UV-exposure, endogenous DNA damage, and DNA replication errors shape the spectra of genome changes in human skin

Abstract

Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual. Mutagenesis in human skin cells can be also caused by endogenous DNA damage and by DNA replication errors. The contributions of these processes to the somatic mutation load in the skin of healthy humans has so far not been accurately assessed because the low numbers of mutations from current sequencing methodologies preclude the distinction between sequencing errors and true somatic genome changes. In this work, we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages. We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells. We demonstrate that UV-induced base substitutions, insertions and deletions are prominent even in sun-shielded skin. In addition, we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as insertions and deletions characteristic of DNA replication errors in these cells. The endogenously induced somatic mutations and indels also demonstrate a linear increase with age, while UV-induced mutation load is age-independent. Finally, we show that DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells. Thus, somatic mutations in skin of healthy individuals reflect the interplay of environmental and endogenous factors in facilitating genome instability and carcinogenesis.

Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex

“…The indel signature observed for all indels identified in TSC-FAF and nonTSC-BCCadj NS skin samples combined ( n = 38 indels) was different from the reference COSMIC UV-related ID13 signature, with a cosine similarity score of 0.24 ( Figure 8C ). It was more similar to the recently reported indel signature identified from whole-genome MPS of single-cell-derived clonal lineages from primary normal skin cells ( 42 ), with a cosine similarity score of 0.46. Similar to the findings of Saini et al ( 42 ), most single-nucleotide deletions, 23 of 38 (61%), occurred in a 2- to 5-nt poly-C:T/G:A homopolymer tract.…”

“…We combined all somatic TSC2 and TP53 mutations from all samples in the respective TSC-FAF and nonTSC-BCCadj NS sets, to enable comparison with canonical mutation signatures from the Catalogue of Somatic Mutations in Cancer (COSMIC) (refs. 40 – 42 and Figure 8, A–C ). The SNV signatures for the TSC-FAF and nonTSC-BCCadj NS sets showed the highest cosine similarity to UV-induced-mutation signature SBS7b, which has a predominance of C>T substitutions, with cosine similarity scores 0.65 and 0.83, respectively ( Figure 8A and ref.…”

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

“…This method was initially developed for evaluating APOBEC mutagenesis in human cancers [ 134 ], however it allows statistical estimate of over-representation with any oligonucleotide motif in mutation datasets [ 133 , 135 , 136 ]. A fraction of mutations in an oligonucleotide motif among mutations of a given nucleotide is compared with the presence of the same oligonucleotide in the genomic context surrounding mutated bases (see also Figure 5 and legend).…”

CTCF binding modulates UV damage formation to promote mutation hot spots in melanoma

“…Finally, it is important to note that the XPC À/À cSCCs (Zheng et al, 2014) were derived from an isolated village in Guatemala (Cleaver et al, 2007), while the WT cSCCs were obtained from a clinical study based in San Francisco (Durinck et al, 2011). Differences in patient age (typically < 10 years old vs. 58-87 years old) and ethnicity-factors that can significantly modulate mutagenesis in skin cells (Saini et al, 2021)-could also affect mutation rates at CBS. These observations suggest that the XPC À/À cSCC mutation data should be analyzed with caution.…”