DISSERTATION RESEARCH: Evolution of transcription factor specificity and cooperativity

这个项目将结合进化遗传学和生物化学来剖析动物基因调控的基本系统是如何进化的。它将探索能够开启或关闭特定基因的特定控制分子是如何进化的。这将通过追踪关键控制分子及其相应基因结构的古代进化变化来完成。它将把蛋白质与DNA结合的实验室测试与分子进化的计算机分析结合起来。更广泛的影响包括培训研究生如何将计算机和实验方法整合到分子进化中。通过软件新兵训练营和科学宣传讲座传播统计编程技术也将增加妇女在跨学科科学领域的代表性。转录是任何基因表达的第一步，因此被许多人认为是调控基因组的基本步骤。对生物体基因的适当调节取决于数千种不同蛋白质（称为转录因子）与其各自基因的正确配对。了解新的控制配对如何在不丧失原有功能的情况下发生，是复杂基因组调控的核心。类固醇受体是生物学上重要的转录因子。它们也是研究转录控制的一个极好的模型系统，因为它们由两个相关但功能不同的群体组成，它们与特定基因的结合方式不同。其中一组主要与DNA分子的主要凹槽结合；另一组与DNA的主要和次要凹槽结合。为了了解这两个群体的DNA结合和识别的进化，本研究利用祖先序列重建以及功能实验室分析。受体功能和进化的计算分析将与实验室蛋白质结合分析相结合，以探索DNA次要凹槽的形状以及DNA序列在新特异性进化中很重要的假设。提出的实验将描述遗传和物理机制，通过不同模式的DNA识别多样化在这组分子。

This project will combine evolutionary genetics and biochemistry to dissect how a fundamental system of gene regulation in animals has evolved. It will explore how specific control molecules that can turn particular genes on or off have evolved. This will be done by tracing the ancient evolutionary changes in the structure of critical control molecules and their corresponding genes. It will integrate laboratory tests of protein to DNA binding with computer analysis of molecular evolution. Broader impacts include training of a graduate student in the integration of computer and experimental approaches to molecular evolution. Dissemination of techniques in statistical programming through software boot camps and science outreach presentations will also increase the representation of women in inter-disciplinary science.Transcription is the first step in the expression of any gene and hence is thought by many to be the fundamental step in regulation of the genome. Proper regulation of an organism's genes depends on the correct pairing of thousands of different proteins, called transcription factors, with their respective genes. Understanding how new control pairing occurs without loss of original functions is central to regulation in complex genomes. Steroid receptors are biologically important transcription factors. They are also an excellent model system for the study of transcriptional control since they consist of two related but functionally divergent groups that differ in the way they bind to specific genes. One group predominantly binds to a major groove of the DNA molecule; the other group binds to both major and minor grooves of DNA. To understand the evolution of DNA binding and recognition in these two groups this research utilizes ancestral sequence reconstruction, along with functional laboratory assays. Computational analysis of receptor function and evolution will be combined with laboratory protein binding assays to explore the hypothesis that the shape of the DNA minor groove as well as the DNA sequence was important in the evolution of novel specificity. The proposed experiments will delineate the genetic and physical mechanisms by which different modes of DNA recognition diversified in this group of molecules.