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Human Molecular Genetics Advance Access published online on October 20, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh325
© 2004 by Oxford University Press
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Article

Somatic deletion events occur during early embryonic development and modify the extent of CAG expansion in subsequent generations

I.V. Kovtun 1, A.R. Thornhill 2, and C.T. McMurray 3*

1 Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905
2 Obstetrics and Gynecology, Mayo Clinic and Foundation, Rochester, Minnesota 55905
3 Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota 55905; Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, Minnesota 55905

* To whom correspondence should be addressed.
C.T. McMurray, E-mail: mcmurray.cynthia{at}mayo.edu


  Abstract

Alterations in trinucleotide repeat length during transmission are important in pathophysiology of Huntington's Disease (HD). However, it is not well understood where, when and by what mechanism expansion occurs. We have followed the fate of CAG repeats during development in mice which can (hHD(-/+)/Msh2(+/+)) or cannot (hHD(-/+)/Msh2(-/-)) expand their repeats. Here we show that long repeats are shortened during somatic replication early in the embryo of the progeny. Our data point to different mechanisms for expansion and deletion. Deletions arise during replication, do not depend on the presence of Msh2, and are largely restricted to early development. In contrast, expansions depend on strand break repair, require the presence of Msh2, and occur later in development. Overall, these results suggest that deletions in early development serve as a safeguard of the genome and protect against expansion of the disease-range repeats during transmission.


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