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: 7837652
• 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/7837652
• 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起作用。包括与近端22 q中的易位、重复和缺失相关的许多临床上显著的人类疾病。这些反复出现的异常暗示了22q11.2上的片段重复参与了这种非随机重组和/或不稳定性，产生了减数分裂和有丝分裂重排“热点”。“对于复发性结构t（11;22）重排，来自许多无关个体的BP连接点与断点（BP）处的回文富含AT重复序列（PATRRs）之间存在显著的相似性。在减数分裂过程中，11 q23和22 q11的BP区域的接近似乎有助于这些染色体结构域之间的相互作用。易位仅发生在减数分裂过程中的机制，提示非同源末端连接的双链断裂（DSB）促进的PATRR。我们希望探讨DSB发生的可能性，作为在11 q23和22 q11的PATRR的复制停滞的结果。此外，我们还发现了另一个显著的复发性易位，一个涉及22q11.2相同区域的t（8;22）和另一个位于8 q24的大PATRR。在减数分裂中促进这种染色体重排的机制以及可能允许它们参与有丝分裂不稳定性的机制知之甚少。因此，这些序列在促进减数分裂重排的作用将被检查。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）检查其在生殖细胞中的复发，以及3）评估BP区域在体细胞组织中的稳定性，来确定物理接近性和DSB是否“驱动”体质t（8; 22）的复发。我们将表征正常染色体8;22 BP处的基因组DNA，以确定1）变异性是否影响其重排倾向2）确定其与22q11.2相同区域的结构重排中涉及的其他常染色体区域（包括11 q23）的相似性。LCR和PATRR附近22 q结构异常的患病率和多样性表明，深入研究它们在染色体重排和稳定性中的作用是必要的，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22 q的复发性易位、重复或缺失相关。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AT的回文重复序列（PATRR）而发生的。本申请的主要目标是通过检查22号染色体及其常见伴侣染色体（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。