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可遗传的信息，而不是DNA序列，它是正常发育的基础，在癌症和其他常见疾病中很重要。自从1983年我发现癌症中DNA甲基化改变以来，我一直参与这一领域。从那时起，我和其他人就一直在努力解决如何将表观遗传学纳入进化思维的问题。有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，这是一种令人难以置信的机制，只有极少数例外。我提出了一个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的表型，但可以通过表观遗传机制改变所观察到的表型的变异性。这些增加表观遗传变异的可遗传变异将在基因中发现，其中环境选择的方向（积极或消极）在很长一段时间内波动。这种变异的变体将由表观遗传学介导，例如，在同基因背景中DNA甲基化的随机变异。与此同时，通过增加表型分布曲线两端的尾部，在最近改变的环境中（如西方饮食），疾病易感性会增加。我发现了三条初步数据支持这一新观点：在同一环境中饲养的近交系小鼠的特定组织中，DNA甲基化的高度可变区域，并调节发育的关键基因;小鼠/人类DNA序列的差异，其中一个物种具有这种变异，另一个物种没有;以及一些这些高度甲基化区域与体重指数之间的联系。我的具体计划是：（1）测试随机表观遗传可塑性在正常分化中的作用;（2）研究模式生物蜂蜜中的发育表观遗传学 蜜蜂，特别是思想，遗传变异与发展的差异， (such作为高和低花粉生产者）具有表观遗传同化位点， 变异性;（3）建立表观遗传可塑性的数学模型， 遗传变异;（4）研究人类群体的表观遗传可塑性， 鉴定调节表观遗传可塑性的序列。这一极具创新性的提案代表了 这是我研究的一个全新方向，可能会对我们的研究产生深远的影响。 了解表观遗传学、发育生物学、种群变异和疾病。 项目描述

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