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

Schopflin R.;Melo U. S.;Moeinzadeh H.;Heller D.;Laupert V.;Hertzberg J.;Holtgrewe M.;Alavi N.;Klever M. -K.;Jungnitsch J.;Comak E.;Turkmen S.;Horn D.;Duffourd Y.;Faivre L.;Callier P.;Sanlaville D.;Zuffardi O.;Tenconi R.;Kurtas N. E.;Giglio S.

Membro del Collaboration Group

;Prager B.;Latos-Bielenska A.;Vogel I.;Bugge M.;Tommerup N.;Spielmann M.;Vitobello A.;Kalscheuer V. M.;Vingron M.;Mundlos S.

2022-01-01

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Abstract

Here the authors characterize structural variations (SVs) in a cohort of individuals with complex genomic rearrangements, identifying breakpoints by employing short- and long-read genome sequencing and investigate their impact on gene expression and the three-dimensional chromatin architecture. They find breakpoints are enriched in inactive regions and can result in chromatin domain fusions.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.