Abstract
Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.
Highlights
Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships
Previous studies reveal a paradox, whereby there is evidence of positive selection of mutant epidermal clones[11], yet clone size distributions are consistent with neutral drift[12,13,14], a process by which the emergence of mutant clones is through genetic drift of mutant alleles that have neither a positive nor a negative effect on clone size
By analysing larger areas of human epidermis, obtaining tissue from individuals of a wide age range, and increasing the number of samples analysed, we have ben able to resolve the current controversy surrounding the evolution of mutant clones[11,12,13,14]
Summary
Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. We reasoned that our understanding of clonal relationships and the potential role of cell competition in sun-exposed human skin could be improved by analysing more and larger samples than previously, by extending the analysis to skin from older individuals, and by sampling skin from donors who were at elevated risk of developing skin cancer. These approaches have led us to discover that clone size cannot be explained solely on the basis of neutral drift, but is influenced by the spatial location of cells that acquire secondary mutations. Genes that are recurrently mutated in cutaneous squamous cell carcinoma are frequently mutated in sun-exposed epidermis (Fig. 2c) and the location of mutations within the NOTCH1 gene in our samples closely parallels that seen in cutaneous squamous cell carcinoma (Fig. 2d, e; Supplementary Fig. 3)
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