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.

中文翻译：

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空间竞争塑造了正常食管上皮的动态突变景观。


在衰老过程中，祖细胞会发生突变，这可能会产生克隆，并在周围组织中定居。到了中年，正常人体组织，包括食管上皮（EE），变成了突变克隆的拼凑而成。尽管它们与理解衰老和癌症相关，但正常组织中支持突变选择的过程仍然知之甚少。在这里，我们在诱变剂处理的小鼠的食管上皮中研究了这个问题。深度测序在正选择下鉴定出许多具有多个基因的突变克隆，包括Notch1、Notch2和Trp53，这些基因也在人类食管上皮中被选择。转基因谱系追踪揭示了随着时间的推移而演变的强烈克隆竞争。克隆动力学与一个简单的模型一致，其中积极选择的突变所赋予的增殖优势取决于邻近细胞的性质。当具有相似竞争适应度的克隆发生碰撞时，突变细胞的命运就会恢复到稳态，这一限制解释了选择如何在正常上皮中进行。