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Building Knowledge About Alternatively-spliced Dual-Coding Exons

建立关于选择性剪接双编码外显子的知识

基本信息

批准号：
10701663
负责人：
Travis John Wheeler
金额：
$ 19.19万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2024-08-31
项目状态：
已结题

项目摘要

Abstract Most protein-coding genes in humans and other eukaryotes are made up of a collection of exons, which are concatenated to form the messenger RNA (mRNA) that encodes a final protein product. The well-known phenomenon of alternative splicing makes it possible for a single gene to encode multiple protein products, by conditionally including only a subset of the gene’s exons into the expressed mRNA. A more surprising mechanism for producing alternate protein products is to utilize an alternate reading frame of a standard exon, through aberrant splicing; using custom software built in our research group, we have found that this mechanism appears to be quite common. Specifically, ~13% of all human genes include at least one exon that conditionally encodes alternate peptides, and these “dual-coding exons” are highly-conserved: 98% correspond to homologous exons in the mouse genome that also encode two open reading frames. Light exploration has identified dozens of human genes that show tissue-specific patterns of reading frame usage, suggesting a functional role for at least some of these variants. Here, we describe a plan to (i) leverage massive public atlases of human tissue-specific and development-specific RNA-Seq and mass spectrometry data to tabulate the extent of differential use of these frame-shifted splicing variants, and to (ii) analyze the computationally-predicted structural and functional impact of dual-coding variants, and the sequence signals controlling them. The results of these analyses will be accumulated for release in an open and accessible web service.

摘要人类和其他真核生物中的大多数蛋白质编码基因由一组外显子组成，它们连接在一起形成信使RNA（mRNA），产品众所周知的选择性剪接现象使得单个基因通过有条件地只包含基因外显子的一个子集，表达的mRNA。一种更令人惊讶的生产替代蛋白质产品的机制是通过异常剪接利用标准外显子的替代阅读框架;使用在我们的研究小组建立的定制软件中，我们发现这种机制似乎是很普通。具体来说，约13%的人类基因包括至少一个外显子，编码交替肽，这些“双重编码外显子”高度保守：98% 对应于小鼠基因组中也编码两个开放阅读的同源外显子跳转光探索已经确定了数十个人类基因，这些基因显示出组织特异性阅读框架使用的模式，表明这些变体中的至少一些的功能作用。在这里，我们描述了一个计划，以（i）利用大量的人类组织特异性的公共图谱，开发特异性RNA-Seq和质谱数据，以列表显示差异程度使用这些移码剪接变体，以及（ii）分析计算预测的双编码变体的结构和功能影响，以及控制他们这些分析的结果将累积起来， web服务