The landscape of human mutually exclusive splicing

Hatje K, Rahman RU, Vidal RO, Simm D, Hammesfahr B, Bansal V, Rajput A, Mickael ME, Sun T, Bonn S, Kollmar M

Molecular Systems Biology 13, 959 (2017)

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.

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