Repair in haploid male germ cells occurs late in differentiation as chromatin is condensing

Huntington's Disease (HD) is one of eight progressive neurodegenerative disorders in which the underlying mutation is a CAG expansion encoding a polyglutamine tract. The mechanism of trinucleotide expansion remains poorly understood. 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 and a sister chromatid. Expansion occurs by gap filling synthesis when DNA loops comprising the CAG trinucleotide repeats are sealed into the DNA strand. Our data support a model in which expansion occurs late in male germ cell development as spermatids are entering the epididymis at a time when chromatin is condensing. These data indicate that repair can be carried out in germ cells as long as the DNA is accessible. The capacity for repair of germ cells may have important implications for future gene therapy.