Journal Article

DKFZ-2022-02904

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional analysis of structural variants in single cells using Strand-seq.

Jeong, H. ; Grimes, K. ; Rauwolf, K. K. ; Bruch, P.-M. ; Rausch, T. ; Hasenfeld, P. ; Benito, E. ; Roider, T. ; Sabarinathan, R. ; Porubsky, D. ; Herbst, S. A. ; Erarslan-Uysal, B. ; Jann, J.-C. ; Marschall, T. ; Nowak, D. ; Bourquin, J.-P. ; Kulozik, A. E. ; Dietrich, S.DKFZ* ; Bornhauser, B. ; Sanders, A. D. ; Korbel, J. (Last author)DKFZ*

2023
Springer Nature New York, NY

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Please use a persistent id in citations: doi:10.1038/s41587-022-01551-4

Abstract: 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.

Note: #LA:B480# / 2023 Jun;41(6):832-844

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Contributing Institute(s):

1. Mechanismen der genetischen Variation und Datenwissenschaft (B480)
2. Translationale Medizinische Onkologie (B340)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 40 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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