Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps

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dc.citation.firstpage1785en_US
dc.citation.issueNumber11en_US
dc.citation.journalTitleGenome Researchen_US
dc.citation.lastpage1797en_US
dc.citation.volumeNumber34en_US
dc.contributor.authorSaether, Kristine Bilgraven_US
dc.contributor.authorEisfeldt, Jesperen_US
dc.contributor.authorBengtsson, Jesse D.en_US
dc.contributor.authorLun, Ming Yinen_US
dc.contributor.authorGrochowski, Christopher M.en_US
dc.contributor.authorMahmoud, Medhaten_US
dc.contributor.authorChao, Hsiao-Tuanen_US
dc.contributor.authorRosenfeld, Jill A.en_US
dc.contributor.authorLiu, Pengfeien_US
dc.contributor.authorEk, Marleneen_US
dc.contributor.authorSchuy, Jakoben_US
dc.contributor.authorAmeur, Adamen_US
dc.contributor.authorDai, Hongzhengen_US
dc.contributor.authorNetwork, Undiagnosed Diseasesen_US
dc.contributor.authorHwang, James Paulen_US
dc.contributor.authorSedlazeck, Fritz J.en_US
dc.contributor.authorBi, Weiminen_US
dc.contributor.authorMarom, Roniten_US
dc.contributor.authorWincent, Josephineen_US
dc.contributor.authorNordgren, Annen_US
dc.contributor.authorCarvalho, Claudia M. B.en_US
dc.contributor.authorLindstrand, Annaen_US
dc.date.accessioned2025-01-09T20:16:57Zen_US
dc.date.available2025-01-09T20:16:57Zen_US
dc.date.issued2024en_US
dc.description.abstractChromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the inversion breakpoint region was missing from at least one of the human reference genomes (GRCh37, GRCh38, T2T-CHM13) and a reference agnostic analysis was needed. One of these cases, an INV9 mappable only in de novo assembled lrGS data using T2T-CHM13 disrupts EHMT1 consistent with a Mendelian diagnosis (Kleefstra syndrome 1; MIM#610253). Next, by pairwise comparison between T2T-CHM13, GRCh37, and GRCh38, as well as the chimpanzee and bonobo, we show that hundreds of megabases of sequence are missing from at least one human reference, highlighting that primate genomes contribute to genomic diversity. Aligning population genomic data to these regions indicated that these regions are variable between individuals. Our analysis emphasizes that T2T-CHM13 is necessary to maximize the value of lrGS for optimal inversion detection in clinical diagnostics. These results highlight the importance of leveraging diverse and comprehensive reference genomes to resolve unsolved molecular cases in rare diseases.en_US
dc.identifier.citationSaether, K. B., Eisfeldt, J., Bengtsson, J. D., Lun, M. Y., Grochowski, C. M., Mahmoud, M., Chao, H.-T., Rosenfeld, J. A., Liu, P., Ek, M., Schuy, J., Ameur, A., Dai, H., Network, U. D., Hwang, J. P., Sedlazeck, F. J., Bi, W., Marom, R., Wincent, J., … Lindstrand, A. (2024). Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps. Genome Research, 34(11), 1785–1797. https://doi.org/10.1101/gr.279346.124en_US
dc.identifier.digitalGenomeRes-2024-Bilgrav-Saether-1785-97en_US
dc.identifier.doihttps://doi.org/10.1101/gr.279346.124en_US
dc.identifier.urihttps://hdl.handle.net/1911/118103en_US
dc.language.isoengen_US
dc.publisherCold Spring Harbor Laboratory Pressen_US
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleLeveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gapsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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