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

Nicholson AM, Olpe C, Hoyle A, Thorsen AS, Rus T, Colombé M, Brunton-Sim R, Kemp R, Marks K, Quirke P, Malhotra S, Ten Hoopen R, Ibrahim A, Lindskog C, Myers MB, Parsons B, Tavaré S, Wilkinson M, Morrissey E, Winton DJ

Cell Stem Cell 22 (6) 909-918.e8 [2018-06-01; online 2018-05-17]

We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt 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 crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.

Affiliated researcher

PubMed 29779891

DOI 10.1016/j.stem.2018.04.020

Crossref 10.1016/j.stem.2018.04.020

pii: S1934-5909(18)30182-6
pmc: PMC5989058

Publications 7.1.2