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。尽管经过多年的研究，人们对转录因子及其在基因组中的结合位点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已有几十年历史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，都促进了对这些遗传元素如何进化和相互作用的理解，并使其更加迫切，因为这将使模型的发展能够在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。该项目旨在验证和开发一个强大的计算框架，用于转录因子及其结合基序在现实基因组环境中的共同进化。该研究将利用遗传算法主干与转录因子创新建模的整合，以分析转录因子及其结合基序在面临特定基因组选择压力、调控需求和基因组大小时如何进化。最重要的是，本研究引入了一种逆向工程方法，旨在推断这些遗传元素行为的基本原理。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素的思考和建模方式。将特别强调编译已发表的数据，以验证系统所做的预测，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功效。该项目将促进我们对转录调控及其进化的理解，从而改进转录因子结合基序的模型。它还将证实一个进步的运动，即在生物学中进行计算机模拟，并使用自下而上的方法分析理论模型。这项研究将为探索转录进化提供一个可扩展的工具，以及转录因子结合位点的最新数据库。这两个项目都将免费提供给公众，促进新的转录因子模型的开发和基准测试。培训和参与研究的本科生是这个项目的重要组成部分，并将集中于采用同行指导的数据库管理系统。该项目还定义了参与式方法，通过使用进化论视频，将研究成果整合到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，并推广进化论。PI将利用哥伦比亚大学项目提供的杠杆作用，指导和让少数民族学生参与研究，特别强调不断增长的西班牙裔社区。该项目的积极推广和传播部分还将利用先前开发进化模拟的努力，以便在广泛的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.