All eukaryotes contain tracts of simple repetitive DNA, in which a single base or a small number of bases is repeated multiple times. Repetitive tracts tend to be unstable, increasing or decreasing in size at a rate that is much higher than that observed for """"""""normal"""""""" non-repeated DNA sequences. Using plasmids with insertions of repetitive DNA in the coding sequence of selectable genes, tract instability can be assayed in the yeast, Saccharomyces cerevisiae. The proposed experiments examine some properties of this type of genetic instability. First, mutants of yeast that have increased levels of instability will be examined. This study should yield evidence relevant to the mechanisms of tract instability. Second, the effects of altering the sequence or the length of the repetitive DNA tracts will be examined. Third, it will be determined whether alterations in tract length are associated with crossing-over. Fourth, a transgenic mouse in which the in vivo instability of simple repeats can be monitored will be developed. Fifth, a search will be made for mechanisms allowing large expansions of simple repeats in yeast cells since most of the alterations detected to date represent small changes.
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