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

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

doi:10.1038/s41467-022-34053-7

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

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

^*Corresponding author for this work

Institute of Human Genetics

38 Citations (Scopus)

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.

Original language	English
Article number	6470
Journal	Nature Communications
Volume	13
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-022-34053-7
Publication status	Published - 12.2022

Funding

We would like to thank the individuals and families for their collaboration and contribution to this project. We thank Volkmar Beensen and Gotthold Barbi for the collaboration on two published cases. We thank Michael Robson, Lila Allou, and Alexandra Despang for their comments on the manuscript. This work was supported by grants MU 880/16-1 from the Deutsche Forschungsgemeinschaft (DFG) to S.M and the Bundesministerium für Bildung und Forschung (BMBF) FKZ 031L0169B to S.M. and FKZ 031L0169A to M.V. M.S. is a DZHK principal investigator and supported by grants from the DFG (SP1532/3-1, SP1532/4-1, and SP1532/5-1) and the Deutsches Zentrum für Luft- und Raumfahrt (DLR 01GM1925). We would like to thank the individuals and families for their collaboration and contribution to this project. We thank Volkmar Beensen and Gotthold Barbi for the collaboration on two published cases. We thank Michael Robson, Lila Allou, and Alexandra Despang for their comments on the manuscript. This work was supported by grants MU 880/16-1 from the Deutsche Forschungsgemeinschaft (DFG) to S.M and the Bundesministerium für Bildung und Forschung (BMBF) FKZ 031L0169B to S.M. and FKZ 031L0169A to M.V. M.S. is a DZHK principal investigator and supported by grants from the DFG (SP1532/3-1, SP1532/4-1, and SP1532/5-1) and the Deutsches Zentrum für Luft- und Raumfahrt (DLR 01GM1925).

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-03 Human Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-022-34053-7

Cite this

Schöpflin, R., Melo, U. S., Moeinzadeh, H., Heller, D., Laupert, V., Hertzberg, J., Holtgrewe, M., Alavi, N., Klever, M. K., Jungnitsch, J., Comak, E., Türkmen, S., Horn, D., Duffourd, Y., Faivre, L., Callier, P., Sanlaville, D., Zuffardi, O., Tenconi, R., ... Mundlos, S. (2022). Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes. Nature Communications, 13(1), Article 6470. https://doi.org/10.1038/s41467-022-34053-7

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

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.",

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Schöpflin, R, Melo, US, Moeinzadeh, H, Heller, D, Laupert, V, Hertzberg, J, Holtgrewe, M, Alavi, N, Klever, MK, Jungnitsch, J, Comak, E, Türkmen, S, Horn, D, Duffourd, Y, Faivre, L, Callier, P, Sanlaville, D, Zuffardi, O, Tenconi, R, Kurtas, NE, Giglio, S, Prager, B, Latos-Bielenska, A, Vogel, I, Bugge, M, Tommerup, N, Spielmann, M, Vitobello, A, Kalscheuer, VM, Vingron, M & Mundlos, S 2022, 'Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes', Nature Communications, vol. 13, no. 1, 6470. https://doi.org/10.1038/s41467-022-34053-7

TY - JOUR

T1 - Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

AU - Schöpflin, Robert

AU - Melo, Uirá Souto

AU - Moeinzadeh, Hossein

AU - Heller, David

AU - Laupert, Verena

AU - Hertzberg, Jakob

AU - Holtgrewe, Manuel

AU - Alavi, Nico

AU - Klever, Marius Konstantin

AU - Jungnitsch, Julius

AU - Comak, Emel

AU - Türkmen, Seval

AU - Horn, Denise

AU - Duffourd, Yannis

AU - Faivre, Laurence

AU - Callier, Patrick

AU - Sanlaville, Damien

AU - Zuffardi, Orsetta

AU - Tenconi, Romano

AU - Kurtas, Nehir Edibe

AU - Giglio, Sabrina

AU - Prager, Bettina

AU - Latos-Bielenska, Anna

AU - Vogel, Ida

AU - Bugge, Merete

AU - Tommerup, Niels

AU - Spielmann, Malte

AU - Vitobello, Antonio

AU - Kalscheuer, Vera M.

AU - Vingron, Martin

AU - Mundlos, Stefan

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85140915097

U2 - 10.1038/s41467-022-34053-7

DO - 10.1038/s41467-022-34053-7

M3 - Journal articles

C2 - 36309531

AN - SCOPUS:85140915097

SN - 1751-8628

VL - 13

JO - Nature Communications

JF - Nature Communications

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M1 - 6470

ER -

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

Abstract

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Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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