MUTATIONAL SIGNATURE OF CHROMOSOMAL REARRANGEMENT MECHANISMS

描述（由申请方提供）：DNA经常受到外源性影响（如辐射）和内源性影响（如复制应激）的损伤。这种损伤的修复可能会导致染色体结构的变化，改变细胞中基因的拷贝数。拷贝数变异是一系列被称为基因组疾病的遗传性疾病的基础，并且是许多癌症的起始、进展和抗性机制的基础。虽然在描述与拷贝数变化相关的详细结构方面取得了很大进展，并且我们对可能产生变化的机制有了具体的想法，但我们无法将特定的机制归因于特定的事件。对模式生物中染色体变化机制的研究表明，与各种染色体变化机制相关的修复DNA合成和单链性具有非常低的保真度，产生许多点突变。由于修复合成和单链性的模式对于不同的变化机制是不同的，我们预计每种机制都会以新点突变的分布和谱的形式在DNA中留下特征签名。使用大量的临床分离株的生殖系和组成型拷贝数变异，我们计划映射这些签名的染色体变化的区域不同类别的拷贝数变化，以揭示相关的修复合成的模式，从而特定事件的机制。初步数据显示，预期的新点突变量完全在检测范围内，并且容易与不参与重排的染色体区域中的点突变区分开。

DESCRIPTION (provided by applicant): 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.