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


  • H. Jeong
  • K. Grimes
  • K.K. Rauwolf
  • P.M. Bruch
  • T. Rausch
  • P. Hasenfeld
  • E. Benito
  • T. Roider
  • R. Sabarinathan
  • D. Porubsky
  • S.A. Herbst
  • B. Erarslan-Uysal
  • J.C. Jann
  • T. Marschall
  • D. Nowak
  • J.P. Bourquin
  • A.E. Kulozik
  • S. Dietrich
  • B. Bornhauser
  • A.D. Sanders
  • J.O. Korbel


  • Nature Biotechnology


  • Nat Biotechnol 41 (6): 832-844


  • 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.