EVOLUTION OF CIS-REGULATORY SEQUENCES

CIS 监管序列的演变

• 批准号: 8721971
• 负责人: Justin C Fay
• 金额: $ 28.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721971
• 关键词: Address; Affect; Binding Sites; Biological Assay; Biological Models; Carbon; Complex; Conserved Sequence; Data; Development; Dissection; Evolution; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic Polymorphism; Goals; Growth; Hereditary Disease; Hybrids; Knowledge; Lead; Libraries; Malate Synthase; Measures; Mediating; Modeling; Mutation; Nucleosomes; Orthologous Gene; Pattern; Physiological; Play; Positioning Attribute; Predictive Value; Relative (related person); Research; Resistance; Role; Saccharomyces cerevisiae; Saccharomycetales; Source; Sulfites; Testing; Time; Variant; Yeasts; Zinc Fingers; base; fitness; human disease; improved; insertion/deletion mutation; insight; promoter; public health relevance; research study; response; trait; transcription factor

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.

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发挥重要作用。目前对顺式调控序列的了解主要基于影响特定时间点的基因表达水平或发育模式的规范转录因子结合位点。然而，基因表达的时间变化通常可能比稳态水平对健康更重要。拟议研究的目标是了解哪些非编码突变改变基因表达以及基因表达的哪些变化具有表型后果。为了实现这一目标，将在芽殖酵母中研究顺式调控序列的功能和进化，首先识别影响适应性的顺式调控变化，然后测量它们对基因表达的影响。将使用适合度测定，因为它们不需要假设哪些突变改变顺式调控序列功能，或者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规范结合位点及其对表达动态和稳态水平的影响有关。对这些关系的剖析将增强我们识别表型变异背后的顺式调控突变的能力，并将有助于确定表达动态在基因调控进化中的作用。