The genomic landscapes of individual melanocytes from human skin

Abstract

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 individual melanocytes from human skin. 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 located adjacent to a 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.

The landscape of driver mutations in cutaneous squamous cell carcinoma

“…1a for an example). To account for each of these potential issues, we used the Footprints software 23 to count the exact number of basepairs in each sample with sufficient sequencing coverage to make a mutation call. For the average sample, we could detect mutations at 91.2% of target bases, though this ranged from 52.3% to nearly 100% (Supplementary Fig.…”

A body map of somatic mutagenesis in morphologically normal human tissues

“…Recent studies have revealed the somatic mutation landscape of different normal human tissues, including the skin 3,4 , esophagus 5,6 , colon and rectum 7 , liver 8 , endometrial epithelium 9 , bronchia 10 , brain 11,12 , embryo 13 , urothelium 14,15 , and blood cells 16,17 , mostly through deep DNA sequencing of biopsied tissue samples. Other studies have implemented bioinformatic algorithms to detect somatic mutations from RNA sequencing data of normal human tissues 18,19 .…”

To identify the panoply of somatic mutations in each cell

“…Dans un travail récent particulièrement bien conduit, les auteurs font progresser ce problème de manière significative [2]. Ayant choisi de s'intéresser aux mélanocytes, ils révèlent un riche paysage mutationnel chez des cellules de personnes âgées (63 à 85 ans) d'origine européenne, vivantes ou récemment décédées et atteintes ou non de mélanomes.…”

“…In a particularly well-conducted recent work, the authors have made significant progress in addressing this problem [2]. Having chosen to focus on melanocytes, they reveal a rich mutational landscape in cells derived from elderly (63 to 85 years old) people of European origin, living or recently deceased, with or without melanoma.…”