2024/09/01 by Benjamin Fair, Carlos F. Buen Abad Najar, Junxing Zhao +6 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · #Molecular Biology Techniques and Applications #RNA Research and Splicing #RNA and protein synthesis mechanisms
paper · pdf · doi:10.1038/s41588-024-01872-x
openalex publication_date 2024/09/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing 'unproductive' transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS-NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome.