Culling the human genome of disease variants using ultraconserved elements

使用超保守元件剔除疾病变异的人类基因组

• 批准号: 9163163
• 负责人: CHAO-TING WU
• 金额: $ 117.9万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9163163
• 关键词: Address; Attention; Benign; Beryllium; Binding Sites; Cancer Biology; Candidate Disease Gene; Cells; Clear Cell; Code; DNA Sequence; Data; Disease; Elements; Enhancers; Funding; Genes; Genetic; Genetic Transcription; Genome; Genomic Instability; Goals; Health; Heart; Human Genome; Imaging technology; Indium; Individual; Lead; Lesion; Letters; Maintenance; Malignant Neoplasms; Modeling; Molecular Genetics; Mosaicism; Neurodevelopmental Disorder; Nucleic Acid Regulatory Sequences; Open Reading Frames; Population; Process; Proteins; System; Testing; Variant; Work; abstracting; base; combat; fighting; fitness; genetic element; genome integrity; genome sequencing; genome-wide; innovation; interest; promoter; reference genome; research study; stem; tool; transcription factor

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.

项目摘要/摘要 使用超保守元素挖掘疾病变体的人类基因组 目的：拟议研究的直接目标是探索一个过程 奇怪的一组序列，称为超保守元件（UCE），似乎识别出有害的ge- 重新排列，然后诱导携带此类重排的细胞，以扑灭自己。 因此，UCES可能会体现一项最终可以实现清理机构的策略的活动 病细胞。鉴于基因组重排在许多疾病的核心，包括癌症 和神经发育障碍，拟议的研究可能有助于治疗 这种疾病。最后，由于UCES仍然是最知名的基因组序列之一，因此 这里提出的研究也可能有助于阐明 这些非常神秘的元素。 健康相关性：拟议的研究将与癌症生物学，神经发育有关 订单，以及与基因组不稳定性相关的任何疾病，因为它们源于令人惊叹的 UCES与结构变化的断点之间的位置关系的非随机变化 代表健康个体的蚂蚁和代表具有有害基因组的个体的人 安排。 创新：拟议的研究提供了两个级别的创新。首先，他们建议uces 可能构成一种新型的遗传元素，其功能仅仅是为了抵抗变化。这是 相反的启动子，增强子和转录单元的功能是产生活动或 产品。拟议研究的长期创新在于uces可能体现的观念 一种内源性活性，允许细胞评估其基因组的有害重排和 因此，最终可能被利用为一种非常敏感的监视系统，以保护我们 反疾病的身体。 具体目的：拟议研究的目标是探索使用UCES清除的潜力 细胞种群，因此是有害重排的身体。因此，提议的目标将使用 计算，遗传，分子遗传和成像技术： 答：确定UCE是否代表一种新型的遗传元素。 B.澄清为什么UCE对结构变化如此敏感。 C.筛选基因组的基因，该基因是UCES对结构变异的反应性。