Somatic structural variant formation is guided by and influences genome architecture

Abstract

The occurrence and formation of genomic structural variants (SV) is known to be influenced by the 3D chromatin architecture , but the extent and magnitude has been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the massive complex rearrangements, which allowed us to study the sources of SV formation and their consequences on gene regulation. We observe an action-reaction interplay whereby the 3D chromatin architecture directly impacts on the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing and gene regulation in cis. We show that genomic compartments and replication timing are important determinants for juxtaposing distant loci to form SVs across 30 different cancer types with a pronounced abundance of SVs between early replicating regions in uterine cancer. We find that SVs frequently occur at 3D loop-anchors, cause compartment switching and changes in replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes.

Cancer Genomic Rearrangements and Copy Number Alterations from Errors in Cell Division

“…We are nonetheless optimistic about further progress in understanding the origins of cancer genome complexity because of two promising developments. The first is the growing ability to identify rearrangement signatures through computational analysis of cancer genomes (Garsed et al 2014;Li et al 2014Li et al , 2020Stephens et al 2011) and relate these signatures to the rearrangement outcomes of chromosomal instability (Bollen et al 2021, Kneissig et al 2019, Ly et al 2019, Maciejowski et al 2015, Mardin et al 2015, Mazzagatti et al 2020, Meier et al 2014, Shoshani et al 2021, Sidiropoulos et al 2021, Umbreit et al 2020, Willis et al 2017. The second is the ability to explain very complex rearrangement patterns in cancer genomes as the compound outcomes of multigenerational evolution of unstable chromosomes (Stachler et al 2021, Umbreit et al 2020.…”