1. Computational and Systems Biology
  2. Chromosomes and Gene Expression
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A new view of transcriptome complexity and regulation through the lens of local splicing variations

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Cite this article as: eLife 2016;5:e11752 doi: 10.7554/eLife.11752

Abstract

Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.

Article and author information

Author details

  1. Jorge Vaquero-Garcia

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alejandro Barrera

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew R Gazzara

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Juan González-Vallinas

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicholas F Lahens

    Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. John B Hogenesch

    Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kristen W Lynch

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yoseph Barash

    Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    yosephb@mail.med.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain

Publication history

  1. Received: September 21, 2015
  2. Accepted: January 31, 2016
  3. Accepted Manuscript published: February 1, 2016 (version 1)
  4. Version of Record published: March 9, 2016 (version 2)

Copyright

© 2016, Vaquero-Garcia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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