The chromosome 22q11 region is susceptible to rearrangement leading to congenital anomaly disorders associated with mental retardation. Cat eye syndrome (CES), der(22) syndrome and velo-cardio-facial syndrome/DiGeorge (VCFS/DGS), are associated with tetrasomy, trisomy or monosomy, respectively, of part of 22q11. Der(22) syndrome occurs in offspring of normal carriers of the constitutional t(11;22) translocation, the only known recurrent non-Robertsonian translocation in humans. We found a low copy repeat that we termed, LCR22, in the vicinity of recurrent chromosome breakpoints for these diseases implicating them in mediating 22q11 rearrangements that lead to congenital anomaly disorders on 22q11. In addition to congenital anomaly disorders, the 22q11 region is susceptible to somatic rearrangement leading to malignant disease. The major goal of this project is to determine the molecular basis of constitutional chromosome 22q11 rearrangements in mental retardation disorders. As our first goal, we propose to determine the mechanism by which the constitutional t(11;22) translocation occurs and understand whether other rearrangements in this interval are mediated by the same mechanism. Second, we will generate a precise map of novel chromosome rearrangement breakpoints within the genomic sequence of chromosome 22q11. One such example of a novel rearrangement is the unbalanced t (1;22) translocation that disrupts chromosomes 1p36 (Project III) and 22q11. We will clone and sequence chromosome breakpoint junctions to understand molecular mechanisms. We will generate a functional assay to examine the role of specific LCR22 motifs in mediating mitotic homologous recombination events. Finally, we will examine the evolutionary origin of LCR22s in primate species to understand the origin and maintenance of the current LCR22 structure. This knowledge will provide tools to be used to identify other architectural features in the human genome that may be susceptible to rearrangements. We believe that the 22qll region serves as a model to understand the molecular basis of chromosome rearrangements associated with mental retardation disorders.
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