A whole-genome analysis of premature termination codons

We sequenced the genomes of ten unrelated individuals and identified heterozygous stop codon-gain variants in protein-coding genes: we then sequenced their transcriptomes and assessed the expression levels of the stop codon-gain alleles. An ANOVA showed statistically significant differences between their expression levels (p = 4 × 10− 16). This difference was almost entirely accounted for by whether the stop codon-gain variant had a second, non-protein-truncating function in or near an alternate transcript: stop codon-gains without alternate functions were generally not found in the cDNA (p = 3 × 10− 5). Additionally, stop codon-gain variants in two intronless genes were not expressed, an unexpected outcome given previous studies. In this study, stop codon-gain variants were either well expressed in all individuals or were never expressed. Our finding that stop codon-gain variants were generally expressed only when they had an alternate function suggests that most naturally occurring stop codon-gain variants in protein-coding genes are either not transcribed or have their transcripts destroyed.