Position effects on gene expression level and noise

项目摘要 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、生物体或其他级别。基因表达是分子水平上的一种表型性状，它对 所有形式的生命。这一建议集中在基因表达的一个方面，称为位置效应，即 基因的染色体位置对其活性的影响。位置效应被牵连到一起 一些遗传性疾病，如性反转、无虹膜(无虹膜)和无前脑畸形(大脑 通常导致胚胎死亡的发育障碍)。任何由基因引起的疾病 没有破坏基因结构的染色体重排可以被认为是位置的结果 效果。在转基因生物中已经多次观察到位置效应，揭示了 转基因在基因组中的位置及其表达。位置效果也被调用了 在解释基因组组织的多个非随机特征时。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有限，关于位置效应的许多假设 头寸效应仍未得到检验。过去对位置效应的研究主要集中在异染色质的作用上，主要是 忽略了绝大多数基因所在的常染色质(并在突变体和 进化论)。位置对平均蛋白质表达和表达噪声影响的基因组学研究 提出了芽生酵母酿酒酵母的概念。生成的数据将用于探测将军 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 检验位置效应在基因组组织非随机性特征形成中的作用。此外， 将在酵母中进行一系列操纵性实验，以测试以前未被认识到的 功能相关基因染色体簇起源中表达噪声的位置效应。 总体而言，该项目有望(I)提供前所未有的全基因组范围的位置效应信息 酵母中的基因表达和表达噪声，(II)揭示定位的分子和机制基础 以及(Iii)加深对位置效应在真核基因组进化中作用的理解 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.