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The yeast [PSI ] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a 'protein only' mechanism *RF 1-3* reminiscent of the 'protein-only' transmission of mammalian prion diseases [1,4]. The underlying molecular mechanisms for both are poorly understood and it is not clear how similar they might be. Sup35, the [PSI ] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats-PQGGYQQYN in Sup35 and PHGGGWGQ in PrP [5,6]. Repeat expansions in PrP produce spontaneous prion diseases [7,8]. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI ( )] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in beta-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.

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