| Autor: |
Fair, Benjamin, Buen Abad Najar, Carlos F., Zhao, Junxing, Lozano, Stephanie, Reilly, Austin, Mossian, Gabriela, Staley, Jonathan P., Wang, Jingxin, Li, Yang I. |
| Zdroj: |
Nature Genetics; September 2024, Vol. 56 Issue: 9 p1851-1861, 11p |
| Abstrakt: |
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. |
| Databáze: |
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