Induced Transgenerational Inheritance Without Epigenetics

表观遗传学，其特征是通过遗传方式将储存在染色体上的调控信息遗传给 是复杂疾病研究的前沿。表观遗传学是一个丰富的术语， 描述了许多现象，然而，与疾病相关性最广泛的研究是 通过有丝分裂和/或减数分裂遗传的基因表达状态的环境诱导的变化。 这种跨代表观遗传被认为是个体累积疾病风险的原因， 以及将疾病风险传递给后代。了解疾病状态是如何表观遗传的 对NIH的使命“.增进健康、延长寿命、减少疾病和残疾”至关重要。 然而，许多关于模式生物中表观遗传的基本机制的数据， 与表观遗传模型如何应用于人类疾病不一致，并强调了在人类疾病中的主要障碍。 research.这些数据不仅挑战了表观遗传的模型，它们还表明， 表观遗传是一个障碍。严重和持久的障碍可能是 考虑到跨代表观遗传缺陷实际上是由特定的遗传因素引起的， 突变类型：由环境诱导，高频率，优先影响特定区域 具有多效性调节和生理作用的基因组。考虑到这个替代解释 创造了一个典型的矛盾，因为它不挑战数据，它质疑“表观遗传”的期望， 并挑战我们如何处理问题，并确定需要通过研究填补的空白。 这一变革性研究奖提案：（i）突出了现有模式的问题， 跨代的“表观遗传”继承，（ii）解释了数据支持的替代模型， 一个新的范式，（iii）解释了为什么范式冲突阻碍了研究，（iv）展示了 效用的替代解决当前的研究问题，（五）解释如何接受的范式 将绕过障碍，重新引导研究，以更好地利用宝贵的资源。 计划进行两套实验方向。第一组-“表观遗传”信息是否被编码 在一个基因，以及是否“表观遗传”的信息可以区分两个相同的基因-重点放在不可调和的 不同的模式，以确定哪些是有效的。第二组-遗传基础 “表观遗传”遗传，以及两个细胞之间的差异，只是在他们的“表观遗传”的状态不同-将 推进我们对疾病中“表观遗传”缺陷的理解。如果我的替代范式是正确的，这些 实验将开辟新的研究领域，研究（i）基因组中固有的不稳定重复DNA如何 响应环境压力，疾病和突变，（ii）如何重复DNA的基因表达的突变， （iii）重复DNA稳定性的缺陷如何导致对整个基因组的永久性损害， 基因组这些领域有望建立预防和治疗复杂疾病的新方法。

Epigenetics, characterized by the inheritance of regulatory information stored on chromosomes by means other than DNA sequence, is at the forefront of complex disease research. Epigenetics is a rich term that describes many phenomena, however the studies with the broadest disease relevance are those of environmentally-induced changes to gene expression states that are inherited through mitosis and/or meiosis. This transgenerational epigenetic inheritance is thought to account for accumulated disease risk in individuals, and for transmission of disease risk to offspring. Understanding how a disease state is epigenetically inherited is critically important to the NIH's mission “…to enhance health, lengthen life, and reduce illness and disability.” However, many data concerning the basic mechanisms of epigenetic inheritance in model organisms are inconsistent with how the epigenetic models are applied to human disease, and highlight major roadblocks in research. These data do not just challenge the models for epigenetic inheritance, they suggest that the way we think about epigenetic inheritance is the impediment. The serious and persistent roadblocks can be immediately removed by considering that transgenerational epigenetic defects are in fact caused by particular types of mutations: induced by the environment, high-frequency, and preferentially affecting specific regions of genomes that have pleiotropic regulatory and physiological effects. Considering this alternative explanation creates a paradigmatic conflict because it doesn't challenge data, it questions the expectations of “epigenetic,” and challenges how we approach the problem and identify the gaps that need to be filled by research. This Transformative Research Award proposal: (i) highlights the problems with the existing model for transgenerational “epigenetic” inheritance, (ii) explains the data-supported alternative model that carries with it a new paradigm, (iii) explains why it is the paradigmatic conflict that impedes research, (iv) demonstrates the utility of the alternative in solving current research problems, and (v) explains how acceptance of the paradigm will sidestep roadblocks and redirect research to better utilize precious resources. Two sets of experimental directions are planned. The first set – whether “epigenetic” information is encoded at a gene, and whether “epigenetic” information can distinguish two identical genes – focuses on irreconcilable differences between the paradigms to determine which is valid. The second set – the genetic basis of “epigenetic” inheritance, and the differences between two cells that differ only in their “epigenetic” status – will advance our understanding of “epigenetic” defects in disease. If my alternative paradigm is correct, these experiments will open new areas of research into (i) how intrinsically unstable repeat DNAs in the genome respond to environmental stress, disease, and mutation, (ii) how repeat DNAs influence expression of gene networks throughout the genome, and (iii) how defects in repeat DNA stability lead to permanent damage to the genome. These areas are expected to establish new approaches to prevent and treat complex diseases.