MUTATIONAL SIGNATURE OF CHROMOSOMAL REARRANGEMENT MECHANISMS

染色体重排机制的突变特征

• 批准号: 9334277
• 负责人: PHILIP John HASTINGS
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334277
• 关键词: 17p11.2; Animal Model; Base Pairing; Biological Models; Categories; Cells; Characteristics; Chromosomal Rearrangement; Chromosomes; Clinical; Collection; Copy Number Polymorphism; DNA; DNA Repair; DNA biosynthesis; DNA copy number; DNA-Directed DNA Polymerase; Data; Deamination; Detection; Diagnosis; Diagnostic; Disease; Double Strand Break Repair; Event; Excision; Gene Dosage; Genomics; Goals; Hereditary Disease; Human; Human Characteristics; Human Genetics; Human Genome; Individual; Inherited; Lead; Length; Malignant Neoplasms; Maps; Modeling; Mutation; Mutation Spectra; Nonhomologous DNA End Joining; Parents; Pathology; Patients; Pattern; Point Mutation; Polymerase; Process; Radiation; Recurrence; Replication Error; Resistance; Resources; Sampling; Series; Severity of illness; Side; Single-Stranded DNA; Site; Stress; Structure; Variant; Work; base; chromothripsis; clinical material; data modeling; disease phenotype; homologous recombination; human data; public health relevance; repaired; resistance mechanism; study characteristics; tumor progression

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.

描述(申请人提供)：DNA经常受到辐射等外源影响和复制应激等内源性影响的破坏。这种损伤的修复可能会导致染色体结构的变化，从而改变细胞中基因的拷贝数。拷贝数变异是一系列称为基因组疾病的遗传性疾病的基础，也是许多癌症发生、发展和耐药机制的基础。尽管在描述与拷贝数变化相关的详细结构方面取得了很大进展，并且我们对哪些机制可能产生这些变化有具体的想法，但我们无法将具体的机制归因于特定的事件。对模式生物染色体改变机制的研究表明，与各种染色体改变机制相关的修复DNA合成和单链是非常低的保真度，产生许多点突变。由于修复合成和单链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在DNA中以新的点突变的分布和谱的形式留下一个特征性的签名。利用大量临床分离的生殖系和构成拷贝数变体，我们计划将这些特征映射到不同类别拷贝数变化的染色体变化区域，以揭示相关修复合成的模式，从而揭示特定事件的潜在机制。初步数据显示，预计的新的点突变数量在检测范围内，并很容易与未参与重排的染色体区域的点突变区分开来。