Mutations primarily alter the inclusion of alternatively spliced exons.
Mutations primarily alter the inclusion of alternatively spliced exons.
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DOI：
10.7554/elife.59959
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发表时间：
2020-10-28
期刊：
影响因子：
7.7
通讯作者：
Lehner B
中科院分区：
文献类型：
--
作者：
Baeza-Centurion P;Miñana B;Valcárcel J;Lehner B
遗传分析和系统诱变已经揭示，同义、非同义和内含子突变经常改变可变剪接外显子的包含水平，这与改变的剪接可能是突变引起疾病的常见机制的概念一致。然而，任何细胞中表达的大多数外显子都高度包含在成熟mRNA中。在这里，通过对高度包含的外显子进行深度诱变，并通过分析基因组序列变异与转录组中外显子包含之间的关联，我们报告突变很少改变高度包含的外显子的包含。这对于外显子和内含子突变以及反式扰动都是如此。因此，影响剪接的突变在初级转录本中并不均匀分布，而是集中在具有中间包含水平的可变剪接外显子中和周围。这些结果提供了一个资源，优先考虑同义和其他变异的致病突变。
Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.