Abstract
Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
Highlights
High-throughput whole-genome sequencing (WGS) has experienced rapid reductions in per-genome costs over the past 10 years [1] driving population-level sequencing projects and precision medicine initiatives at an unprecedented scale [2,3,4,5,6,7]
We demonstrate that ExpansionHunter Denovo (EHdn) can be used to rediscover the repeat expansions (REs) associated with fragile X syndrome (FXS), Friedreich ataxia (FRDA), myotonic dystrophy type 1 (DM1), and Huntington disease (HD) using case-control analysis to compare a small number of affected individuals (N = 14–35) to control samples (N = 150)
Subsequent comparisons of short tandem repeats (STRs) profiles across multiple samples can reveal the locations of the pathogenic repeat expansions
Summary
High-throughput whole-genome sequencing (WGS) has experienced rapid reductions in per-genome costs over the past 10 years [1] driving population-level sequencing projects and precision medicine initiatives at an unprecedented scale [2,3,4,5,6,7]. The primary limitations of these studies are the completeness of the reference genome and the ability to identify putative causal variations against the reference background. A wide variety of software tools can identify variations relative to the reference genome such as single nucleotide variants and short (1–50 bp) insertions and deletions [8,9,10,11,12,13], copy number variants [14, 15], and Dolzhenko et al Genome Biology (2020) 21:102 structural variants [15,16,17]. Because some variants include large amounts of inserted sequence relative to the reference, methods that can analyze reads that do not align to the reference are needed
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