Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes
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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.
Originalsprog | Engelsk |
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Artikelnummer | 6470 |
Tidsskrift | Nature Communications |
Vol/bind | 13 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
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).
Funding Information:
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).
Publisher Copyright:
© 2022, The Author(s).
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