Searching Genomes for Non-Coding RNAs by Their Structure

描述(申请人提供)：RNA分子及其功能是细胞和分子生物学的中心；它们的功能范围从中央信使的经典信使到执行酶活动的核酶，再到作为调节分子。非编码RNA的存在及其重要性对生物信息学提出了挑战。生物学家如何在新测序的基因组或序列数据库中识别这些分子？一种关键的方法是使用生物信息学方法，可以在基因组和数据库中搜索特定的RNA二级结构。我们提出的研究旨在开发计算工具来模拟RNA的结构，执行RNA结构比对和数据库搜索，然后实验测试我们的预测。我们的方法是基于构象图模型和图论技术，基于图树分解的概念开发快速而准确的RNA结构同源搜索工具。这些方法既可以描述茎环结构，也可以描述伪结结构。我们的初步结果包括根据大而复杂的RNA的结构成功地搜索原核和真核基因组。建议工作的具体步骤是：(1)将构象图-树分解方法发展成为生物学家容易使用的高通量RNA结构搜索工具；(2)开发用于非注释、未比对的RNA序列的自动比较分析和建模的工具；(3)将我们的方法应用于发现和注释特定的RNA基因家族，包括对预测的实验验证；(4)分发搜索和建模工具，包括用户友好的界面，以及构象图结构图谱数据库。我们的目标是开发一个实用的RNA结构建模和搜索工具集，以便生物学家可以很容易地在基因组或数据库中找到RNA结构，帮助他们生成关于RNA基因家族的数量、功能和进化的可测试假说。RNA分子是基础生物学和公共卫生的中心，可能是未来医学实践的关键组成部分。我们提出的研究将帮助生物学家在产生的大量基因组序列数据中找到感兴趣的RNA分子。

DESCRIPTION (provided by applicant): RNA molecules and their functions are central to cellular and molecular biology; their functions range from the classic messengers of the central dogma, to ribozymes that carry out enzymatic activities, to acting as regulatory molecules. The existence and important of non-coding RNAs poses a challenge to bioinformatics. How are biologists to identify these molecules in newly sequenced genomes or sequence databases? One key approach is to use bioinformatic methods that can search genomes and databases for specific RNA secondary structures. The research we propose is directed towards developing computational tools to model the structures of RNAs, to perform RNA structure alignment and database searches, and then to experimentally test our predictions. Our approach is based upon conformational graph models and graph theoretic techniques, developing fast, yet accurate, RNA structural homology search tools based upon the notion of graph tree decomposition. These methods can describe both stem-loop and pseudoknot structures. Our preliminary results include successful searches of prokaryotic and eukaryotic genomes for large and complex RNAs by their structure. The specific steps of the proposed work are: (1) development of the conformational graph - tree decomposition method into high throughput tools for RNA structure search that biologists can readily use; (2) development of tools for automated comparative analysis and modeling of non-annotated, unaligned, RNA sequences; (3) application of our method to discovery and annotation of specific RNA gene families, including experimental verification of the predictions; (4) distribution of the search and modeling tools, including a user-friendly interface, together with a conformational graph structure profile database. Our goal is to develop a practical RNA structure modeling and search tool set that biologists can readily use to find RNA structures in genomes or databases, to help them generate testable hypotheses about the numbers, functions and evolution of RNA gene families. RNA molecules are at the center of basic biology as well as public health, and may be a key component of future medical practice. Our proposed research will help biologists find RNA molecules of interest in the mass of genome sequence data being generated.