Genereux Diane P
Department of Biology, University of Washington, Seattle, WA, USA.
PLoS Genet. 2009 Jun;5(6):e1000509. doi: 10.1371/journal.pgen.1000509. Epub 2009 Jun 5.
Asymmetric strand segregation has been proposed as a mechanism to minimize effective mutation rates in epithelial tissues. Under asymmetric strand segregation, the double-stranded molecule that contains the oldest DNA strand is preferentially targeted to the somatic stem cell after each round of DNA replication. This oldest DNA strand is expected to have fewer errors than younger strands because some of the errors that arise on daughter strands during their synthesis fail to be repaired. Empirical findings suggest the possibility of asymmetric strand segregation in a subset of mammalian cell lineages, indicating that it may indeed function to increase genetic fidelity. However, the implications of asymmetric strand segregation for the fidelity of epigenetic information remain unexplored. Here, I explore the impact of strand-segregation dynamics on epigenetic fidelity using a mathematical-modelling approach that draws on the known molecular mechanisms of DNA methylation and existing rate estimates from empirical methylation data. I find that, for a wide range of starting methylation densities, asymmetric -- but not symmetric -- strand segregation leads to systematic increases in methylation levels if parent strands are subject to de novo methylation events. I found that epigenetic fidelity can be compromised when enhanced genetic fidelity is achieved through asymmetric strand segregation. Strand segregation dynamics could thus explain the increased DNA methylation densities that are observed in structured cellular populations during aging and in disease.
非对称链分离被认为是一种可将上皮组织中有效突变率降至最低的机制。在非对称链分离过程中，每一轮DNA复制后，含有最古老DNA链的双链分子会优先进入体细胞干细胞。这条最古老的DNA链预计比年轻链的错误更少，因为子链在合成过程中出现的一些错误未能得到修复。实证研究结果表明，在一部分哺乳动物细胞谱系中存在非对称链分离的可能性，这表明它确实可能起到提高遗传保真度的作用。然而，非对称链分离对表观遗传信息保真度的影响仍未得到探索。在此，我运用一种数学建模方法来探究链分离动态对表观遗传保真度的影响，该方法借鉴了DNA甲基化的已知分子机制以及来自实证甲基化数据的现有速率估计。我发现，对于广泛的起始甲基化密度范围，如果亲代链经历从头甲基化事件，非对称而非对称的链分离会导致甲基化水平系统性增加。我发现，当通过非对称链分离实现更高的遗传保真度时，表观遗传保真度可能会受到损害。因此，链分离动态可以解释在衰老和疾病过程中结构化细胞群体中观察到的DNA甲基化密度增加现象。
