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DNA Mutations and Genetic DiseasesAs mentioned, chromosomes select characteristics such as sex (Men have different copies of the sex chromosome, X and Ywheras females have two X chromosomes) but also cause diseases through chromosomal abnormalities:

Downs SyndromeCaused by 3 copies of chromosome 21. This is referred to as trisomy. Turner Syndrome (women)only 1 X chromosome. Klinefelter Syndrome (men)YXX (trisomy) rather than YX. Cystic Fibrosis3 nucleotides removed in DELTAF508 genestopping production of phenylalanine. Sickle Cell AnaemiaA changed to T in gene for haemaglobin.

Materials can be traslocated from one chromosome to another, nucleotides added or removed or bases substituted. Thesechanges can cause diseases and other genetic problems. Usually these are seen during protein synthesis.

- Downs Syndrome

Downs Syndrome is a genetic disease caused by an extra copy (which may be complete or partial) or chromosome 21(trisomy 21). The disease is often associated with lessened cognitive ability & physical development and features a common

set of facial characteristics. Further implications of Downs Syndrome vary greatly from one individual to another. Fertility isanother affected function, with very few males able to successfully reproduce and only some females when mating withunaffected males. Incidence rates of the disease in their children are much greater at approximately half.

While treatment can be provided to improve a sufferers quality of life there is no cure.

Fig 2 - Trisomy 21 Causing Down's Syndrome (Female Karyotype)

It is estimated 1 in 800-1000 people are born with the disease, with several factors contributing to the likelyhood of a childhaving it. The most notable of these seems to be the age of the mother, with the chance of the disease increasing as amother gets older.

The Mutation in Downs Syndrome

There are several ways Downs Syndrome has been discovered to occur. About 95% of all cases occur via the first route,Trisomy-21.

1. Trisomy 2195% of casesWhere the extra chromosome 21 is added to a gamete innondisjunction(whereeither homologous chromosomes fail to come apart in meiosis 1 or sister chromatids fail to come apart duringmeiosis 2 or mitosis) event during production in the parent; then joining with a gamete from the other parent toproduce an embryo with 47 chromosomes. The vast majority (~88%) of this mutation occurs in the mother.

2. Mosiac Downs Syndrome1-2% of casesWhere some of the cells in the embryo (and later body) haveTrisomy-21 and some are normal. This can occur as Trisomy-21 above followed by a reversion to normal cells

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during cell division in the embryo; or the other way around where cell division in a normal embryo somehowchange to Trisomy-21.

3. Robertson Translocation2-3% of casesIn the karyotype of one of the parents, the long arm of chromosome21 is attached to another chromosome (often 14) and following normal disjunctions during cell replication there is ahigh possibility of a child receiving the ex tra chromosome. This is also known as familial Downs syndrome, as it ispassed directly down and the parents show a normal phenotypewith this type there is no age effect and malesare as likely as females to cause the disease in their offspring.

A final, very rare occurance is the duplication of a portion of chromosome 21, meaning that there are copies of some of thegenes. If these are the genes responsible for the effects seen in Downs syndrome then these effects will be expressed butotherwise the phenotype will be normal.

- Sickle Cell Anaemia

Sickle cell anaemia affects the red blood cells in the body, by producing cells which hold a rigid sickle shape rather than theusual doughnut. As this is a genetic disease based on a recessive allele there is a possibility for offspring to be carriers,suffer the disease or not carry it at all, depending on their parents. Sickle cell disease is caused by having both recessivealleles (SS) while people can also have sickle cell trait which means they are a carrier but do not show the effects of thedisease (HbS).

As the cells are more rigid than normal, and combined with their unusual shape there are many complications which canoccur within the body. These include blockages of blood vessels, increased destruction of blood cells (and so reducedoxygen capacity), problems with the spleen and a host of other blood & circulation related problems.

A sickled red blood cell sits among normal cells

It is interesting to note that the disease is found in higher levels in areas where Malaria is more common, as being a carrier(so the sickle cell trait rather than sickle cell disease) is a benefit as sickling of blood cells as they are attacked by malariahalts its spread.

Sickle cell disease is caused by a mutation on the haemoglobin genewhere A is changed to T at position 17 in a basesubstitution (mis-sense). This changes a glutamic acid on the protein (GAG) to a valine (GTG).

- Types of Mutation in DNA

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Fig 1 - Showing di f ferent types of ch romosomal mutat ion

Wild Type = Normal Sequence of DNA

Point MutationsSingle nucleotide changes in the DNA strand which result in different codons. Miss-sense = Resulting in a different amino acid. Non-sense = Resulting in a STOP codon and possible termination of protein chain. Silent = Codon codes for the same amino acid as wild type so the protein is the same. Frameshift Base Insertions or Deletions = One nucleotide added or removed, resulting in the change of most of the

following amino acids.

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