Heritable variation of mRNA decay rates: An unappreciated source of gene express

描述(由申请人提供)：基因表达是一种重要的分子表型，它在静态基因组信息和动态生物表型之间架起了桥梁。因此，深入了解基因表达变异的遗传结构将对基础和生物医学研究产生深远的影响。尽管在刻画个体间转录丰度模式和定位基因表达数量性状基因座方面取得了重大进展，但基本问题仍然存在。具体地说，人们对调控基因多态的确切作用机制知之甚少。到目前为止，相当多的注意力集中在通过转录启动来理解基因表达的调节。尽管基因的整体表达水平是通过转录起始和衰退的平衡来决定的，但通过mRNA衰退来调节转录丰度的研究却少有人关注。尤其是，对基因表达变异的基因表达变异的贡献还没有得到系统的研究。这项建议的目的是以酿酒酵母为模型系统，检验信使核糖核酸衰减率变异是可遗传基因表达变异的重要来源这一假说，并确定影响信使核糖核酸衰减率的因果调控多态。为此，我们将在两种环境条件下使用大规模并行测序来测量等位基因特异的mRNA衰减率，这些二倍体杂交是由遗传多样性的酿酒酵母菌株构建的，其基因组序列最近已经被确定。此外，将通过对10个表现出等位基因特异性mRNA衰减率的基因进行定点突变来鉴定因果调控多态。该项目的成功完成将为基因表达变异的一个基本未被探索的但潜在的重要方面提供实质性的新见解，导致mRNA衰减率可遗传变异的调控多态的类型，以及环境扰动如何调节这些多态的影响。这些数据最终将成为开发可遗传基因表达变异的定量和预测模型的关键资源，这将有助于解释下一代测序技术和个人基因组学倡议产生的海量数据。基因表达是将DNA序列信息转化为表型的第一步。人类的许多疾病，如癌症，都是由基因表达不当引起的。该项目将为基因变异如何影响基因表达水平以及最终影响疾病的分子机制提供关键的新见解。 公共卫生相关性：基因表达是将DNA序列信息转化为表型的第一步。人类的许多疾病，如癌症，都是由基因表达不当引起的。该项目将为基因变异如何影响基因表达水平以及最终影响疾病的分子机制提供关键的新见解。

DESCRIPTION (provided by applicant): Gene expression is an important molecular phenotype that bridges the divide between static genomic information and dynamic organismal phenotypes. Therefore, a deeper understanding of the genetic architecture of gene expression variation will have profound consequences for basic and biomedical research. Despite significant progress in characterizing patterns of transcript abundance among individuals and mapping gene expression quantitative trait loci, fundamental questions remain. Specifically, very little is known about the precise mechanisms through which regulatory polymorphisms act. To date, considerable attention has focused on understanding the regulation of gene expression through transcriptional initiation. Although overall gene expression levels are determined through a balance of transcriptional initiation and decay, the regulation of transcript abundance through mRNA decay has received far less attention. In particular, the contribution of heritable variation in mRNA decay rates to gene expression variation has not been systematically explored. The goal of this proposal is to use Saccharomyces cerevisiae as a model system to test the hypothesis that variation in mRNA decay rates constitutes an important source of heritable gene expression variation and to identify causal regulatory polymorphisms that affect mRNA decay rates. To this end, we will measure allele- specific mRNA decay rates in two environmental conditions using massively parallel sequencing in a panel of diploid hybrids constructed from genetically diverse S. cerevisiae strains, whose genome sequences have recently been determined. Furthermore, causal regulatory polymorphisms will be identified by site-directed mutagenesis for 10 genes that exhibit allele-specific mRNA decay rates. The successful completion of this project will provide substantial new insights into a largely unexplored, but potentially important aspect of gene expression variation, the types of regulatory polymorphisms that generate heritable variation in mRNA decay rates, and how environmental perturbations modulate the effects of such polymorphisms. These data will ultimately be a key resource in developing quantitative and predictive models of heritable gene expression variation, which will facilitate interpretations of the deluge of data being generated from next-generation sequencing technology and personal genomics initiatives. Gene expression is the first step in converting DNA sequence information into phenotypes. Many human diseases, such as cancer, arise from improper gene expression. This project will provide critical new insights into how genetic variation influences gene expression levels and ultimately the molecular mechanisms of disease. PUBLIC HEALTH RELEVANCE: Gene expression is the first step in converting DNA sequence information into phenotypes. Many human diseases, such as cancer, arise from improper gene expression. This project will provide critical new insights into how genetic variation influences gene expression levels and ultimately the molecular mechanisms of disease.