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

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Item Type:Article
Title:Functional analysis of structural variants in single cells using Strand-seq
Creators Name:Jeong, H. and Grimes, K. and Rauwolf, K.K. and Bruch, P.M. and Rausch, T. and Hasenfeld, P. and Benito, E. and Roider, T. and Sabarinathan, R. and Porubsky, D. and Herbst, S.A. and Erarslan-Uysal, B. and Jann, J.C. and Marschall, T. and Nowak, D. and Bourquin, J.P. and Kulozik, A.E. and Dietrich, S. and Bornhauser, B. and Sanders, A.D. and Korbel, J.O.
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.
Keywords:Cell Line, Chromothripsis, Gene Rearrangement, Genomic Structural Variation, Leukemia, Neoplasms
Source:Nature Biotechnology
Publisher:Nature Publishing Group
Page Range:832-844
Date:June 2023
Official Publication:https://doi.org/10.1038/s41587-022-01551-4
PubMed:View item in PubMed

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