Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Catalonia, Spain.
Section of Statistics, Faculty of Biology, Universitat de Barcelona (UB), Av. Diagonal 643, Barcelona, 08028, Spain.
Nat Commun. 2021 Feb 1;12(1):727. doi: 10.1038/s41467-020-20578-2.
Alternative splicing (AS) is a fundamental step in eukaryotic mRNA biogenesis. Here, we develop an efficient and reproducible pipeline for the discovery of genetic variants that affect AS (splicing QTLs, sQTLs). We use it to analyze the GTEx dataset, generating a comprehensive catalog of sQTLs in the human genome. Downstream analysis of this catalog provides insight into the mechanisms underlying splicing regulation. We report that a core set of sQTLs is shared across multiple tissues. sQTLs often target the global splicing pattern of genes, rather than individual splicing events. Many also affect the expression of the same or other genes, uncovering regulatory loci that act through different mechanisms. sQTLs tend to be located in post-transcriptionally spliced introns, which would function as hotspots for splicing regulation. While many variants affect splicing patterns by altering the sequence of splice sites, many more modify the binding sites of RNA-binding proteins. Genetic variants affecting splicing can have a stronger phenotypic impact than those affecting gene expression.
选择性剪接（AS）是真核生物 mRNA 生物发生的基本步骤。在这里，我们开发了一种高效且可重复的用于发现影响 AS（剪接 QTL，sQTL）的遗传变异的方法。我们使用它来分析 GTEx 数据集，生成人类基因组中 sQTL 的综合目录。对该目录的下游分析提供了对剪接调控机制的深入了解。我们报告说，一组核心的 sQTL 在多个组织中是共享的。sQTL 通常针对基因的全局剪接模式，而不是单个剪接事件。许多 sQTL 还影响相同或其他基因的表达，揭示了通过不同机制起作用的调节基因座。sQTL 倾向于位于转录后剪接的内含子中，这将作为剪接调控的热点。虽然许多变体通过改变剪接位点的序列来影响剪接模式，但更多的变体修饰 RNA 结合蛋白的结合位点。影响剪接的遗传变异比影响基因表达的遗传变异具有更强的表型影响。
