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

Taylor, A. S. et al. (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. (doi: 10.1093/nargab/lqac089) (PMID:36478959) (PMCID:PMC9719798)

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: Articles
• Additional Information: Funding: Academy of Medical Sciences Professorship [AMSPR1\1014 to V.D.]; UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK (to V.D.); Cardiff University School of Medicine Studentship (to B.M.); MRC Centre [MR/L010305/1 to L.J.]; CHDI (to D.G.M., L.J., T.H.M.); Welsh Clinical Academic Track Fellowship (to T.H.M.); MRC Clinical Research Training Fellowship [MR/P001629/1 to T.H.M.]; Patrick Berthoud Charitable Trust Fellowship, Association of British Neurologists (to T.H.M.); Brain Research Trust [201617–06 to B.M., T.M., L.J.]; UKRI Future Leader Fellowship [MR/S031820/1 to A.E.D.]; Moorfields Eye Charity PhD studentship (to N.J.H.T.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Monckton, Professor Darren and Ciosi, Dr Marc
• Authors: Taylor, A. S., Barros, D., Gobet, N., Schuepbach, T., McAllister, B., Aeschbach, L., Randall, E. L., Trofimenko, E., Heuchan, E. R., Barszcz, P., Ciosi, M., Morgan, J., Hafford-Tear, N. J., Davidson, A. E., Massey, T. H., Monckton, D. G., Jones, L., network, R. I. o. t. E. H.’s. d., Xenarios, I., and Dion, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: NAR Genomics and Bioinformatics
• Publisher: Oxford University Press
• ISSN: 2631-9268
• ISSN (Online): 2631-9268
• Published Online: 05 December 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in NAR Genomics and Bioinformatics 4(4): lqac089
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.5281/zenodo.7299814