Position effect variegation in the fruit fly, Drosophila melanogaster, results from chromosome rearrangements where normal genes, having been placed next to centromeric heterochromatin, are inactivated in some cells, but not others, thereby producing a mosaic or variegated tissue. A similar variegating phenomenon occurs in mammals when an inactivated X chromosome has been translocated to an autosome, resulting in the repression of neighboring autosomal loci. The most reasonable hypothesis to explain these observations is that in variegating rearrangements, the usual compacted structure of heterochromatin is propagated past the breakpoint into the adjoining euchromatic loci, thereby repressing or inactivating genes that would otherwise be expressed. In Drosophila, mutants have been described that may either enhance or suppress variegating position effects. We have obtained, by mobilizing transposable P-elements, a number of dominant enhancers of variegation. We intend to continue our search for such mutants, to define them genetically and in terms of their phenotype. Since these mutants contain P-elements, they can be easily identified by screening appropriate recombinant DNA libraries with a P-element probe. We also propose to clone such loci by recombinant DNA techniques and to completely characterize their transcription and translation products in terms of both their structure and their function. Such information should provide insight not only into the mechanism by which variegating position effects arise, but into the constitution of heterochromatic domains themselves. We also intend to use our Drosophila enhancer genes as probes to obtain homologous sequences in mammals, particularly, in mouse and humans. These, in turn, may provide a means to study the molecular basis of chromosome inactivation.
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