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

进化、发育和疾病的通用随机表观遗传模型

• 批准号: 8541855
• 负责人: ANDREW P. FEINBERG
• 金额: $ 78.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541855
• 关键词: Body mass index; Cell division; DNA Methylation; DNA Sequence; Data; Development; Developmental Biology; Diet; Disease; Disease susceptibility; Environment; Epigenetic Process; Evolution; Genes; Human; Immunoglobulin Variable Region; Inbred Mouse; Inherited; Link; Malignant Neoplasms; Mediating; Modeling; Mus; Phenotype; Tail; Testing; Thinking; Time; Tissues; Variant; abstracting; genetic variant; innovation; theories

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. My specific plans are: (1) to test th

描述 抽象的： 该建议是追求一种高度创新的一般理论，该理论融合了进化，发育生物学，表观遗传学和疾病。表观遗传学是对DNA序列以外的细胞分裂过程中可遗传的信息的研究，它是正常发育的基础，在癌症和可能其他常见疾病中很重要。自从1983年发现癌症中DNA甲基化改变以来，我就参与了这一领域。从那时起，我和其他人一直在努力将表观遗传学纳入进化思维。一些人提出了表观遗传标记的拉马克遗传，即环保的表观遗传变化，在我看来，由于强大的配子重编程，我认为这是罕见的例外机制。我建议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的表型，但可以通过表观遗传机制改变观察到的表型的变异性。这些可遗传的遗传变异可在表观遗传方差增加的基因上发现环境选择方向（正或负）在长时间内波动。这种变异的变异将是表观遗传介导的，例如，在等源性背景下DNA甲基化的随机变化。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（例如西方饮食）中，疾病的敏感性将增加。我发现了支持这一新想法的三条初步数据：在同一环境中提出的近交小鼠中给定组织中DNA甲基化的高度可变区域，并调节关键基因的发育；小鼠/人类在DNA序列中的差异，其中一个物种具有这种变异，另一种变异没有；以及一些这些可变的甲基化区域和体重指数之间的联系。我的具体计划是：（1）测试