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Amanda Lyon Week 4 Executive Summary

Laird: Fragile Sites in Human Chromosomes as Regions of Late-Replicating DNA The researches working on this project addressed the topic of fragile sites on the human chromosomes, their development, and their consequences. Fragile sites are spots on the chromosome that are more prone to break or gap. Laird and his team focused on the Xq27 chromosome that is predisposed to cause mental retardation in individuals. They found that fragile sites existed on the chromosome near the centromere and were usually due to latereplicating DNA at that site, which may be caused by a block at the normal replication site. Fragile sites can also be formed artificially by prematurely ending DNA synthesis, because the DNA near the centromere will not have completed replication. Lairds team concluded two things: first, many alterations must occur and second, the alterations must be cis- because most individuals do not carry or express other fragile sites. They also found that an individual could only get the fragile X chromosome from females because the female can inactivate it and pass it onto offspring. As a result, the mother passes along this chromosome which has a block but has been inactivated for her, which leads to the fragile X chromosome in her offspring. The X-linked fragile site Xq27 leads to mental retardation syndrome. Question: Recessive X-linked diseases are generally seen in the phenotypes of males, and usually skip generations. Was this seen in the Xq27 fragile site. If not why was the pedigree different? Question: Can you test for fragile sites in humans, and how would you test for them? Would you expect results to be similar to the results you found with the Drosophila melanogaster, and if they were different how and why would they differ? Question: Laird and his partners mention that the combination of folate deficiencies and large ingestion of caffeine decreases the time between DNA replication and chromosome condensation, which leads to fragile sites. Have studied cases shown this to be true? Is there a way to test this hypothesis in humans, and would it be ethical to do so? Could it be tested in a different test subject? And, is there a known reason why this particular combination is proven to form fragile sites? (page 275) Suggestion: Fragile sites can be induced experimentally by prematurely shortening the time DNA has for synthesis. Do we know how this could affect future studies or investigations, and what does that mean for the future of mental retardation syndrome in individuals who suffer from imprinted X-linked Xq27? (page 275) Suggestion: Can a test be done that measures whether there is a gene by environment interaction in fragile sites, and specifically with the expression of the Xq27 chromosome. Does environment play a role in the expression of the disease, and if so what could that lead to for individuals suffering from mental retardation syndrome? Stoger: Epigenetic Variation Illustrated by DNA Methylation Patterns of the Fragile-X Gene FMR1 In Lairds paper, he notes that methylation might be another cause for late replication at fragile sites, and states that it is especially plausible for the Xq27 site which causes mental retardation syndrome. Stogers team investigates this claim, and found that the FMR1 gene is a predominant cause of fragile-X syndrome, based on the extent of methylation at the site. Fragile-X alleles exhibited higher levels of methylation, whereas normal alleles had substantially lower levels of methylation. This result was consistent in both males and females. They also found a correlation between the proportion of hypermethylated alleles and the degree of retardation in an individual; the more hypermethylated alleles, the more severe the retardation. Stogers study supports, in more detail, the works done by Laird and his team.