The long-term objectives are to understand (l) how the genes of the homeotic gene complex (HOM-C) and its cis-regulatory regions program the develop of the head, thorax and abdomen of higher organisms, and (2) why the complexes have been able to remain intact for a time period estimated to predate the separation of the vertebrates and invertebrates, estimated to be over 500 million years. The proposal concentrates on determining how the cis- regulatory regions of the bithorax complex (BX-C) in Drosophila interact with one another to bring about the regulation of the protein-coding genes of the complex.
The specific aims are (1) to dissect the genetic basis for the colinearity of the genes; namely, that their order in the chromosome parallels their order of expression along the antero-posterior body axis of the organism -- a rule that is now known to apply not only to Drosophila but to all vertebrates studied, including human beings; (2) to understand the basis of two highly unusual phenomena, cis-overexpression (COE) and cis-inactivation (CIN), that underlie the regulation of the genes of the BX-C; and (3) to make use of deletions within specific cis- regulatory regions to determine, by means of classical cis-trans tests, the degree to which the two abdominal domains of the complex (abd-A and Abd-B) require proximity for their normal functioning. The experiments proposed involve using x-rays to generate (l) modifiers that are expected to enhance and in other cases to suppress specific COE effects and, indirectly, CIN effects, and (2) deletions of specific cis-regulatory regions. Ultimately, the research has implications for understanding the basis of genetically determined developmental abnormalities, including birth defects and cancer, when these are brought about by mutations in the master control genes which make up the HOM-C.
