%0 Journal Article
%A Jeong, Hyobin
%A Grimes, Karen
%A Rauwolf, Kerstin K
%A Bruch, Peter-Martin
%A Rausch, Tobias
%A Hasenfeld, Patrick
%A Benito, Eva
%A Roider, Tobias
%A Sabarinathan, Radhakrishnan
%A Porubsky, David
%A Herbst, Sophie A
%A Erarslan-Uysal, Büşra
%A Jann, Johann-Christoph
%A Marschall, Tobias
%A Nowak, Daniel
%A Bourquin, Jean-Pierre
%A Kulozik, Andreas E
%A Dietrich, Sascha
%A Bornhauser, Beat
%A Sanders, Ashley D
%A Korbel, Jan
%T Functional analysis of structural variants in single cells using Strand-seq.
%J Nature biotechnology
%V 41
%N 6
%@ 0733-222X
%C New York, NY
%I Springer Nature
%M DKFZ-2022-02904
%P 832-844
%D 2023
%Z #LA:B480# / 2023 Jun;41(6):832-844
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36424487
%R 10.1038/s41587-022-01551-4
%U https://inrepo02.dkfz.de/record/182764