nature20121220-8

一直以来人们认为身体内的每个细胞具有完全相同的DNA。然而来自耶鲁大学医学院的研究人员在一项针对皮肤细胞诱导生成的iPS细胞研究中发现人体组织广泛存在遗传变异,这一研究对于遗传筛选将产生深远的影响。

-2012年12月20日《自然》


中文翻译


【题目】诱导多能性干细胞揭示人类皮肤中体细胞拷贝数镶嵌现象

【译文】重编程的体细胞成诱导多能性干细胞(iPSCs)一直受到可能导致新发拷贝数突变的怀疑。为了阐释这一问题,本研究利用下一代测序对来源于7个个体主要皮肤成纤维细胞的20个人类iPSC全基因组和转录组分析。我们发现,平均来说,一种iPSC表现出两种拷贝数突变(CNVs),而在iPSC来源的成纤维细胞中不明显。利用PCR和微流体液滴数字PCR技术,本研究表明至少50%的CNV以低频率体细胞基因组突变体出现在亲本成纤维细胞(即,每个相应人iPSC来源的成纤维细胞)中,由于它们无性起源,这些CNV被在iPSC细胞系中得以证明。因此,iPSCs中重编程不能引起新生CNV,因为人类皮肤中大多数细胞系显示的CNV反应了体细胞镶嵌现象。 而且,我们的发现证实了无性扩增,尤其是iPSC细胞系,可用于可靠地检测起源组织中低频CNV的发现工具。总之,我们评估了约30%的成纤维细胞在它们基因组上有体细胞CNV,表明人类中广泛存在体细胞镶嵌现象。我们的研究为理解人类细胞获得DNA后合子结构变化程度的基本问题铺平了道路。

英文原稿


[Title]: Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells

[Authors]:Alexej Abyzov,1, 2, 3 Jessica Mariani,1, 4, 14 Dean Palejev,1, 4, 14 Ying Zhang,1, 5, 14 Michael Seamus Haney,6, 7, 14 Livia Tomasini,1, 4, 14 Anthony F. Ferrandino,1, 4 Lior A. Rosenberg Belmaker,1, 4 Anna Szekely,1, 5, 8 Michael Wilson,1, 2, 4 Arif Kocabas,1, 4 Nathaniel E. Calixto,1, 4 Elena L. Grigorenko,1, 4, 9, 10 Anita Huttner,1, 11 Katarzyna Chawarska,1, 4 Sherman Weissman,1, 5 Alexander Eckehart Urban,1, 6, 7 Mark Gerstein1, 2, 3, 12 & Flora M. Vaccarino1, 4, 13

[Abstract]Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) has been suspected of causing de novo copy number variation. To explore this issue, here we perform a whole-genome and transcriptome analysis of 20 human iPSC lines derived from the primary skin fibroblasts of seven individuals using next-generation sequencing. We find that, on average, an iPSC line manifests two copy number variants (CNVs) not apparent in the fibroblasts from which the iPSC was derived. Using PCR and digital droplet PCR, we show that at least 50% of those CNVs are present as low-frequency somatic genomic variants in parental fibroblasts (that is, the fibroblasts from which each corresponding human iPSC line is derived), and are manifested in iPSC lines owing to their clonal origin. Hence, reprogramming does not necessarily lead to de novo CNVs in iPSCs, because most of the line-manifested CNVs reflect somatic mosaicism in the human skin. Moreover, our findings demonstrate that clonal expansion, and iPSC lines in particular, can be used as a discovery tool to reliably detect low-frequency CNVs in the tissue of origin. Overall, we estimate that approximately 30% of the fibroblast cells have somatic CNVs in their genomes, suggesting widespread somatic mosaicism in the human body. Our study paves the way to understanding the fundamental question of the extent to which cells of the human body normally acquire structural alterations in their DNA post-zygotically.

原文地址

http://www.nature.com/nature/journal/v492/n7429/full/nature11629.html

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