Genomic and Physiological Impact of Transposable Elements.

项目总结 转座元件(TES)构成了脊椎动物基因组的很大一部分，包括一半的 人类基因组。TES的诱变特性是有据可查的，它们是 物种间和物种内的遗传变异。然而，这种巨大的基因变异来源是如何 已经塑造了物种的进化和生物学仍然鲜为人知。我们的Mira项目是 旨在对TES在进化和疾病中的生物学意义产生变革性的见解。 我们之前的研究重点是脊椎动物在驱动基因的长期影响 创新。值得注意的是，我们发现TES一直是原始序列材料co- 在脊椎动物进化期间选择创造新的顺式调控元件来驱动基因的变化 表达和新的蛋白质编码基因是新的细胞功能出现的基础。大部分 这些事件涉及古代TES长期不活跃的换位作用。在下一个资金周期中，我们将把 我们关注的是年轻的TE--那些最近或现在流动的人。我们关注的是发展的影响 在人类和斑马鱼中，斑马鱼是研究脊椎动物的强大模式生物 发展。通过关注年轻逆转录元件在胚胎发育中的功能影响，我们 将揭示进化上最新的生物创新的分子基础。值得注意的是，我们将 研究TES在确定人类胎盘特征方面的调节作用，如其深度 母体蜕膜组织的侵袭及内源性病毒样颗粒的功能意义 在人类胚胎发育的早期阶段生产的。我们的工作还将揭示一般原则 这导致了用于细胞功能的特定TE序列的共同选择。具体来说，我们将测试一个新的 宿主-TE相互作用的挑衅性模型，其中生物体的发育变得依赖于TE- 编码产品。我们将通过研究Gag(衣壳)的反式调节活动来测试这个‘成瘾模型’。 我们初步获得的人和斑马鱼内源性逆转录病毒编码的蛋白质 有证据表明它们能调节胚胎发育过程。预计这一项目的成果将 将我们对主持人与TE互动的看法从冲突转变为互惠互利。我们的研究还将产生新的机制 对鲜为人知的疾病过程的洞察，如先兆子痫和 神经发育障碍，牵涉到年轻TES的调节失调。

PROJECT SUMMARY Transposable Elements (TEs) make up a large fraction of vertebrate genomes, including half of the human genome. The mutagenic properties of TEs are well documented and they are important drivers of genetic variation between and within species. However, how this enormous source of genetic variation has shaped the evolution and biology of species remains poorly understood. Our MIRA project is designed to yield transformative insights into the biological significance of TEs in evolution and disease. Our previous research has focused on the long-term impact of vertebrate TEs in driving genetic innovations. Notably, we showed that TEs have been a recurrent source of raw sequence material co- opted during vertebrate evolution to create new cis-regulatory elements driving changes in gene expression and new protein-coding genes underlying the emergence of novel cellular functions. Most of these events involved ancient TEs long inactive transpositionally. In this next funding cycle, we are turning our attention to young TEs -- those recently or currently mobile. We focus on the developmental impact of young TEs in humans and in zebrafish, a powerful model organism for studies of vertebrate development. By focusing on the functional impact of young retroelements in embryonic development we will uncover the molecular underpinnings of evolutionarily recent biological innovations. Notably, we will investigate the regulatory contribution of TEs in defining features of the human placenta, such as its deep invasion into maternal decidual tissue, and the functional significance of endogenous viral-like particles produced in the early stages of human embryonic development. Our work will also uncover general principles that lead to the cooption of specific TE sequences for cellular function. Specifically, we will test a new provocative model of host-TE interaction in which organismal development becomes dependent on TE- encoded products. We will test this ‘addiction model’ by studying the trans-regulatory activities of Gag (capsid) proteins encoded by endogenous retroviruses in human and zebrafish for which we have obtained preliminary evidence they modulate embryonic developmental processes. The outcomes of this project are expected to shift our view of host-TE interactions from conflicting to mutualistic. Our studies will also yield new mechanistic insights into poorly understood disease processes, such as pregnancy loss by preeclampsia and neurodevelopmental disorders, implicating the dysregulation of young TEs.