Relating evolutionary selection and mutant clonal dynamics in normal epithelia

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behavior. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental data set showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection. Significance Statement Aging normal epithelial tissues are extensively colonized by clones carrying cancer associated mutations. Insight into the emergence of mutant clones is key to guide cancer prevention. However, the statistical evidence as to whether mutant clones emerge by neutral competition or due to a competitive advantage conferred by mutation is conflicted. We reconcile this apparent contradiction by demonstrating that the previously presented metrics for measuring neutrality from clone sizes are dependent on the spatial constraints imposed by the tissue structure and experimental design. Furthermore, we show that clonal competition within a recently reported dataset of healthy human esophageal tissue is non-neutral. Finally, we discuss how discrepancies between measures of clone size and genetic selection can provide insight into early carcinogenesis.