Harriet Dashnow, Ph.D.: 'I expect long-read sequencing to become standard for diagnosing rare disease cases.'
[Editor's note: Harriet Dashnow, Ph.D., an Assistant Professor of Biomedical Informatics at the University of Colorado Anschutz, will be the keynote speaker at the upcoming long-read symposium on October 26 at the Seattle Children's Research Center. Here, she addresses her background, the thesis of her address, and the promise of long-read sequencing. For more information about the symposium, including the deadline to register, visit here.]
Please briefly describe your background and experience with long-read sequencing.
I'm a computational biologist in the Department of Biomedical Informatics at the University of Colorado Anschutz. My lab studies tandem repeats: how they cause disease, how they vary across populations, and how they mutate and become mosaic over time. We're fully computational, developing and applying methods to diagnose rare diseases and discover their genetic basis. Given this focus, my lab has worked almost exclusively with long-read sequencing for the past several years. I contributed to the development of TRGT and ATaRVa, two widely used tools for genotyping tandem repeats from long-read data, and TRGT-denovo for identifying de novo mutations. I contribute to the 1000 Genomes Project Long-Read Sequencing Consortium, characterizing tandem repeat variation across population cohorts and building the reference catalogs that make that variation usable for genome-wide analyses. I’ve applied long-read sequencing to detect de novo tandem repeat mutations across generations and to characterize somatic mosaicism in post-mortem brain tissue.
What are you hoping to hear about at the upcoming long-read symposium?
I'm interested in how long reads are being translated into clinical contexts to solve rare disease cases, how they're being used to understand mosaicism, and how they can be used to better understand methylation and transcriptional variation.
What is the theme or thesis of your remarks and what do you hope participants will take away from it?
'I want participants to come away understanding that long-read sequencing makes it possible to ask new questions to understand the sheer complexity of our genomes'
We have demonstrated that tandem repeats are among the most mutable parts of the genome, yet have been systematically underexplored because short-read sequencing can't resolve them accurately. I want participants to come away understanding that long-read sequencing makes it possible to ask new questions to understand the sheer complexity of our genomes: how repeats mutate generation to generation, how they become somatically unstable within a single tissue over a lifetime, and how that instability drives rare disease pathogenesis, especially in the context of neurodegeneration, focusing on Fragile X-associated conditions.
Stepping back, how do you view the future of long-read sequencing in precision medicine?
I expect long-read sequencing to become standard for diagnosing rare disease cases, particularly repeat expansions and structural variation that short reads systematically miss. These technologies will also drive mechanistic understanding by providing insights into methylation and transcriptional regulation, enabling us to interpret novel variants. As costs keep dropping, I think the bigger shift is toward using long reads not just for a one-time diagnosis but also for tracking how a person's genome changes over time and across tissues, which matters in particular for progressive repeat-expansion disorders as well as cancer and other somatic variation diseases.
