MUTATIONAL SIGNATURE OF CHROMOSOMAL REARRANGEMENT MECHANISMS

项目摘要 DNA经常受到外源性影响，如辐射，以及内源性效应，如 复制压力。这种损伤的修复可能会导致染色体结构的变化，从而改变数量 在细胞中复制基因。拷贝数变异是一系列遗传性疾病的基础，称为 基因组紊乱是许多癌症发生、发展和耐药机制的基础。 尽管在描述与拷贝数相关联的详细结构方面已经取得了很大进展 变化，我们对可能产生变化的机制有具体的想法，我们无法 将特定机制归因于特定事件。模型大鼠染色体改变机制的研究 生物体已经揭示了与DNA合成和单链修复相关的各种 染色体变化机制的保真度很低，会产生许多点突变。因为 对于不同的变化机制，修复合成和单链的模式是不同的，我们预计 每一种机制都会在DNA中以分布和光谱的形式留下一个特征签名 新的点突变。使用大量临床分离株的种系和构成拷贝数 对于不同类型的复制，我们计划将这些特征映射到染色体变化区域 数字变化以揭示相关修复合成的模式，从而揭示潜在的机制 具体事件。初步数据显示，预计的新点突变数量在 检测限，并容易与未涉及到的染色体区域的检测限区分 重新安排。

Project Summary DNA is frequently damaged by exogenous influences such as radiation, and endogenous effects such as replication stress. Repair of this damage may lead to chromosomal structural changes that change the number of copies of genes in the cells. Copy number variation is the basis of a series of inherited diseases known as genomic disorders and underlies the initiation, progression and resistance mechanisms of many cancers. Although great progress has been made in describing the detailed structures associated with copy number changes, and we have specific ideas on what mechanisms might generate the changes, we are unable to ascribe specific mechanisms to specific events. Study of the mechanisms of chromosomal change in model organisms has revealed that the repair DNA synthesis and single-strandedness associated with various mechanisms of chromosomal change is of very low fidelity, generating many point mutations. Because the pattern of repair synthesis and single-strandedness is different for different mechanisms of change, we expect that each mechanism will leave a characteristic signature in the DNA in the form of distribution and spectrum of new point mutations. Using a large collection of clinical isolates of germline and constitutive copy number variants, we plan to map these signatures to the regions of chromosomal change for different classes of copy number change to reveal the pattern of associated repair synthesis and hence the mechanism underlying specific events. Preliminary data show that the amount of new point mutation to be expected is well within the limits of detection and readily differentiated from that in chromosomal regions that are not involved in rearrangements.