Molecular Genetics of the Drosophila Triplo-lethal Locus

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Christensen9808209Alterations in gene dosage often have profound effects on the development and/or viability of organisms, yet little is known about the molecular basis of gene dosage effects. The Triplo-lethal locus of Drosophila (Tpl) is a unique and interesting model for understanding gene dosage effects. Tpl is the only genetic locus known that is lethal when present in anything other than two copies. Diploid animals with either zero, one, three or four copies of Tpl die as late embryos or early first-instar larvae. Tpl may also have an unusual genetic structure. While duplications and deficiencies of Tpl are readily isolated, point mutations that eliminate Tpl's function have never been found, suggesting that Tpl may consist of redundant information or it may code for a non-translated RNA molecule. Recent data suggest that the DNA that is necessary for Tpl function has been cloned. This region will be analyzed by standard molecular techniques, including cDNA cloning and sequencing to identify transcription units. Candidate genes will be used in Drosophila transformation experiments to identify Tpl. This region of the genome will be sequenced in the near future by the Berkeley Drosophila Genome Project, which will greatly aid the analysis of this novel genetic locus. Cloning and sequencing the Suppressor-of Tpl locus, Su(Tpl), will also be done. Su(Tpl) mutant embryos survive in spite of having three doses of Tpl, which shows an interaction of these two genes. Genomic clones of Su(Tpl) have already been obtained and cDNA clones will be isolated and analyzed. Understanding Su(Tpl) will lead to greater understanding of why Tpl is so dosage sensitive and the basis for the lethality.Tpl has two features that make it novel. One is its extreme dosage sensitivity. The other is its resistance to mutagenesis, suggesting an unusual structure. Both make its study especially challenging, but such genes may not be rare in the cell. It may only be that they are not easily discovered. Non-protein-coding genes will also not easily be identified via DNA sequence analysis. Understanding Tpl may lead to the discovery of many more genes of this type, and a further understanding of the importance of gene dosage.