Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

Nat Genet. 2020 Jun;52(6):604-614. doi: 10.1038/s41588-020-0624-3. Epub 2020 May 18.


During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / genetics
  • Amyloid Precursor Protein Secretases / genetics
  • Animals
  • Cell Lineage
  • Diethylnitrosamine / toxicity
  • Epithelium / drug effects
  • Epithelium / pathology
  • Epithelium / physiology
  • Esophagus / cytology*
  • Esophagus / physiology
  • Female
  • High-Throughput Nucleotide Sequencing
  • Male
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation*
  • Receptor, Notch1 / genetics
  • Receptor, Notch2 / genetics
  • Reproducibility of Results
  • Tumor Suppressor Protein p53 / genetics


  • Membrane Proteins
  • Notch1 protein, mouse
  • Notch2 protein, mouse
  • Receptor, Notch1
  • Receptor, Notch2
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Diethylnitrosamine
  • Amyloid Precursor Protein Secretases
  • ADAM10 Protein
  • Adam10 protein, mouse