Are all of the human exons alternatively spliced?

Abstract

Alternative mRNA splicing (AS) is a major mechanism for increasing regulatory complexity. A key concept in AS is the distinction between alternatively and constitutively spliced exons (ASEs and CSEs, respectively). ASEs and CSEs have been reported to be differentially regulated, and to have distinct biological properties. However, the recent flood of RNA-sequencing data has obscured the boundary between ASEs and CSEs. Researchers are beginning to question whether ‘authentic CSEs’ do exist, and whether the ASE/CSE distinction is biologically invalid. Here, I examine the influences of increasing transcriptome data on the human ASE/CSE classification and our past understanding of the properties of these two types of exons. Interestingly, although the percentage of human ASEs has increased dramatically in recent years, the overall distinction between ASEs and CSEs remain valid. For example, CSEs are longer, evolve more slowly, and less frequently correspond to intrinsically disordered protein regions than ASEs. In addition, only a relatively small number of human genes have their transcripts composed entirely of ASEs despite the large amount of high-throughput transcriptome information. Therefore, the ‘backbone’ concept of AS, in which CSEs constitute the invariant part and ASEs the flexible part of the transcript, appears to be generally true despite the increasing percentage of ASEs in the human exome.

Mutations primarily alter the inclusion of alternatively spliced exons

“…However, the effects of mutations on inclusion levels have recently been proposed to scale with the level of inclusion, predicting mutations will only rarely have large effects on the inclusion levels of highly included exons (Baeza-Centurion et al, 2019). Since highly included exons make up most of the expressed exons in the genome in any cell type ( figure 4B and (Chen, 2014)), this leads to the prediction that exonic mutations will actually only rarely change exon inclusion and that mutations having large effects on splicing correspond to the minority of exons included at intermediate levels in a cell type.…”

Alternative RNA Structure-Coupled Gene Regulations in Tumorigenesis

“…ARS may occur in 5' and 3'UTRs [ 72 ]. 5'UTRs contain at least two types of translational regulatory elements—uORFs and G4s.…”

Digested disorder

“…F.C. Chen 80 argues that a number of differentiating factors-including different levels of regulation, distinct biological properties, and enrichment of disordered regions-demonstrate that this distinction is still valid. However, due to the ubiquity of alternative splicing, the line is beginning to blur.…”