Department: Human Genetics

E-mail: aletsou@genetics.utah.edu
Address: EIHG Rm 7160
Phone: 585-5409

Research Title: Development of Drosophila Models of Human Disease

Research Description:

Global analyses of gene expression in the fruit fly Drosophila melanogaster indicate that large fractions of the genome are expressed in spatially restricted patterns.  We are exploiting patterned expression in the fruit fly for the identification of candidate human disease genes, and we are testing the validity of our approach in the development of fly models of two human diseases: Adrenoleukodystrophy and X-linked hypohidrotic ectodermal dysplasia.

We and others have successfully exploited high-throughput expression screening techniques and reverse genetic methods to identify spatially-restricted (patterned) transcripts corresponding to essential signaling targets.  We were at the forefront of this endeavor- exploiting robotic technologies and the whole-genome sequence of Drosophila to screen for patterned transcripts.  In the course of our work, we predicted that many of the transcriptionally-regulated targets that we identified would play critical roles in signaling output, as effectors of development, and we have shown that for some genes this is indeed the case (e.g. scylla [scyl] and charybde [chrb]).  We also suspected that mutation of many of the effectors (like scyl and chrb) would lead to subtle embryonic phenotypes at best, as signaling pathways branch extensively at the level of their transcriptional readout.  A corollary to this prediction is that patterned expression screens will lead us rapidly to important (first response) genes whose human homologues may not necessarily be essential for developmental patterning (e.g. death in utero as is seen for mutations in the signaling molecules that direct early embryonic development and include BMPs, FGFs and Wnts), but rather whose human homologues may correspond to genes that when disrupted lead to heritable human adult diseases.  The objective of our current studies is to test this idea using two gene pairs (bubblegum [bgm]/double bubble [dbb] and eiger [egr]/Furin 1 [Fur1]) that we identified based on their compelling spatially-restricted patterns of embryonic gene expression.  Another important objective of our studies is to extend our analyses of these gene pairs to the generation of two fly models of human disease: adrenoleukodystrophy (ALD) and X-linked hypohidrotic ectodermal dysplasia (XLHED), and ultimately to the development of therapies for these debilitating conditions. 

1/2008