Nonsense-mediated decay is highly stable across individuals and tissues.
Document Type
Article
Publication Date
8-5-2021
Identifier
DOI: 10.1016/j.ajhg.2021.06.008
Abstract
Precise interpretation of the effects of rare protein-truncating variants (PTVs) is important for accurate determination of variant impact. Current methods for assessing the ability of PTVs to induce nonsense-mediated decay (NMD) focus primarily on the position of the variant in the transcript. We used RNA sequencing of the Genotype Tissue Expression v.8 cohort to compute the efficiency of NMD using allelic imbalance for 2,320 rare (genome aggregation database minor allele frequency ≤ 1%) PTVs across 809 individuals in 49 tissues. We created an interpretable predictive model using penalized logistic regression in order to evaluate the comprehensive influence of variant annotation, tissue, and inter-individual variation on NMD. We found that variant position, allele frequency, the inclusion of ultra-rare and singleton variants, and conservation were predictive of allelic imbalance. Furthermore, we found that NMD effects were highly concordant across tissues and individuals. Due to this high consistency, we demonstrate in silico that utilizing peripheral tissues or cell lines provides accurate prediction of NMD for PTVs.
Journal Title
American journal of human genetics
Volume
108
Issue
8
First Page
1401
Last Page
1408
Keywords
nonsense-mediated decay; rare variants; variant annotation
Recommended Citation
Teran NA, Nachun DC, Eulalio T, et al. Nonsense-mediated decay is highly stable across individuals and tissues. Am J Hum Genet. 2021;108(8):1401-1408. doi:10.1016/j.ajhg.2021.06.008
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