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Research Article

A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases

  • Shai Kaplan,

    Affiliations: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel, Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

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  • Shalev Itzkovitz,

    Affiliations: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel, Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

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  • Ehud Shapiro mail

    To whom correspondence should be addressed. E-mail: ehud.shapiro@weizmann.ac.il

    Affiliations: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel, Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel

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  • Published: November 23, 2007
  • DOI: 10.1371/journal.pcbi.0030235

Reader Comments (1)

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Brain development and somatic mutations in HD

Posted by wassinkt on 27 Feb 2009 at 03:19 GMT

A couple of questions about the premises for these calculations. First and foremost, they seem to assume that somatic cell multiplication is linear in the brain, which is certainly not the case. Most cells are formed early, then pruned, with limited on-going somatic cell formation. How does this impact the model? Also. HD stands in contrast to other expansion disorders as having little somatic cell CAG expansion variation. Therefore, the human biological data seems to contradict the proposed model.


RE: Brain development and somatic mutations in HD

shaik replied to wassinkt on 27 Feb 2009 at 22:10 GMT

Thanks for the questions.
Several comments regarding your first comment:
First we do not claim that the brain cells continue to accomulate mutations via cell multiplications. Other mechanisms may cause the somatic mutations also in non-dividing cells. For example when the DNA strands are seperated for transcription the repeats may miss hybridize following DNA damage repair mechanism that extend the repeats during the correction.

Second, it is still possible that the disease are triggered by a yet uncarchterized group of cells which exist in the brain but do devide continuesly (such as stem cells). The fact that the damage is seen in non-dividing cells does not mean that it is being trigered by those cells. We don't know which cells are the disease triger and they may be different between diseases we simply predict that such a group of cells exist and responsible for the disease timing. These cells may divide or not but we predict that they accomulate somatic repeat mutations according to our model and triger the disease timing. The major damage seen in other cells may just be a following response to this trigger. Several litreture reports identify large somatic expansions in brain tissue (cited in the paper) which support our assumption that some cells has somatic repeat expansion in the brain.

I belive the above clarification also explain your second comment. Only one group of cells is likely to be the triger for each disease and this group may be veryu small and hard to detect. Despite what you say about the difference between HD and other diseases from this family the similar behavior of the timing mechanism and the similar underlying genetic phenomena strongly implies that those diseases share the same mechanism for the timing. The exact cells and the exact damage may differe between the diseases however the HD looks very similar to all the other when you look on the onset curve. I hope this clarifies our points and thanks for the comments.