A human genome-wide screen for transgenerational epigenetic inheritance

在过去的50年里，几项研究挑战了DNA是哺乳动物等多细胞生物遗传的唯一生物单位的观点。在这些研究中，观察到了个体间的表型差异，这些差异不能用遗传或环境异质性来解释，但令人惊讶的是，这些差异会遗传给后代。我们现在开始意识到，这些现象的核心生物机制是表观遗传的。表观遗传修饰，如向DNA中添加甲基，自然并稳定地影响基因组功能，而不改变潜在的DNA序列。具体地说，表观遗传修饰在调节基因表达方面发挥着核心作用，因此，细胞仔细控制基因组中表观遗传修饰建立的时间和位置也就不足为奇了。然而，最近的证据表明，哺乳动物的表观遗传修饰可能会受到环境或随机因素的干扰，在某些情况下，与个体表型的改变有关。但是，这种表观遗传变异能遗传给后代吗？从理论上讲，这种表观遗传变异不应该遗传给下一代，因为它们可能会干扰后代的胚胎发育。事实上，在正常的哺乳动物发育过程中，表观遗传修饰在早期胚胎发育过程中被重新编程。然而，对小鼠模型的研究表明，有时表观遗传变异逃脱了这种重新编程事件，并持续存在于后代的细胞中，即表观遗传--不是严格在DNA序列中编码的生物遗传。如果常见，表观遗传可能会对健康和疾病背景下的表型结果产生重大影响。然而，关于这一现象在人类身上的确凿证据仍然缺乏。到目前为止，只有三项单基因研究声称人类存在跨代表观遗传效应，即使是这些也一直存在争议。主要的绊脚石是：(I)可以将表观遗传与遗传学或环境的影响区分开来的合适的人类队列；(Ii)进行相对公正的实验以寻找这些表观遗传变异的技术。我们打算对人类的表观遗传进行首次系统的大规模研究。实验设计使用了一种强大的方法，整合了一群同卵双胞胎及其后代、尖端基因组学技术和定制的计算生物学方法。我们的研究结果将对表观遗传现象产生重要的见解，从而显著影响我们对人类可遗传表型变异的生物学基础的理解。

During the last 50 years, several studies have challenged the view that DNA is the sole biological unit of heredity in multi-cellular organisms such as mammals. In these studies, inter-individual phenotypic differences were observed that could not be explained by genetic or environmental heterogeneity and yet, surprisingly, were passed on to the offspring. We are now beginning to realize that the biological mechanisms at the heart of these phenomena are epigenetic. Epigenetic modifications, such as the addition of methyl groups to the DNA, occur naturally and stably influence genome function without changing the underlying DNA sequence. Specifically, epigenetic modifications play central roles in regulating gene expression, and therefore it is not surprising that the cell carefully controls when and where in the genome epigenetic modifications are established. However, recent evidence suggests that epigenetic modifications in mammals can be perturbed by environmental or stochastic factors, in some cases correlating with altered phenotypes in the individual. But could such epigenetic variants, be transmitted to the offspring? Theoretically, such epigenetic variants should not be passed on to the next generation as they might interfere with embryonic development of the offspring. Indeed, during normal mammalian development, epigenetic modifications are reprogrammed during early embryogenesis. However, studies in mouse models show that occasionally epigenetic variants escape this reprogramming event and persist in the cells of the offspring i.e. epigenetic inheritance - biological inheritance that is not encoded strictly in the DNA sequence. If common, epigenetic inheritance could have a significant impact on phenotypic outcomes in the context of both health and disease. However, conclusive evidence of this phenomenon in humans is still lacking. To date, only three single-gene studies have claimed transgenerational epigenetic inheritance-like effects in humans, and even these have been controversial. The main stumbling blocks have been access to: (i) suitable human cohorts in which epigenetic inheritance can be distinguished from the effects of genetics or environment; (ii) technologies for performing relatively unbiased experiments to search for these epigenetic variants. We intend to perform the first-ever systematic large-scale study of epigenetic inheritance in humans. The experimental design uses a powerful approach that integrates a cohort of identical twins and their offspring, cutting-edge genomics technologies, and custom computational biology methodologies. The results of our study will yield crucial insights into the phenomenon of epigenetic inheritance, thereby significantly impacting on our understanding of the biological basis of heritable phenotypic variation in humans.