The landscape of human mutually exclusive splicing

Mol Syst Biol. 2017 Dec 14;13(12):959. doi: 10.15252/msb.20177728.


Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology.

Keywords: alternative splicing; differential expression; mutually exclusive splicing; splicing mechanisms.

MeSH terms

  • Animals
  • Cluster Analysis
  • Disease / genetics
  • Evolution, Molecular
  • Exons / genetics
  • Genetic Loci
  • Genome, Human
  • Humans
  • Mammals / genetics
  • Mutation / genetics
  • Protein Folding
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • RNA, Messenger