Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing

Taylor, Alysha S., Barros, Dinis, Gobet, Nastassia, Schuepbach, Thierry, McAllister, Branduff, Aeschbach, Lorene, Randall, Emma L., Trofimenko, Evgeniya, Heuchan, Eleanor R., Barszcz, Paula, Ciosi, Marc, Morgan, Joanne, Hafford-Tear, Nathaniel J., Davidson, Alice E., Massey, Thomas H. ORCID: https://orcid.org/0000-0002-9804-2131, Monckton, Darren G., Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, network, REGISTRY Investigators of the European Huntington's disease, Xenarios, Ioannis and Dion, Vincent ORCID: https://orcid.org/0000-0003-4953-7637 2022. Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing. NAR Genomics and Bioinformatics 4 (4) , lqac089. 10.1093/nargab/lqac089

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Abstract

Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and preclinical studies. The expansion of these sequences causes dozens of disorders, with longer tracts generally leading to a more severe disease. Interrupted alleles are sometimes present within repeats and can alter disease manifestation. Determining repeat size mosaicism and identifying interruptions in targeted sequencing datasets remains a major challenge. This is in part because standard alignment tools are ill-suited for repetitive and unstable sequences. To address this, we have developed Repeat Detector (RD), a deterministic profile weighting algorithm for counting repeats in targeted sequencing data. We tested RD using blood-derived DNA samples from Huntington’s disease and Fuchs endothelial corneal dystrophy patients sequenced using either Illumina MiSeq or Pacific Biosciences single-molecule, real-time sequencing platforms. RD was highly accurate in determining repeat sizes of 609 blood-derived samples from Huntington’s disease individuals and did not require prior knowledge of the flanking sequences. Furthermore, RD can be used to identify alleles with interruptions and provide a measure of repeat instability within an individual. RD is therefore highly versatile and may find applications in the diagnosis of expanded repeat disorders and in the development of novel therapies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine
Publisher:	Oxford University Press
ISSN:	2631-9268
Funders:	MRC
Date of First Compliant Deposit:	17 January 2023
Date of Acceptance:	8 November 2022
Last Modified:	29 Oct 2024 15:30
URI:	https://orca.cardiff.ac.uk/id/eprint/155975

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