Innovations in RNA Structure Prediction

描述（由申请人提供）：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是遗传信息的瞬时载体，也是读取密码的衔接分子。RNA催化反应并在转录后基因调控、发育和免疫中起作用。RNA也在人类疾病中发挥作用，包括Praeder-Willi和强直性肌营养不良。理解和利用RNA的力量，例如RNAi、反义技术或治疗性核酶，需要理解这些RNA序列的结构。该提案的目标是（1）自动化RNA的比较序列分析，以使用Dynalign的成对结构预测来确定RNA二级结构，Dynalign是我们的算法，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，并且依赖于进行比较的科学家的技能。随着新的非编码RNA（ncRNA）序列的发现，其在没有编码信息的情况下起作用，显著需要新的工具来自动化二级结构的测定。(2)通过编写一个名为Dynafind的新软件包，进一步开发我们使用Dynalign进行ncRNA发现的方法。我们的方法为ncRNA的发现采取粗略对齐的序列作为输入，并确定推定的ncRNA的基础上的折叠自由能变化的共同结构的比对。(3)使用Dynafind扫描人类和酵母基因组中的新型ncRNA基因。我们将与我们的合作研究者Eric Phizicky博士和托德洛博士合作，测试我们鉴定的推定ncRNA的功能。这项工作对人类健康具有广泛的影响。改进的预测RNA结构的工具将有助于发现RNA或靶RNA的治疗方法。人类基因组中新ncRNA的发现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.