EXCEED THE SPACE PROVIDED. - .... 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 or deletions in proximal 22q. These recurrent abnormalities suggest non-random involvement of specific regions in recombination and/or instability indicating meiotic and mitotic rearrangement 'hot spots.' The remarkable similarity between constitutional t(11;22) BP junctions derived from numerous unrelated individuals suggest proximity of and/or permissive interactions between these two chromatin domains in the interphase nucleus during meiosis and even mitosis. This extreme BP clustering is unprecedented in human genetics. We have proposed that the t(ll;22)s occur after repair of double strand breaks mediated by the palindromic AT-rich repeats (PATRRs) located at the 22qll and 11q23 BPs. In addition, chromosome 22-specific low copy repeats (LCRs) appear to play a role in this disorder. They also facilitate several other structural rearrangements of 22q by 'misalignment followed by slipped recombination' both in meiosis and mitosis. The mechanisms that promote these chromosomal rearrangements in meiosis and that even permit their involvement in mitotic instability are poorly understood. Thus, we will determine whether physical proximity and double strand breaks 'drive' the recurrence of the constitutional t(11;22) by analysis of the t(11;22) BP regions in germ cells/gametes and by assessing the stability of the BP region in somatic tissues. We will investigate the prevalence of the 22q11.2 deletion in gametes and begin to assess whether direct involvement of the LCRs and the 11q23 PATRR in recombination nodules facilitates the recurrence of the rearrangements. We will characterize the genomic DNA from normal chromosome 11s at the 11;22 BP and examine its similarity to that of other autosomal regions engaged in constitutional rearrangements involving the same region of 22q11.2. Finally, we will attempt to develop an in vitro system in which to test the recombinogenic potential of these specific 22ql 1 and 11q23 sequences. The prevalence and diversity of the structural abnormalities of 22q in the vicinity of the LCRs and the PATRRs at the t(11;22) BP suggest that an in depth examination of their role in chromosomal rearrangement and stability is warranted. PERFORMANCE SITE ========================================Section End===========================================
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