A General Stochastic Epigenetic Model for Evolution, Development, and Disease

描述 摘要： 这项提议是为了追求一种高度创新的一般理论，将进化论、发育生物学、表观遗传学和疾病结合在一起。表观遗传学是研究细胞分裂过程中可遗传的信息，而不是DNA序列，它是正常发育的基础，对癌症和可能的其他常见疾病都很重要。自从1983年我在癌症中发现DNA甲基化改变以来，我一直从事这一领域。从那时起，我和其他人一直在努力解决如何将表观遗传学纳入进化思维的问题。一些人提出了表观遗传标记的拉马克遗传，即环境导向的表观遗传变化，在我看来，这在很少的例外情况下是一种长期不可信的机制，因为强大的配子重编程。我建议一个新的遗传随机变异模型，在该模型中，遗传变异不会导致平均可观察到的表型，但可以通过表观遗传机制改变观察到的表型的可变性。这些表观遗传变异增加的可遗传遗传变异可以在环境选择方向(正或负)长时间波动的基因中找到。这样的变异将通过表观遗传学进行调节，例如，在相同的基因背景下，DNA甲基化的随机变异。同时，通过增加表型分布曲线两端的尾巴，在最近改变的环境中，例如西方饮食，疾病的易感性会增加。我发现了三条支持这一新观点的初步数据：在相同环境中长大的近亲交配小鼠的特定组织中，DNA甲基化的高度可变区，以及调节发育的关键基因；小鼠和人在DNA序列上的差异，一个物种有这种变异，而另一个物种没有；以及一些不同的甲基化区域与体重指数之间的联系。

DESCRIPTION Abstract: This proposal is to pursue a highly innovative general theory that integrates evolution, developmental biology, epigenetics, and disease. Epigenetics is the study of information heritable during cell division other than the DNA sequence, and it underlies normal development and is important in cancer and possibly other common disease. I have been involved in this field since my discovery of altered DNA methylation in cancer in 1983. Since that time, I and others have grappled with how to incorporate epigenetics into evolutionary thinking. Some have proposed a Lamarckian inheritance of epigenetic marks, that is, environmentally directed epigenetic changes, which in my view is with rare exceptions an implausible mechanism over the long term because of powerful gametic reprogramming. I suggest a new inherited stochastic variation model in which genetic variants that do not result in mean observable phenotypes, but could change the variability of the observed phenotypes through epigenetic mechanisms. These heritable genetic variants for increased epigenetic variance would be found at genes in which the direction of environmental selection (positive or negative) fluctuates over long periods of time. Such variants for variation would be mediated epigenetically, for example, stochastic variation in DNA methylation in an isogenic background. At the same time, by increasing the tails at both ends of a phenotype distribution curve, there would be increased disease susceptibility in a recently changed environment, such as the Western diet. I have found three lines of preliminary data supporting this new idea: highly variable regions of DNA methylation in a given tissue in inbred mice raised in the same environment, and regulating key genes for development; mouse/human differences in DNA sequence in which one species has this variation and another does not; and a link between some these variably methylated regions and body mass index.