Abstract
Alternative splicing is a commonly-used mechanism of diversifying gene products. Mutually exclusive exons (MXE) represent a particular type of alternative splicing, in which one and only one exon from an array is included in the mature RNA. A number of genes with MXE do so by using a mechanism that depends on RNA structure. Transcripts of these genes contain multiple sites called selector sequences that are all complementary to a regulatory element called the docking site; only one of the competing base pairings can form at a time, which exposes one exon from the cluster to the spliceosome. MXE tend to have similar lengths and sequence content and are believed to originate through tandem genomic duplications. Here, we report that pre-mRNAs of this class of exons have an increased capacity to fold into competing secondary structures. We propose an evolutionary mechanism for the generation of such structures via duplications that affect not only exons, but also their adjacent introns with stem-loop structures. If one of the two arms of a stem-loop is duplicated, it will generate two selector sequences that compete for the same docking site, a pattern that is associated with MXE splicing. A similar partial duplication of two independent stem-loops produces a pattern that is consistent with the so-called bidirectional pairing model. These models explain why tandem exon duplications frequently result in mutually exclusive splicing.
Highlights
Exclusive exon selection, a pattern in which one and only one of tandemly-arranged exons is included in the pre-mRNA, is intrinsic to many eukaryotic genes [1]
While many examples were described in model organisms [2,3], recent reports based on the analysis of RNA sequencing experiments confirm that large multi-cluster mutually exclusive exons (MXEs) are frequent in higher vertebrates, nematodes and plants [4,5,6] and that they are associated with mutations involved in human pathogenic states [7]
This suggests that the mechanism of mutually exclusive exon selection that is based on docker and selector sequences, which was proposed for mutually exclusive splicing in Dscam, could be common in many other MXE clusters
Summary
A pattern in which one and only one of tandemly-arranged exons is included in the pre-mRNA, is intrinsic to many eukaryotic genes [1]. The fact that MXE clusters often exhibit high sequence similarity suggests that they have evolved through tandem exon duplication [8]. Tandemly-duplicated MXE in eukaryotes were predicted based on the properties of exon length and sequence homology [9]. Case studies, such as phylogenetic analysis of tandem exon arrays in metazoan multidrug resistance-associated protein (MRP) genes, revealed multiple independent exon duplications across different phyla and suggested convergent evolution of splicing patterns [10]. Non-homologous MXE exist, suggesting that not all mutually exclusive splicing patterns originate from exon duplications [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
