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    • The following are the supplementary

    2018-10-24

    The following are the supplementary data related to this article.
    Acknowledgments This study was supported by the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (Grant no. A120262) and a 2012 grant (10172KFDA993) from the Korea Food & Drug Administration (awarded to M. Kim).
    Introduction The immortal DNA strand hypothesis has been proposed (Cairns, 1975) as a mechanism used by stem simvastin in order to minimize the accumulation of mutations in their genomes. This hypothesis proposes that stem cells divide predominantly asymmetrically, producing one stem cell and one differentiated cell, and that at each division, a template set of DNA strands (known as the “parental” or “immortal strands”) is transferred to the daughter stem cell and not to the non-stem cell daughter. The fundamental idea behind this hypothesis is that, by retaining the immortal strands within the stem cell progeny, the accumulation of random DNA replication errors in the stem cell compartment would be greatly reduced, therefore decreasing the risk of genetic disorders such as cancer. Indeed, errors in DNA duplication would be passed on to non-stem, more differentiated, and shorter-lived daughter cells. The earliest experimental evidence for the non-random segregation of stem cell DNA strands in mammalian tissues comes from studies by Potten et al. of tongue epithelia and intestinal crypts (Potten et al., 1978). Although some further experimental work appears to support this hypothesis (Potten et al., 2002; Smith, 2005; Karpowicz et al., 2005; Shinin et al., 2006; Conboy et al., 2007; Armakolas and Klar, 2007), whether such a mechanism is operational in adult stem cells in vivo or not is still controversial (Haber, 2006), with reports arguing against the existence of immortal strands in intestinal crypts (Steinhauser et al., 2012) and hematopoietic stem cells (Kiel et al., 2007). Most of the studies arguing for or against the immortal strand relied on labeling early stem cells and testing whether segregation of label followed a random or non-random pattern. Here we use a different approach that utilizes genetic sequencing data and provide new evidence against the immortal strand hypothesis, by showing that stem cells in hematopoietic, colorectal and head and neck epithelial tissues contain as many somatic mutations as would be expected if no protection mechanism were in place.
    Results Tomasetti et al. (2013). recently provided a new methodology for estimating the number of mutations that accumulate in healthy self-renewing tissues. Their results were obtained via the analysis of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) whole-exome sequencing data on somatic mutations from patients with a given tumor type. Tomasetti et al. found statistically significant strong positive correlations between age and number of somatic mutations in tumors of several self-renewing tissues, in patients with matched tumor stages (Fig. 1A). For example, the data show that colorectal cancers from 85-year-old patients have, on average, 47 mutations more than colorectal cancers at the same stage from 45-year-old patients. Since the cancer stage is the same, those extra 47 mutations are, on average, not due to the cancer phase, but to the normal accumulation of somatic mutations occurring in the healthy tissue during the extra time the older patients had before tumorigenesis started (Fig. 1B). This allows the estimation of the rate at which mutations accumulate in healthy cells, prior to the first driver mutation hit. This method represents a unique way of indirect single cell sequencing, since all tumor cells carry the changes present in their last healthy ancestor in addition to changes accumulated during tumor evolution (Fig. 1B). Importantly, their results yielded estimates for the rate of accumulation of somatic mutations in healthy tissues that are remarkably in line with estimates obtained via completely different methodologies (Tomasetti et al., 2013).