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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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Hauptverfasser: Jeong, Hyobin (VerfasserIn) , Grimes, Karen (VerfasserIn) , Rauwolf, Kerstin K. (VerfasserIn) , Bruch, Peter-Martin (VerfasserIn) , Rausch, Tobias (VerfasserIn) , Hasenfeld, Patrick (VerfasserIn) , Benito, Eva (VerfasserIn) , Roider, Tobias (VerfasserIn) , Sabarinathan, Radhakrishnan (VerfasserIn) , Porubsky, David (VerfasserIn) , Herbst, Sophie (VerfasserIn) , Erarslan-Uysal, Büşra (VerfasserIn) , Jann, Johann-Christoph (VerfasserIn) , Marschall, Tobias (VerfasserIn) , Nowak, Daniel (VerfasserIn) , Bourquin, Jean-Pierre (VerfasserIn) , Kulozik, Andreas (VerfasserIn) , Dietrich, Sascha (VerfasserIn) , Bornhauser, Beat (VerfasserIn) , Sanders, Ashley D. (VerfasserIn) , Korbel, Jan Oliver (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: June 2023
In: Nature biotechnology
Year: 2023, Jahrgang: 41, Heft: 6, Pages: 832-844
ISSN:1546-1696
DOI:10.1038/s41587-022-01551-4
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41587-022-01551-4
Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41587-022-01551-4
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Online veröffentlicht: 24. November 2022
Gesehen am 01.07.2024
Beschreibung:Online Resource
ISSN:1546-1696
DOI:10.1038/s41587-022-01551-4

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