Epigenetic variation in early human development

人类生物学中一个有趣的问题是，为什么具有相同基因组成的同卵双胞胎在许多复杂特征上仍然存在差异，比如身高、眼睛颜色以及对各种精神和疾病状态的易感性。很明显，这种变化并不总是简单地归因于环境。我们在这个应用程序中提出，即使在同卵双胞胎的遗传密码是相同的，表观遗传标记，如DNA甲基化和组蛋白修饰可以在关键基因之间变化，从而导致基因表达模式的差异。我们提出，甲基化模式的变化发生在两个胚胎分裂之后，此时发育中的胚胎经历全基因组去甲基化，然后是从头再甲基化。这个项目的重要性不在于它告诉我们双胞胎本身，而是双胞胎可以为影响人群中每个人的疾病过程提供线索。这些实验的结果将确定胚胎发育早期发生的基因组表观遗传变化在多大程度上为基因表达变异提供了额外的来源，从而可能导致表型变异。通过使用同卵双胞胎，我们消除了我们观察到的表观遗传修饰本身受基因型影响的可能性。确定这些表观遗传差异将有助于深入了解复杂性状和人类疾病的潜在机制。

One of the interesting questions in human biology is why monozygotic twins, which have an identical genetic make up, can still vary in many complex traits such as height, eye colour and susceptibility to various mental and disease states. It is clear that this variation is not always due simply to environment. We propose in this application to show that, even if the genetic code is identical in monozygotic twins, epigenetic marks such as DNA methylation and histone modifications can vary between critical genes giving rise to differences in gene expression patterns. We propose that the variation in the methylation pattern arises after the two embryos have split, at a time when the developing embryo undergoes genome-wide demethylation followed by de novo re-methylation. The importance of this project is NOT what it tells us about twins themselves, but that twins can provide the clue to disease processes which affect everybody in the population. The results of these experiments will determine the extent to which epigenetic changes to the genome that occur early in embryonic development provide an additional source of variation in gene expression that could contribute to phenotypic variation. By using identical twins we eliminate the possibility that epigenetic modifications that we observe are themselves influenced by genotype. Determining these epigenetic differences will provide an insight into the mechanisms underlying complex traits and human disease.