Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
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人类疾病基因中的异常5'剪接位点：突变模式，核苷酸结构和预测其利用的计算工具的比较。
DOI：
10.1093/nar/gkm402
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发表时间：
2007
影响因子：
14.9
通讯作者：
Vorechovsky I
中科院分区：
文献类型：
--
作者：
Buratti E;Chivers M;Královicová J;Romano M;Baralle M;Krainer AR;Vorechovsky I
尽管在遗传性疾病中发现了越来越多的剪接突变，但异常剪接位点的利用及其对基因表达的影响仍然难以预测。我们汇编了346个异常5′剪接位点（5′ss）的序列，这些位点被166个人类疾病基因的突变激活。5′ss共有序列内的突变导致254个隐藏的5′ss，其他地方的突变激活了92个从头开始的5′ss。导致隐蔽5′ss激活的点突变在第一内含子核苷酸中最常见，其次是第五核苷酸。在+5位的取代完全是G>A转换，这在很大程度上归因于C/G>T/A的高突变率。然而，+5位点的点突变频率显著高于人类基因突变数据库中观察到的频率，这表明该位点的改变特别容易发生异常剪接，可能是由于需要与U1和U6 snRNA发生顺序相互作用。隐藏的5′ss最好的预测计算算法，适应核苷酸的依赖性，而不是权重矩阵模型。内含子5′ss与其真实对应物的区分不如外显子位点有效，因为前者本质上比后者更强。计算预测外显子de novo 5′ss的能力较差，这表明它们的激活关键取决于外显子剪接增强子或沉默子。异常5′ss的真实对应物明显弱于平均人类5′ss。异常5′ss数据库的建立将有助于研究剪接位点选择的基本机制，识别剪接突变和优化剪接位点预测算法。
Despite a growing number of splicing mutations found in hereditary diseases, utilization of aberrant splice sites and their effects on gene expression remain challenging to predict. We compiled sequences of 346 aberrant 5′splice sites (5′ss) that were activated by mutations in 166 human disease genes. Mutations within the 5′ss consensus accounted for 254 cryptic 5′ss and mutations elsewhere activated 92 de novo 5′ss. Point mutations leading to cryptic 5′ss activation were most common in the first intron nucleotide, followed by the fifth nucleotide. Substitutions at position +5 were exclusively G>A transitions, which was largely attributable to high mutability rates of C/G>T/A. However, the frequency of point mutations at position +5 was significantly higher than that observed in the Human Gene Mutation Database, suggesting that alterations of this position are particularly prone to aberrant splicing, possibly due to a requirement for sequential interactions with U1 and U6 snRNAs. Cryptic 5′ss were best predicted by computational algorithms that accommodate nucleotide dependencies and not by weight-matrix models. Discrimination of intronic 5′ss from their authentic counterparts was less effective than for exonic sites, as the former were intrinsically stronger than the latter. Computational prediction of exonic de novo 5′ss was poor, suggesting that their activation critically depends on exonic splicing enhancers or silencers. The authentic counterparts of aberrant 5′ss were significantly weaker than the average human 5′ss. The development of an online database of aberrant 5′ss will be useful for studying basic mechanisms of splice-site selection, identifying splicing mutations and optimizing splice-site prediction algorithms.
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影响因子：
4.5
作者：
Alvarez, CJ;Wise, JA
通讯作者：
Wise, JA
DOI：
10.1073/pnas.91.22.10470
发表时间：
1994-10-25
影响因子：
11.1
作者：
COHEN, JB;SNOW, JE;LEVINSON, AD
通讯作者：
LEVINSON, AD
影响因子：
11.4
作者：
Brackenridge, S;Wilkie, AOM;Screaton, GR
通讯作者：
Screaton, GR
影响因子：
5.6
作者：
BRUNAK, S;ENGELBRECHT, J;KNUDSEN, S
通讯作者：
KNUDSEN, S
影响因子：
14.9
作者：
Buratti, E;Baralle, M;Baralle, FE
通讯作者：
Baralle, FE