Scientists from the University of Toronto, the Sloan Kettering Institute, King’s College London, and the Francis Crick Institute have published data that points to a role for several new microexons in the development of autism spectrum disorder (ASD). According to the findings, published today in Nature, the scientists identified hundreds of new microexons that appear to be involved in ASD and other neurological conditions, and developed a machine learning approach to predict the impact of ASD-associated genetic variants on how these segments are regulated. 

Full details are available in a paper titled “A microexon regulatory code reveals autism-linked genetic variation.” In it, the scientists described how they used a computational tool dubbed MicroExonator to analyze over 100 terabytes of publicly available RNA sequencing data. The tool was developed by Guillermo Parada, PhD, the study’s co-lead author and a postdoctoral fellow in the laboratory of Benjamin Blencowe, PhD,  at King’s and the Crick. Using the tool, he identified more than 1,500 new microexons, of which nearly 300 appeared to be specifically spliced in the brain. Furthermore, many are concentrated in genes associated with critical brain-specific processes, supporting a potential link to neurological health. 

The scientists also explored whether DNA variants found in people with autism might preferentially impact the expanded repertoire of microexons. Specifically they built and applied a machine learning model designed to identify the key regulatory features governing whether a microexon is spliced in or out of messenger RNAs. “What surprised me was that the sequences the model identified as important closely matched those conserved throughout vertebrate evolution,” says Parada.

Next, the scientists applied the model to whole-genome sequence data from thousands of people with autism and neurotypical sibling pairs. Specifically, they analyzed the predicted impact of ASD-associated genetic variants on the microexon regulatory code. “We were able to show that rare genetic variants generally have the largest predicted effects on the splicing of neuronal microexons,” says Blencowe, one of the study’s senior authors and a professor of molecular genetics at University of Toronto. The model further pinpointed a subset of rare variants predicted to alter microexon splicing that are associated with autism.

Additionally, the team found that the variants predicted to affect microexons are predominantly detected among the 85% of autistic individuals that previously lacked a genetic link to autism. This is an important point because “hundreds of genomic variants have been associated with autism, and these deliver a genetic diagnosis in 15 percent of autistic individuals,” says Blencowe, who is also a part-time professor at King’s and the Crick. That means that for 85 percent of people with an ASD diagnosis, the genetic explanation for their condition remains unknown. The findings from this study could provide some answers. 

“In terms of future work, it will be important to understand how disrupted microexons affect interactions between proteins that are important for nervous system development and function,” Blencowe adds. One of the research programs in his lab is also exploring new therapeutic approaches to target microexon dysregulation.

Furthermore, the scientists believe that the machine learning model they developed can be used to characterize other newly discovered genetic variants and their effects in neurological conditions like schizophrenia and epilepsy where microexons are believed to play a role.