The chromosome 22ql 1.2 region is susceptible to rearrangements leading to mental retardation disorders. Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with hemizygous 1.5-3 Mb 22ql 1.2 deletions mediated by unequal homologous recombination events between >225 kb low copy repeats (LCR22). We are interested in the mechanisms responsible for meiotic 22ql 1.2 rearrangements. As part of this program, we propose to understand the structure and evolutionary origin of the LCR22s. We hypothesize that some of the same mechanisms may be responsible for both the etiology of chromosome rearrangement disorders and LCR22 evolution. We found that LCR22s are composed of blocks or modules containing genes and partially duplicated copies creating a complex mosaic. To define sequences that could be responsible for shaping the LCR22s during evolution, we examined the full-length LCR22 genes and their partially duplicated copies. We have found that specific Alu-mediated recombination mechanisms are responsible for LCR22 gene evolution. We will examine the substrates and products of recombination in the sequences comprising LCR genes in non-human primates to validate recombination mechanisms as Specific Aim 1. Sequence analysis revealed evidence for frequent gene conversion events within LCR22-2 and LCR22-4, the two LCR22s responsible for the common recurrent VCFS/DGS deletion, suggesting that they are more dynamic than originally thought. Regions containing gene conversion sites are not distributed evenly across the two LCR22s. It is possible that regions containing higher rates of gene conversion might represent recombination hotspots and/or be more susceptible to chromosome rearrangements. We will assess gene conversion rates across the LCR22-2 and LCR22-4 by sequencing analysis of specific sites within multiple BAC clones and by assessing multigeneration families as Specific Aim 2. This knowledge will provide tools to be used to identify architectural features in the human genome relevant to this P01. ? ?
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