4. Many studies have shown an association between tandem repeats in the nuclear

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4. Many studies have shown an association between tandem repeats in the nuclear genome and some diseases. One of these diseases is Huntington's disease (HD), which is an autosomal dominant disorder. From: http://ghr.nlm.nih.gov The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder. As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTTgene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats. Individuals who have 27 to 35 CAG repeats in the HTTgene do not develop Huntington disease, but they are at risk ofhaving children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with H untington disease (36 repeats or more). A couple (mother-MI: father Fl) is expecting a baby. MI's brother started showing symptoms of neurological disorder that may be related to Huntington's disease. This led all individuals in the instant families for both MI and Fi (including the couple's daughter and fetus) to undergo screening for the disorder. Huntington's and other disorders with trinucleotide repeat expansions show a genetic phenomenon called anticipation (the age of onset of a disorder becomes more severe and shows earlier with every generation). Microsatellite screening gave the following results. Assume that the variation in size is due to the CAG repeat and the flanking region size is 100 base pairs. M1's Family F1's Family Age Genotype Age Genotype Father 52 151/166 Father 80 151/151 Mother 50 175/208 Mother 72 172/175 26 151/208 M1 F1 151/271 27 Brother 20 151/301 M1 X F1 Genotype Daughter (3 yrs.) 151/223 Fetus 208/298

Explanation / Answer

a) Microsatellite analysis shows that the fetus of M1 and F1 is affected with Huntington's disease. CAG repeats are almost equal to the number of repeats found in M1's brother. It is important to note that 'CAG' repeats in F1 are also in the range 30-35. So, he is at a risk of children with HD.

b) M1's brother is affected from Huntington's disease. In his genotype, "CAG" has been repeated more than 40 times. This disease is related to chromosome number 4. This process occurs during DNA replication.

During replication, two DNA strands are pulled apart. One strand acts as a template for synthesis of new DNA strand. DNA repair proteins do not remove the extra nucleotides (CAG repeats) attached.

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