Abstract
BackgroundMost eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of protein variants or to the regulation of gene expression via nonsense-mediated messenger RNA (mRNA) decay (NMD). However, a fraction of splice variants might correspond to spurious transcripts and the question of the relative proportion of splicing errors to functional splice variants remains highly debated.ResultsWe propose a test to quantify the fraction of AS events corresponding to errors. This test is based on the fact that the fitness cost of splicing errors increases with the number of introns in a gene and with expression level. We analyzed the transcriptome of the intron-rich eukaryote Paramecium tetraurelia. We show that in both normal and in NMD-deficient cells, AS rates strongly decrease with increasing expression level and with increasing number of introns. This relationship is observed for AS events that are detectable by NMD as well as for those that are not, which invalidates the hypothesis of a link with the regulation of gene expression. Our results show that in genes with a median expression level, 92–98% of observed splice variants correspond to errors. We observed the same patterns in human transcriptomes and we further show that AS rates correlate with the fitness cost of splicing errors.ConclusionsThese observations indicate that genes under weaker selective pressure accumulate more maladaptive substitutions and are more prone to splicing errors. Thus, to a large extent, patterns of gene expression variants simply reflect the balance between selection, mutation, and drift.
Highlights
Most eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of protein variants or to the regulation of gene expression via nonsense-mediated messenger RNA decay (NMD)
The inactivation of Upf genes leads to stabilization of premature termination codons (PTCs)-containing transcripts that would normally be degraded by the nonsense-mediated messenger RNA (mRNA) decay (NMD) machinery, providing a proxy for the intrinsic splicing efficiency of introns
The efficiency of excision of introns by the spliceosome is affected by different signals, located within introns and flanking exons
Summary
Most eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of protein variants or to the regulation of gene expression via nonsense-mediated messenger RNA (mRNA) decay (NMD). The subset of AS variants that are detected in proteomic studies shows clear signs of protein functionality: 96% of Saudemont et al Genome Biology (2017) 18:208 them maintain the reading frame [8]; they rarely disrupt protein domains [7, 9]; and they are highly conserved, from mammals to bony fish [7] This contrasts with the bulk of AS events detected within transcriptomes: 58% of them induce frameshifts [10] and 70% disrupt protein domains [7]. The subset of exon-skipping events that are strongly tissue-specific and that preserve the reading frame is generally more conserved, which clearly suggests that this subset includes some functional events [11,12,13,14] These cases represent only a small fraction of all AS events [11,12,13,14]. This led some authors to conclude that the vast majority of AS events correspond to splicing errors [10, 16,17,18] (we will hereafter refer to this hypothesis as the “noisy splicing” model)
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