Form and function of our Janus faced genome

项目标题：我们的Janus Face基因组的形式和功能 通过逆转录将RNA转化为DNA已经改变了 人类基因组：RNA衍生的DNA拷贝的插入大约使 我们的遗传材料。然而，反转录RNA的整合是一种 低效的过程，即使对于最成功的基因组寄生虫(例如逆转录病毒， 反转录转座子和假基因)。反转录的复制品不能 整合可以被认为是罗马神雅努斯的缩影：他们只有一张脸，他们 将过去视为前世的不完美复制(即它们是RNA 源自)，用另一张脸，面向未来，有能力指导 它们的分子环境的命运。值得注意的是，这些生物的身份和功能 传统DNA图谱之外的基因组错配在很大程度上是 未被开发，但预计将是巨大和强大的。 我们发现，内源性cDNA的形成(即逆转录的DNA源自 来自宿主RNA)是强大的，并具有重要的生物学和疾病修正功能。 阻断反转录可以阻止内源性cdna的形成，有趣的是， 还能阻断内源性cdna介导的小鼠失明模型。在这里，我们将 将这些观察结果推广到系统地分析宿主衍生的反向 转录组制作内源基因的身份和功能图谱初稿 C DNA，与健康和疾病有关。我们还将通过实验证明 内源c DNA到分子和代谢途径，并提供一种替代 核苷逆转录酶抑制剂的毒性解释(例如 周围神经病和发育缺陷)。我们希望我们的工作能证明 宿主来源的RNA的碰撞和遗传信息的双向流动 产生了一种强大的调节类，因此被低估的分子控制 健康和疾病，并可被利用来理解和操纵 细胞生物学。

Project title: Form and function of our Janus faced genome The conversion of RNA into DNA via reverse transcription has transformed the human genome: insertion of RNA-derived DNA copies has roughly doubled the mass of our hereditary material. However, integration of reverse transcribed RNAs is an inefficient process, even for the most successful genomic parasites (e.g. retroviruses, retrotransposons, and pseudogenes). The reverse transcribed copies that fail to integrate may be considered microcosms of the Roman god Janus: with one face, they gaze towards the past as an imperfect copy of a previous life (i.e. the RNA they are derived from), and with another face, they look towards the future, capable of directing the fate of their molecular environment. Remarkably, the identity and function of these genomic misfits that lie outside the confines of the traditional landscape of DNA is largely unexplored, but expected to be vast and powerful. We find that endogenous cDNA formation (i.e. reverse transcribed DNA derived from host RNA) is robust and has important biological and disease-modifying function. Blocking reverse transcription prevents endogenous cDNA formation, and interestingly, also blocks an endogenous cDNA-mediated mouse model of blindness. Here, we will extend these observations to systematically analyze the host-derived reverse transcriptome to produce the first draft atlas of the identity and function of endogenous cDNA, in health and disease. We will also experimentally demonstrate the relevance of endogenous cDNA to molecular and metabolic pathways, and provide an alternate explanation of toxicity attributed nucleoside reverse transcriptase inhibitors (e.g. peripheral neuropathy and developmental defects). We expect our work to demonstrate that the collision of host-derived RNA and the bidirectional flow of genetic information produces a powerful regulatory class of hereto underappreciated molecules that control health and disease, and can be harnessed to understand and manipulate basic tenets of cellular biology.