Culling the human genome of disease variants using ultraconserved elements

项目摘要/摘要 利用超辐射元素筛选人类疾病变异体基因组 目标：拟议研究的直接目标是探索一个非常 一组奇特的序列，称为超配位元件(UCES)，似乎识别有害的GE- NOME重排，然后诱导携带这种重排的细胞自行剔除。 因此，统一消费电子交易可能体现一项活动，最终可能使清算机构能够制定战略。 病态细胞。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- 这类疾病的危害。最后，由于UCES仍然是基因组中最鲜为人知的序列之一， 在这里提出的研究也可能有助于阐明结构和功能方面的 这些非常神秘的元素。 与健康相关：拟议的研究将与癌症生物学、神经发育障碍有关。 以及可能与基因组不稳定相关的任何疾病，因为它们源于令人震惊的 UCES与构造变异性断裂点位置关系的非随机性变化 代表健康个体和代表携带有害基因组的个体的蚂蚁 安排好了。 创新：拟议的研究提供了两个层面的创新。首先，他们建议UCES 可能构成一种新的遗传元素，其功能只是抵抗变化。这将是 相反，启动子、增强子和转录单位的功能是产生活性或 一种产品。拟议研究的长期创新在于UCES可能体现的概念 一种内源性活动，允许细胞评估其基因组的有害重排， 因此，可能最终会被利用为一个极其敏感的监视系统来保护我们的 身体抵抗疾病。 具体目标：拟议研究的目标是探索使用UCES清除 细胞群，因此，有害的重排的身体。因此，拟议的目标将使用 计算、遗传、分子遗传和成像技术可： 确定UCES是否代表了一种新的遗传元素。 阐明为什么UCES对结构变化如此敏感。 C.从基因组中筛选构成UCES对结构变异反应的基因。

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.