EVOLUTION OF CIS-REGULATORY SEQUENCES

描述（由申请人提供）： 基因调控的变化可能在适应性进化和遗传疾病中起重要作用。目前对顺式调控序列的认识主要基于在特定时间点影响基因表达水平或发育模式的典型转录因子结合位点。然而，基因表达的时间变化可能往往比稳态水平更重要的健身。这项研究的目的是了解哪些非编码突变会改变基因表达，哪些基因表达的变化会产生表型后果。为了实现这一目标，顺式调控序列的功能和进化将在芽殖酵母中进行研究，首先确定影响健身顺式调控的变化，然后测量它们对基因表达的影响。将使用适合性测定，因为它们不需要假设哪些突变改变顺式调控序列功能，或它们如何影响基因表达。影响适应性的顺式调控序列的变化将与典型的结合位点及其对表达动力学和稳态水平的影响有关。这些关系的解剖将提高我们的能力，以确定顺式调控突变的基础表型变异，并将有助于确定表达动态的基因调控的进化中的作用。

DESCRIPTION (provided by applicant): Changes in gene regulation may play an important role in both adaptive evolution and genetic disease. Current knowledge of cis-regulatory sequences is based largely on canonical transcription factor binding sites that affect gene expression levels or developmental patterns at specific time-points. Yet, temporal changes in gene expression may often be more important to fitness than steady-state levels. The goal of the proposed research is to understand which noncoding mutations alter gene expression and which changes in gene expression have phenotypic consequences. To accomplish this goal, cis-regulatory sequence function and evolution will be investigated in budding yeast by first identifying cis-regulatory changes that affect fitness and then measuring their effects on gene expression. Fitness assays will be used because they require no assumption as to which mutations alter cis-regulatory sequence function, or how they affect gene expression. Changes in cis-regulatory sequences that affect fitness will be related to canonical binding sites and to their effects on expression dynamics and steady-state levels. Dissection of these relationships will enhance our ability to identify cis- regulatory mutations that underlie phenotypic variation and will help define the role of expression dynamics in the evolution of gene regulation.