Peer-reviewedCC BYCell
Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome
14 affiliations
- 1Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA; Department of Human Genetics, Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA. Electronic address: [email protected]
- 2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
- 3Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA
- 4Department of Genetics, Stanford University, Palo Alto, CA, USA
- 5Center for Systems Immunology, Benaroya Research Institute at Virginia Mason Franciscan Health, Seattle, WA, USA
- 6Talus Bioscience, Seattle, WA, USA
- 7Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA
- 8Department of Laboratory Medicine and Pathology, Mayo Clinic Hospital, Rochester, MN, USA
- 9Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
- 10Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA
- 11Departments of Statistics & Biostatistics, University of Washington, Seattle, WA, USA
- 12Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Department of Pediatrics, University of Washington, Seattle, WA, USA
- 13Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Center for Systems Immunology, Benaroya Research Institute at Virginia Mason Franciscan Health, Seattle, WA, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA
- 14Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA. Electronic address: [email protected]
Abstract
Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq inferred regulatory elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing imprinted elements lacking underlying parent-of-origin differences in DNA methylation and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.
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BibTeX
@article{vollger2026somatic,
title = {{Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome}},
author = {Mitchell Robert Vollger and Elliott G. Swanson and Shane J. Neph and Benjamin J. Mallory and Danilo Dubocanin and Ching‐Huang Ho and Yong-Han Hank Cheng and Jane Ranchalis and Katherine M. Munson and Adriana Estela Sedeño-Cortés and Devaraja Gouda Mudeppa and William E. Fondrie and Stephanie C. Bohaczuk and Maxwell A. Dippel and Yizi Mao and Nancy L. Parmalee and William T. Harvey and Young-Jun Kwon and Gage H. Garcia and Kendra Hoekzema and Jeffrey G. Meyer and Mine S. Cicek and Evan E. Eichler and William Stafford Noble and Daniela Witten and James T. Bennett and John P. Ray and Andrew B. Stergachis},
journal = {Cell},
year = {2026},
month = oct,
doi = {10.1016/j.cell.2026.09.034},
url = {https://doi.org/10.1016/j.cell.2026.09.034},
note = {CC BY},
}
RIS
TY - JOUR
TI - Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome
AU - Mitchell Robert Vollger
AU - Elliott G. Swanson
AU - Shane J. Neph
AU - Benjamin J. Mallory
AU - Danilo Dubocanin
AU - Ching‐Huang Ho
AU - Yong-Han Hank Cheng
AU - Jane Ranchalis
AU - Katherine M. Munson
AU - Adriana Estela Sedeño-Cortés
AU - Devaraja Gouda Mudeppa
AU - William E. Fondrie
AU - Stephanie C. Bohaczuk
AU - Maxwell A. Dippel
AU - Yizi Mao
AU - Nancy L. Parmalee
AU - William T. Harvey
AU - Young-Jun Kwon
AU - Gage H. Garcia
AU - Kendra Hoekzema
AU - Jeffrey G. Meyer
AU - Mine S. Cicek
AU - Evan E. Eichler
AU - William Stafford Noble
AU - Daniela Witten
AU - James T. Bennett
AU - John P. Ray
AU - Andrew B. Stergachis
PY - 2026
DA - 2026/10/01
JO - Cell
DO - 10.1016/j.cell.2026.09.034
UR - https://doi.org/10.1016/j.cell.2026.09.034
AB - Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq inferred regulatory elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing imprinted elements lacking underlying parent-of-origin differences in DNA methylation and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.
SN - 0092-8674
SN - 1097-4172
ER -