Cited by 96Cancer Genomics and DiagnosticsDNA Repair MechanismsCarcinogens and Genotoxicity Assessment

The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts

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Saini, Natalie, Roberts, Steven A., Klimczak, Leszek J., Chan, Kin, Grimm, Sara A., Dai, Shuangshuang, Fargo, David C., Boyer, Jayne C. +9 more·2016·PLOS Genetics

Abstract

Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts. Trial Registration: ClinicalTrials.gov NCT01087307.

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Authors
Saini, N., Roberts, S. A., Klimczak, L. J., Chan, K., Grimm, S. A., Dai, S., Fargo, D. C., Boyer, J. C., Kaufmann, W. K., Taylor, J. A., Lee, E., Cortes-Ciriano, I., Park, P. J., Schurman, S. H., Malc, E. P., Mieczkowski, P. A., & Gordenin, D. A.
Affiliations
  • National Institutes of Health (US)
  • Washington State University (US)
  • University of North Carolina at Chapel Hill (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Gordenin, Dmitry A.
Venue
PLOS Genetics
Published
2016-10-27
Volume
12
Issue
10
Pages
e1006385
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
OpenAlex
W2542991120
Cited by
94
References
78
Citations by year
2026: 7 · 2024: 3 · 2023: 10 · 2022: 7 · 2021: 13 · 2020: 14 · 2019: 14 · 2018: 12 · 2017: 14
FWCI
5.56
Type
journal article
Language
en
Open access
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • National Institute of Environmental Health Sciences (US) (Z1AES103266)
  • National Institutes of Health (US) (R00ES022633-03)
  • U.S. Department of Defense (US) (BC141727)
  • National Institute for Occupational Safety and Health (R21-OH010550)
  • National Institutes of Health (1U01MH106883)
  • Eleanor and Miles Shore Fellowship and the William Randolph Hearst Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
dermal fibroblasts, UV-induced DNA damage, endogenous DNA damage, chromosomal rearrangements, epigenomic features, sun exposure, aging, cancer etiology, single-cell DNA sequencing
MeSH terms
Biopsy, Clone Cells, DNA Damage, Fibroblasts, Humans, Male, Middle Aged, Mutation, Neoplasms, Skin, Sunlight, Genome, Human, Mutagenesis, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Mutation Rate

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