Cytogenetic and Molecular Studies of Chromosome 22

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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.