Evolution of Regulatory Sequence Motifs

转录因子是通过在特定位置与DNA结合来调节基因表达的蛋白质。尽管进行了多年的研究，但对转录因子及其在基因组中的结合部位所面临的进化限制知之甚少。因此，很难改进至今仍在使用的数十年前的转录因子结合模型。高通量技术的出现、比较基因组学技术的广泛使用以及合成生物学的迅速出现，都促进并更加迫切地需要了解这些遗传因素是如何进化和相互作用的，因为这将使能够在DNA序列上的转录编码及其对其产生的调控网络的影响之间建立急需的联系的模型的开发成为可能。该项目旨在验证和开发一个强大的计算框架，用于在现实的基因组环境中转录因子及其结合基序的共同进化。这项研究将利用遗传算法骨干与转录因子的创新建模相结合，以分析当面临特定的基因组选择压力、调控需求和基因组大小时，转录因子及其结合基序是如何进化的。最重要的是，这项研究引入了一种反向工程方法，旨在推断这些遗传因素行为的基本原理。该项目将首次系统地分析和量化结合位点进化中的关键限制因素，从而有可能重塑我们对这些基因组元件的思考和建模方式。将特别强调汇编已发表的数据以验证系统做出的预测，并测试推断的模型约束在改进转录因子结合位点的计算发现方面的有效性。广泛影响这个项目将促进我们对转录调控及其进化的理解，导致转录因子结合基序的改进模型。它还将证实生物学中的计算机模拟和使用自下而上的方法分析理论模型的进步趋势。这项研究将为转录进化的探索提供一个可扩展的工具，以及一个最新的转录因子结合位点数据库。这两个项目都将向公众免费提供，以促进新转录因子模型的开发和基准确定。本科生的培训和参与研究是该项目的一个重要组成部分，将集中于采用同行指导的数据库管理系统。该项目还规定了参与式方法，通过使用进化视频，将研究成果融入到PI和其他人教授的课程中，并在针对K-12学生的特定活动中使用这些元素，并在普及进化理论方面使用这些元素。PI将利用UMBC项目提供的杠杆作用，指导少数族裔学生并让他们参与研究，特别强调不断增长的拉美裔社区。该项目的主动外联和传播部分还将利用以往利用进化模拟进行的努力，以便在广大受众中促进关于进化问题的知情辩论。

Transcription factors are proteins that regulate the expression of genes by binding to DNA at specific locations. In spite of years of research, little is known about the evolutionary constraints faced by transcription factors and their binding sites in the genome. As a result, it is difficult to improve on the decades-old models of transcription factor binding that are still in use today. The advent of high-throughput technologies, the widespread use of comparative genomics techniques and the rapid emergence of synthetic biology both facilitate and make more pressing the need for understanding how these genetic elements evolve and interact, since this will enable the development of models capable of establishing a much needed link between the encoding of transcription on DNA sequence and its effects on the regulatory networks it spawns. This project aims at validating and exploiting a robust computational framework for the co-evolution of transcription factors and their binding motifs in a realistic genome environment. The research will capitalize on the integration of a genetic algorithm backbone with innovative modeling of transcription factors in order to analyze how transcription factors and their binding motifs evolve when confronted with specific genomic selective pressures, regulatory needs and genome sizes. Most importantly, this research introduces a reverse engineering approach aimed at infering basic principles on the behavior of these genetic elements. The project will systematically analyze and quantify for the first time key constraints in the evolution of binding sites and thus has the potential to reshape the way we think about and model these genomic elements. Specific emphasis will be made in compiling published data to validate the predictions made by the system and in testing the efficacy of inferred model constraints at improving computational discovery of transcription factor binding sites.Broader ImpactsThis project will advance our understanding of transcriptional regulation and its evolution, leading to improved models of transcription factor binding motifs. It will also substantiate a progressive movement towards in-silico simulations in biology, and to the analysis of theoretical models using a bottom-up approach. The research will provide a scalable tool for the exploration of transcriptional evolution, as well as an up-to-date curated database of transcription factor binding sites. Both items will be made freely available to the public, facilitating the development and benchmarking of new transcription factor models. Training and involvement of undergraduates in research is an essential component of this project and will be centralized on the adoption of a peer-mentored system for database curation. The project also defines participative methods for integrating research results into courses taught by the PI and others through the use of evolutionary videos, and the use of these elements in specific events targeting K-12 students and in popularizing evolutionary theory. The PI will exploit the leverage provided by UMBC programs to mentor and involve minority students in research, with particular emphasis on the growing Hispanic community. The pro-active outreach and dissemination components of the project will also capitalize on previous efforts to exploit evolutionary simulations in order to foster an informed debate on evolutionary questions across a broad range of audiences.