Tomasetti Cristian, Bozic Ivana
Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Program for Evolutionary Dynamics and Department of Mathematics, Harvard University, Cambridge, MA, USA.
Stem Cell Res. 2015 Mar;14(2):238-41. doi: 10.1016/j.scr.2015.01.005. Epub 2015 Jan 24.
Non-random segregation of DNA strands during stem cell replication has been proposed as a mechanism to minimize accumulated genetic errors in stem cells of rapidly dividing tissues. According to this hypothesis, an "immortal" DNA strand is passed to the stem cell daughter and not the more differentiated cell, keeping the stem cell lineage replication error-free. After it was introduced, experimental evidence both in favor and against the hypothesis has been presented.
Using a novel methodology that utilizes cancer sequencing data we are able to estimate the rate of accumulation of mutations in healthy stem cells of the colon, blood and head and neck tissues. We find that in these tissues mutations in stem cells accumulate at rates strikingly similar to those expected without the protection from the immortal strand mechanism.
Utilizing an approach that is fundamentally different from previous efforts to confirm or refute the immortal strand hypothesis, we provide evidence against non-random segregation of DNA during stem cell replication. Our results strongly suggest that parental DNA is passed randomly to stem cell daughters and provides new insight into the mechanism of DNA replication in stem cells.
干细胞复制过程中DNA链的非随机分离被认为是一种机制，可将快速分裂组织的干细胞中累积的遗传错误降至最低。根据这一假设，一条“不朽”的DNA链会传递给干细胞子代，而非更分化的细胞，从而使干细胞谱系的复制无错误。该假设提出后，出现了支持和反对这一假设的实验证据。
使用一种利用癌症测序数据的新方法，我们能够估计结肠、血液以及头颈部组织的健康干细胞中突变的累积速率。我们发现，在这些组织中，干细胞中的突变累积速率与没有“不朽链”机制保护时预期的速率惊人地相似。
利用一种与之前证实或反驳“不朽链”假设的努力根本不同的方法，我们提供了反对干细胞复制过程中DNA非随机分离的证据。我们的结果强烈表明，亲代DNA是随机传递给干细胞子代的，并为干细胞中DNA复制的机制提供了新的见解。
