Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium

Cell Stem Cell
Anna M NicholsonD J Winton

Abstract

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.

Citations

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Datasets Mentioned

BETA
SRP139051

Methods Mentioned

BETA
surgical resection
amplicon sequencing
PCR

Software Mentioned

- docs
STAG2
HASH
Aperio
Block Viewer
opencv
DeCryptICS
openslide
PANDAseq
Google maps

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