Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids.

Abstract

Transcriptional adaptation (TA) is a regulatory process in which loss or disruption of gene function caused by protein-truncating variants (PTVs) triggers compensatory changes in expression of the healthy allele or in expression of related genes. Nonsense-mediated mRNA decay (NMD), a conserved RNA surveillance pathway that degrades transcripts containing premature termination codons, is required to initiate this process. In natural yeast populations, PTV mutations occur relatively frequently, raising the question of whether and how their effects are mitigated. In this study, we investigated TA and NMD among PTVs occurring in natural yeast populations. We observed a strong reduction in the abundance of PTV-containing transcripts, suggesting efficient recognition and degradation of transcripts containing premature stop codons. However, despite evidence of this mRNA surveillance activity, we did not detect a clear signature of transcriptional adaptation. While compensation may still occur in specific contexts, particularly for dosage-sensitive genes, it does not appear to represent a general response to PTVs in yeast. The transcriptional deregulation caused by PTVs in natural isolates may be causing too little harm to favor the evolution or maintenance of complex mechanisms required for adequate compensation. The ability to resist specific transcriptomic ruptures would thus rely mostly on the general robustness of genetic networks. Overall, our findings suggest that TA is not a universal response to loss-of-function mutations in yeast.