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Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Author

Listed:
  • Robert Schöpflin

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin
    Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Uirá Souto Melo

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin)

  • Hossein Moeinzadeh

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • David Heller

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Verena Laupert

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Jakob Hertzberg

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin
    Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Manuel Holtgrewe

    (Berlin Institute of Health
    Charité—University Medicine Berlin)

  • Nico Alavi

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Marius-Konstantin Klever

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin)

  • Julius Jungnitsch

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin)

  • Emel Comak

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Seval Türkmen

    (Charité Universitätsmedizin Berlin
    Laboratoire national de santé)

  • Denise Horn

    (Charité Universitätsmedizin Berlin)

  • Yannis Duffourd

    (UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
    CHU Dijon Bourgogne)

  • Laurence Faivre

    (UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
    University Hospital Dijon)

  • Patrick Callier

    (UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
    CHU Dijon Bourgogne)

  • Damien Sanlaville

    (University Hospital of Lyon)

  • Orsetta Zuffardi

    (University of Pavia)

  • Romano Tenconi

    (Università di Padova)

  • Nehir Edibe Kurtas

    (Meyer Children’s University Hospital)

  • Sabrina Giglio

    (University of Cagliari)

  • Bettina Prager

    (Praxis für Humangenetik, Kinderzentrum Dresden-Friedrichstadt)

  • Anna Latos-Bielenska

    (University of Medical Sciences in Poznan)

  • Ida Vogel

    (Aarhus University)

  • Merete Bugge

    (University of Copenhagen)

  • Niels Tommerup

    (University of Copenhagen)

  • Malte Spielmann

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    University of Lübeck and Kiel University
    DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel)

  • Antonio Vitobello

    (UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
    CHU Dijon Bourgogne)

  • Vera M. Kalscheuer

    (Max Planck Institute for Molecular Genetics, RG Development & Disease)

  • Martin Vingron

    (Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology)

  • Stefan Mundlos

    (Max Planck Institute for Molecular Genetics, RG Development & Disease
    Charité Universitätsmedizin Berlin)

Abstract

Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.

Suggested Citation

  • Robert Schöpflin & Uirá Souto Melo & Hossein Moeinzadeh & David Heller & Verena Laupert & Jakob Hertzberg & Manuel Holtgrewe & Nico Alavi & Marius-Konstantin Klever & Julius Jungnitsch & Emel Comak & , 2022. "Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34053-7
    DOI: 10.1038/s41467-022-34053-7
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    References listed on IDEAS

    as
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