ArticleNature structural & molecular biology2022
Mechanism and modeling of human disease-associated near-exon intronic variants that perturb RNA splicing.
Article in Nature structural & molecular biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 30 citations in OpenAlex.
- Advances and challenges of splicing prediction with AI.Nature genetics · 2026Review
- Fundamentals and emerging frontiers in p53-targeted drug development.Biochemistry and biophysics reports · 2026Review
- Unveiling potential genetic markers: associations ofArchives animal breeding · 2026Article
- Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4.Nature structural & molecular biology · 2025Article
- Hidden Splicing Variants in Inherited Retinal Degeneration: Discovery and Functional Insight.Investigative ophthalmology & visual science · 2025Article
- Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay.Molecular psychiatry · 2025Article
- Association Analysis of ENPP1 Tissue Expression, Polymorphism, and Growth Traits in Xiangsu Pigs.Genes · 2025Article
- From computational models of the splicing code to regulatory mechanisms and therapeutic implications.Nature reviews. Genetics · 2025Review
- Article
- The Establishment of Artificial RNA Cascade Circuits for Gene Regulation Based on Doxycycline-Induced Pre-mRNA Alternative Splicing.International journal of molecular sciences · 2025Article
- Decoding biology with massively parallel reporter assays and machine learning.Genes & development · 2024Review
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- SpliceAPP: an interactive web server to predict splicing errors arising from human mutations.BMC genomics · 2024Article
- Identifying pleiotropic genes via the composite test amidst the complexity of polygenic traits.Briefings in bioinformatics · 2024Article
- Regulation of alternative splicing and polyadenylation in neurons.Life science alliance · 2023Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
It is estimated that 10%-30% of disease-associated genetic variants affect splicing. Splicing variants may generate deleteriously altered gene product and are potential therapeutic targets. However, systematic diagnosis or prediction of splicing variants is yet to be established, especially for the near-exon intronic splice region. The major challenge lies in the redundant and ill-defined branch sites and other splicing motifs therein. Here, we carried out unbiased massively parallel splicing assays on 5,307 disease-associated variants that overlapped with branch sites and collected 5,884 variants across the 5' splice region. We found that strong splice sites and exonic features preserve splicing from intronic sequence variation. Whereas the splice-altering mechanism of the 3' intronic variants is complex, that of the 5' is mainly splice-site destruction. Statistical learning combined with these molecular features allows precise prediction of altered splicing from an intronic variant. This statistical model provides the identity and ranking of biological features that determine splicing, which serves as transferable knowledge and out-performs the benchmarking predictive tool. Moreover, we demonstrated that intronic splicing variants may associate with disease risks in the human population. Our study elucidates the mechanism of splicing response of intronic variants, which classify disease-associated splicing variants for the promise of precision medicine.
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