Innovations in RNA Structure Prediction

描述（申请人提供）：RNA在细胞功能中起着许多重要作用。在生物学的中心法则中，RNA是遗传信息的短暂载体，也是读取密码的适配分子。RNA催化反应，并在转录后基因调控、发育和免疫中发挥作用。RNA也在人类疾病中发挥作用，包括praader - willi和肌强直性营养不良。理解和利用RNA的力量，例如使用RNAi、反义技术或治疗性核酶，需要了解这些RNA序列的结构。本提案的目标是：(1)自动化RNA的比较序列分析，以确定RNA二级结构，使用来自dynamalign的配对结构预测，我们的算法可以找到两个序列共有的二级结构。比较序列分析是在没有晶体结构的情况下确定RNA二级结构的金标准，但目前是劳动密集型的，并且依赖于做比较的科学家的技能。随着新类别的非编码RNA （ncRNA）序列在没有编码信息的情况下发挥作用，迫切需要新的工具来自动确定二级结构。(2)通过编写一个名为Dynafind的新软件包，进一步发展我们使用Dynalign发现ncRNA的方法。我们的ncRNA发现方法以粗排列序列为输入，并根据排列中共同结构的折叠自由能变化来识别假定的ncRNA。(3)使用Dynafind扫描人类和酵母基因组寻找新的ncRNA基因。我们将与共同研究人员Eric Phizicky博士和Todd Lowe博士合作，测试我们确定的假定ncrna的功能。这项工作对人类健康具有广泛的影响。预测RNA结构的改进工具将有助于发现RNA或靶RNA的治疗方法。在人类基因组中发现新的ncRNA将有助于我们对发育和细胞生理学的理解。

DESCRIPTION (provided by applicant): RNA plays many important roles in cellular function. In the Central Dogma of Biology, RNA serves as a transient carrier of genetic information and as the adapter molecule that reads the code. RNA catalyzes reactions and serves in post-transcriptional gene regulation, development, and immunity. RNA also plays roles in human disease, including Praeder-Willi and myotonic dystrophy. Understanding and harnessing the power of RNA, e.g. with RNAi, antisense technology, or with therapeutic ribozymes, requires an understanding of the structures of these RNA sequences. The goals of this proposal are to (1) Automate comparative sequence analysis of RNA to determine RNA secondary structure using pairwise structure predictions from Dynalign, our algorithm that finds the secondary structure common to two sequences. Comparative sequence analysis is the gold standard for determining RNA secondary structure in the absence of a crystal structure, but is currently labor intensive and dependent on the skill of the scientist doing the comparison. With the discovery of new classes of non-coding RNA (ncRNA) sequences that function without coding message, there is a significant need for new tools to automate the determination of secondary structure. (2) Further develop our method using Dynalign for ncRNA discovery by writing a new software package called Dynafind. Our method for ncRNA discovery takes crudely aligned sequence as input and identifies putative ncRNAs on the basis of the folding free energy change of the common structure in the alignment. (3) Scan the human and yeast genomes for novel ncRNA genes using Dynafind. We will collaborate with our co-investigators, Dr. Eric Phizicky and Dr. Todd Lowe, to test the function of putative ncRNAs that we identify. This work has broad implications for human health. Improved tools for predicting RNA structure will help in the discovery of therapeutics that are either RNA or target RNA. The discovery of novel ncRNA in the human genome will contribute to our understanding of development and cellular physiology.