%0 Journal Article
%A Baeza-Centurión, Pablo
%A Miñana, Belén
%A Faure, Andre J
%A Thompson, Mike
%A Bonnal, Sophie
%A Quarantani, Gioia
%A Clarke, Joseph
%A Lehner, Ben
%A Valcárcel, Juan
%T Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-01812
%P 8117
%D 2025
%Z Pablo Baeza-Centurión
%X While altered pre-mRNA splicing is a frequent mechanism by which genetic variants cause disease, the regulatory architecture of human exons remains poorly understood. Antisense oligonucleotides (AONs) that target pre-mRNA splicing have been approved as therapeutics for various pathologies including patient-customised treatments for rare diseases, but AON discovery is currently slow and expensive, limiting the wider adoption of the approach. Here we show that deep indel mutagenesis (DIM) -which can be made experimentally at very low cost - provides an efficient strategy to chart the regulatory landscape of human exons and rapidly identify candidate splicing-modulating oligonucleotides. DIM reveals autonomous effects of insertions, while systematic deletion scans delineate the checkerboard architecture of sequential enhancers and silencers in a model alternative exon. The results also suggest a mechanism for repression of transmembrane domain-encoding exons and for the generation of microexons. Leveraging deep learning tools, we provide a resource, DANGO, that predicts the splicing regulatory landscape of all human exons and can help to identify effective splicing-modulating antisense oligonucleotides.
%K Exons: genetics
%K Humans
%K Alternative Splicing: genetics
%K INDEL Mutation: genetics
%K Oligonucleotides, Antisense: genetics
%K Mutagenesis
%K Deep Learning
%K RNA Precursors: genetics
%K Oligonucleotides, Antisense (NLM Chemicals)
%K RNA Precursors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40885722
%R 10.1038/s41467-025-62957-7
%U https://inrepo02.dkfz.de/record/304271