TitleFunctional analysis of structural variants in single cells using Strand-seq.
Publication TypeJournal Article
Year of Publication2023
AuthorsJeong H, Grimes K, Rauwolf KK, Bruch P-M, Rausch T, Hasenfeld P, Benito E, Roider T, Sabarinathan R, Porubsky D, Herbst SA, Erarslan-Uysal B, Jann J-C, Marschall T, Nowak D, Bourquin J-P, Kulozik AE, Dietrich S, Bornhauser B, Sanders AD, Korbel JO
JournalNat Biotechnol
Start Page6
Date Published2022 Nov 24

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.

Alternate JournalNat Biotechnol
PubMed ID36424487
PubMed Central ID6872491