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Noncoding structural variations (SVs) exert deleterious phenotypic effects by remodeling chromatin architecture. The nonlinear nature of the remodeling process makes case-by-case prediction of SVs’ effects arduous. This study employs MiChroM, a maximum-entropy polymer model, to systematize the prediction of the architectural effects of SVs. MiChroM trains a pairwise potential matrix on a Hi-C contact map to build an in-silico model of a genomic locus. By applying SVs to our simulated polymer, we investigate the architectural mechanisms involved in SV-associated phenotypic alterations. As our procedure predicts the effects of SVs by training on a wild-type contact map, it does not require Hi-C data from SV-bearing tissue. We benchmark our model on six limb-development-associated structural variations at the EPHA4 locus. Our model correctly predicts changes in key ectopic, disease-associated enhancer-promoter interactions. Analysis of structural ensembles reveals architectural reorganization consistent with prior hypotheses for this set of mutations. To enhance predictive capacity, we develop matrix adjustment techniques grounded in polymer physics and chromatin folding theory. We also employ a simultaneous kinetic/thermodynamic model of chromatin folding by simulating chromatin organizing motors on the polymer. Comparisons of the adjusted-thermodynamic and kinetic/thermodynamic approaches highlight fundamental principles of genome architecture organization. With the EPHA4 mutation as a successful benchmark, we turn our model’s predictive capacities to previously unsimulated structural variations. We predict the effects of architectural SVs to the SOX9 locus and of complex contact domain shuffling SVs. Our predicted SV contact maps are of higher resolution than their experimental counterparts while reproducing the expected ectopic interactions. This procedure enables predictions of the architectural effects of SV at high resolution based solely on already-published WT contact map data. It thus opens up new avenues for laboratory and clinical investigation of genetic disease.
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Somatic structural variant formation is guided by and influences genome architecture
The occurrence and formation of genomic structural variants (SVs) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have 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 occurrence of massive complex rearrangements, which allows 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 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 SVs have a strong tendency to occur between similar chromatin compartments and replication timing regions. Moreover, we find that SVs frequently occur at 3D loop anchors, that SVs can cause a switch in chromatin compartments and replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes. Finally, we provide evidence for a general mechanistic bias of the 3D chromatin on SV occurrence using data from more than 2700 patient-derived cancer genomes.
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- Award ID(s):
- 2019745
- PAR ID:
- 10417150
- Date Published:
- Journal Name:
- Genome Research
- Volume:
- 32
- Issue:
- 4
- ISSN:
- 1088-9051
- Page Range / eLocation ID:
- 643 to 655
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1101/gr.275790.121
