The landscape of human mutually exclusive splicing

Abstract

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.

Mutually exclusive alternative splicing of pre‐mRNAs

“…This special type of dynamic RNA secondary structure interaction was initially identified within the exon 6 cluster of Dscam , which at that time was believed to be unique (Anastassiou et al, ; Graveley, ). Similar structural codes have recently been revealed in several exon clusters, such as Drosophila 14‐3‐3ξ , the exon 4 and 9 clusters in the Drosophila Dscam (Yang et al, ), Branchiostoma MRP (Yue et al, ), and human dynamin 1 (Suyama, ) and CD55 genes (Hatje et al, ). In contrast to the exon 6 cluster of Dscam , the docking sites are located in the introns downstream of the exon cluster in these genes.…”

“…An example of switch‐like inclusion is seen with the human mitochondrial phosphate transporter gene SLC25A3 : exon 3A of this gene is included in heart and skeletal muscle, whereas exon 3B is almost exclusively included in testes and liver (Wang et al, ). Consistently, recent studies have indicated that 65% of the total 1,399 human MXEs are regulated in development‐ and tissue‐specific manners (Hatje et al, ). In most clusters, one exon was expressed in most or all tissues, whereas the others were preferentially included in specific tissues and at specific developmental stages (Hatje et al, ).…”

“…Consistently, recent studies have indicated that 65% of the total 1,399 human MXEs are regulated in development‐ and tissue‐specific manners (Hatje et al, ). In most clusters, one exon was expressed in most or all tissues, whereas the others were preferentially included in specific tissues and at specific developmental stages (Hatje et al, ).…”

“…This model involves a specific arrangement of splice sites that are flanked by U2‐ and U12‐type introns on either side of the exons. This model may be applicable to human stress‐activated protein kinase genes (Hatje et al, ; Letunic et al, ). (c) Nonsense‐mediated mRNA decay (NMD).…”

“…These distinct splice sites are recognized by the major and minor spliceosomes, and an intron with a mixture of splice sites cannot be spliced (Sharp & Burge, ). This model might be readily applicable to the mutually exclusive splicing of two or more than two alternative exons, such as those of a human stress‐activated protein kinase (MAPK8/JNK1) gene (Letunic et al, ), and other MAPK genes (Hatje et al, ). However, few U12‐type splice junctions have been found within MXE clusters in C. elegans (Kuroyanagi et al, ) or Drosophila (Hatje & Kollmar, ).…”