Site Specific Non Robertsonian Chromosome Translocations

A second line of evidence in establishing the role for DNA structural features in rearrangements was the recent identification of extremely large blocks of repeated sequences termed LCRs (duplicons, segmental duplications) (19). Such blocks constitute a fertile substrate for recurrent rearrangements associated with more than 30 human genomic disorders (Table 1) (20-23) because they may adopt conformations of unprecedented complexity and size. Chromosome 22q11 is characterized by four large LCRs (LCR-A to D) that encompass approx 350 kb of DNA over an approx 3-Mb region (24,25). Sequence analyses of constitutional translocation breakpoints between chromosomes 22 and 1, 4, 11, or 17 have shown the hallmarks of cruciform DNA structures. For example, the breakpoints on LCR-B clustered in a narrow IR A/T-rich region that, in conjunction with flanking nuclear factor-1-like sequences (20,26), is predicted to form an approx 600 bp-long cruciform. Furthermore, the clustering of breakpoints occurred within 15 bp from the IR center and involved the symmetric deletion of a few basepair on either side of the IR apex (27), consistent with the prediction that cruciform loops are susceptible to cleavage, and, hence, to repair (28). The breakpoints on chromosomes 1p21.2, 4q35.1, 11q23, and 17q11.2, also occurred at, or near, the centers of IR A/T-rich sequences (20). Sperm analyses (29) confirm that the t(11;22) translocation recurs at high frequency (approx 1-9 x 10-5) in the cell population as a de novo mutation and, concurrently, in vitro studies provide direct evidence that the chromosome 11 IR has the capacity to fold into stable cruciform conformations (30). These data support the strong destabilizing role for the sequences/structures involved. Interestingly, a case of ependymoma associated with the t(1;22) translocation revealed that the breakpoint on chromosome 1 was flanked by six copies of a 33 bp-long motif with IR symmetry (20). Conversely, the human genome assembly sequenced clone indicated the presence of only two such repeats; if the number of repeats is indeed polymorphic in the general population, this finding suggests that expansion may predispose to DNA instability, possibly by increasing the propensity (and/or stability) for cruciform formation. Recombination events between highly homologous (97-98%) sequences within LCR-A to D are associated with recurrent deletions and duplications (approx 1:3000 live births), leading to the DiGeorge, velocardiofacial, conotruncal anomaly face and cat-eye syndromes (24,25,31) (Table 1), suggesting that non-B DNA conformations may also be involved in these conditions.

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