Evolutionary Modeling/Prediction of ncRNA Genes in Flies

果蝇 ncRNA 基因的进化建模/预测

• 批准号: 7028700
• 负责人: Ian H Holmes
• 金额: $ 22.44万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028700
• 关键词: Drosophilidae; RNA biosynthesis; biochemical evolution; computer assisted sequence analysis; computer program /software; computer simulation; computer system design /evaluation; genetic library; genetic translation; mathematical model; model design /development; molecular biology information system; nucleic acid sequence; statistics /biometry

DESCRIPTION (provided by applicant): The use of probabilistic evolutionary models is an integral part of comparative genomics. Applications include design of evolutionary genefinding software; screening of coding DNA sequences for sites under selection; identification of regulatory elements in genomes; improved detection of homologues; and prediction of deleterious SNPs. Such evolutionary models remain under-developed, particularly for the subclass of genes expressed solely as noncoding RNA (ncRNA). However, there is increasing biomedical interest in this class of genes: microRNAs are now suspected to regulate a wide range of targets, and are used by viruses to silence host transcription; small interfering RNAs are being explored as a therapeutic treatment; drugs exist that specifically target RNA structure (e.g. bacterial ribosomes, or retroviral binding sites such as HIV's Rev Response Element); RNA motifs known as "riboswitches", echoing genetically- engineered "aptamers" in their ability to discriminatively bind small-molecule ligands, have recently been discovered in prokaryotes; many catalytic ncRNAs ("ribozymes") are active in human and bacterial cells; and many of the above technologies (e.g. riboswitches/ aptamers/ ribozymes) are beginning to be exploited by synthetic biologists e.g. as novel reporter constructs, with great biomedical potential. Here, we propose to develop ncRNA evolutionary models for a focused, biologically testable case study: the identification of ncRNA genes by comparative analysis of twelve fruit fly genomes. Computationally, we will use this example to drive forward our ongoing methods development in RNA analysis and evolutionary modeling, adapting our successful "xrate" and "stemloc" programs for use with evolutionary stochastic context-free grammars. Experimentally, we will test our predictions by wet-lab validation methods such as RT-PCR and sequencing, with the help of our collaborators and locally available resources such as the Berkeley Drosophila Genome Project's cDNA libraries. All our software will be freely available online.

描述（由申请人提供）：概率进化模型的使用是比较基因组学不可或缺的一部分。应用包括进化基因定义软件的设计；筛选在选择处的位点编码DNA序列；鉴定基因组中的调节元素；改善了同源物的检测；和有害SNP的预测。这种进化模型仍然不发达，特别是对于仅以非编码RNA（NCRNA）表示的基因亚类。但是，在这类基因中，生物医学的兴趣越来越高：现在怀疑microRNA可以调节广泛的靶标，并被病毒用来沉默宿主转录；小型干扰RNA被探讨为治疗治疗。存在专门针对RNA结构的药物（例如细菌核糖体或逆转录病毒结合位点，例如HIV的REV反应元件）；最近在原核生物中发现了被称为“核糖开关”的RNA图案，称为“核糖开关”，以其遗传设计的“适体”的鉴别能力与鉴别性结合的小分子配体的能力相呼应。许多催化NCRNA（“核酶”）在人和细菌细胞中活跃。并开始利用上述许多技术（例如核糖开关/适体/核酶），例如合成生物学家，例如作为新的记者构造，具有巨大的生物医学潜力。 在这里，我们建议开发NCRNA进化模型，以进行专注的，可生物学测试的案例研究：通过对十二个果蝇基因组的比较分析来鉴定NCRNA基因。在计算上，我们将使用此示例来推动我们正在进行的RNA分析和进化建模中的方法开发，从而适应了我们成功的“ Xrate”和“ STENLOC”程序，用于与进化随机上下文无上下文的语法一起使用。在实验上，我们将通过我们的合作者和当地可用的资源（例如伯克利果蝇基因组项目的cDNA库）的帮助，通过湿lab验证方法（例如RT-PCR和测序）测试我们的预测。我们所有的软件将在线免费提供。