theoretically, if the mistake happens just in cells that are destined to become the placenta then the abnormal cells may be confined to the placenta and may not be found in the baby. Or if trisomic rescue occurs in the cells that are destined to become the baby, then the abnormal cells may be confined to the placenta and not found in the baby. This is called confined placental mosaicism. If the mistake happens just in cells that are destined to become the baby, then the abnormal cells will be confined to the baby. This is called confined embryonic mosaicism. Many more cells contribute to the placenta. It is extremely difficult to diagnose confined mosaicism with certainty because it is impossible to sample all tissues in an individual. We will explore this in greater detail in the clinical diagnosis section. 2. Type of cells involved The development and health of the affected baby also depends on the type of cells affected by the mistake. The change in number of chromosomes is only important if it affects the function of the tissue(s) involved. If the duplicated chromosome contains genetic instructions that are crucial to the function of that tissue, the effect on the overall function of the tissue might be impaired or, on the other hand, there may even be selection against the affected cells. 3. Survival of trisomic cells Also important in determining the outcome is the ability of the abnormal cells to survive. The question is, can the cells with the chromosome mistake continue to reproduce? Certain mechanisms involved in cell selection may prevent the abnormal trisomic cells from reproducing, thus minimizing or eliminating the effect of the original non-disjunction error. The specific chromosome involved seems to play a role in determining the survival of the cells. Studies of cell cultures suggest that trisomic cells generally divide less quickly and undergo cell death more commonly than diploid cells.
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In this section we begin with some background information on the early stages of growth of the zygote.
