Abstract
Exonic splice enhancers (ESEs) are short nucleotide motifs, enriched near exon ends, that enhance the recognition of the splice site and thus promote splicing. Are intronless genes under selection to avoid these motifs so as not to attract the splicing machinery to an mRNA that should not be spliced, thereby preventing the production of an aberrant transcript? Consistent with this possibility, we find that ESEs in putative recent retrocopies are at a higher density and evolving faster than those in other intronless genes, suggesting that they are being lost. Moreover, intronless genes are less dense in putative ESEs than intron-containing ones. However, this latter difference is likely due to the skewed base composition of intronless sequences, a skew that is in line with the general GC richness of few exon genes. Indeed, after controlling for such biases, we find that both intronless and intron-containing genes are denser in ESEs than expected by chance. Importantly, nucleotide-controlled analysis of evolutionary rates at synonymous sites in ESEs indicates that the ESEs in intronless genes are under purifying selection in both human and mouse. We conclude that on the loss of introns, some but not all, ESE motifs are lost, the remainder having functions beyond a role in splice promotion. These results have implications for the design of intronless transgenes and for understanding the causes of selection on synonymous sites.
Highlights
Purifying selection, the purging of deleterious variants from the population, is the most common mode of operation of selection (Kimura 1984)
The aim of the current study was to test the hypothesis that Exonic splice enhancers (ESEs) are avoided in intronless genes, as we speculated that an abundance of such motifs could lead to a potentially deleterious recruitment of the splicing machinery to a transcript that should not be spliced
While raw ESE density is low in intronless genes, we found intronless genes to be denser in ESEs than expected by chance given their nucleotide composition
Summary
The purging of deleterious variants from the population, is the most common mode of operation of selection (Kimura 1984). There is evidence that selection can act to avoid a particular sequence motif if its presence in a given context is deleterious. This phenomenon, that we term avoidance selection, constitutes another facet of purifying selection and has been documented in a wide variety of biological systems There is evidence to suggest that the 3’UTRs of mRNA genes that are highly and co-expressed with a microRNA are under selection to avoid complementary sites to the seed region of that microRNA so as to prevent inappropriate down-regulation (Farh, et al 2005). Human exons that are less efficiently monitored by nonsense-mediated decay (NMD), such as final exons, are depleted in codons that are only a single point mutation away from a stop codon, presumably to enhance robustness to transcriptional or missplicing-induced errors (Cusack, et al 2011)
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