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

I. V. Kovtun, A. R. Thornhill, Cynthia T. McMurray

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Alterations in trinucleotide repeat length during transmission are important in the 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 that 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.

Original languageEnglish (US)
Pages (from-to)3057-3068
Number of pages12
JournalHuman molecular genetics
Volume13
Issue number24
DOIs
StatePublished - Dec 15 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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