MECHANISMS OF TRINUCLEOTIDE REPEAT INSTABILITY

此应用程序的总体目标是定义参数， 在人类中发现的三核苷酸重复序列， 易患病的体质 突变的三核苷酸重复序列已经被 与七种具有神经肌肉效应的人类遗传疾病有关， 约会 这些突变的特征之一是极端的易变性，即。 这些突变赋予它们自身超变性。 突变 重复涉及改变疾病的严重性和/或发作。 因此，产生这些新突变的机制是 与这些疾病的研究非常相关。 这项工作将测试假设，在CCGG重复不稳定 在脆性X综合征中发现的FMR 1基因是固有的， 不断重复 另一种假设认为， 还将测试涉及的序列。 这将是完成 通过以下目标： 1)鉴定减数分裂不稳定性的分子基础 在人类家庭中发现的稳定和不稳定重复序列的实证研究。 2)开发能够测试重复元件的模型系统， 稳定 30人类和其他物种基因组中相似重复序列的研究 以便在没有人类功能磁共振成像重复的情况下进行比较和对比。 4)CGG重复序列甲基化及其在细胞稳定性中作用的研究 在早期发展中重复。 5)将这些研究扩展到其他三核苷酸重复序列，特别是 CAG重复序列在其他几种人类遗传中被发现是不稳定的， 紊乱 6)向感兴趣的合作者提供医学相关样本 三核苷酸重复序列的研究，使用各种生化和 酶促措施。 确定所涉及的重复序列（或其他邻近序列）的类型 将提供更准确的行为预测 这些元素，并应允许改进的诊断测试。 在 此外，这些信息与其他研究相结合， 该计划项目的成员将提供重要的洞察力， 复制和/或修复错误的类型的行为，这些 序列的 这些数据将提供新的理解的基本 DNA复制和修复的酶学和生物化学 人类，也可能导致体细胞突变。

The overall aim of this application is to define parameters in trinucleotide repeats found in humans which confer instability and predisposition to disease. Mutant trinucleotide repeats have been implicated in seven human genetic disorders with neuromuscular effects to date. One of the hallmarks of these mutations is extreme mutability, i.e. the mutations confer hypermutability onto themselves. Mutations of the repeats are involve in altering the severity an/or onset of the disease. Therefore, the mechanisms involved in generating these novel mutations are quite relevant to the study of these disorders. This effort will test the hypothesis that instability in the CCGG repeat found at the FMR1 gene involved in fragile X syndrome is intrinsic to the repeat itself. The alternative hypothesis that other closely linked sequences are involved will also be tested. This will be accomplished through the following aims: 1) Identification of the molecular basis of meiotic instability using empirical studies of stable and unstable repeats found in human families. 2) Development of a model system capable of testing repeat elements for stability. 30 Study of similar repeats in the human and other species' genomes in order to compare and contrast these without the human FMRI repeat. 4) Study of the methylation of CGG repeats in and its role in stability of the repeat during early development. 5) Extension of these studies to other trinucleotide repeats, particularly the CAG repeat found to be unstable in several other human genetic disorders. 6) Provision of medically relevant samples to collaborators interested in the study of trinucleotide repeats using a variety of biochemical and enzymatic measures. Determination of the types of repeats (or other nearby sequences) involved in instability will provide for more accurate forecasting of the behavior of these elements and should allow for improved diagnostic testing. In addition, this information in combination with the studies of the other members of this program project will provide significant insight into the types of replication and/or repair errors underlying the behavior of these sequences. These data will provide new understanding of the basic enzymology and biochemistry underpinning DNA replication and repair in humans, with likely consequences for somatic mutation as well.