1. Academic Validation
  2. Functional analysis of structural variants in single cells using Strand-seq

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

  • Nat Biotechnol. 2022 Nov 24. doi: 10.1038/s41587-022-01551-4.
Hyobin Jeong # 1 2 Karen Grimes # 1 3 Kerstin K Rauwolf 4 Peter-Martin Bruch 5 6 7 Tobias Rausch 1 6 Patrick Hasenfeld 1 Eva Benito 1 Tobias Roider 1 5 6 Radhakrishnan Sabarinathan 8 David Porubsky 9 10 11 Sophie A Herbst 5 6 Büşra Erarslan-Uysal 6 12 Johann-Christoph Jann 13 Tobias Marschall 14 Daniel Nowak 13 Jean-Pierre Bourquin 4 Andreas E Kulozik 6 12 Sascha Dietrich 5 6 7 15 Beat Bornhauser 4 Ashley D Sanders 16 17 18 19 Jan O Korbel 20 21 22
Affiliations

Affiliations

  • 1 Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • 2 Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea.
  • 3 Faculty of Biosciences, EMBL and Heidelberg University, Heidelberg, Germany.
  • 4 Division of Pediatric Oncology, University Children's Hospital, Zürich, Switzerland.
  • 5 Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
  • 6 Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
  • 7 Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 8 National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
  • 9 Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
  • 10 Max Planck Institute for Informatics, Saarbrücken, Germany.
  • 11 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
  • 12 Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg and Hopp Children's Cancer Center, Heidelberg, Germany.
  • 13 Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Heidelberg, Germany.
  • 14 Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
  • 15 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 16 Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. [email protected]
  • 17 Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [email protected]
  • 18 Berlin Institute of Health (BIH), Berlin, Germany. [email protected]
  • 19 Charité-Universitätsmedizin, Berlin, Germany. [email protected]
  • 20 Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. [email protected]
  • 21 Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany. [email protected]
  • 22 Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected]
  • # Contributed equally.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-135145
    99.77%, Notch Inhibitor