Spatial constraints govern competition of mutant clones in human epidermis.
Spatial constraints govern competition of mutant clones in human epidermis.
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DOI：
10.1038/s41467-017-00993-8
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发表时间：
2017-10-24
影响因子：
16.6
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Lynch MD;Lynch CNS;Craythorne E;Liakath-Ali K;Mallipeddi R;Barker JN;Watt FM
深度测序可以检测组织中允许推断克隆关系的体细胞DNA突变。这已经应用于人类表皮，阳光照射导致突变的积累和皮肤癌的风险增加。然而，以前的研究已经得出了相互矛盾的结论，积极选择和中性漂移在克隆进化中的相对重要性。在这里，我们对比以前更大的皮肤区域进行了测序，重点关注了50年来易患癌症的皮肤。鉴定的突变克隆太大，不能仅用中性漂变来解释。相反，使用数学建模和基于计算格子的模拟，我们表明观察到的克隆大小分布可以通过具有竞争优势的扩展突变克隆边界处的中性漂移和突变随机成核的组合来解释。这些发现表明，空间环境和细胞竞争合作，以确定突变干细胞的命运。深度测序技术允许研究人类癌症中的克隆进化。在这里，作者将人类皮肤的测序数据与数学建模和模拟相结合，表明突变相对于其他突变克隆的空间背景可能导致差异克隆进化。
Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell. Deep sequencing technologies allow for the investigation of clonal evolution in human cancers. Here the authors, combining sequencing data from human skin with mathematical modelling and simulations, suggest that the spatial context of a mutation with respect to other mutant clones may lead to differential clonal evolution.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.1220353110
发表时间：
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影响因子：
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通讯作者：
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