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

Author

Listed:
  • 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
    Universitat Pompeu Fabra (UPF))

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.

Suggested Citation

  • Diego Garrido-Martín & Beatrice Borsari & Miquel Calvo & Ferran Reverter & Roderic Guigó, 2021. "Identification and analysis of splicing quantitative trait loci across multiple tissues in the human genome," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20578-2
    DOI: 10.1038/s41467-020-20578-2
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    Cited by:

    1. Marie C. Sadler & Chiara Auwerx & Kaido Lepik & Eleonora Porcu & Zoltán Kutalik, 2022. "Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Anneke Brümmer & Sven Bergmann, 2024. "Disentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Jennifer P. Nguyen & Timothy D. Arthur & Kyohei Fujita & Bianca M. Salgado & Margaret K. R. Donovan & Hiroko Matsui & Ji Hyun Kim & Agnieszka D’Antonio-Chronowska & Matteo D’Antonio & Kelly A. Frazer, 2023. "eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Matteo D’Antonio & Jennifer P. Nguyen & Timothy D. Arthur & Hiroko Matsui & Agnieszka D’Antonio-Chronowska & Kelly A. Frazer, 2023. "Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Xena Marie Mapel & Naveen Kumar Kadri & Alexander S. Leonard & Qiongyu He & Audald Lloret-Villas & Meenu Bhati & Maya Hiltpold & Hubert Pausch, 2024. "Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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