An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes
- Chong Li1,2,
- Marc Jan Bonder3,4,
- Sabriya Syed5,
- Matthew Jensen6,7,
- Human Genome Structural Variation Consortium (HGSVC),
- HGSVC Functional Analysis Working Group,
- Mark B. Gerstein6,7,
- Michael C. Zody8,
- Mark J.P. Chaisson9,
- Michael E. Talkowski10,11,12,13,
- Tobias Marschall14,15,
- Jan O. Korbel16,
- Evan E. Eichler17,18,
- Charles Lee5,19 and
- Xinghua Shi1,2
- 1Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA;
- 2Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, Pennsylvania 19122, USA;
- 3Department of Genetics, Groningen, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, Netherlands;
- 4Division of Computational Genomics and Systems Genetics, German Cancer Research Center, 69120 Heidelberg, Germany;
- 5The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA;
- 6Department of Molecular Biochemistry and Biophysics, Yale University, New Haven, Connecticut 06510, USA;
- 7Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA;
- 8New York Genome Center, New York, New York 10013, USA;
- 9Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, California 90089, USA;
- 10Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 11Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 12Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA;
- 13Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 14Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital, Heinrich Heine University, 40225 Düsseldorf, Germany;
- 15Center for Digital Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany;
- 16European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany;
- 17Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195-5065, USA;
- 18Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA;
- 19Department of Genetics and Genome Sciences, UConn Health, Farmington, Connecticut 06030-6403, USA
Abstract
The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements’ aberrant regulation. However, how SV affects the 3D genome structure and their association among different aspects of gene regulation and candidate cis-regulatory elements (cCREs) have rarely been studied systematically. Here, we assess the impact of SVs intersecting with TAD boundaries by developing an integrative Hi-C analysis pipeline, which enables the generation of an in-depth catalog of TADs and TAD boundaries in human lymphoblastoid cell lines (LCLs) to fill the gap of limited resources. Our catalog contains 18,865 TADs, including 4596 sub-TADs, with 185 SVs (TAD–SVs) that alter chromatin architecture. By leveraging the ENCODE registry of cCREs in humans, we determine that 34 of 185 TAD–SVs intersect with cCREs and observe significant enrichment of TAD–SVs within cCREs. This study provides a database of TADs and TAD–SVs in the human genome that will facilitate future investigations of the impact of SVs on chromatin structure and gene regulation in health and disease.
Footnotes
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Human Genome Structural Variation Consortium (HGSVC)
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The members of the Human Genome Structural Variation Consortium (HGSVC) are Evan E. Eichler (Cochair), Jan O. Korbel (Cochair), Charles Lee (Cochair), Tobias Marschall (Cochair), Hufsah Ashraf, Peter A. Audano, Ola Austine, Anna O. Basile, Christine R. Beck, Marc Jan Bonder, Marta Byrska-Bishop, Mark J.P. Chaisson, Zechen Chong, André Corvelo, Scott E. Devine, Peter Ebert, Jana Ebler, Mark B. Gerstein, Pille Hallast, William T. Harvey, Patrick Hasenfeld, Alex R. Hastie, Mir Henglin, Kendra Hoekzema, Wolfram Höps, PingHsun Hsieh, Sarah Hunt, Matthew Jensen, Miriam K. Konkel, Jennifer Kordosky, Peter M. Lansdorp, Charles Lee, Wan-Ping Lee, Alexandra P. Lewis, Chong Li, Jiadong Lin, Mark Loftus, Glennis A. Logsdon, Ryan E. Mills, Yulia Mostovoy, Katherine M. Munson, Giuseppe Narzisi, Andy Pang, David Porubsky, Timofey Prodanov, Tobias Rausch, Bernardo Rodriguez-Martin, Xinghua Shi, Likhitha Surapaneni, Michael E. Talkowski, Feyza Yilmaz, DongAhn Yoo, Xuefang Zhao, Weichen Zhou, and Michael C. Zody.
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HGSVC Functional Analysis Working Group
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The members of the Human Genome Structural Variation Consortium (HGSVC) functional analysis working group are Xinghua Shi (colead), Jan O. Korbel (colead), Anna O. Basile, Christine Beck, Marta Byrska-Bishop, Marc Jan Bonder, Mark J.P. Chaisson, Ken Chen, Evan E. Eichler, Mark B. Gerstein, Pille Hallast, Wolfram Höps, Daniel Ben-Isvy, Matthew Jensen, Yunzhe Jiang, Kwondo Kim, Miriam Konkel, Tobias Marschall, Bernardo Rodriguez-Martin, Gianni Martino, Ryan E. Mills, Nicholas Moskwa, Yuia Mostovoy, Lingbin Ni, Charles Lee, Chong Li, Jiaqi Li, Yang I. Li, Qingnan Liang, Glennis A. Logsdon, Carolyn Paisie, Oliver Stegle, Sabriya Syed, Michael E. Talkowski, Yukun Tan, Xuefang Zhao, Weichen Zhou, Michael C. Zody, Alex Yenkin, and DongAhn Yoo.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279419.124.
- Received March 29, 2024.
- Accepted October 4, 2024.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
