We have developed an efficient and reproducible pipeline for the discovery of genetic variants affecting splicing (sQTLs), based on an approach that captures the intrinsically multivariate nature of this phenomenon. We employed it to analyze the multi-tissue transcriptome GTEx dataset, generating a comprehensive catalogue of sQTLs in the human genome. A core set of these sQTLs is shared across multiple tissues. Downstream analyses of this catalogue contribute to the understanding of the mechanisms underlying splicing regulation. We found that sQTLs often target the global splicing pattern of genes, rather than individual splicing events. Many of them also affect gene expression, but not always of the same gene, potentially uncovering regulatory loci that act on different genes through different mechanisms. sQTLs tend to be preferentially located in introns that are post-transcriptionally spliced, which would act as hotspots for splicing regulation. While many variants affect splicing patterns by directly altering the sequence of splice sites, many more modify the binding of RNA-binding proteins (RBPs) to target sequences within the transcripts. Genetic variants affecting splicing can have a phenotypic impact comparable or even stronger than variants affecting expression, with those that alter RBP binding playing a prominent role in disease.

中文翻译：

---

鉴定和分析人类基因组中多个组织的剪接数量性状基因座

我们已经开发了一种有效且可重现的管道，用于发现影响剪接（sQTL）的遗传变异，其方法是捕获这种现象的本质上是多变量的。我们使用它来分析多组织转录组GTEx数据集，从而生成人类基因组中sQTL的全面目录。这些sQTL的核心集在多个组织之间共享。该目录的下游分析有助于理解剪接调控的机制。我们发现，sQTL通常针对基因的整体剪接模式，而不是针对单个剪接事件。它们中的许多也影响基因表达，但并不总是影响同一基因，可能会揭示通过不同机制作用于不同基因的调控位点。sQTL倾向于优先位于转录后剪接的内含子中，这将成为剪接调控的热点。尽管许多变体通过直接改变剪接位点的序列来影响剪接模式，但还有更多变体修饰RNA结合蛋白（RBP）与转录本内靶序列的结合。影响剪接的遗传变体的表型影响与影响表达的变体相当甚至更强，而改变RBP结合的变体在疾病中起着重要作用。