Identification and analysis of splicing quantitative trait loci across multiple tissues in the human genome

Diego Garrido-Martín (), Beatrice Borsari, Miquel Calvo, Ferran Reverter and Roderic Guigó ()
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Diego Garrido-Martín: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Beatrice Borsari: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Miquel Calvo: Section of Statistics, Faculty of Biology, Universitat de Barcelona (UB)
Ferran Reverter: Section of Statistics, Faculty of Biology, Universitat de Barcelona (UB)
Roderic Guigó: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20578-2

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