Single nucleotide polymorphism-based validation of exonic splicing enhancers.
Single nucleotide polymorphism-based validation of exonic splicing enhancers.
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DOI：
10.1371/journal.pbio.0020268
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发表时间：
2004-09
期刊：
影响因子：
9.8
通讯作者：
Sharp PA
中科院分区：
文献类型：
--
作者：
Fairbrother WG;Holste D;Burge CB;Sharp PA
由于突变产生的有害等位基因会被自然选择过滤掉，因此在任何给定时间，产生这种等位基因的突变在种群中存在的常见遗传变异中的代表性都将不足。在这里，我们描述了一种基于这种想法的方法，称为验证（变体消除增强功能），它可以用来评估自然选择作用于预测具有生物活性的寡核苷酸基序或基序集的程度。作为这种方法的应用，我们分析了一组238个六核苷酸先前预测有外显子剪接增强子（ESE）的活动，在人类外显子使用相对增强子和沉默分类一致富集（RESCUE）-ESE方法。将公共人类SNP数据库中的单核苷酸多态性（SNP）与黑猩猩基因组进行比对，可以推断出产生当今SNP的突变方向。通过分析与RESCUE-ESE六聚体重叠的SNP组，我们得出结论，近五分之一的破坏预期ESE的突变已被自然选择消除（比值比= 0.82 ± 0.05）。这种选择对于位于剪接位点附近的预测的ESE是最强的。我们的研究结果证明了一种新的方法，用于量化作用于候选功能基序的自然选择的程度，也表明突变/SNP的某些功能，如接近剪接位点和预测的ESE的破坏或改变，这应该是有用的，在确定可能导致生物表型的变体。单核苷酸多态性的计算分析表明，五分之一的破坏预测外显子剪接增强子的突变已被自然选择消除。
Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant elimination reinforces functionality), which can be used to assess the extent of natural selection acting on an oligonucleotide motif or set of motifs predicted to have biological activity. As an application of this approach, we analyzed a set of 238 hexanucleotides previously predicted to have exonic splicing enhancer (ESE) activity in human exons using the relative enhancer and silencer classification by unanimous enrichment (RESCUE)-ESE method. Aligning the single nucleotide polymorphisms (SNPs) from the public human SNP database to the chimpanzee genome allowed inference of the direction of the mutations that created present-day SNPs. Analyzing the set of SNPs that overlap RESCUE-ESE hexamers, we conclude that nearly one-fifth of the mutations that disrupt predicted ESEs have been eliminated by natural selection (odds ratio = 0.82 ± 0.05). This selection is strongest for the predicted ESEs that are located near splice sites. Our results demonstrate a novel approach for quantifying the extent of natural selection acting on candidate functional motifs and also suggest certain features of mutations/SNPs, such as proximity to the splice site and disruption or alteration of predicted ESEs, that should be useful in identifying variants that might cause a biological phenotype. A computational analysis of single nucleotide polymorphisms showed that one-fifth of mutations that disrupt predicted exonic splicing enhancers have been eliminated by natural selection
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LAVIGUEUR, A;LABRANCHE, H;CHABOT, B
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