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

Schöpflin, Robert; Melo, Uirá Souto; Moeinzadeh, Mohammad Hossein; Heller, David; Laupert, Verena; Hertzberg, Jakob; Holtgrewe, Manuel; Alavi, Nico; Klever, Marius-Konstantin; Jungnitsch, Julius; Comak, Emel; Türkmen, Seval; Horn, Denise; Duffourd, Yannis; Faivre, Laurence; Callier, Patrick; Sanlaville, Damien; Zuffardi, Orsetta; Tenconi, Romano; Kurtas, Nehir Edibe; Giglio, Sabrina; Prager, Bettina; Latos-Bielenska, Anna; Vogel, Ida; Bugge, Merete; Tommerup, Niels; Spielmann, Malte; Vitobello, Antonio; Kalscheuer, Vera M.; Vingron, Martin; Mundlos, Stefan

doi:10.1038/s41467-022-34053-7

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

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Schöpflin, Robert
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Melo, Uirá Souto
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Moeinzadeh, Mohammad Hossein
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Heller, David
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Laupert, Verena
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hertzberg, Jakob
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Alavi, Nico
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Klever, Marius-Konstantin
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Jungnitsch, Julius
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Comak, Emel
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Spielmann, Malte
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kalscheuer, Vera M.
Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vingron, Martin
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos, Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Schöpflin, R., Melo, U. S., Moeinzadeh, M. H., Heller, D., Laupert, V., Hertzberg, J., et al. (2022). Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes. Nature Communications, 13(1): 6470. doi:10.1038/s41467-022-34053-7.

Cite as: https://hdl.handle.net/21.11116/0000-000B-60AD-6

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.