Haeno Hiroshi, Maruvka Yosef E, Iwasa Yoh, Michor Franziska
Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
PLoS One. 2013 Jun 26;8(6):e65724. doi: 10.1371/journal.pone.0065724. Print 2013.
Cancer initiation, progression, and the emergence of drug resistance are driven by specific genetic and/or epigenetic alterations such as point mutations, structural alterations, DNA methylation and histone modification changes. These alterations may confer advantageous, deleterious or neutral effects to mutated cells. Previous studies showed that cells harboring two particular alterations may arise in a fixed-size population even in the absence of an intermediate state in which cells harboring only the first alteration take over the population; this phenomenon is called stochastic tunneling. Here, we investigated a stochastic Moran model in which two alterations emerge in a cell population of fixed size. We developed a novel approach to comprehensively describe the evolutionary dynamics of stochastic tunneling of two mutations. We considered the scenarios of large mutation rates and various fitness values and validated the accuracy of the mathematical predictions with exact stochastic computer simulations. Our theory is applicable to situations in which two alterations are accumulated in a fixed-size population of binary dividing cells.
癌症的起始、进展以及耐药性的出现是由特定的基因和/或表观遗传改变驱动的，如点突变、结构改变、DNA甲基化和组蛋白修饰变化。这些改变可能对突变细胞产生有利、有害或中性影响。先前的研究表明，即使在不存在仅携带第一种改变的细胞占据群体的中间状态的情况下，在固定大小的群体中也可能出现携带两种特定改变的细胞；这种现象称为随机隧穿。在这里，我们研究了一个随机莫兰模型，其中在固定大小的细胞群体中出现两种改变。我们开发了一种新颖的方法来全面描述两个突变的随机隧穿的进化动力学。我们考虑了大突变率和各种适应度值的情况，并用精确的随机计算机模拟验证了数学预测的准确性。我们的理论适用于在固定大小的二元分裂细胞群体中积累两种改变的情况。
