Position effects on gene expression level and noise

项目概要 我的研究计划的长期目标是了解分子遗传机制和 表型变异和进化的驱动力，其中表型可能是分子、细胞、组织、 器官、组织或其他层面。基因表达是分子水平上的表型特征，对于 所有形式的生命。该提案集中于基因表达的一个方面，即位置效应，即位置效应 基因的染色体位置对其活性的影响。位置效应与 许多遗传性疾病，如性逆转、无虹膜症（虹膜缺失）和前脑无裂畸形（大脑 通常会导致胚胎死亡的发育障碍）。任何由以下原因引起的遗传病 不破坏基因结构的染色体重排可以被视为位置的结果 效果。位置效应在转基因生物中已被多次观察到，揭示了位置效应的重要性 转基因在其表达时被置于基因组中的位置。位置效应也已被调用 解释基因组组织的多个非随机特征。尽管它很重要，但我们的 关于位置效应的模式和机制的知识是有限的，并且关于位置效应的许多假设 位置效应尚未测试。过去关于位置效应的研究主要集中在异染色质的作用上 忽略绝大多数基因所在的常染色质（并在突变体和突变体中易位） 进化）。位置对平均蛋白质表达和表达噪声影响的基因组研究 建议使用芽殖酵母酿酒酵母。生成的数据将用于探测一般情况 位置效应的模式，研究位置效应的潜在遗传和表观遗传机制，以及 测试位置效应在基因组组织非随机特征形成中的作用。此外， 将在酵母中进行一系列操作实验，以测试以前未被认识到的作用 功能相关基因染色体聚类起源中表达噪声的位置效应。 总体而言，该项目预计将（i）提供前所未有的全基因组位置效应信息 酵母中的基因表达和表达噪音，(ii) 揭示位置的分子和机制基础 效应，以及（iii）加深我们对位置效应在真核基因组进化中的作用的理解 组织。

Project Summary The long-term objective of my research program is to understand the molecular genetic mechanisms and driving forces of phenotypic variation and evolution, where the phenotype may be at molecular, cellular, tissue, organ, organismal or other levels. Gene expression is a phenotypic trait at the molecular level that is critical to all forms of life. This proposal centers on one aspect of gene expression known as position effect, which refers to the influence of the chromosomal location of a gene on its activity. Position effect has been implicated in a number of genetic diseases such as sex reversal, aniridia (absence of iris), and holoprosencephaly (a brain developmental disorder that typically leads to embryonic death). Any genetic disease caused by a chromosomal rearrangement that does not disrupt gene structure may be regarded as a result of position effect. Position effect has been observed many times in transgenic organisms, revealing the significance of the location at which the transgene is placed in a genome on its expression. Position effect has also been invoked in the explanations of multiple nonrandom features of genome organization. Despite its importance, our knowledge about the pattern and mechanism of position effect is limited and many hypotheses regarding position effect remain untested. Past studies of position effect focused on the role of heterochromatin, largely ignoring euchromatin where the vast majority of genes are located (and translocated in mutants and in evolution). A genomic study of position effects on mean protein expression and expression noise in the budding yeast Saccharomyces cerevisiae is proposed. The generated data will be used to probe the general patterns of position effects, to study the underlying genetic and epigenetic mechanisms of position effects, and to test the role of position effects in the formation of nonrandom features of genome organization. Furthermore, a series of manipulative experiments will be conducted in yeast to test a previously unrecognized role of position effect on expression noise in the origin of chromosomal clustering of functionally related genes. Overall, this project is expected to (i) provide unprecedented genome-wide information of position effect on gene expression and expression noise in yeast, (ii) uncover the molecular and mechanistic basis of position effects, and (iii) deepen our understanding of the role of position effect in the evolution of eukaryotic genome organization.