Genome-wide association between branch point properties and alternative splicing.
Genome-wide association between branch point properties and alternative splicing.
复制标题
DOI：
10.1371/journal.pcbi.1001016
复制
发表时间：
2010-11-24
影响因子：
4.3
通讯作者：
Eyras E
中科院分区：
文献类型：
--
作者：
Corvelo A;Hallegger M;Smith CW;Eyras E
分支点（BP）是前体mRNA剪接所需的三个必需信号之一。在哺乳动物中，基序的简并性与缺乏大量实验验证的BP相结合，使得在计算机中对其进行建模的任务变得复杂，因此预测天然BP的位置变得复杂。因此，在哺乳动物剪接调控的全基因组研究中，有相当一部分的BP被忽视了。我们提出了一种新的计算方法，哺乳动物BP预测。使用序列保守性和位置偏差，我们获得了一组与U2 snRNA结合稳定性具有良好一致性的基序。使用支持向量机算法，我们创建了一个模型，补充了聚嘧啶道功能，大大提高了预测精度比以前公布的方法。将我们的算法应用于人类内含子，我们发现BP位置高度依赖于内含子3′端AG二核苷酸的存在，与3′剪接位点的距离和BP强度与选择性剪接密切相关。此外，实验BP映射5个外显子之前长AG-二核苷酸禁区显示，对于一个给定的内含子，可以选择一个以上的BP在整个过程中的剪接。最后，不同进化年龄的外显子和假外显子之间的比较表明BP在人类外显子产生途径中的关键作用。我们的计算和实验分析表明，BP识别比以前假设的更灵活，它似乎高度依赖于下游多聚嘧啶束的存在。BP功能和剪接结果之间的关联表明，这一点，迄今为止被忽视，但至关重要的，元素埋葬的信息，可以补充目前的受体位点模型。从转录到翻译，从DNA序列产生蛋白质的事件对细胞功能的各个方面都至关重要。真核生物中的前mRNA在输出到细胞质之前经历几个加工步骤。其中，剪接-内含子去除和外显子连接的过程-已被证明在基因表达的调控中发挥核心作用。据估计，人类中超过一半的致病突变是通过干扰剪接来实现的。描述这些疾病机制的困难通常在于预测前体mRNA中功能性剪接信号的方法的准确性低。这尤其是分支点的情况，主要是由于其高序列变异性。我们已经开发了一种方法，哺乳动物分支点预测的基础上，机器学习算法，这表明提高了准确性比以前公布的方法。此外，使用实验和生物信息学的方法相结合，我们发现了重要的位置特性的分支点，并揭示了它的一些功能可能有助于最终的剪接结果。这些发现可能有助于更好地理解剪接相关突变如何导致疾病。
The branch point (BP) is one of the three obligatory signals required for pre-mRNA splicing. In mammals, the degeneracy of the motif combined with the lack of a large set of experimentally verified BPs complicates the task of modeling it in silico, and therefore of predicting the location of natural BPs. Consequently, BPs have been disregarded in a considerable fraction of the genome-wide studies on the regulation of splicing in mammals. We present a new computational approach for mammalian BP prediction. Using sequence conservation and positional bias we obtained a set of motifs with good agreement with U2 snRNA binding stability. Using a Support Vector Machine algorithm, we created a model complemented with polypyrimidine tract features, which considerably improves the prediction accuracy over previously published methods. Applying our algorithm to human introns, we show that BP position is highly dependent on the presence of AG dinucleotides in the 3′ end of introns, with distance to the 3′ splice site and BP strength strongly correlating with alternative splicing. Furthermore, experimental BP mapping for five exons preceded by long AG-dinucleotide exclusion zones revealed that, for a given intron, more than one BP can be chosen throughout the course of splicing. Finally, the comparison between exons of different evolutionary ages and pseudo exons suggests a key role of the BP in the pathway of exon creation in human. Our computational and experimental analyses suggest that BP recognition is more flexible than previously assumed, and it appears highly dependent on the presence of downstream polypyrimidine tracts. The reported association between BP features and the splicing outcome suggests that this, so far disregarded but yet crucial, element buries information that can complement current acceptor site models. From transcription to translation, the events underlying protein production from DNA sequence are paramount to all aspects of cellular function. Pre-mRNAs in eukaryotes undergo several processing steps prior to their export to the cytoplasm. Among these, splicing – the process of intron removal and exon ligation – has been shown to play a central role in the regulation of gene expression. It has been estimated that more than half of the disease-causing mutations in humans do so by interfering with splicing. The difficulty in describing these disease mechanisms often lies in the low accuracy of the methods for prediction of functional splicing signals in the pre-mRNA. This is especially the case of the branch point, mainly due to its high sequence variability. We have developed a methodology for mammalian branch point prediction based on a machine-learning algorithm, which shows improved accuracy over previous published methods. Moreover, using a combination of experimental and bioinformatics approaches, we uncovered important positional properties of the branch point and shed new light on how some of its features may contribute to the final splicing outcome. These findings might prove useful for a better understanding of how splicing-associated mutations can lead to disease.
登录
查看更多内容
影响因子：
12.3
作者：
Corvelo A;Eyras E
通讯作者：
Eyras E
影响因子：
5.8
作者：
Castelo, Robert;Guigo, Roderic
通讯作者：
Guigo, Roderic
影响因子：
14.9
作者：
Gao K;Masuda A;Matsuura T;Ohno K
通讯作者：
Ohno K
影响因子：
--
作者：
Blanco, Enrique;Parra, Genis;Guigo, Roderic
通讯作者：
Guigo, Roderic
影响因子：
--
作者：
Kupfer, DM;Drabenstot, SD;Murphy, JW
通讯作者：
Murphy, JW