Long-read sequencing of single cell-derived melanoma sublines reveals divergent and parallel genomic and epigenomic evolutionary trajectories
Tumor evolution is driven by various mutational processes, ranging from single-nucleotide variants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alterations due to inherent technical limitations. To overcome that, here we introduce an approach to identify and analyze the genomic and epigenetic events in different stages of tumoral evolution from long-read sequencing of single-cell derived sublines. We then use it to profile 23 sublines of a mouse cutaneous melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational framework for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by independent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development and benchmarking of computational methods.
Authors
- Chi‐Ping Day (ORCID: https://orcid.org/0000-0001-5200-2372)
- Yuelin Liu (ORCID: https://orcid.org/0000-0002-1051-7236)
- Kimberley J. Billingsley (ORCID: https://orcid.org/0000-0002-8003-4029)
- Michael C. Kelly (ORCID: https://orcid.org/0000-0003-0654-2778)
- Anton Goretsky (ORCID: https://orcid.org/0009-0007-6595-9318)
- Mikhail Kolmogorov (ORCID: https://orcid.org/0000-0002-5489-9045)
- Arindam Ghosh (ORCID: https://orcid.org/0000-0002-8779-0986)
- Yongmei Zhao (ORCID: https://orcid.org/0000-0003-0800-4658)
- Erin K. Molloy (ORCID: https://orcid.org/0000-0001-5553-3312)
- Salem Malikić (ORCID: https://orcid.org/0000-0002-4215-5655)
- Charlie Seibert
- Laksh Malik (ORCID: https://orcid.org/0000-0002-2498-146X)
- Farid Rashidi Mehrabadi (ORCID: https://orcid.org/0000-0003-4103-4904)
- Ayse G. Keskus (ORCID: https://orcid.org/0000-0002-3934-8587)
- Antonella Sassano (ORCID: https://orcid.org/0000-0002-3957-6723)
- Breeana Baker
- Sandra Burkett (ORCID: https://orcid.org/0000-0002-5476-4028)
- Juan Manuel Caravaca (ORCID: https://orcid.org/0000-0003-2974-1833)
- Cornelis Blauwendraat (ORCID: https://orcid.org/0000-0001-9358-8111)
- Eva Pérez‐Guijarro (ORCID: https://orcid.org/0000-0003-2570-7697)
- S. Cenk Şahinalp (ORCID: https://orcid.org/0000-0002-2170-2808)
- Biraj Shrestha
- Bao Tran
- Maria O. Hernandez
- Kayla Kline
- Ying Wu
- Tanveer Ahmad
- E. Michael Gertz
- Xiwen Cui
- Glenn Merlino
Institutions
- National Institutes of Health (US)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- National Institute of Neurological Disorders and Stroke (US)
- Frederick National Laboratory for Cancer Research (US)
- National Institute on Aging (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Universidad Autónoma de Madrid (ES)
- University of Maryland, College Park (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1038/s41467-026-75172-9
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute