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Genetic time bombs

Weizmann Institute of Science scientists have created a mathematical model that predicts the time of onset of tri-nucleotide genetic diseases such as Huntington's disease

Huntington's disease is a genetic time bomb, encoded in the genetic material from birth, and erupts in adulthood, after a fixed and predictable period of time. The disease causes a gradual deterioration in the neurological, thinking and mental functions, and eventually death. As of today, it is an incurable disease. The cause of Huntington's disease, as well as a number of similar diseases, is an unusual genetic mutation: a sequence of three DNA bases (nucleotides) is duplicated and repeated over and over again, in a single gene. Therefore, the diseases from this group are known as diseases caused by trinucleotide repeats. Scientists at the Weizmann Institute of Science recently proposed a model that explains, for the first time, the time bomb mechanism responsible for the exact timing of the outbreak of this type of disease. This model may open new directions of research, which will help scientists develop methods to prevent and treat Huntington's disease and other trinucleotide diseases.

The number of repeats of the triple sequence in Huntington's patients ranges from 40 to more than 70. Scientists have noticed that the number of recurrences makes it possible to accurately predict both the age at which the disease will break out, and the rate of its progression. The three repeating bases code for the amino acid glutamine. The basic assumption was that protein fragments made of repeating units of the amino acid glutamine gradually accumulate inside the cell, eventually reaching a toxic concentration. However, there are clinical data that contradict this theory. Thus, for example, the onset of the disease and its progression in patients who carry two copies of the defective gene are not faster than those of patients who carry a single defective copy. In addition to this, only in some trinucleotide diseases is the amino acid glutamine produced. But the correlation between the number of repetitions of the triple code and the age of onset of the disease obeys common rules in all diseases - a fact that points to a common mechanism, which does not depend on the accumulation of glutamine.

Research student Shay Kaplan from the laboratory of Prof. Ehud Shapira from the Department of Biological Chemistry, and from the Department of Computer Science and Applied Mathematics at the Weizmann Institute of Science recently discovered that the explanation for the course of the disease may lie in somatic mutations: an accumulation of genetic mutations that occurs during the life of the cell and causes changes in the number of repetitions of the DNA sequences AN The more the DNA sequence is duplicated and lengthened, the greater the chance of additional mutations forming. The scientists hypothesized that the gene carrying the triple sequence, which codes for the disease, accumulates more and more repetitions in this process, until the amount crosses a certain threshold value.

Prof. Shapira and his research students Shai Kaplan (who also belonged to the Department of Molecular Biology of the Cell), and Shalo Itzkowitz were based on studies dealing with about twenty recognized tri-nucleotide diseases, and on the mechanism that controls the formation of somatic mutations. They created a mathematical model that predicts the time of the outbreak of the disease, and the manner of its progression, according to the number of genetic repetitions of the triple sequence. Their findings are published today in the scientific journal PLoS Computational Biology.

The new model matches all the known clinical facts about trinucleotide diseases, and offers an explanation for the timing of the outbreak and the rate of their progression. The scientists say that future experiments will be able to confirm - or disprove - the validity of the theoretical model. Since the model predicts that all diseases of this type occur due to the accumulation of mutations of triple repeats, it is possible that in the future a treatment will be developed that targets all these diseases, based on stopping or delaying the process of mutation accumulation.

3 תגובות

  1. Is it just me or did everyone get it wrong (and go crazy for a moment) and call it "Harrington's disease"?

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