A research team including scientists at the University of Toronto has identified new gene segments implicated in autism spectrum disorder (ASD) and other neurological conditions - and developed a machine learning approach to predict the impact of genetic variants on their regulation.
In a study published in Nature , researchers from U of T's Temerty Faculty of Medicine, the Sloan Kettering Institute, King's College London and the Francis Crick Institute describe hundreds of newly discovered short gene segments, or microexons.
The research could help piece together the missing genetics of ASD, says the study's co-senior author Benjamin Blencowe, a professor at the Donnelly Centre for Cellular and Biomolecular Research and the department of molecular genetics at Temerty Medicine.
"Autism is characterized by multifactorial genetics," says Blencowe, who is also a part-time professor at King's and the Crick. "Hundreds of genomic variants have been associated with autism, and these deliver a genetic diagnosis in 15 per cent of autistic individuals."
That means a genetic explanation for ASD diagnosis remains unknown for 85 per cent of people with the condition. Blencowe says many contributing genetic factors may have remained undetected because they occur in regions of the genome that do not have a known function.
The genomic regions surrounding microexons are one such example. Through a process known as alternative splicing, microexons can be included or excluded from the genetic instructions used to make proteins. The resulting proteins vary slightly in composition yet contribute to a greater diversity of critical protein functions.
The study's co-lead author Guillermo Parada, a postdoctoral fellow in Blencowe's London research group at King's and the Crick, used a computational tool he developed called MicroExonator to analyze more than 100 terabytes of publicly available RNA sequencing data. He identified more than 1,500 new microexons, nearly 300 of which appeared to be specifically spliced in the brain.
Many of the microexons were found to be concentrated in genes associated with critical brain-specific processes, further supporting the idea that these tiny DNA fragments play a role in neurological health.
The researchers then asked whether DNA variants found in individuals with ASD might preferentially impact the expanded repertoire of microexons.
To answer that question, Parada and study co-lead author and postdoctoral fellow Hannes Bretschneider teamed up with Quaid Morris, a faculty member at Memorial Sloan Kettering Cancer Center and the Vector Institute for Artificial Intelligence and co-senior author on the study, to build and apply a machine learning model that predicts how DNA variants affect the regulation of microexons.
"What surprised me was that the sequences the model identified as important closely matched those conserved throughout vertebrate evolution," says Parada, noting that DNA sequences that are highly conserved - or the same - between species generally have critical functions.
Collaborating with Stephen Scherer and Brett Trost, scientists at The Hospital for Sick Children (SickKids) and University Professor and professor, respectively, of molecular genetics at Temerty Medicine, the researchers applied their model to whole-genome sequence data from thousands of people with ASD and neurotypical sibling pairs, and analyzed the predicted impact of ASD-associated genetic variants on the microexon regulatory code.
"Using our model, we were able to show that rare genetic variants generally have the largest predicted effects on the splicing of neuronal microexons," says Blencowe. The model further pinpointed a subset of rare variants predicted to alter microexon splicing that are associated with autism.
The research team also found that the variants predicted to affect microexons are predominantly detected among the 85 per cent of individuals previously lacking a genetic link to autism.
These new findings build on over a decade of research from the Blencowe lab to uncover the role of microexons in ASD, including earlier work showing that microexons are frequently misregulated in the brains of autistic people and that mice lacking microexon splicing display multiple ASD-like behaviours.
"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," says Blencowe, whose lab is also exploring new therapeutic approaches to target microexon dysregulation.
The researchers also believe that the machine learning model they developed can be used to characterize newly discovered genetic variants and their effects in other neurological conditions, like schizophrenia and epilepsy, where microexons are believed to play a role.
This research was supported by the Simons Foundation, Canadian Institutes for Health Research, Wellcome Trust, Autism Speaks, SickKids Foundation, National Institutes of Health, Vector Institute for Artificial Intelligence, Canadian Institute for Advanced Research, the Natural Sciences and Engineering Research Council of Canada and the U of T McLaughlin Centre.
