Interview: Exploring the potential of long-read whole-genome sequencing for identification of individuals with autism spectrum disorder

Sarah Dada is a PhD candidate in Dr. Steven Jones’ group at Canada’s Michael Smith Genome Sciences Centre in Vancouver, where she focuses on genetic characterisation of autism spectrum disorders (ASD), applying the long read capabilities of nanopore sequencing to identify variants of clinical importance in ASD, particularly structural variants, tandem repeats, and methylation variability.

We caught up with Sarah to discuss her research into the structural variants in ASD, how long nanopore sequencing reads are driving our understanding of the genetic basis of ASD, and the potential impact this could have for individuals with ASD in the clinic.

What are your current research interests?

My current interest is in the discovery of structural variants, copy number variants, and variation of DNA methylation in individuals with ASD, specifically how we can use long reads to uncover new information about these in the genome. The goal is that personalised diagnosis will allow clinicians to provide improved treatment, targeted counselling, and increased services for individuals with ASD.

What first ignited your interest in genomics and what lead you to focus on neurodevelopmental disorders?

I was in awe when I saw a Dr. Martin Hirst give a talk about personalised cancer treatment programs at the Michael Smith Genome Sciences Centre. I switched from cancer immunology to genomics shortly after. At the time, I had been co-hosting a radio show about accessibility for several years alongside individuals with various disabilities and worked with many people on the spectrum. I also knew and had a lot of respect for the clinician I work with, Dr. Suzanne Lewis.

How is nanopore sequencing changing our understanding of genomic variation? How has it benefitted your work?

Nanopore sequencing and the tools being developed for interrogation of specific types of variants make it possible to discover variants that were previously difficult to investigate due to the limitations of short-read whole-genome sequencing or bisulphite sequencing. Long nanopore sequencing reads are particularly good at uncovering large or complex variants that were difficult to solve due to their complexity or their repetitive nature, and tools are even being developed to uncover these variant’s hereditary background and origin. This information is helpful in informing patient care and family planning.

What impact could the ability to comprehensively interrogate individual genomes have for researchers?

Of primary importance for individuals with ASD and clinicians, is personalised diagnosis that can improve treatment for individuals and give them earlier access to therapies and educational and social services that improve their quality of life. It’s critical for understanding regions of the genomes that may contribute to the disorder, the hereditary contribution, and mechanisms by which these genetic variants arise among individuals with ASD.

What have been the main challenges in your work and how have you approached them?

The main challenges have been around the discovery of impactful variants among 3 billion base pair genomes that inherently have variation — which is why we are unique! It’s difficult to make the case for why we believe a particular change could contribute to a disorder. The technology, including the tools and chemistry have been changing quickly, but it’s still an exploratory project involving looking for clues and evidence of suspect variants.

What’s next for your research?

We are taking a foray into methylation signatures for various neurodevelopmental and neuropsychiatric disorders that are tied to ASD genes, and alongside structural variants, I hope to work more in the methylation and imprinting realm of ASD.