Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping
Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping
复制标题
DOI：
10.1038/ejhg.2008.257
复制
发表时间：
2009-06-01
影响因子：
5.2
通讯作者：
Vorechovsky, Igor
中科院分区：
文献类型：
--
作者：
Divina, Petr;Kvitkovicova, Andrea;Vorechovsky, Igor
影响前体信使RNA剪接的突变在遗传性疾病的发展中起主要作用。已经发现大多数剪接突变消除了限定内含子的50和30末端的GT或AG二核苷酸，导致外显子跳跃或隐蔽剪接位点激活。虽然准确描述错误剪接的转录本对于预测这些改变的表型后果至关重要，但它们在受影响个体中的确切性质通常无法通过实验确定。使用一个全面的收集外显子，持续隐蔽的剪接位点激活或跳过的剪接位点突变的结果，我们已经开发出一个多元逻辑判别程序，区分两个异常剪接的结果从DNA序列。新算法使用外显子的独立样本进行验证，并作为一个免费的在线实用程序，称为密码P-SKIP（http：//www.dn.org.uk/cryp-skip/）。网络应用程序采用一个或多个突变的等位基因，每个等位基因由一个外显子和侧翼内含子序列组成，并提供一系列重要的预测变量及其值、激活隐蔽剪接与外显子跳跃的总体概率以及输入序列中预测的隐蔽剪接位点的位置和内在强度。这些结果将有助于剪接突变的表型预测，并提供进一步的见解剪接增强子和沉默元件及其在体内剪接位点选择的相对重要性。European Journal of Human Genetics（2009）17，759-765; doi：10.1038/ejhg.2008.257; 2009年1月14日在线发表
Mutations that affect splicing of precursor messenger RNAs play a major role in the development of hereditary diseases. Most splicing mutations have been found to eliminate GT or AG dinucleotides that define the 50 and 30 ends of introns, leading to exon skipping or cryptic splice-site activation. Although accurate description of the mis-spliced transcripts is critical for predicting phenotypic consequences of these alterations, their exact nature in affected individuals cannot often be determined experimentally. Using a comprehensive collection of exons that sustained cryptic splice-site activation or were skipped as a result of splice-site mutations, we have developed a multivariate logistic discrimination procedure that distinguishes the two aberrant splicing outcomes from DNA sequences. The new algorithm was validated using an independent sample of exons and implemented as a free online utility termed CRYP-SKIP (http://www.dbass.org.uk/cryp-skip/). The web application takes up one or more mutated alleles, each consisting of one exon and flanking intronic sequences, and provides a list of important predictor variables and their values, the overall probability of activating cryptic splice vs exon skipping, and the location and intrinsic strength of predicted cryptic splice sites in the input sequence. These results will facilitate phenotypic prediction of splicing mutations and provide further insights into splicing enhancer and silencer elements and their relative importance for splice-site selection in vivo. European Journal of Human Genetics (2009) 17, 759-765; doi: 10.1038/ejhg.2008.257; published online 14 January 2009