Building Knowledge About Alternatively-spliced Dual-Coding Exons

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， 发育特定的RNA测序和质谱数据，以表格形式列出差异程度 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

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.