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Nonsense Mediated Decay (NMD) degrades transcripts that contain a premature STOP codon resulting from mistranscription or missplicing. However NMD's surveillance of gene expression varies in efficiency both among and within human genes. Previous work has shown that the intron content of human genes is influenced by missplicing events invisible to NMD. Given the high rate of transcriptional errors in eukaryotes, we hypothesized that natural selection has promoted a dual strategy of “prevention and cure” to alleviate the problem of nonsense transcriptional errors. A prediction of this hypothesis is that NMD's inefficiency should leave a signature of “transcriptional robustness” in human gene sequences that reduces the frequency of nonsense transcriptional errors. For human genes we determined the usage of “fragile” codons, prone to mistranscription into STOP codons, relative to the usage of “robust” codons that do not generate nonsense errors. We observe that single-exon genes have evolved to become robust to mistranscription, because they show a significant tendency to avoid fragile codons relative to robust codons when compared to multi-exon genes. A similar depletion is evident in last exons of multi-exon genes. Histone genes are particularly depleted of fragile codons and thus highly robust to transcriptional errors. Finally, the protein products of single-exon genes show a strong tendency to avoid those amino acids that can only be encoded using fragile codons. Each of these observations can be attributed to NMD deficiency. Thus, in the human genome, wherever the “cure” for nonsense (i.e. NMD) is inefficient, there is increased reliance on the strategy of nonsense “prevention” (i.e. transcriptional robustness). This study shows that human genes are exposed to the deleterious influence of transcriptional errors. Moreover, it suggests that gene expression errors are an underestimated phenomenon, in molecular evolution in general and in selection for genomic robustness in particular.

Preventing Dangerous Nonsense: Selection for Robustness to Transcriptional Error in Human Genes