Evolution of regulatory sequences and systems

“我们认为，调节系统的进化变化解释了解剖学水平及以上的进化”*--Wilson et al. Proc. Nat. Acad. Sci.美国，1974年7月 * 对发育和生理机制的理解不断加深，最近，与物种间表型差异相关的特定调控变化的鉴定为Wilson等人的研究提供了详细的支持。的提议。 然而，由于许多表型是由调控网络和信号通路中的基因组决定的，我们必须考虑基因和调控序列的变化如何影响环境中的功能。功能基因组学技术已经开始允许系统表征调控机制的演变，并已确定了数千个潜在的调控变化。 目前还不知道这些变化中哪些是自然选择的结果，或者是由遗传漂变固定的中性变化。 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学数据，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转录因子结合或翻译后修饰位点的数千种推定变化中，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。在这项提案中，我们的目标是将数量遗传学的思想应用于调控系统的进化。第二，我们直接使用芽殖酵母作为模式生物，在实验室中测试有关调节系统进化的假设，为此，我们可以将联合收割机基因工程和定量适应性测量相结合。这些实验使我们能够超越推论，从经验上检验进化实际上是如何发生的模型。在这项提案中，我们的目标是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演变。这项研究将解决有关导致调控序列和系统变化的进化力量的基本问题，以及这些分子变化如何影响调控系统控制的细胞过程。理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：我们将采用分子进化的经典方法，包括比较序列分析，群体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，如位点特异性诱变和基于荧光的健身测定。 *****

“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. *****