A telomere-to-telomere map of somatic mutation burden and functional impact in a cancer
Year: 2026
Type: article
Abstract: Cancer genomes harbor extensive somatic genetic and epigenetic variation, yet large portions of the genome remain inaccessible to conventional reference-based analyses. Here, we demonstrate that pairing a near-telomere-to-telomere (near-T2T) diploid assembly of a donor with deep short- and long-read sequencing of their melanoma reveals that 16% of somatic variants localize to sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-associated mutagenesis. Centromere kinetochore binding domains emerge as focal sites of chromosome arm aneuploidy breakpoints and somatic genetic variation, features we further demonstrate are also present in non-cancerous tissues. By contrast, extensive epigenetic remodeling of kinetochore binding domains appears specific to oncogenesis. Single-molecule telomere analyses reconstruct the cycle of telomere erosion and telomerase-mediated extension during tumor evolution, while haplotype-resolved chromatin maps reveal widespread somatic epimutations impacting regulatory elements. Together, these findings define previously inaccessible dimensions of somatic variation and establish a framework for telomere-to-telomere studies of human mosaicism.
Source: Cell
Authors: Min-Hwan Sohn, Danilo Dubocanin, Mitchell R. Vollger, Youngjun Kwon, Anna Minkina, Katherine M. Munson, Samuel F.M. Hart, Jane E. Ranchalis, Nancy L. Parmalee, Adriana E. Sedeño-Cortés, Jeffrey Ou, Shane J. Neph, Natalie Y.T. Au, Stephanie Bohaczuk, Brianne Carroll, Christian D. Frazar, William T. Harvey, Kendra Hoekzema, Meng-Fan Huang, Caitlin N. Jacques, Dana M. Jensen, J. Thomas Kolar, Rosa Lee, Jiadong Lin, Kelsey Loy, Taralynn Mack, Yizi Mao, Matthew W. Mitchell, Meranda M. Pham, Laura B. Scheinfeldt, Gretchen Smith, Erica Ryke, Joshua D. Smith, Lila Sutherlin, Elliott G. Swanson, Jeffrey M. Weiss, Claudia M.B. Carvalho, Tim H.H. Coorens, Kelley Harris, Chia-Lin Wei, Evan E. Eichler, Nicolas Altemose, James T. Bennett, Andrew B. Stergachis
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Google.org, Burroughs Wellcome Fund, Pew Charitable Trusts, Google, National Institutes of Health, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Office of Strategic Coordination, Common Fund
Awards: G1422669444, G1526483288, G1727748880, G1867981061, G1970872724, A reference-free computational algorithm for comprehensive somatic mosaic mutation detection, G2271162994, G228011417, Hybrid approach for comprehensive mutation detection in a cell, G237722789, Investigating the contribution of non-coding genetic variation to rare disorders, Establishing and benchmarking advanced methods to comprehensively characterize somatic genome variation in single human cells, G3156696751, varCUT&Tag: A Method for Simultaneous Identification and Characterization of Sequence Variants in Regulatory Elements and Genes, G3315850437, Identification of somatic/ mosaic SV and transposon activity and their crosstalk to DNA epigenetic Modifications, Single-Cell Multi-omics to Link Clonal Mosaicism (CM) Genotypes with Chromatin, Epigenomic, Transcriptomic and Protein Phenotypes, G3953904728, Tooling for accurately studying the epigenome along the human pangenome reference, Detection and Characterization of Somatic Mutations in Human Tissue Utilizing Duplex-Consensus Sequencing, G4536151059, G4803920666, Ultra-High Fidelity Single-Molecule Profiling of Mosaic Double- and Single-Strand DNA Mutations and Damage, G4830056104, G4843998213, G5242689380, Develop accurate high-coverage and high-throughput single-cell Duplex-seq chemistry and multi-omics platforms for simultaneous profiling of somatic mutation and the transcriptome in single human cells, G5554292223, G5734286933, Molecular and Computational Tools for Identifying Somatic Mosaicism in Human Tissues, Tissue Procurement Center (TPC) Supporting the Somatic Mosaicism across Human Tissues (SMaHT) Network, The regulatory landscape of segmentally duplicated genes: Implications for human evolution and disease, G6727592391, G6747253664, Simultaneous mapping of somatic mosaicism and kb-resolution 3D genome in single cells., A Platform for Scalable Spatial Somatic Variant Profiling, G735755363, G7455536634, Single Molecule Detection of L1 Insertions and Intermediates, G7726112287, Development of an Efficient High Throughput Technique for the Identification of High-Impact Non-Coding Somatic Variants Across Multiple Tissue Types, G8470453247, G861148879, G8725848054, WashU Somatic Mosaicism across Human Tissues (SMaHT) Program Organizational Center, 'Mosaicism in Human Tissues, from Telomere to Telomere to RFA-22-013: "Somatic Mosaicism across Human Tissues Program: Genome Characterization Centers.", Comprehensive Somatic Variant Characterization at the HGSC, WashU-VAI Somatic Mosaicism across Human Tissues (SMaHT) Program Genome Characterization Center, New York Genome Characterization Center: Somatic Mosaicism across Human Tissues, Medical Genetics Postdoctoral Fellowship, Genetics and Developmental Biology Training Program, Interdisciplinary Training in Genome Sciences, Whole Individual Comprehensive KnowlEDge: Somatic Mosaicism across Human Tissues (WICKed SMaHT), Data Analysis Center for Somatic Mosaicism Across Human Tissues Network
OpenAlex ID: W7222160977