Feinberg Andrew P, Irizarry Rafael A
Center for Epigenetics, Johns Hopkins University, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1(Suppl 1):1757-64. doi: 10.1073/pnas.0906183107. Epub 2009 Dec 22.
Neo-Darwinian evolutionary theory is based on exquisite selection of phenotypes caused by small genetic variations, which is the basis of quantitative trait contribution to phenotype and disease. Epigenetics is the study of nonsequence-based changes, such as DNA methylation, heritable during cell division. Previous attempts to incorporate epigenetics into evolutionary thinking have focused on Lamarckian inheritance, that is, environmentally directed epigenetic changes. Here, we propose a new non-Lamarckian theory for a role of epigenetics in evolution. We suggest that genetic variants that do not change the mean phenotype could change the variability of phenotype; and this could be mediated epigenetically. This inherited stochastic variation model would provide a mechanism to explain an epigenetic role of developmental biology in selectable phenotypic variation, as well as the largely unexplained heritable genetic variation underlying common complex disease. We provide two experimental results as proof of principle. The first result is direct evidence for stochastic epigenetic variation, identifying highly variably DNA-methylated regions in mouse and human liver and mouse brain, associated with development and morphogenesis. The second is a heritable genetic mechanism for variable methylation, namely the loss or gain of CpG dinucleotides over evolutionary time. Finally, we model genetically inherited stochastic variation in evolution, showing that it provides a powerful mechanism for evolutionary adaptation in changing environments that can be mediated epigenetically. These data suggest that genetically inherited propensity to phenotypic variability, even with no change in the mean phenotype, substantially increases fitness while increasing the disease susceptibility of a population with a changing environment.
新达尔文进化理论基于由微小基因变异引起的对表型的精细选择，这是数量性状对表型和疾病产生影响的基础。表观遗传学是对基于非序列变化的研究，如DNA甲基化，这种变化在细胞分裂过程中可遗传。先前将表观遗传学纳入进化思维的尝试主要集中在拉马克遗传，即环境导向的表观遗传变化。在此，我们提出一种新的非拉马克理论，阐述表观遗传学在进化中的作用。我们认为，不改变平均表型的基因变异可能会改变表型的变异性；而这可能由表观遗传介导。这种遗传随机变异模型将提供一种机制，用以解释发育生物学在可选择表型变异中的表观遗传作用，以及常见复杂疾病背后很大程度上尚未得到解释的可遗传基因变异。我们提供两个实验结果作为原理证明。第一个结果是随机表观遗传变异的直接证据，在小鼠和人类肝脏以及小鼠大脑中识别出与发育和形态发生相关的高度可变的DNA甲基化区域。第二个是可变甲基化的可遗传基因机制，即在进化过程中CpG二核苷酸的丢失或获得。最后，我们对进化中的遗传随机变异进行建模，表明它为在不断变化的环境中进行进化适应提供了一种强大机制，这种适应可由表观遗传介导。这些数据表明，即使平均表型没有变化，遗传上对表型变异性的倾向也会显著提高适应性，同时在环境变化时增加群体的疾病易感性。
