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 () and Stefan Mundlos ()
Additional contact information
Robert Schöpflin: Max Planck Institute for Molecular Genetics, RG Development & Disease
Uirá Souto Melo: Max Planck Institute for Molecular Genetics, RG Development & Disease
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
Manuel Holtgrewe: Berlin Institute of Health
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
Julius Jungnitsch: Max Planck Institute for Molecular Genetics, RG Development & Disease
Emel Comak: Max Planck Institute for Molecular Genetics, Department of Computational Molecular Biology
Seval Türkmen: Charité Universitätsmedizin Berlin
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
Laurence Faivre: UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
Patrick Callier: UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
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
Antonio Vitobello: UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD
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

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34053-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34053-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34053-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().