Skin Sheltered from Sunlight Still Gathers UV-Linked Mutations

Gordenin, Saini, and colleagues started by sequencing fibroblasts from skin biopsies taken from the hip and forearm of two individuals. In a 2016 study, they reported a range of somatic mutations and could see a UV-related mutation signature in forearms that was much greater than in hips, indicating that sun exposure made a difference in mutation rate.

“Then the question was—that was just two people, and they were both Caucasian and male—so what does the rest of the world look like?” Saini tells The Scientist. For the current study, the researchers isolated 34 fibroblasts and five melanocytes from biopsies taken from the healthy, noncancerous skin of the hips of 21 volunteers, ranging in age from 25 to 79 years, and expanded clones of those cells in culture. According to Saini, getting skin biopsies from people without cancer was key to the group’s goal of understanding mutation rates in normal tissue. Previous studies have used cells isolated from people who come in for cancer therapy, Saini explains. “When they’re taking biopsies from the tumors, they also try and take normal tissue, but this is not a healthy individual.”

The researchers isolated and sequenced genomic DNA from each of these cell lineages. Because they knew that UV light is more likely to cause mutations at specific sequence patterns in the genome, the team looked for those mutational signatures and evaluated how much they were enriched compared to all other mutations. They determined that UV-induced mutations were prevalent in all the cells they looked at, ranging from 400 to more than 14,000 base substitutions. The incidence of UV-related mutations did not increase with the age of the donors nor was it related to sex.

Skin cells from Black individuals carried a much lower median mutational load—about 700 base substitutions—than the median of 1,800 base substitutions seen in cells from white donors. Mutations unrelated to UV light damage did not differ between the cells of the two groups, pointing to the protective role that the melanin in skin provides against sun exposure.

“If you look at the numbers of mutations that they detect, they’re using quite stringent strategies, so . . . the numbers here are probably on the lower end of what [the cells] actually have,” says Maria Eriksson, who studies genetic mechanisms of aging at the Karolinska Institute in Sweden and was not involved in the work. The “open question is, does it matter if you have all these mutations?”

Along these lines, another important question is, “when is a normal cell not a normal cell anymore?” 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 you eventually become something else?”

“For skin, I think we gave a pretty good baseline” of what is normal in terms of somatic mutation rates, says Gordenin. “Baseline levels of genome changes in skin defined by our study may help researchers to develop testing procedures for detecting high, disease-prone levels in otherwise healthy individuals.”

N. Saini et al., “UV-exposure, endogenous DNA damage, and DNA replication errors shape the spectra of genome changes in human skin,” PLOS Genet, doi:10.1371/journal.pgen.1009302, 2021.