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| Item Type: | Article |
|---|---|
| Title: | Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes |
| Creators Name: | 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, Yannis, Faivre, L., Callier, P., Sanlaville, D., Zuffardi, O., Tenconi, R., Kurtas, N.E., Giglio, S., Prager, B., Latos-Bielenska, A., Vogel, I., Bugge, M., Tommerup, N., Spielmann, M., Vitobello, A., Kalscheuer, V.M., Vingron, M. and Mundlos, S. |
| 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. |
| Keywords: | Base Sequence, Chromatin, Chromosome Mapping, Genome, Germ Cells |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 13 |
| Number: | 1 |
| Page Range: | 6470 |
| Date: | 29 October 2022 |
| Official Publication: | https://doi.org/10.1038/s41467-022-34053-7 |
| PubMed: | View item in PubMed |
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