Researchers identified more than 1,500 previously unknown microexons, including hundreds specific to the brain, and found rare variants that may disrupt their role in neural development.
Researchers have uncovered a broader set of tiny genetic segments that may help explain why autism spectrum disorder develops in some people but not others, a finding that could sharpen the search for biological clues in the disorder’s most elusive cases. In work published in Nature, scientists from the University of Toronto, Sloan Kettering Institute, King’s College London and the Francis Crick Institute identified hundreds of previously unrecognised microexons, short stretches of genetic code that are stitched into RNA during gene expression and appear to be especially important in the brain.
The team analysed more than 100 terabytes of publicly available RNA sequencing data using a computational tool called MicroExonator, developed by co-lead author Guillermo Parada, a postdoctoral researcher in Benjamin Blencowe’s laboratory. The analysis turned up more than 1,500 new microexons, including nearly 300 that seem to be used specifically in the brain. Many were found in genes tied to processes that matter for nervous system development and communication between brain cells, strengthening the case that these minute sequences have outsized biological importance.
To test whether autism-linked DNA changes might disturb these microexons, the researchers built a machine learning model to predict how regulatory features control whether a microexon is included in a messenger RNA molecule or left out. Parada said the features the model flagged as most important closely matched sequences preserved across vertebrate evolution, suggesting the regulatory code has deep biological roots. When the model was applied to whole-genome data from thousands of autistic people and their neurotypical siblings, the strongest predicted effects came from rare variants, which appeared most likely to alter the splicing of microexons in neurons.
Blencowe said the model also identified a subset of rare variants with predicted effects on microexon splicing that were associated with autism. The study is especially notable because, according to the authors, about 85% of autistic people still do not have a known genetic explanation for their diagnosis, despite hundreds of genomic variants already being linked to the condition. The new findings do not close that gap, but they may help explain part of the missing heritability by pointing to a class of variants that has been overlooked in many analyses.
The Nature paper builds on earlier research showing that microexons are enriched in the brain and can shape protein interactions crucial for neural function. A separate Nature study last year linked mis-splicing of a neuronal microexon in the CPEB4 protein to autism, while earlier work in Nature Genetics found that a sizeable fraction of alternatively spliced microexons were misregulated in some autistic brains. Taken together, the studies suggest that these tiny sequences may influence synaptic biology and other pathways central to brain development, and could eventually become targets for future diagnostics or therapies.
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