New research from scientists at King’s College London, the University of Toronto, the Sloan Kettering Institute and the Francis Crick Institute advances understanding of the genetics of autism spectrum disorder (ASD).
In a study published in Nature, researchers identified hundreds of new microexons – short gene segments that appear to play a key role in ASD and other neurological conditions – and developed a machine-learning approach to predict the impact of ASD-associated genetic variants on the regulation of these segments.
Autism is characterised by multifactorial genetics. Hundreds of genomic variants have been associated with autism, and these deliver a genetic diagnosis in 15 per cent of people with autism diagnoses.
Dr Benjamin Blencowe, King’s College London and University of Toronto
That means that for 85 per cent of people with an ASD diagnosis, a genetic link is unknown. Dr Benjamin Blencowe, the study’s co-senior author, believes that 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 alternative splicing, these very short snippets of DNA – which range from three to 27 DNA “letters” long – can be included or excluded from the messenger RNA instructions used to make proteins. The resulting proteins vary slightly in composition yet contribute to a greater diversity of critical protein functions.
In the newly published study, Dr Guillermo Parada, the study’s co-lead author and a postdoctoral fellow at King’s College London and the Francis Crick Institute, used a computational tool he developed called MicroExonator to analyse over 100 terabytes – enough storage for 25 million smartphone photos – of publicly available RNA sequencing data. He identified more than 1500 new microexons, of which nearly 300 appeared to be specifically spliced in the brain.
The researchers also observed that many of the newly discovered microexons are concentrated in genes associated with critical brain-specific processes, further supporting the idea that these tiny DNA fragments contribute to neurological function.
The researchers then asked whether DNA variants found in the genome of people with autism might preferentially impact the expanded repertoire of microexons.
To answer that question, Dr Parada and study co-lead author and postdoctoral fellow Dr Hannes Bretschneider teamed up with Dr Quaid Morris, a faculty member at Memorial Sloan Kettering Cancer Center and Vector Institute and co-senior author on the study, to build and apply a machine-learning model that identifies the key regulatory features governing whether a microexon is spliced in or out of messenger RNAs. This so-called regulatory code encompasses specific sequences of DNA letters flanking microexons.
What surprised me was that the sequences the model identified as important closely matched those conserved throughout vertebrate evolution.
Dr Guillermo Parada, King’s College London and the Francis Crick Institute
DNA sequences that are highly conserved, or the same, between species generally have critical functions.
Through a collaboration with Dr Stephen Scherer and Brett Trost, both scientists at The Hospital for Sick Children and professors of molecular genetics at Temerty Medicine, the researchers applied their model to whole-genome sequence data from thousands of people with autism and neurotypical sibling pairs, and analysed 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.
Dr Benjamin 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 people with an autism diagnosis 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 people with autism 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 Dr Blencowe. One of the research programmes in his lab is also exploring new therapeutic approaches to target microexon dysregulation.
Dr Blencowe says that beyond helping to define some of the missing genetics of ASD, their study provides a valuable resource to advance research in the field.
The researchers believe that the machine-learning model they developed can be used to characterise newly discovered genetic variants and their effects in other neurological conditions, like schizophrenia and epilepsy, where microexons are believed to play a role.
This story has been adapted from a version that appears on the University of Toronto website.
Source: King’s College London
