Cytogenetic and Molecular Studies of Chromosome 22

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。包括许多与近端22q易位、重复和缺失相关的临床显著的人类疾病。这些反复出现的异常暗示22q11.2上的片段复制参与了这种非随机重组和/或不稳定性，产生减数分裂和有丝分裂重排“热点”。对于重复的构造性t（11;22）重排，来自许多不相关个体的BP连接与断点（BP）上存在的富含at的回文重复序列（PATRRs）之间存在显著的相似性。在减数分裂期间，来自11q23和22q11的BP区域的接近似乎促进了这些染色体结构域之间的允许相互作用。易位仅在减数分裂期间发生，其机制提示由PATRRs促进的双链断裂（DSBs）的非同源末端连接。我们希望探索dsb发生的可能性是由于11q23和22q11的PATRRs复制停滞的结果。此外，我们还发现了另一个显著的反复易位，t（8;22）涉及22q11.2的相同区域和8q24的另一个大的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的机制尚不清楚。因此，这些序列在促进减数分裂重排中的作用将被研究。我们将研究22号染色体低拷贝重复（lcr）在易位形成中的作用。我们将通过1)生殖细胞/配子中t(8;22) BP区域的分析，2)生殖细胞中BP区域的检查，以及3)评估体细胞组织中BP区域的稳定性，来确定物理邻近性和DSBs是否“驱动”了构成性t（8;22）的复发。我们将在8处描述正常8号染色体的基因组DNA；1)变异是否影响其重排倾向；2)确定其与其他常染色体区域（包括11q23）与22q11.2相同区域的结构重排的相似性。lcr和PATRRs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，并将对基因组重排和稳定性产生深入的了解。

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.