Genomic Analysis of hESC Pedigrees Identifies De Novo Mutations and Enables Determination of the Timing and Origin of Mutational Events
Genomic Analysis of hESC Pedigrees Identifies De Novo Mutations and Enables Determination of the Timing and Origin of Mutational Events
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DOI：
10.1016/j.celrep.2013.08.009
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发表时间：
2013-09-01
期刊：
影响因子：
8.8
通讯作者：
Laurent, Louise C.
中科院分区：
文献类型：
--
作者：
Ben-Yosef, Dalit;Boscolo, Francesca S.;Laurent, Louise C.
鉴于突变负荷与癌症之间的关系，在人类多能干细胞（hPSCs）中经常发现的遗传畸变引起了人们的关注。先前对人类诱导多能干细胞（hiPSCs）的研究表明，在重编程和早期培养过程中，缺失和杂合性缺失（LOH）区域往往会出现，而在长期培养过程中，复制更频繁地发生。为了在人类胚胎干细胞（hESCs）中进行相应的实验，我们研究了两组hESC系：一组包含相应的亲本DNA，另一组来自四个兄弟胚胎的单个卵裂球。在这里，我们发现在hESCs中观察到的遗传畸变可能起源于胚胎着床前发育和/或早期分化。这些早期畸变主要是缺失和LOH，而在hESCs长期培养过程中出现的畸变更常见的是重复。我们的结果强调了密切监测基因组完整性和开发改进的方法来衍生和培养人造血干细胞的重要性。
Given the association between mutational load and cancer, the observation that genetic aberrations are frequently found in human pluripotent stem cells (hPSCs) is of concern. Prior studies in human induced pluripotent stem cells (hiPSCs) have shown that deletions and regions of loss of heterozygosity (LOH) tend to arise during reprogramming and early culture, whereas duplications more frequently occur during long-term culture. For the corresponding experiments in human embryonic stem cells (hESCs), we studied two sets of hESC lines: one including the corresponding parental DNA and the other generated from single blastomeres from four sibling embryos. Here, we show that genetic aberrations observed in hESCs can originate during preimplantation embryo development and/or early derivation. These early aberrations are mainly deletions and LOH, whereas aberrations arising during long-term culture of hESCs are more frequently duplications. Our results highlight the importance of close monitoring of genomic integrity and the development of improved methods for derivation and culture of hPSCs.