Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA.
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.
Nat Genet. 2024 Sep;56(9):1851-1861. doi: 10.1038/s41588-024-01872-x. Epub 2024 Sep 2.
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.
人类基因中的可变剪接（AS）被广泛认为是增强蛋白质组多样性的一种机制。AS 还可以通过产生被无意义介导的衰变（NMD）靶向快速降解的“无功能”转录本，从而在不增加蛋白质多样性的情况下影响基因表达水平。然而，这种调节机制的相对重要性仍未得到充分探索。为了更好地了解 AS-NMD 相对于其他调节机制的影响，我们分析了跨越八个分子测定的人群规模基因组数据，涵盖了从转录到细胞质降解的各个阶段。我们报告称，与使用稳态 RNA 的先前估计相比，无功能剪接增加了三倍。这种无功能剪接在多内含子基因中累积，导致来自蛋白质编码基因的 15%的转录分子是无功能的。利用细胞系中的遗传变异，我们发现 AS 解释的 GWAS 性状相关位点与 NMD 诱导的表达水平差异相关的频率与与蛋白质同工型使用差异相关的频率一样高。我们的研究结果表明，AS 的大部分影响是由 NMD 诱导的基因表达变化介导的，而不是蛋白质组的多样化。
