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一组外显子组成的，连接起来形成编码最终蛋白质的信使 RNA (mRNA) 众所周知的选择性剪接现象使得单个基因成为可能。通过有条件地仅包含基因外显子的子集来编码多种蛋白质产物到表达的 mRNA 中，产生替代蛋白质产物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；我们的研究小组构建了定制软件，我们发现这种机制似乎是具体来说，约 13% 的人类基因至少包含一个有条件的外显子。编码替代肽，这些“双编码外显子”高度保守：98% 对应于小鼠基因组中的同源外显子，也编码两个开放阅读光探索已经识别出数十种具有组织特异性的人类基因。阅读框的使用模式，表明至少其中一些变体具有功能性作用。在这里，我们描述了一项计划：（i）利用大量人体组织特异性和发育特异性 RNA-Seq 和质谱数据，用于将差异程度制成表格使用这些移码剪接变体，并（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序列信号这些分析的结果将被累积并以开放且可访问的方式发布。网络服务。