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Functional analysis of structural variants in single cells using Strand-seq

Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration o...

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Main Authors: Jeong, Hyobin (Author) , Grimes, Karen (Author) , Rauwolf, Kerstin K. (Author) , Bruch, Peter-Martin (Author) , Rausch, Tobias (Author) , Hasenfeld, Patrick (Author) , Benito, Eva (Author) , Roider, Tobias (Author) , Sabarinathan, Radhakrishnan (Author) , Porubsky, David (Author) , Herbst, Sophie (Author) , Erarslan-Uysal, Büşra (Author) , Jann, Johann-Christoph (Author) , Marschall, Tobias (Author) , Nowak, Daniel (Author) , Bourquin, Jean-Pierre (Author) , Kulozik, Andreas (Author) , Dietrich, Sascha (Author) , Bornhauser, Beat (Author) , Sanders, Ashley D. (Author) , Korbel, Jan Oliver (Author)
Format: Article (Journal)
Language:English
Published: June 2023
In: Nature biotechnology
Year: 2023, Volume: 41, Issue: 6, Pages: 832-844
ISSN:1546-1696
DOI:10.1038/s41587-022-01551-4
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41587-022-01551-4
Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41587-022-01551-4
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Author Notes:Hyobin Jeong, Karen Grimes, Kerstin K. Rauwolf, Peter-Martin Bruch, Tobias Rausch, Patrick Hasenfeld, Eva Benito, Tobias Roider, Radhakrishnan Sabarinathan, David Porubsky, Sophie A. Herbst, Büşra Erarslan-Uysal, Johann-Christoph Jann, Tobias Marschall, Daniel Nowak, Jean-Pierre Bourquin, Andreas E. Kulozik, Sascha Dietrich, Beat Bornhauser, Ashley D. Sanders and Jan O. Korbel
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Summary:Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations.
Item Description:Online veröffentlicht: 24. November 2022
Gesehen am 01.07.2024
Physical Description:Online Resource
ISSN:1546-1696
DOI:10.1038/s41587-022-01551-4

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