Abstract
BackgroundNonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. That some exons have premature termination codons at fixation is paradoxical: why make a transcript if it is only to be destroyed? One model supposes that splicing is inherently noisy and spurious transcripts are common. The evolution of a premature termination codon in a regularly made unwanted transcript can be a means to prevent costly translation. Alternatively, nonsense-mediated decay can be regulated under certain conditions so the presence of a premature termination codon can be a means to up-regulate transcripts needed when nonsense-mediated decay is suppressed.ResultsTo resolve this issue we examined the properties of putative nonsense-mediated decay targets in humans and mice. We started with a well-annotated set of protein coding genes and found that 2 to 4% of genes are probably subject to nonsense-mediated decay, and that the premature termination codon reflects neither rare mutations nor sequencing artefacts. Several lines of evidence suggested that the noisy splicing model has considerable relevance: 1) exons that are uniquely found in nonsense-mediated decay transcripts (nonsense-mediated decay-specific exons) tend to be newly created; 2) have low-inclusion level; 3) tend not to be a multiple of three long; 4) belong to genes with multiple splice isoforms more often than expected; and 5) these genes are not obviously enriched for any functional class nor conserved as nonsense-mediated decay candidates in other species. However, nonsense-mediated decay-specific exons for which distant orthologous exons can be found tend to have been under purifying selection, consistent with the regulation model.ConclusionWe conclude that for recently evolved exons the noisy splicing model is the better explanation of their properties, while for ancient exons the nonsense-mediated decay regulated gene expression is a viable explanation.
Highlights
Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon
A priori such methods are expected to overestimate the number of genuine nonsense-mediated mRNA decay (NMD) targets [37]
As expected from the noisy splicing model we found that a larger proportion of NMD-specific exons (48%) were spliced in minor form compared with non-NMD-single exons (26.1%) (Figure 2) (One-sided Kolmogorov-Smirnov test, P = 0.02443)
Summary
Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. Nonsense-mediated mRNA decay (NMD) is a mechanism for rapid degradation of mRNA transcripts with premature stop/termination codons (PTCs) [1,2,3,4,5,6,7]. The species we consider here, the recognition of premature termination codons generally depends on the distance between nonsense codons and the exon-exon junction closest to the 3' end. When this distance is > 50 to 55 nucleotides, NMD is triggered and the mRNA is degraded [1,16]. This is known as the NMD 55-nt rule (Figure 1) [16,17]
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