A Prion Reveals Complex Traits and Phenotypic Diversity

描述（由申请人提供）：酵母Sup35蛋白是一种翻译终止因子，具有形成自我延续有序聚集体（朊病毒[PSI+]）的不寻常能力，导致翻译终止保真度的遗传变化。在不同的遗传背景中，[PSI+]产生不同的表型，改变不同条件下的生长和存活。要理解这种朊病毒成分的全部生物学意义，仍有几个问题有待解决。 1)[PSI+]朊病毒揭示的表型多样性的分子本质是什么？ [PSI+]依赖性状的分析表明，它们是由无义抑制和蛋白质聚集引起的。2)最近的数据表明，几个[PSI+]依赖的表型是复杂的性状。这些性状需要许多因素的组合，并提供了一个可行的模型，以调查环境条件的表型效应加上遗传和表观遗传因素。在一个这样的性状，朊病毒依赖的形态学改变，一个贡献的途径已被确定，和无义抑制，蛋白质聚集，和环境，产生的表型的相互作用将被调查。3)这种表观遗传因素是如何调节的？这种朊病毒的生物学后果是什么？解决这些问题将有助于更好地了解[PSI+]对酵母菌群体生物学、生存和进化的影响。这项研究将剖析[PSI+]元件的机械性质，并确定这种朊病毒是否为表型可塑性提供了一种独特的机制，这种机制可能促进复杂性状的进化。此外，这项工作可能会提供额外的见解丰富的朊病毒生物学和生理影响，这种类型的表观遗传调控。此外，这种酵母朊病毒提供了一个模型系统，以了解触发蛋白质聚集的环境线索，这在理解与几种神经退行性疾病相关的蛋白质错误折叠的起始方面具有广泛的意义。

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.