Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium.

Abstract

The means and timing by which mutations become fixed in the human colonic epithelium was investigated by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic gland has to be mutated. Second, the mutated stem cell has to replace neighbours to populate the entire gland in a process that takes several years. Subsequent clonal expansion due to gland fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by gland fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviours allows the advantage associated with different gene specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.