Cytogenetic and Molecular Studies of Chromosome 22

22 号染色体的细胞遗传学和分子研究

• 批准号: 7728361
• 负责人: BEVERLY S EMANUEL
• 金额: $ 37.75万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728361
• 关键词: 11q23; 22q; 22q11; 22q11.2; 22q11.23; 8q24; Adopted; Affect; Architecture; Behavior; Cell Nucleus; Chromosomal Instability; Chromosomal Rearrangement; Chromosomal Stability; Chromosome Markers; Chromosomes; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 8; Constitutional; DNA; DNA Sequence; DNA Sequence Rearrangement; Distant; Double Strand Break Repair; Etiology; Female; Genetic Recombination; Genomics; Germ Cells; Goals; Hot Spot; Human; Individual; Interphase; Malignant - descriptor; Mediating; Meiosis; Mitosis; Mitotic; Molecular Conformation; Molecular Cytogenetics; Nonhomologous DNA End Joining; Play; Population; Prevalence; Recurrence; Role; Site; Structure; Syndrome; Tissues; Variant; autosome; base; clinically relevant; clinically significant; developmental disease; homologous recombination; human disease; insight; male; public health relevance

DESCRIPTION (provided by applicant): Specific chromosomal rearrangements are known to play a role in the etiology of human malignant disorders and developmental syndromes. Included are numerous clinically significant human diseases associated with translocations, duplications and deletions in proximal 22q. These recurrent abnormalities have implicated the segmental duplications on 22q11.2 as involved in this non-random recombination and/or instability, creating meiotic and mitotic rearrangement "hot-spots." For the recurrent constitutional t(11;22) rearrangement, there is remarkable similarity between the BP junctions derived from numerous unrelated individuals and the presence of palindromic AT-rich repeats (PATRRs) at the breakpoints (BPs). The demonstrated proximity of the BP regions from 11q23 and 22q11 during meiosis seem to facilitate permissive interactions between these chromosomal domains. The translocation occurs only during meiosis by a mechanism suggestive of non-homologous end joining of double strand breaks (DSBs) facilitated by the PATRRs. We wish to explore the possibility that DSBs occur as a result of replication stalling at the PATRRs at 11q23 and 22q11. Further, we have discovered another remarkably recurrent translocation, a t(8;22) that involves the same region of 22q11.2 and another large PATRR at 8q24. The mechanisms that promote such chromosomal rearrangements in meiosis and that likely permit their involvement in mitotic instability are poorly understood. Thus, the role of these sequences in promoting rearrangements in meiosis will be examined. We will examine the role of the chromosome 22 low copy repeats (LCRs) in translocation formation. We will determine whether physical proximity and DSBs "drive" the recurrence of the constitutional t(8;22) by 1) analysis of the t(8;22) BP regions in germ cells/gametes, 2) by examining its recurrence in germ cells and by 3) assessing the stability of the BP region in somatic tissues. We will characterize the genomic DNA from normal chromosome 8s at the 8;22 BP to determine whether 1) variability affects its propensity to rearrange 2) determine its similarity to other autosomal regions (including 11q23) involved in constitutional rearrangements with the same region of 22q11.2. The prevalence and diversity of the structural abnormalities of 22q in the vicinity of the LCRs and PATRRs suggest that an in depth examination of their role in chromosomal rearrangement and stability is warranted and will yield insight into genomic rearrangement and stability. PUBLIC HEALTH RELEVANCE: Numerous clinically significant human diseases are associated with recurrent translocations, duplications or deletions in proximal 22q. Many of the rearrangements occur as the result of chromosome-22 specific low copy repeats (LCRs) or palindromic AT-rich repeats (PATRRs). The principal goal of this application is to elucidate mechanisms that facilitate these rearrangements by examining the genomic architecture of 22 and its frequent partner chromosomes (8, 11) and their behavior in mitosis and meiosis.

描述（由申请人提供）：已知特定的染色体重排在人类恶性疾病和发育综合征的病因学中发挥作用。其中包括许多与近端 22q 易位、重复和缺失相关的具有临床意义的人类疾病。这些反复出现的异常表明 22q11.2 上的节段重复参与了这种非随机重组和/或不稳定性，从而产生了减数分裂和有丝分裂重排“热点”。对于经常性的t(11;22)重排，来自许多无关个体的BP连接与断点(BP)处存在富含AT的回文重复序列(PATRR)之间存在显着的相似性。减数分裂过程中 11q23 和 22q11 BP 区域的接近性似乎促进了这些染色体结构域之间的允许相互作用。这种易位仅在减数分裂期间发生，其机制表明由 PATRR 促进的双链断裂 (DSB) 的非同源末端连接。我们希望探讨 DSB 因 11q23 和 22q11 的 PATRR 复制停滞而发生的可能性。此外，我们还发现了另一个显着重复的易位，t(8;22)，涉及 22q11.2 的相同区域和 8q24 的另一个大 PATRR。人们对减数分裂中促进染色体重排以及可能参与有丝分裂不稳定的机制知之甚少。因此，将检查这些序列在促进减数分裂重排中的作用。我们将研究 22 号染色体低拷贝重复序列 (LCR) 在易位形成中的作用。我们将通过 1) 分析生殖细胞/配子中的 t(8;22) BP 区域，2) 通过检查其在生殖细胞中的复发，以及 3) 评估体细胞组织中 BP 区域的稳定性来确定物理接近性和 DSB 是否“驱动”构成性 t(8;22) 的复发。我们将表征 8;22 BP 处正常 8 号染色体的基因组 DNA，以确定 1) 变异性是否影响其重排倾向 2) 确定其与参与 22q11.2 相同区域构成重排的其他常染色体区域（包括 11q23）的相似性。 LCR 和 PATRR 附近 22q 结构异常的普遍性和多样性表明，有必要深入研究它们在染色体重排和稳定性中的作用，并将深入了解基因组重排和稳定性。 公共卫生相关性：许多具有临床意义的人类疾病与近端 22q 的反复易位、重复或缺失有关。许多重排是由于 22 号染色体特异性低拷贝重复序列 (LCR) 或富含回文 AT 重复序列 (PATRR) 造成的。本申请的主要目标是通过检查 22 及其常见伙伴染色体（8、11）的基因组结构及其在有丝分裂和减数分裂中的行为来阐明促进这些重排的机制。