A simple physical model predicts small exon length variations.
A simple physical model predicts small exon length variations.
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DOI：
10.1371/journal.pgen.0020045
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发表时间：
2006-04
期刊：
影响因子：
4.5
通讯作者：
Zavolan, Mihaela
中科院分区：
文献类型：
--
作者：
Chern, Tzu-Ming;van Nimwegen, Erik;Kai, Chikatoshi;Kawai, Jun;Carninci, Piero;Hayashizaki, Yoshihide;Zavolan, Mihaela
最常见的剪接变异之一是由于使用与Pre-mRNA非常接近的供体或受体剪接位点而引起的小的外显子长度差异。其中，NAGNAG串联受体位点上的三个核苷酸变异最近引起了相当大的关注，有人认为这些变异是受调控的，并通过添加或移除单一氨基酸来微调蛋白质的形式。在这篇文章中，我们首先证明了框架内外显子长度变化通常被过度表达，并且这种过度表达可以用无义介导的衰变效应来定量解释。我们的分析使我们能够估计，大约50%的帧移位编码转录本是无意义介导的衰退的目标。其次，我们证明了一个简单的物理模型，该模型假设剪接机械与附近的剪接位点随机结合，与位点的亲和力成比例，该模型正确地预测了在两个边界上不同的小长度变化的相对丰度。最后，使用同样简单的物理模型，我们证明了对于NAGNAG位点，剪接机制相邻位点的亲和力差异准确地预测了剪接是只发生在第一个位点，只发生在第二个位点，还是可能发生三核苷酸剪接变体。因此，我们的分析表明，较小的外显子长度差异是剪接体在邻近剪接点的随机结合的结果。当附近有与剪接机制有类似亲和力的选择性剪接位点时，就会发生小的外显子长度变化。最近发现剪接变异会影响大多数哺乳动物的基因。然而，目前还不太清楚这些剪接变异在多大程度上是由细胞发挥作用和调节的，而不是简单地由于剪接过程中的噪音造成的。剪接变异最常见的形式之一是外显子长度的微小变异，即外显子的边界在不同的转录本之间发生了少量的移位。在这项工作中，作者对这些剪接变异的统计进行了详细的研究，结果表明，这些变异主要是剪接过程中噪声的结果。特别是，他们提出了一个简单的物理模型，其中剪接的最后一步涉及剪接机械与剪接位点的序列特异性结合。在这个模型中，当附近有与剪接机械具有类似亲和力的剪接位点时，可能会发生小的长度变化。作者发现，该模型不仅能准确预测不同剪接变异的相对丰度，而且还能预测哪些剪接位点可能经历较小的外显子长度变异。
One of the most common splice variations are small exon length variations caused by the use of alternative donor or acceptor splice sites that are in very close proximity on the pre-mRNA. Among these, three-nucleotide variations at so-called NAGNAG tandem acceptor sites have recently attracted considerable attention, and it has been suggested that these variations are regulated and serve to fine-tune protein forms by the addition or removal of a single amino acid. In this paper we first show that in-frame exon length variations are generally overrepresented and that this overrepresentation can be quantitatively explained by the effect of nonsense-mediated decay. Our analysis allows us to estimate that about 50% of frame-shifted coding transcripts are targeted by nonsense-mediated decay. Second, we show that a simple physical model that assumes that the splicing machinery stochastically binds to nearby splice sites in proportion to the affinities of the sites correctly predicts the relative abundances of different small length variations at both boundaries. Finally, using the same simple physical model, we show that for NAGNAG sites, the difference in affinities of the neighboring sites for the splicing machinery accurately predicts whether splicing will occur only at the first site, splicing will occur only at the second site, or three-nucleotide splice variants are likely to occur. Our analysis thus suggests that small exon length variations are the result of stochastic binding of the spliceosome at neighboring splice sites. Small exon length variations occur when there are nearby alternative splice sites that have similar affinity for the splicing machinery. It has recently become clear that splice variation affects most mammalian genes. It is, however, less clear to what extent these splice variations are functional and regulated by the cell as opposed to simply a result of noise in the splicing process. One of the most frequently observed forms of splice variation are small variations in exon length in which the boundary of an exon is shifted by small amounts between different transcripts. In this work the authors study the statistics of these splice variations in detail, and the results suggest that these variations are mostly the result of noise in the splicing process. In particular, they propose a simple physical model in which the last step of splicing involves the sequence-specific binding of the splicing machinery to the splice site. In this model, small length variations can occur when there are nearby splice sites with comparable affinity for the splicing machinery. The authors show that this model not only accurately predicts the relative abundances of different splice variations but also predicts which splice sites are likely to undergo small exon length variations.
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