A spectrum of nonsense-mediated mRNA decay efficiency along the degree of mutational constraint

Abstract A landmark study has proposed several factors on nonsense-mediated mRNA decay (NMD) efficiency using matched genome and transcriptome data of human cancer but was highly affected by random variance caused by the indirect measure of NMD efficiency. In this study, using a more direct, allele-specific expression-based measure of NMD efficiency, a more precise NMD efficiency model was developed. Combining this model with the public germline variant database stratified by allele frequency, we showed that there is a spectrum of NMD efficiency, from common variants to somatic variants in the cancer genome. The spectrum in NMD efficiency was also evident from the change in the gene-level mutational constraint measured by the loss-of-function observed/expected upper bound fraction (LOEUF). Based on the clear association observed between the NMD efficiency and LOEUF, we propose that NMD may be a key player in shaping the landscape of gene-level mutational constraint.