Single base-pair substitutions in exon-intron junctions of human genes: Nature, distribution, and consequences for mRNA splicing
Single base-pair substitutions in exon-intron junctions of human genes: Nature, distribution, and consequences for mRNA splicing
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DOI：
10.1002/humu.20400
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发表时间：
2007-02-01
期刊：
影响因子：
3.9
通讯作者：
Cooper, David N.
中科院分区：
文献类型：
--
作者：
Krawczak, Michael;Thomas, Nick S. T.;Cooper, David N.
尽管剪接点中的单碱基对取代至少占导致人类遗传性疾病的所有突变的10%，但在RNA水平上决定其表型后果的因素仍有待充分阐明。采用神经网络进行剪接位点识别，我们对38个不同基因中的478个疾病相关剪接突变进行了荟萃分析，并对其进行了详细的基于实验室的mRNA表型评估。对突变的+/-50-bp DNA序列背景的检查显示，当受影响的外显子-内含子连接的紧邻区域缺乏替代剪接位点时，外显子跳跃是优选的表型。相比之下，在至少一个这样的基序的存在下，隐蔽的剪接位点的利用，变得更加普遍。然而，这种关联仅限于供体剪接位点。在专性二核苷酸之外，发现病理性突变的空间分布与SNP的空间分布显著不同。尽管疾病相关病变聚集在供体位点的位置-1和+3至+6以及受体位点的位置-3处，但发现SNP几乎均匀地分布在所考虑的所有序列位置上。当从人类基因突变数据库中提取38个研究基因的剪接位点附近的所有推定错义突变时，发现供体位点（37/152; 24.3%）的变化比例显著高于受体剪接位点（1/142; 0.7%），以减少相应剪接位点发出的神经网络信号。基于这些发现，我们估计约1.6%的人类基因中的致病错义置换可能影响mRNA剪接表型。两者合计，我们的结果是一致的正确的供体剪接位点识别是一个关键步骤，外显子识别。
Although single base-pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice-site recognition, we performed a meta-analysis of 478 disease-associated splicing mutations, in 38 different genes, for which detailed laboratory-based mRNA phenotype assessment had been performed. Inspection of the +/- 50-bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon-intron junctions was devoid of alternative splice-sites. By contrast, in the presence of at least one such motif, cryptic splice-site utilization, became more prevalent. This association was, however, confined to donor splice-sites. Outside the obligate dinucleotide, the spatial distribution of pathological mutations was found to differ significantly from that of SNPs. Whereas disease-associated lesions clustered at positions -1 and +3 to +6 for donor sites and -3 for acceptor sites, SNPs were found to be almost evenly distributed over all sequence positions considered. When all putative missense mutations in the vicinity of splice-sites were extracted from the Human Gene Mutation Database for the 38 studied genes, a significantly higher proportion of changes at donor sites (37/152; 24.3%) than at acceptor splice-sites (1/142; 0.7%) was found to reduce the neural network signal emitted by the respective splice-site. Based upon these findings, we estimate that some 1.6% of disease-causing missense substitutions in human genes are likely to affect the mRNA splicing phenotype. Taken together, our results are consistent with correct donor splice-site recognition being a key step in exon recognition.