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

这个建议是追求一个高度创新的一般理论，整合了进化，发育生物学，表观遗传学和疾病。表观遗传学是研究细胞分裂过程中DNA序列以外的遗传信息，它是正常发育的基础，在癌症和其他常见疾病中很重要。自1983年发现癌症中DNA甲基化的改变以来，我一直参与这一领域。从那时起，我和其他人一直在努力研究如何将表观遗传学与进化思想结合起来。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，由于强大的配子重编程，从长远来看，这是一种罕见的难以置信的机制。我提出了一种新的遗传随机变异模型，其中遗传变异不会导致平均可观察表型，但可以通过表观遗传机制改变观察表型的可变性。这些增加表观遗传变异的可遗传遗传变异将在环境选择方向（积极或消极）长期波动的基因中发现。这些变异可能是由表观遗传介导的，例如，等基因背景下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部，在最近改变的环境（如西方饮食）中会增加疾病易感性。我发现了三组支持这一新观点的初步数据：在相同环境下饲养的近亲繁殖小鼠的特定组织中，高度可变的DNA甲基化区域，以及调节发育的关键基因；老鼠和人类在DNA序列上的差异，一个物种有这种变异，而另一个物种没有；这些可变甲基化区域和身体质量指数之间存在联系。我的具体计划是：(1)检验随机表观遗传可塑性在正常分化中的作用；(2)研究模式生物——蜂蜜的发育表观遗传学

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. My specific plans are: (1) to test the role of stochastic epigenetic plasticity in normal differentiation; (2) to study developmental epigenetics in a model organism, the honey bee Apis mellifera, in particular the idea that genetic variants with developmental differences (such as high and low pollen producers) have genetically assimilated sites of epigenetic variability; (3) to develop a mathematical model for epigenetic plasticity and its relationship to genetic variation; and (4) to investigate epigenetic plasticity in human populations, and to identify sequences regulating epigenetic plasticity. This highly innovative proposal represents a completely new direction for my research, and could have profound influence on our understanding of epigenetics, developmental biology, population variation and disease. Project Description