Abstract
Chromothripsis is a mutational phenomenon representing a unique type of tremendously complex genomic structural alteration. It was initially described and was broadly observed in cancer with lower frequencies in other genetic disorders. Chromothripsis manifests massive genomic structural alterations during a single catastrophic event in the cell. It is considered to be characterized by the simultaneous shattering of chromosomes followed by random reassembly of the DNA fragments, ultimately resulting in newly formed, mosaic derivative chromosomes and with a potential for a drastic oncogenic transformation. Here, we consider a question of whether the genomic locations involved in chromothripsis rearrangements’ are randomly distributed in 3D genomic packing space or have some spatial organization’s predispositions. To that end, we investigated the structural variations (SVs) observed in previously sequenced cancer genomes via juxtaposition of involved breakpoints onto the Hi-C contact genome map of normal tissue. We found that the average Hi-C contact score for SVs breakpoints appearing at the same chromosome (cis-SVs) in an individual patient is significantly higher than the average Hi-C matrix signal, which indicates that SVs tend to involve spatially proximal regions of the chromosome. Furthermore, we overlaid the chromothripsis annotation of groups of SVs’ breakpoints and demonstrated that the Hi-C signals for both chromothripsis breakpoint regions as well as regular SVs breakpoints are statistically significantly higher than random control, suggesting that chromothripsis cis-SVs have the same tendency to rearrange the proximal sites in 3D-genome space. Last but not least, our analysis revealed a statistically higher Hi-C score for all pairwise combinations of breakpoints involved in chromothripsis event when compared to both background Hi-C signal as well as to combination of non-chromothripsis breakpoint pairs. This observation indicates that breakpoints could be assumed to describe a given chromothripsis 3D-cluster as a proximal bundle in genome space. These results provide valuable new insights into the spatial relationships of the SVs loci for both chromothripsis and regular genomic alterations, laying the foundation for the development of a more precise method for chromothripsis identification and annotation.
N. Petukhova and A. Zabelkin—These authors contributed equally. N. Alexeev—Independent researcher
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Petukhova, N., Zabelkin, A., Dravgelis, V., Aganezov, S., Alexeev, N. (2022). Chromothripsis Rearrangements Are Informed by 3D-Genome Organization. In: Jin, L., Durand, D. (eds) Comparative Genomics. RECOMB-CG 2022. Lecture Notes in Computer Science(), vol 13234. Springer, Cham. https://doi.org/10.1007/978-3-031-06220-9_13
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