A Prion Reveals Complex Traits and Phenotypic Diversity

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DESCRIPTION (provided by applicant): The yeast Sup35 protein is a translation termination factor with the unusual capacity to form a self-perpetuating ordered aggregate (the prion [PSI+]), resulting in heritable changes in the fidelity of translation termination. In different genetic backgrounds [PSI+] produces distinct sets of phenotypes, altering growth and survival in diverse conditions. Several questions remain to be addressed to understand the full biological implications of this prion element. 1) What is the molecular nature of the phenotypic diversity revealed by the [PSI+] prion? Analyses of the [PSI+]-dependent traits suggest that they result from both nonsense suppression and protein aggregation. 2) Recent data suggests that several [PSI+] - dependent phenotypes are complex traits. These traits require a combination of many factors and provide a viable model to investigate the phenotypic effects of environmental conditions coupled with both genetic and epigenetic factors. In one such trait, a prion dependent alteration in morphology, a contributing pathway has been identified, and the interplay of nonsense suppression, protein aggregation, and the environment that produces the phenotype will be investigated. 3) How is this epigenetic element regulated? What are the biological consequences of this prion? Addressing these questions will allow for a greater understanding of the impact of [PSI+] on population biology, survival, and evolution of yeast. This research will dissect the mechanistic nature of the [PSI+] element and determine if this prion provides a unique mechanism for phenotypic plasticity that might promote the evolution of complex traits. Moreover, this work may provide additional insights into the wealth of prion biology and the physiological impact of this type of epigenetic regulation. Furthermore, this yeast prion provides a model system to understand the environmental cues that trigger protein aggregation, which has broad implications in understanding the initiation of protein misfolding associated with several neurodegenerative disorders.