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PreprintCC BY-NC-NDbioRxiv

3D-genome impacts of TAD-boundary-disrupting ultra-rare structural variants identified in schizophrenia

  • Luz M. Porras1
  • Martilias Farrell2
  • Isabelle Rodriguez-Lausell1
  • Gabriel A. Iglesias-Maldonado1
  • Emily Val F. Tuliao1
  • Elizabeth Wright1
  • Amphitreatte Kreiman1
  • NaEshia Ancalade2
  • Christopher Stoddard3
  • Jin P. Szatkiewicz2
  • Paola Giusti-Rodríguez1
  1. 1Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA
  2. 2Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  3. 3Department of Genetic and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA
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Abstract

Schizophrenia is a complex and multifactorial brain disorder that impacts ~1% of the U.S. population. The genetic architecture of schizophrenia includes 10 large rare structural variants (SVs) ~10 exonic variants, and over 250 common variants. Previously we combined whole genome sequencing (WGS) with brain-specific epigenomic data and found an excess of ultrarare SVs in schizophrenia localizing to the boundaries of topologically associated domains (TADs). Alterations in TAD boundaries (TAD-b) may lead to disarrangement of enhancer-promoter contacts and dysregulation of gene expression and have been associated with several human diseases. Our study sought to functionally characterize two of these TAD-b SVs using chromatin conformation capture (e.g., Hi-C) and RNA sequencing, to unveil mechanistic insight into the effects of these variants on 3D-genome organization and gene expression. To achieve this, we genetically engineered these two TAD-b SVs in isogenic induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. iPSCs were differentiated into neuronal precursor cells, excitatory glutamatergic neurons, and medium spiny neurons. We found that these TAD-boundary-disrupting SVs could reshape the 3D-genome and transcriptional networks in a cell-type-specific manner.

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Cite

BibTeXRIS
BibTeX
@misc{porras20263dgenome,
  title = {{3D-genome impacts of TAD-boundary-disrupting ultra-rare structural variants identified in schizophrenia}},
  author = {Luz M. Porras and Martilias Farrell and Isabelle Rodriguez-Lausell and Gabriel A. Iglesias-Maldonado and Emily Val F. Tuliao and Elizabeth Wright and Amphitreatte Kreiman and NaEshia Ancalade and Christopher Stoddard and Jin P. Szatkiewicz and Paola Giusti-Rodríguez},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.26.761993},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761993v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - 3D-genome impacts of TAD-boundary-disrupting ultra-rare structural variants identified in schizophrenia
AU  - Luz M. Porras
AU  - Martilias Farrell
AU  - Isabelle Rodriguez-Lausell
AU  - Gabriel A. Iglesias-Maldonado
AU  - Emily Val F. Tuliao
AU  - Elizabeth Wright
AU  - Amphitreatte Kreiman
AU  - NaEshia Ancalade
AU  - Christopher Stoddard
AU  - Jin P. Szatkiewicz
AU  - Paola Giusti-Rodríguez
PY  - 2026
DA  - 2026/10/26
PB  - bioRxiv
DO  - 10.64898/2026.10.26.761993
UR  - https://www.biorxiv.org/content/10.64898/2026.10.26.761993v1
AB  - Schizophrenia is a complex and multifactorial brain disorder that impacts ~1% of the U.S. population. The genetic architecture of schizophrenia includes 10 large rare structural variants (SVs) ~10 exonic variants, and over 250 common variants. Previously we combined whole genome sequencing (WGS) with brain-specific epigenomic data and found an excess of ultrarare SVs in schizophrenia localizing to the boundaries of topologically associated domains (TADs). Alterations in TAD boundaries (TAD-b) may lead to disarrangement of enhancer-promoter contacts and dysregulation of gene expression and have been associated with several human diseases. Our study sought to functionally characterize two of these TAD-b SVs using chromatin conformation capture (e.g., Hi-C) and RNA sequencing, to unveil mechanistic insight into the effects of these variants on 3D-genome organization and gene expression. To achieve this, we genetically engineered these two TAD-b SVs in isogenic induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. iPSCs were differentiated into neuronal precursor cells, excitatory glutamatergic neurons, and medium spiny neurons. We found that these TAD-boundary-disrupting SVs could reshape the 3D-genome and transcriptional networks in a cell-type-specific manner.
SN  - 2692-8205
ER  -