Development and application of new tools to identify repeat expansions in human diseases

单个重复DNA序列的扩增，称为串联重复序列（TR），导致超过30个 罕见但毁灭性的疾病尽管它们对单基因疾病很重要，但它们的频率和功能 重复扩增在复杂的人类疾病中是未知的。未能对这些重复的事件进行分类和理解， 人类疾病的扩展将使我们无法利用这些信息来开发新的TR， 靶向治疗，我之前已经证明，可以挽救疾病中失调的基因表达， （Erwin等人，Science 2017）。 我的中心假设是，重复扩增在复杂的人类疾病中反复发生，并改变了细胞 通过调节基因表达发挥作用。虽然我在这项研究中有广泛的训练和经验 在化学生物学、分子生物学和功能基因组学方面，我是生物信息学的新手， 人类遗传学因此，我的总体目标是获得生物信息学和人类学方面的额外培训。 基因组学和目录经常重复扩增，并确定其与人类疾病的相关性。这 我的目标是成为一名研究TR序列的独立研究者，而这项研究是实现这一目标的下一个合乎逻辑的步骤 在基因组中。为了实现我的目标，我将充分利用斯坦福大学优良的培训环境 大学 预期成果包括一套新的生物信息学工具，以确定重复扩增（目标1） 以及人类疾病中经常性重复扩增的目录（Aim 2），这将提供一个新的角度， 分析数千个NIH资助的公开的人类基因组数据集。此外，表征 以前未被识别的功能，经常性的重复扩增将决定其中一些是否 扩增对于人类疾病是功能上重要的（目的3）。这项拟议的研究将使我能够申请 我在TR生物学的背景，同时接受生物信息学的额外培训， 人类遗传学和准备我成功的职业生涯作为一个独立的调查员。这些结果将 阐明了我们对人类基因组的理解，并为一类新的精确靶向 治疗学

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), causes more than 30 rare but devastating diseases. Despite their importance to monogenic disease, the frequency and function of repeat expansions are unknown in complex human diseases. A failure to catalog and understand these repeat expansions in human disease will make it impossible to capitalize on this information to develop new TR- targeting therapeutics, which I previously showed can rescue expression of genes dysregulated in disease (Erwin et al., Science 2017). My central hypothesis is that repeat expansions are recurrent in complex human diseases and alter cell function through the regulation of gene expression. While I have extensive training and experience in the study of TRs with chemical biology, molecular biology, and functional genomics, I am new to bioinformatics and human genetics. Therefore, my overall objective is to obtain additional training in bioinformatics and human genetics and to catalog recurrent repeat expansions and determine their relevance to human disease. This study is the next logical step toward my goal of becoming an independent investigator studying TR sequences in the genome. To achieve my goal, I will take full advantage of the excellent training environment at Stanford University. The expected outcomes include a new set of bioinformatic tools to identify repeat expansions (Aim 1) and a catalog of recurrent repeat expansions in human disease (Aim 2), which will provide a new angle to analyze thousands of NIH-funded, publicly-available human genome datasets. Furthermore, characterizing the function of previously-unrecognized, recurrent repeat expansions will determine whether some of these expansions are functionally important for human disease (Aim 3). The proposed study will enable me to apply my background in TR biology to an important problem while receiving additional training in bioinformatics and human genetics and preparing me for a successful career as an independent investigator. These results will illuminate our understanding of the human genome and set the stage for a new class of precision-targeted therapeutics.