ArticleGenome research2018
Saturation mutagenesis reveals manifold determinants of exon definition.
Article in Genome research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 75 citations in OpenAlex.
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Control of gene output by intron RNA structure.bioRxiv : the preprint server for biology · 2025Article
- Massively parallel assay of human splice variants reveals cis-regulatory drivers of disease-associated and cell type-specific splicing regulation.bioRxiv : the preprint server for biology · 2025Article
- Core splicing architecture and early spliceosomal recognition determine microexon sensitivity to SRRM3/4.Nature structural & molecular biology · 2025Article
- Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing.Nature communications · 2025Article
- Mapping MAVE data for use in human genomics applications.Genome biology · 2025Article
- From computational models of the splicing code to regulatory mechanisms and therapeutic implications.Nature reviews. Genetics · 2025Review
- MaveDB 2024: a curated community database with over seven million variant effects from multiplexed functional assays.Genome biology · 2025Article
- Decoding biology with massively parallel reporter assays and machine learning.Genes & development · 2024Review
- An interpretable model of pre-mRNA splicing for animal and plant genes.Science advances · 2024Article
- Exonic splicing code and coordination of divalent metals in proteins.Nucleic acids research · 2024Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.Genome biology · 2023Article
- Deciphering RNA splicing logic with interpretable machine learning.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- High-Throughput Splicing Assays Identify Known and NovelKidney international reports · 2023Article
- Benchmarking splice variant prediction algorithms using massively parallel splicing assays.bioRxiv : the preprint server for biology · 2023Article
- Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects.Nature reviews. Genetics · 2023Review
- Bridging the splicing gap in human genetics with long-read RNA sequencing: finding the protein isoform drivers of disease.Human molecular genetics · 2022Review
- Higher-order epistasis and phenotypic prediction.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance.Nature communications · 2022Article
- Exonic splicing code and protein binding sites for calcium.Nucleic acids research · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
To illuminate the extent and roles of exonic sequences in the splicing of human RNA transcripts, we conducted saturation mutagenesis of a 51-nt internal exon in a three-exon minigene. All possible single and tandem dinucleotide substitutions were surveyed. Using high-throughput genetics, 5560 minigene molecules were assayed for splicing in human HEK293 cells. Up to 70% of mutations produced substantial (greater than twofold) phenotypes of either increased or decreased splicing. Of all predicted secondary structural elements, only a single 15-nt stem-loop showed a strong correlation with splicing, acting negatively. The in vitro formation of exon-protein complexes between the mutant molecules and proteins associated with spliceosome formation (U2AF35, U2AF65, U1A, and U1-70K) correlated with splicing efficiencies, suggesting exon definition as the step affected by most mutations. The measured relative binding affinities of dozens of human RNA binding protein domains as reported in the CISBP-RNA database were found to correlate either positively or negatively with splicing efficiency, more than could fit on the 51-nt test exon simultaneously. The large number of these functional protein binding correlations point to a dynamic and heterogeneous population of pre-mRNA molecules, each responding to a particular collection of binding proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.