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，它连接了静态基因组信息和动态生物体表型之间的鸿沟。因此，更深入地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。尽管在表征个体间转录物丰度模式和定位基因表达数量性状位点方面取得了重大进展，但基本问题仍然存在。具体来说，我们对调控多态性发挥作用的确切机制知之甚少。迄今为止，相当多的注意力集中在通过转录起始来理解基因表达的调控。尽管总体基因表达水平是通过转录起始和衰变的平衡来决定的，但通过mRNA衰变来调节转录物丰度却很少受到关注。特别是，mRNA衰减率的遗传变异对基因表达变异的贡献尚未得到系统的探讨。本研究的目的是利用酿酒酵母作为模型系统来验证mRNA衰减率的变异是遗传基因表达变异的重要来源这一假设，并确定影响mRNA衰减率的因果调节多态性。为此，我们将在一组由遗传多样性酿酒酵母菌株构建的二倍体杂交中使用大规模平行测序来测量两种环境条件下等位基因特异性mRNA的衰减率，这些菌株的基因组序列最近已经确定。此外，将通过位点定向诱变对10个表现出等位基因特异性mRNA衰减率的基因进行因果调节多态性鉴定。这个项目的成功完成将为基因表达变异的一个很大程度上未被探索，但潜在重要的方面，产生mRNA衰减率遗传变异的调节多态性的类型，以及环境扰动如何调节这种多态性的影响提供实质性的新见解。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计划产生的大量数据。基因表达是将DNA序列信息转化为表型的第一步。许多人类疾病，如癌症，都是由基因表达不当引起的。该项目将为遗传变异如何影响基因表达水平以及最终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.