A microexon regulatory code reveals autism-linked genetic variation
Abstract Neuronal microexons are a highly conserved class of alternative splicing events enriched in genes with critical functions in nervous system biology 1,2 . Microexon splicing is often disrupted in the brains of autistic individuals, and mice with microexon deficiencies display autism-like phenotypes 1,3,4 . However, the full landscape of microexons is not known, and the impact of genetic variation on these exons has not been systematically investigated. Here, through extensive transcriptome profiling, we detect hundreds of new microexons, including many with neuronal subtype-specific splicing patterns, and others that activate nonsense-mediated mRNA decay. Using machine learning, we define a sequence code predictive of neuronally spliced microexons and use this to identify critical regulatory elements surrounding the expanded microexon repertoire. This code further reveals genomic variants predicted to alter microexon splicing in individuals affected by autism, with rare variants having the strongest estimated impact. These variants are mostly detected in idiopathic individuals and are associated with autism status. They also converge on synaptic and other autism-linked genes, as well as genes not previously linked to autism. Our results collectively define an expanded repertoire of microexons, delineate their regulatory code, and pinpoint variants predicted to affect their splicing, with implications for the disruption of functions central to neuronal biology and brain disorders.
Authors
- Manuel Irimia (ORCID: https://orcid.org/0000-0002-2179-2567)
- Martin Hemberg (ORCID: https://orcid.org/0000-0001-8895-5239)
- Benjamin J. Blencowe (ORCID: https://orcid.org/0000-0002-4461-0340)
- James Ellis (ORCID: https://orcid.org/0000-0002-4400-0091)
- Hannes Bretschneider (ORCID: https://orcid.org/0000-0003-0109-3774)
- Quaid Morris (ORCID: https://orcid.org/0000-0002-2760-6999)
- Steven J. Dupas (ORCID: https://orcid.org/0000-0002-6253-8442)
- Stephen W. Scherer (ORCID: https://orcid.org/0000-0002-8326-1999)
- Brett Trost (ORCID: https://orcid.org/0000-0003-4863-7273)
- Worrawat Engchuan (ORCID: https://orcid.org/0000-0001-6138-1925)
- Mehdi Zarrei
- Sophie Bonnal (ORCID: https://orcid.org/0000-0001-6096-3042)
- Michael Wainberg (ORCID: https://orcid.org/0000-0001-6061-0239)
- Jacob L. Fine (ORCID: https://orcid.org/0009-0003-1611-5398)
- Jack Daiyang Li
- Ulrich Braunschweig (ORCID: https://orcid.org/0000-0001-6653-0926)
- Liliana Attisano (ORCID: https://orcid.org/0000-0003-4824-2642)
- Guillermo E. Parada (ORCID: https://orcid.org/0000-0003-1018-9882)
- Taykhoom Dalal (ORCID: https://orcid.org/0000-0003-3944-631X)
- Jonathan D. Ellis
- Nadia Zafar
- Wei Wei
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Brigham and Women's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Universitat Pompeu Fabra (ES)
- King's College London (GB)
- University of Toronto (CA)
- Cornell University (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- The Francis Crick Institute (GB)
- Hospital for Sick Children (CA)
- Massachusetts General Hospital (US)
- Vector Institute (CA)
- Sinai Health System (CA)
- Barcelona Institute of Science and Technology (ES)
- Centre for Genomic Regulation (ES)
- Weill Cornell Medicine (US)
- Centre for Applied Genomics (CA)
Publication Details
- Journal
- Nature
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1038/s41586-026-11119-w
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.00