Abstract
The spatial organization of the genome within the nucleus — also known as genome architecture or 3D genome — is important to the regulation of gene expression. Disruption of the 3D genome, for example, by structural variation, can contribute to disease, including developmental disorders and cancer. Structural variants can rearrange higher-order chromatin structures, such as topologically associating domains, and disrupt interactions between cis-regulatory elements, which can lead to altered gene expression, a phenomenon known as position effects. New experimental and computational approaches are revealing the effect of structural variants on the 3D genome and gene expression and can help interpret their pathogenic potential, which has important implications for patients. Here, we review mechanisms of disease caused by position effects owing to disruptions of genome architecture, and more specifically topologically associating domains, as well as their consequences and clinical impact.
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Acknowledgements
The authors thank the members of the Spielmann Lab for discussions and suggestions. M.S. is a DZHK principal investigator and is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SP1532/3-2, SP1532/13-1, SP1532/4-1, SP1532/5-1, 515637292 (SFB 1665)) and the CRC 1665, the Max Planck Society and the Deutsches Zentrum für Luft- und Raumfahrt (DLR 01GM1925).
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Sreenivasan, V.K.A., Yumiceba, V. & Spielmann, M. Structural variants in the 3D genome as drivers of disease. Nat Rev Genet 26, 742–760 (2025). https://doi.org/10.1038/s41576-025-00862-x
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DOI: https://doi.org/10.1038/s41576-025-00862-x
