Comprehensive characterization of tandem repeat expansions using STRcount | LC 25

Biography

Mahreen Khan is a final year PhD candidate in the Department of Molecular Genetics at The University of Toronto. She is carrying out her research in the labs of Dr Christopher Pearson and Dr Ryan Yuen at The Hospital for Sick Children. Her primary research interests are understanding the contribution of tandem repeats to human disease, and she has been using Oxford Nanopore Technologies sequencing to help advance her understanding of this field for several years.

Abstract

Over 7% of the human genome is comprised of tandem repeats (TRs), which are polymorphic in sequence and length across the population. TR expansions (TREs) beyond a pathogenic length are associated with over 60 neurological, neurodevelopmental, and neuromuscular disorders. Larger TREs lead to earlier onset, increased severity, and faster progression of disease. Repeat methylation and sequence purity are also important modifiers of disease outcome, and a combination of these factors may explain phenotypic heterogeneity in complex disorders. We have developed STRcount, a novel tool to estimate TR size, methylation, and sequence composition from Oxford Nanopore Technologies long-read sequencing data. Here, we discuss optimized methods for TR characterization using targeted and whole-genome sequencing approaches. We have also benchmarked our tool against other existing repeat-sizing tools. Benchmarking experiments reveal that our tool is up to 95.5% accurate at sizing tandem repeats with low read depths (5x reads). We also demonstrate the ability to detect and quantify somatic repeat instability using STRcount. We have comprehensively characterized the tandem repeat size, methylation, and sequence purity in rare disease and trio cohorts using STRcount. Here, we discuss TREs that in addition to being expanded, also show methylation and/or sequence differences that may explain disease heterogeneity. Therefore, we highlight the benefit of TRE characterization using STRcount and Oxford Nanopore Technologies sequencing over short-read sequencing or molecular assays. This method can ultimately result in faster characterization of TREs, more accurate prognosis, and faster clinical diagnosis of tandem-repeat associated diseases.