Essay On Describe Chromosomal Abnormalities And The Diseases They Cause Notes

Describe how chromosomal abnormalities arise and their consequences. Why do X linked conditions have less of an effect than autosomal conditions?

Structure of chromosomes

The genetic information of a cell is found within the nucleus which contains 46 chromosomes; 22 pairs of autosomes and a single pair of sex chromosomes. The ability of a cell to synthesise functional proteins relies on the structure and the number of chromosomes. The structure of chromosomes, which is best seen during metaphase, consists of 2 identical sister strands known as chromatids that are attached to each other by a centromere. The centromere consists of repetitive DNA sequences that divide the chromosome into a short ‘p’ arm and a long ‘q’ arm. It is primarily responsible for movement of chromosomes at cell division but the position of the centromere is also used in chromosome classification; if the centromere is towards the end, the chromosomes are acrocentric, if in the middle it is metacentric whilst if the centromere is an intermediate position it is submetacentric. At the end of each chromosome arm is a highly repeptitive sequence of TTAGGG nucleotides which forms a structure known as the telomere. The main function of the telomere is to prevent the ends of the chromosome from binding to each other and also reduces chromosome shortening during proliferation.

Chromosomal abnormalities account for a large proportion of spontaneous pregnancy loss and childhood disability. These damaging changes usually occur when there is an error during cell division following mitosis or meiosis and they can be classed into two main groups; structural and numerical.

Numerical abnormalities

The gain or a loss of one or more chromosomes in a cell results in aneuploidy and can lead to a wide variety of disorders depending on the chromosome affected. The main cause of aneuploidy is nondisjunction where there is a failure of the chromosome pairs to separate during anaphase of either meisosis 1 or 2. Nondisjunction in meisosis 1 leads to the formation of a gamete with 2 homologs of one chromosome pair, whereas nondisjunction in meisos 2 results in the gamete containing 2 copies of one homologos of the chromosome pair. The occurrence of nondisjunction in oocytes and the diseases associated with it increase with maternal age.

Monosomy occurs in fertilised gametes that are missing a single chromosome. This can be due to a gamete with an absence of a specific chromosome as a result of nondisjucntion fusing with a gamete that contains a single copy of the chromosome. One example of monosomy includes the Turner syndrome which is due to the absence of an X chromosome. Symptoms often include a webbed neck, widely spaced nipples, short stature and a wide carrying angle. Another diagnostic sign of turner syndrome is primary amenorrhoea and infertility.

In comparison trisomy is due to the presence of an extra chromosome in fused gametes. This occurs when a gamete with 2 copies of the chromosome due to nondisjunction fuses with a chromosome with only one copy of the chromosome. A well known trisomy that doesn’t lead to spontaneous abortion is Down’s syndrome where the cells have 3 copies of chromosome 21 and the occurance of this disease is 1 in 700. In the majority of patients Down’s syndrome was due to the failure of separation of the pair of chromosomes during anaphase of maternal meiosis 1. Symptoms that are associated with having this disorder include mental retardation, severe hypotonia, thyroid problems and congenital cardiovascular defects. Similarly Patau syndrome is due to trisomy 13 and the occurance rate is 1 in every 5000. Children with Patau syndrome often suffer from clefting, finger and toe abnormalities, severe mental abnormalities and heart and scalp defects. The last type of viable trisomy is trisomy 18 which similarly also causes severe mental retardation but the most characteristic sign is rocker bottom feet and clenched fingers. Patients with trisomies can be rapidly diagnosed using fluorescent in-situ hybridisation where radioactively labelled specific centromeric probes are used to bind with their complementary target sequences. If trisomies are present, when the chromosomes are viewed under a fluorescent microscope there will be three highlighted regions indicating three chromosomes of the same type.

Structural abnormalities

The second main class of chromosomal abnormalities are structural abnormalities which include translocations, deletions, insertations, inversions, rings and isochromosomes.

a) Translocations

In translocations there is a transfer of genetic material form one chromosome to another and there are two types. Reciprocal translocations occur when breaks occur in 2 chromosomes and the two segments detached are exchanged to form new derivatives of chromosomes. Geneticists often identify these translocations through using chromosome painting where a mixture of colour labelled probes specific for each chromosome is used. This method allows us to see if there has been a translocation as the chromosome will appear as having 2 colours and the origin of the additional chromosome material can also be identified. Diseases are often caused by reciprocal translocations when the segment of chromosome is inserted into a key regulatory element of another gene in the chromosome. One example of a pathogenic translocation is philidelphia translocation where there is a reciprocal translocation between chromosome 9 and chromosome 22. This type of structural abnormality often leads to myelogenous leukemia as the fusion gene is created by joining the Abl gene on chromosome 9 to part of the BCR gene on chromosome 22. This creates the Philadelphia chromosome which is a truncated chromosome 22. The ABL gene normally expresses a membrane associated protein tyrosine kinase so the BCR-ABL gene expresses a mutant form of the membrane associated protein kinase that is always activated which leads to unregulated cell division. In...

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