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

Details

• Personal Author:
  Boyer JC ; Chan K ; Cortes-Ciriano I ; Dai S ; Fargo DC ; Gordenin DA ; Grimm SA ; Kaufmann WK ; Klimczak LJ ; Lee E ; Malc EP ; Mieczkowski PA ; Park PJ ; Roberts SA ; Saini N ; Schurman SH ; Taylor JA
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Environmental Exposure Genetics Occupational Health Safety Skin
• Keywords:
  Environmental Exposure Fibroblasts Gene Mutation Genetic Factors Genomics Humans
• ISSN:
  1553-7404
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Massachusetts ; North Carolina ; OSHA Region 1 ; OSHA Region 10 ; OSHA Region 4 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  12
• Issue:
  10
• NIOSHTIC Number:
  nn:20061919
• Citation:
  PLoS Genet 2016 Oct; 12(10):e1006385
• Contact Point Address:
  Dmitry A, Gordenin, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, United States of America
• Email:
  gordenin@niehs.nih.gov
• Federal Fiscal Year:
  2017
• Performing Organization:
  University of North Carolina Chapel Hill
• Peer Reviewed:
  True
• Start Date:
  20140901
• Source Full Name:
  Public Library of Science Genetics
• End Date:
  20170831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:13070472a3e3e8e53b891cccf9aa1c9bf7f660258c2bb2b383f7a22ab50e6c7a9539e009e565fd7604f8242a70901cb2cacbfac4b72dd05703254314be965ba1
• Download URL:
  https://stacks.cdc.gov/view/cdc/225264/cdc_225264_DS1.pdf
• File Type:
  [PDF - 2.45 MB ]