Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease
Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease
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DOI：
10.1073/pnas.0906183107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Irizarry, Rafael A.
中科院分区：
文献类型：
--
作者：
Feinberg, Andrew P.;Irizarry, Rafael A.
新达尔文进化论的基础是微小的遗传变异引起的表型的精细选择，这是数量性状对表型和疾病贡献的基础。表观遗传学是研究细胞分裂过程中可遗传的非序列变化，如DNA甲基化。以前将表观遗传学纳入进化思想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。在这里，我们提出了一个新的非拉马克理论的表观遗传学在进化中的作用。我们认为，不改变平均表型的遗传变异可能会改变表型的变异性，这可能是介导的表观遗传。这种遗传的随机变异模型将提供一种机制来解释发育生物学在可选择的表型变异中的表观遗传作用，以及常见的复杂疾病背后的大部分无法解释的遗传变异。我们提供了两个实验结果作为原则的证明。第一个结果是随机表观遗传变异的直接证据，确定了小鼠和人类肝脏和小鼠大脑中与发育和形态发生相关的高度DNA甲基化区域。第二个是可变甲基化的遗传遗传机制，即随着进化时间的推移，CpG二核苷酸的丢失或获得。最后，我们遗传遗传的随机变异的进化模型，表明它提供了一个强大的机制，在不断变化的环境中，可以介导的表观遗传的进化适应。这些数据表明，遗传遗传倾向表型变异，即使没有变化的平均表型，大大增加健身，同时增加疾病的易感性的人口与不断变化的环境。
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.