Evolution of regulatory sequences and systems

“我们认为，调控系统的进化变化解释了解剖学水平上和之外的进化”*--威尔逊等人。程序纳特。阿卡德。SCI。美国，1974年7月*对发育和生理机制的日益了解，以及最近对与物种间表型差异相关的特定调控变化的识别，为威尔逊等人的S建议提供了详细的支持。然而，由于许多表型是由组织在调控网络和信号通路中的一组基因决定的，我们必须考虑基因和调控序列的变化如何影响上下文中的功能。功能基因组技术已经开始能够系统地描述调控机制的演变，并确定了数千种潜在的调控变化。目前尚不清楚其中哪些是自然选择的结果，或者是遗传漂移造成的中性变化。我的研究计划解决了两个主要领域的挑战：*首先，我们将新的和现有的统计方法应用于功能基因组数据，以研究转录和翻译后水平上调控系统的进化。在高通量分子实验中发现的数千个转录因子结合或翻译后修饰位点的假定变化中，我们的目标是确定这些变化中的哪些(如果有的话)是自然选择的结果。在这项建议中，我们的目标是将数量遗传学的思想应用到调控系统进化中。*第二，我们直接使用萌芽酵母作为模式生物，在实验室中测试调控系统进化的假说，为此，我们可以结合基因工程和数量适合度测量。这些实验使我们能够超越推理，对进化如何实际发生的模型进行经验测试。在这项研究中，我们旨在测试自发突变和人工选择对信号通路的影响，并研究钙信号通路中脉冲的进化。*这项研究将解决导致调控序列和系统变化的进化力量以及这些分子变化如何影响调控系统控制的细胞过程的基本问题。了解进化的机制有助于我们解释生物多样性是如何产生的。我实验室的工具和技术是跨学科的：我们将使用分子进化的经典方法，包括比较序列分析、种群遗传学建模和选择测试，以及系统生物学调控网络模拟，以及芽殖酵母的分子生物学实验，如定点突变和基于荧光的适应性分析。*****

“We propose that evolutionary change in regulatory systems accounts for evolution at and beyond the anatomical level”***--Wilson et al. Proc. Nat. Acad. Sci. USA, July 1974******Increasing understanding of the mechanisms of development and physiology and, more recently, the identification of specific regulatory changes that are associated with phenotypic differences between species has provided detailed support for Wilson et al.'s proposal. However, since many phenotypes are determined by groups of genes organized in regulatory networks and signaling pathways, we must consider how changes in genes and regulatory sequences affect function in context. Functional genomic technologies have begun to allow systematic characterization of the evolution of regulatory mechanisms and have identified thousands of potential regulatory changes. It is yet unknown which (of any) of these were the result of natural selection, or neutral changes fixed by genetic drift. My research program addresses challenges in two major areas:******First, we apply novel and existing statistical methods to functional genomics data to study evolution of regulatory systems at the transcriptional and posttranslational levels. Among the thousands of putative changes in transcription factor binding or post-translational modification sites identified in high-throughput molecular experiments, we aim to identify which (if any) of these changes are the results of natural selection. In this proposal we aim to apply ideas from quantitative genetics to regulatory system evolution.******Second, we test hypotheses about regulatory system evolution in the lab directly using budding yeast as a model organism, for which we can combine genetic engineering and quantitative fitness measurements. These experiments allow us to go beyond inference to empirically test models of how evolution actually happens. In this proposal we aim to test the effects of spontaneous mutations and artificial selection on signaling pathways, and study the evolution of pulsing in the calcium signaling pathway.******This research will address basic questions about the evolutionary forces that cause changes in regulatory sequences and systems, and how these molecular changes affect the cellular processes that regulatory systems control. Understanding the mechanisms of evolution helps us explain how the diversity of living things arises. The tools and techniques in my lab are interdisciplinary: we will employ classical methods from molecular evolution including comparative sequence analysis, population genetics modeling and tests for selection, as well as systems biology regulatory network simulations, and molecular biology experiments in budding yeast, such as site-specific mutagenesis and fluorescence-based fitness assays. *****