Influences of environmental agents on Alu/Alu recombination

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Unequal recombination events between Alu elements contribute to a significant portion of human genome instabilities associated with cancer and birth defects. There are over 50 independent examples of Alu/Alu recombination events causing different human diseases. Previous studies have shown that various mutagenic compounds contribute to increased recombination rates between randomly repeated sequences. These assays have demonstrated that recombination environmental pollutants often have different influences on small mutations versus recombination. We hypothesize that mutagens will also contribute to the more recombination between dispersed Alu elements, although the stimulation by different mutagens may not be identical between these two different types of recombinant. Thus, we have designed a reported system that will be introduced into tissue culture cells and transgenic mice to allow the direct measurement of Alu/Alu recombination rates. We believe that this assay will be more representative of typical recombination events occurring in the human genome than previous assays. The Alu/Alu recombination assay will be utilized to test for increases in recombination rate upon exposure to a broad range of mutagens. Particular attention will be paid to the aryl hydrocarbons because they represent such a ubiquitous and stable class of pollutants. In particular, studies of benzo[a]pyrene versus. various halogenated aromatic hydrocarbons will be carried out to determine whether there are differences in recombination potential between the more metabolizable hydrocarbons versus no-.metabolizable ones. In addition, studies to determine the role of the aryl hydrocarbon receptor in any recombination stimulation will be carried out.