How Efforts to Understand Somatic Mosaicism Will Impact Dermatology

View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although inheritance contributes to the risk of common and rare disorders, we have come to appreciate that the genome we are born with is only one factor that drives disease risk. Somatic mosaicism, commonly appreciated in nevoid and hamartomatous diseases presenting at birth, is active over the course of our lifetime, and our genome is constantly changing as we acquire somatic variants in tissues. Therefore, as we age, disease risk is dictated not entirely by the genetic code at birth but rather by the mosaic of genetic codes found across organismal tissues.Clinical Implications•Somatic mosaicism impacts skin biology in health and disease.•A database of somatic variants in the skin will be a valuable resource.•New sequencing and variant detection methods will improve gene discovery in dermatology. •Somatic mosaicism impacts skin biology in health and disease.•A database of somatic variants in the skin will be a valuable resource.•New sequencing and variant detection methods will improve gene discovery in dermatology. Mosaicism describes the presence of differences in genetic code between cells in the same organism. As tissues are exposed to the environment, DNA is under constant assault from ionizing and UV irradiation, polymerase errors during replication, viral integration, and myriad other factors that drive the formation of single-nucleotide variants (SNVs) and other genetic changes. A damaging SNV is one which results in a pathogenic effect in the encoded protein, occurs at a highly conserved site in the genome, and is typically absent or found in low frequency in databases of genomic variation. When these SNVs arise in somatic tissues and are absent from the genome, there is little risk of transmission to progeny, yet they can have significant effects on skin function and skin disease. Somatic mosaicism is evident in aging skin in the form of acquired benign and malignant lesions and new-onset skin disease. The skin harbors unique SNV signatures compared with other tissues. A higher proportion of somatic SNVs in skin are related to UV light exposure, and skin has a higher overall SNV burden than any other tissue. Damaging SNVs in genes related to skin cancer can be found in normal sun-exposed skin (Martincorena et al., 2015Martincorena I. Roshan A. Gerstung M. Ellis P. Van Loo P. McLaren S. et al.Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.Science. 2015; 348: 880-886Crossref PubMed Scopus (1172) Google Scholar), and their proportion increases with age. In addition, the number of somatic SNVs and the specific signatures in sun-exposed skin were found to be different in geographically separated populations with different genetic backgrounds (King et al., 2023King C. Fowler J.C. Abnizova I. Sood R.K. Hall M.W.J. Szeverényi I. et al.Somatic mutations in facial skin from countries of contrasting skin cancer risk.Nat Genet. 2023; 55: 1440-1447Crossref PubMed Scopus (3) Google Scholar). Single base substitutions in certain genes, including NOTCH1 and TP53, were enriched for nonsynonymous variants relative to those for synonymous variants, indicating a positive selection of clones with these protein-altering SNVs. Somatic SNVs in the skin lead to a variety of benign and malignant skin diseases (Lim et al., 2017Lim Y.H. Moscato Z. Choate K.A. Mosaicism in cutaneous disorders.Annu Rev Genet. 2017; 51: 123-141Crossref PubMed Scopus (23) Google Scholar). Somatic mosaicism has been shown to contribute to basal cell carcinoma, squamous cell carcinoma, and melanoma as well as benign acquired lesions such as seborrheic keratosis, capillary hemangiomas, and porokeratosis. More recently, evidence that somatic mosaicism contributes to inflammatory diseases that wax and wane was provided by a study that showed that somatic single nucleotide variants in the ATP2A2 gene are associated with Grover disease or transient acantholytic dermatosis, which presents with inflammatory flares after environmental triggers (Seli et al., 2023Seli D. Ellis K.T. Goldust M. Shah K. Hu R. Zhou J. et al.Association of somatic ATP2A2 damaging variants with Grover disease.JAMA Dermatol. 2023; 159: 745-749Crossref Scopus (4) Google Scholar). The variants shared UV light signatures, consistent with the clinical presentation of lesions in sun-exposed skin increasing with age. Cutaneous symptoms can also give clues to multisystem somatic mosaicism. Skin lesions were the most common clinical feature in patients with VEXAS (vacuoles, E1, X-linked, autoinflammation, somatic) syndrome (Georgin-Lavialle et al., 2022Georgin-Lavialle S. Terrier B. Guedon A.F. Heiblig M. Comont T. Lazaro E. et al.Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.Br J Dermatol. 2022; 186: 564-574Crossref PubMed Scopus (155) Google Scholar), which is caused by somatic inactivating variants in the UBA1 gene and leads to systemic inflammation, including pulmonary and hematologic dysfunction. In rare cases, somatic variation in the skin can lead to correction of damaging variants. These instances of revertant mosaicism appear as healthy skin on a background of lesional skin and represent a form of natural gene therapy. This can occur owing to multiple mechanisms, including mitotic recombination and second-site SNVs. Revertant mosaicism has been shown in patients with epidermolysis bullosa (Jonkman et al., 1997Jonkman M.F. Scheffer H. Stulp R. Pas H.H. Nijenhuis M. Heeres K. et al.Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion.Cell. 1997; 88: 543-551Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) and ichthyosis with confetti (Choate et al., 2010Choate K.A. Lu Y. Zhou J. Choi M. Elias P.M. Farhi A. et al.Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10.Science. 2010; 330: 94-97Crossref PubMed Scopus (151) Google Scholar). A National Institutes of Health (NIH) funded initiative, Somatic Mosaicism across Human Tissues (SMaHT), aims to shed light on somatic mosaicism across diverse tissues, including the skin (National Institutes of Health, 2021National Institutes of HealthSomatic Mosaicism Across Human Tissues (SMaHT).https://commonfund.nih.gov/smahtDate: 2021Date accessed: September 4, 2023Google Scholar). One of the planned outcomes of this initiative is a reference dataset of somatic variants across 15 tissues from diverse human donors. The majority of the initial grants from this NIH initiative focus on tool development, including sequencing technologies and computational tools to aid in detection of somatic variants. Novel sequencing technologies will benefit the study of mosaic cutaneous disorders and the field of dermatology more broadly. For example, one SMaHT-funded project (SlideDNASeq) from the Broad Institute aims to utilize a previously developed platform for spatial genomics (Zhao et al., 2022Zhao T. Chiang Z.D. Morriss J.W. LaFave L.M. Murray E.M. Del Priore I. et al.Spatial genomics enables multi-modal study of clonal heterogeneity in tissues.Nature. 2022; 601: 85-91Crossref PubMed Scopus (95) Google Scholar) to study somatic mosaicism of tissues in situ. This platform for spatial DNA sequencing can be combined with transcriptomic and epigenetic profiling to enable insight into how somatic mosaicism may affect the cell-type composition and functional state of cells within tissues. Spatial technologies such as this may be especially impactful in the field of skin biology, in which the complex and tightly regulated architecture of skin is of particular importance. Another funded sequencing-based proposal from New York University aims to develop a technology, termed Hairpin Duplex Enhanced Fidelity Sequencing (ie, HiDEF-seq), which accurately detects variants in a single strand of DNA. This approach may be particularly useful for the detection of somatic changes due to DNA damage (Liu et al, 2023 1Liu MH, Costa B, Choi U, Bandler RC, Lassen E, Grońska-Pęski M, et al. Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing. bioRxiv 2023.), which are important drivers of skin cancer and other skin pathologies. Other funded proposals will attempt to incorporate transcriptomics, chromatin profiling, and novel amplification techniques to improve the ability to detect and functionally dissect somatic mosaicism. Second, novel technologies for variant detection could improve our ability to diagnose cutaneous mosaic disorders in which the mutant allele frequency can be very low. One SMaHT-funded project from the University of Utah aims to apply a reference-free computational approach to improve variant detection in somatic tissues. Finally, a growing database of somatic variants in healthy human skin will aid in determining which somatic variants contribute to skin diseases (Figure 1). To identify drivers of cutaneous mosaic disorders, researchers typically sequence DNA from involved skin and compare it with that from uninvolved skin or another tissue such as blood or saliva. The genetic variants identified in the involved skin form a list of candidate genes for the cause of the cutaneous mosaic disorder. A database containing allele frequencies for variants detected in healthy human skin would improve researchers' ability to filter variants by discarding variants that are commonly seen in normal skin and thus less likely to be disease causing. Owing to the unique properties of the skin and its disorders, the field of dermatology is especially poised to contribute to the study of somatic mosaicism. Advances in the field of somatic mosaicism will improve our understanding of cutaneous mosaic disorders and skin biology.