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在人类老化食道中的克隆进化的大规模单细胞遗传映射
Tamara Prieto1,2, Dennis J Yuan1,2, John Zinno1,2
1New York Genome Center, New York, NY, USA.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
人体体内基因组在整个生命过程中不断演变,创造出马赛克个体. 这项研究引入了一种新方法来追踪固体组织中的克隆进化,揭示了突变如何随着时间的推移积累并影响细胞状态.
科学领域:
- 基因组学就是基因组学.
- 进化生物学 进化生物学
- 细胞生物学 细胞生物学
背景情况:
- 人体体质基因组在整个生命中都会积累突变,导致组织间的马赛克主义.
- 克隆扩张在血液中得到了很好的研究,但在固体组织中不太了解.
- 关于克隆在正常固体组织中的时间,进化和扩张机制的关键问题仍然存在.
研究的目的:
- 开发一种可扩展和具有成本效益的方法,用于联合单细胞全基因组和全转录组测序.
- 重建高分辨率的单细胞血统,并了解表型正常的人类组织中的体质进化.
- 调查驱动克隆扩张的机制,并确定相关的遗传和转录组变化.
主要方法:
- 为匹配的单细胞WGS和WTS开发了单细胞小型化自动反向转录和初级模板导向放大 (SMART-PTA).
- 应用SMART-PTA对来自四位老年捐赠者的表型正常食道组织的2700个细胞进行了分析.
- 利用体质变异来进行遗传学重建,并整合转录基因数据来进行表型注释.
主要成果:
- 在食道上皮层中重建了超过70年的体质进化,具有高分辨率.
- 确定了携带驱动突变 (例如TP53,FAT1) 的克隆扩张,并绘制了它们的演变图,包括双基TP53损失.
- 在突变克隆中观察到细胞类型偏差和9q染色体上的反复复制-中性异构性丧失 (CNLOH) 事件,表明融合进化和选择性优势.
结论:
- SMART-PTA是一种高效且可扩展的方法,用于分析正常组织中的体质进化.
- 高分辨率的族系学揭示了克隆扩张的动态及其整个生命周期的表型后果.
- 该研究提供了对形成表型正常组织的进化过程的见解,并确定了早期克隆变化的潜在驱动因素.
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