Genomic Landscape of Human Skin at a Single-Cell Resolution

Every cell in the human body has a unique set of somatic mutations, yet it remains difficult to comprehensively genotype an individual cell. Here, we developed solutions to overcome this obstacle in the context of normal human skin, thus offering the first glimpse into the genomic landscapes of melanocytes at single-cell resolution. We comprehensively genotyped 133 melanocytes from 19 sites across 6 donors. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, within sun-exposed sites, melanocytes on chronically sun-exposed skin (e.g. the face) displayed a lower mutation burden than melanocytes on intermittently sun-exposed skin (e.g. the back). Melanocytes from donors with a history of skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be harnessed to measure cumulative sun damage and skin cancer risk. Moreover, melanocytes from healthy skin commonly harbor pathogenic mutations, likely explaining the origins of the melanomas that arise in the absence of a pre-existing nevus. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells, invisible to the naked eye. Overall, our study offers an unprecedented view into the genomic landscapes of individual melanocytes, revealing key insights into the causes and origins of melanoma.

• Study Design:
  • Cross-Sectional
• Study Type:
  • Cross-Sectional
• Total number of consented subjects: 7
• Subject Sample Telemetry Report (SSTR)

• BioProject
• Sequence Read Archive
• BioSample
• MeSH

Physiologically normal skin tissue was collected from cadavers (up to 8 days post-mortem) or from surgical discard tissue of living donors. Skin tissue from cadavers was collected from either the UCSF Autopsy program or the UCSF Willed Body Program. All donors were of light skin tone, European ancestry and ranged from 63 to 85 years in age.

• Primary Phenotype: Melanoma

• Principal Investigator
  • A. Hunter Shain, PhD. University of California San Francisco, Department of Dermatology.
• Funding Source
  • K22 CA217997. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.