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.

抽象的人类和其他真核生物中的大多数蛋白质编码基因都是由外显子组成的，将其连接形成编码最终蛋白质的使者RNA（mRNA）产品。众所周知的替代剪接现象使单个基因成为可能通过条件编码多种蛋白质产品，仅包括基因外显子的一个子集进入表达的mRNA。生产替代蛋白质产品的更令人惊讶的机制是通过异常剪接利用标准外显子的替代阅读框；使用在我们的研究小组中建立的自定义软件，我们发现这种机制似乎是非常常见。特别是，所有人类基因中约有13％至少包括一个有条件的外显子编码替代肽，这些“双编码外显子”高度保存：98％对应于鼠标基因组中的同源外显子，该外显子也编码两个开放式读数帧。光探索已经确定了数十种显示组织特异性的人类基因阅读框架用法的模式，表明至少其中一些变体具有功能作用。在这里，我们描述了一项计划，以（i）利用人类组织特异性的大规模公共地图开发特异性的RNA-seq和质谱数据，以列表差异的程度使用这些框架偏移的剪接变体，以及（ii）分析计算预测的双编码变体的结构和功能影响，以及控制的序列信号他们。这些分析的结果将累积在开放且可访问中 Web服务。