A The genomic examination of skin cells shows that the normal number of somatic mutations caused by UV light varies widely and that these mutations are independent of age. The work published today (January 14th) in PLOS genetics, also confirms that darker skin is better protected from UV-induced mutations – something scientists have long suspected.
Researchers “got the idea that the pigment protects you from the DNA damage that sunlight causes, and they show that really well,” says Ruben van Boxtel, a cancer biologist at the Princess Máxima Center for Pediatric Oncology in the Netherlands did not attend At work. Previous sequencing efforts were mostly done on Caucasians, but these authors include samples from people with darker skin.
When Natalie Saini came to Dmitry Gordenin’s lab at the National Institute for Environmental Health Sciences (NIEHS) in North Carolina in 2014, tons of cancer genomes were sequenced from groups around the world. However, it was not yet clear what the significance of many of the mutations the researchers saw was. “To say that cancer genomes have more or less mutations, or even something [different] You had to know what was normal about normal, ”says Saini, who now runs her own laboratory at the Medical University of South Carolina.
Gordenin, Saini, and colleagues began sequencing fibroblasts from skin biopsies taken from the hip and forearm of two people. In a 2016 study, they reported a number of somatic mutations and were able to find a UV-related mutation signature in the forearms that was much larger than the hips, suggesting that sun exposure made a difference in the mutation rate.
“Then the question was – there were only two people and they were both Caucasian and male – so what is the rest of the world like?” Saini tells The scientist. For the current study, the researchers isolated 34 fibroblasts and five melanocytes from biopsies taken from healthy, non-cancerous skin on the hips of 21 volunteers aged 25 to 79 years, and expanded clones of these cells in culture. Taking skin biopsies from people without cancer was key to the group’s goal of understanding mutation rates in normal tissue, according to Saini. Previous studies have used cells isolated from people who come for cancer therapy, explains Saini. “When they take biopsies from the tumors, they are also trying to take normal tissue, but this is not a healthy person.”
The researchers isolated and sequenced genomic DNA from each of these cell lines. Knowing that UV light was more likely to cause mutations in certain sequence patterns in the genome, the team looked for these mutation signatures and assessed how much they were enriched compared to all other mutations. They found that UV-induced mutations were predominant in all cells examined, ranging from 400 to more than 14,000 base substitutions. The incidence of UV-related mutations did not increase with donor age, nor was it gender-specific.
Skin cells from black individuals carried a much lower mean mutation load – approximately 700 base substitutions – than the median of 1,800 base substitutions observed in cells from white donors. Mutations that are not related to UV light damage did not differ between the cells of the two groups, indicating the protective function that melanin plays in the skin against solar radiation.
“If you look at the number of mutations they discover, they use pretty strict strategies. . . The numbers here are probably on the lower end of what [the cells] actually have, ”says Maria Eriksson, who studied genetic mechanisms of aging at the Swedish Karolinska Institute and was not involved in the work. The “open question is, does it matter if you have all of these mutations?”
With this in mind, another important question is: “When is a normal cell no longer a normal cell?” van Boxtel tells The scientist. “Normal cells are actually not as normal as we think they are,” he adds. “Some of these mutations are really sky high. Is there a limit to the number of mutations a normal cell can have, or do they eventually become something else? “
“For the skin, I think we gave a pretty good baseline,” says Gordenin. “The basic values for genome changes in the skin defined in our study can help researchers to develop test procedures to detect high, disease-prone values in otherwise healthy people.”
N. Saini et al., “UV exposure, endogenous DNA damage and DNA replication errors shape the spectra of genomic changes in human skin”. PLOS Genet, doi: 10.1371 / journal.pgen.1009302, 2021.