MUTATIONAL SIGNATURE OF CHROMOSOMAL REARRANGEMENT MECHANISMS

项目摘要 DNA经常受到辐射等外源性影响和辐射等内源性影响的破坏。 复制应力这种损伤的修复可能导致染色体结构的改变， 基因拷贝的数量。拷贝数变异是一系列遗传性疾病的基础， 基因组疾病和基础的起始，发展和耐药机制的许多癌症。 尽管在描述与拷贝数相关的详细结构方面已经取得了很大进展， 变化，我们对什么机制可能产生变化有具体的想法，我们无法 将特定机制归因于特定事件。动物模型染色体改变机制的研究 生物体已经揭示，修复DNA合成和单链性与各种 染色体改变的机制是非常低的保真度，产生许多点突变。因为 我们预计，对于不同的变化机制，修复合成和单链的模式是不同的， 每种机制都会在DNA中留下一个特征性的签名，其形式是DNA的分布和光谱。 新的点突变使用大量临床分离株的生殖系和组成型拷贝数 我们计划将这些特征映射到不同类型拷贝的染色体变化区域， 数字的变化，以揭示相关的修复合成的模式，因此， 具体事件。初步数据显示，预期的新点突变量完全在预期范围内。 检测极限，并容易与不参与的染色体区域区分开来。 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.