Trans-generational epigenetic phenomena, such as contamination with endocrine-disrupting chemicals (EDCs) that decrease fertility and the global methylation status of DNA in the offspring, are of great concern because they may affect health, particularly the health of children. However, of even greater concern is the possibility that trans-generational changes in the methylation status of the DNA might lead to permanent changes in the DNA sequence itself. By contaminating the environment with EDCs, mankind might be permanently affecting the health of future generations. In this section, we present evidence from our laboratory and others that trans-generational epigenetic changes in DNA might lead to mutations directed to genes encoding amino acid repeat-containing proteins (RCPs) that are important for adaptive evolution or cancer progression. Such epigenetic changes can be induced "naturally" by hormones or "unnaturally" by EDCs or environmental stress. To illustrate the phenomenon, we present new bioinformatic evidence that the only RCP ontological categories conserved from Drosophila to humans are "regulation of splicing," "regulation of transcription," and "regulation of synaptogenesis," which are classes of genes likely to be important for evolutionary processes. Based on that and other evidence, we propose a model for evolution that we call the EDGE (Epigenetically Directed Genetic Errors) hypothesis for the mechanism by which mutations are targeted at epigenetically modified "contingency genes" encoding RCPs. In the model, "epigenetic assimilation" of metastable epialleles of RCPs over many generations can lead to mutations directed to those genes, thereby permanently stabilizing the adaptive phenotype.

中文翻译：

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EDGE 假说：参与进化、神经内分泌信号传导和癌症的重复序列蛋白 (RCP) 中存在表观遗传定向遗传错误


跨代表观遗传现象，例如会降低生育能力的内分泌干扰化学物质 (EDC) 污染以及后代 DNA 的整体甲基化状态，引起了人们的高度关注，因为它们可能会影响健康，尤其是儿童的健康。然而，更令人担忧的是，DNA 甲基化状态的跨代变化可能会导致 DNA 序列本身的永久性变化。通过使用 EDC 污染环境，人类可能会永久影响子孙后代的健康。在本节中，我们提出了来自我们实验室和其他实验室的证据，表明 DNA 中的跨代表观遗传变化可能会导致针对编码含氨基酸重复蛋白 (RCP) 的基因的突变，这对于适应性进化或癌症进展很重要。这种表观遗传变化可以由激素“自然”诱导，也可以由 EDC 或环境压力“非自然”诱导。为了说明这一现象，我们提出了新的生物信息学证据，表明从果蝇到人类唯一保守的 RCP 本体类别是“剪接调节”、“转录调节”和“突触发生调节”，这些基因类别可能很重要对于进化过程。基于这一证据和其他证据，我们提出了一种进化模型，我们称之为 EDGE（表观遗传定向遗传错误）假说，该假说的机制是突变针对编码 RCP 的表观遗传修饰“偶然基因”。在该模型中，RCP亚稳态表观等位基因经过多代的“表观遗传同化”可以导致针对这些基因的突变，从而永久稳定适应性表型。