Culling the human genome of disease variants using ultraconserved elements

项目总结/摘要 使用超保守元件剔除疾病变异的人类基因组 目的：拟议研究的直接目标是探索一个非常 一组奇怪的序列，称为超保守元件（UCE），似乎可以识别有害的基因， nome重排，然后诱导携带这种重排的细胞淘汰自己。 因此，统一竞争环境可能体现一种活动，最终能够实现清算机构的战略， 病变细胞鉴于基因组重排是包括癌症在内的许多疾病的核心 和神经发育障碍，拟议的研究有可能有助于治疗- 这类疾病的症状。最后，由于UCE仍然是基因组中了解最少的序列之一， 这里提出的研究也可能有助于阐明的结构和功能方面的 这些神秘的元素 健康相关性：拟议的研究将涉及癌症生物学，神经发育障碍， 订单，以及潜在的任何与基因组不稳定性相关的疾病，因为它们源于一个惊人的 UCE和结构瓦里断点之间位置关系的非随机变化， 代表健康个体的蚂蚁和代表携带有害基因组的个体的蚂蚁。 安排 创新：拟议的研究提供了两个层次的创新。首先，他们认为， 可能构成了一种新的遗传元素，其功能只是抵抗变化。这将是 相反，启动子、增强子和转录单位，其功能是产生活性或 一种产品。拟议研究的长期创新在于UCE可能体现的概念 允许细胞评估其基因组的有害重排的内源性活性， 因此，最终可能被利用作为一个精致的敏感监视系统，以保护我们的 身体对抗疾病 具体目标：拟议研究的目标是探索使用UCE清除 细胞群，因此，有害重排的机构。因此，拟议目标将使用 计算、遗传、分子遗传和成像技术： A.确定UCE是否代表一种新的遗传元件。 B。阐明为什么UCE对结构变化如此敏感。 C.在基因组中筛选UCE对结构变异反应性的基础基因。

Project Summary/Abstract Culling the human genome of disease variants using ultraconserved elements Objectives: The immediate goal of the proposed studies is to explore the process by which a very curious set of sequences, called ultraconserved elements (UCEs), appear to recognize deleterious ge- nome rearrangements and then induce cells that carry such rearrangements to cull themselves away. As such, UCEs may embody an activity that could ultimately enable strategies for clearing bodies of diseased cells. Given that genome rearrangements lie at the heart of many diseases, including cancers and neurodevelopmental disorders, the proposed studies have the potential to contribute to the treat- ment of such diseases. Finally, as UCEs remain one of the least understood sequences of the genome, the studies proposed here may also contribute to elucidating the structural and functional aspects of these very enigmatic elements. Health relatedness: The proposed studies will pertain to cancer biology, neurodevelopmental dis- orders, and potentially any disease associated with genome instability, as they stem from a stunningly nonrandom change in the positional relationship between UCEs and the breakpoints of structural vari- ants representing healthy individuals and those representing individuals bearing deleterious genome re- arrangements. Innovation: The proposed studies offer two levels of innovation. First, they suggest that UCEs may constitute a new kind of genetic element, whose function is simply to resist change. This would be in contrast promoters, enhancers, and transcription units, whose functions are to produce an activity or a product. The long-term innovation of the proposed studies lies with the notion that UCEs may embody an endogenous activity which permits cells to assess their genome for deleterious rearrangements and, thus, may ultimately be harnessed as an exquisitely sensitive surveillance system for protecting our bodies against disease. Specific Aims: The goal of the proposed studies is to explore the potential of using UCEs to clear cell populations and, thus, bodies of deleterious rearrangements. As such, the proposed aims will use computational, genetic, molecular genetic, and imaging technologies to: A. Determine whether UCEs represent a new kind of genetic element. B. Clarify why UCEs appear so responsive to structural variation. C. Screen the genome for genes that underlie the responsiveness of UCEs to structural variation.