Nature Genetics
27, 407 - 411 (2001)
doi:10.1038/86906
Trinucleotide expansion in haploid germ cells by gap repairIrina V. Kovtun1
& Cynthia T. McMurray1, 2, 31
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, Rochester, Minnesota, USA. 2
Department of Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota, USA. 3
Department of Molecular Neuroscience Program, Mayo Clinic and Foundation, Rochester, Minnesota, USA.
Correspondence should be addressed to Cynthia T. McMurray mcmurray.cynthia@mayo.eduHuntington disease (HD) is one of eight progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion encoding a polyglutamine tract1. The mechanism of trinucleotide expansion is poorly understood. Expansion is mediated by misaligned pairing of repeats and the inappropriate formation of DNA secondary structure as the duplex unpairs2,
3,
4,
5,
6,
7. It has never been clear, however, whether duplex unpairing occurs during mitotic replication or during strand-break repair. In simple organisms, trinucleotide expansion arises by replication slippage on either the leading8 or the lagging strand9,
10,
11,
12, homologous recombination13,
14, gene conversion15,
16, double-strand break repair13,
14,
15,
16,
17 and base excision repair18; it is not clear which of these mechanisms is used in mammalian cells in vivo. We have followed heritable changes in CAG length in male transgenic mice. In germ cells, expansion is limited to the post-meiotic, haploid cell and therefore cannot involve mitotic replication or recombination between a homologous chromosome or a sister chromatid. Our data support a model in which expansion in the germ cells arises by gap repair and depends on a complex containing Msh2. Expansion occurs during gap-filling synthesis when DNA loops comprising the CAG trinucleotide repeats are sealed into the DNA strand.
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