Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by …


  1. Patrick Concannon3,6

  1. 1Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida 32610, USA;

  2. 2Department of Microbiology and Cell Science, Institute for Food and Agricultural Sciences, University of Florida, Gainesville,
    Florida 32610, USA;

  3. 3Genetics Institute, University of Florida, Gainesville, Florida 32610, USA;

  4. 4Center for Public Health Genomics and Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
    22908, USA;

  5. 5Diabetes Institute, University of Florida, Gainesville, Florida 32610, USA;

  6. 6Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida 32610, USA
  • Corresponding author: patcon{at}pathology.ufl.edu
  • Abstract

    Genome-wide association studies (GWAS) have identified multiple, shared allelic associations with many autoimmune diseases.
    However, the pathogenic contributions of variants residing in risk loci remain unresolved. The location of the majority of
    shared disease-associated variants in noncoding regions suggests they contribute to risk of autoimmunity through effects on
    gene expression in the immune system. In the current study, we test this hypothesis by applying RNA sequencing to CD4+, CD8+, and CD19+ lymphocyte populations isolated from 81 subjects with type 1 diabetes (T1D). We characterize and compare the expression patterns
    across these cell types for three gene sets: all genes, the set of genes implicated in autoimmune disease risk by GWAS, and
    the subset of these genes specifically implicated in T1D. We performed RNA sequencing and aligned the reads to both the human
    reference genome and a catalog of all possible splicing events developed from the genome, thereby providing a comprehensive
    evaluation of the roles of gene expression and alternative splicing (AS) in autoimmunity. Autoimmune candidate genes displayed
    greater expression specificity in the three lymphocyte populations relative to other genes, with significantly increased levels
    of splicing events, particularly those predicted to have substantial effects on protein isoform structure and function (e.g.,
    intron retention, exon skipping). The majority of single-nucleotide polymorphisms within T1D-associated loci were also associated
    with one or more cis-expression quantitative trait loci (cis-eQTLs) and/or splicing eQTLs. Our findings highlight a substantial, and previously underrecognized, role for AS in the pathogenesis
    of autoimmune disorders and particularly for T1D.

    • Received November 1, 2016.
    • Accepted September 13, 2017.



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