A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogaster

Abstract

We performed a systematic BLAST analysis of 929 human disease gene entries associated with at least one mutant allele in the Online Mendelian Inheritance in Man (OMIM) database against the recently completed genome sequence of Drosophila melanogaster. The results of this search have been formatted as an updateable and searchable on-line database called Homophila. Our analysis identified 714 distinct human disease genes (77% of disease genes searched) matching 548 unique Drosophila sequences, which we have summarized by disease category. This breakdown into disease classes creates a picture of disease genes that are amenable to study usingDrosophila as the model organism. Of the 548Drosophila genes related to human disease genes, 153 are associated with known mutant alleles and 56 more are tagged byP-element insertions in or near the gene. Examples of how to use the database to identify Drosophila genes related to human disease genes are presented. We anticipate that cross-genomic analysis of human disease genes using the power of Drosophilasecond-site modifier screens will promote interaction between human andDrosophila research groups, accelerating the understanding of the pathogenesis of human genetic disease. The Homophila database is available at http://homophila.sdsc.edu.

Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders

“…In a recent comparative sequence analysis of nearly 300 molecularly identified human MR genes, we found that 87% have a highly similar relative in Drosophila [Inlow and Restifo, 2004]. This percentage is higher than previous reports that used the same sequence-similarity criteria to compare Drosophila genes and human disease genes of diverse types [Fortini et al, 2000;Reiter et al, 2001]. Furthermore, the extent and type of amino acid sequence similarity between the human MR genes and their fruit fly counterparts were sufficient in 76% to suggest that they have similar biological functions in the two species [Inlow and Restifo, 2004].…”

Model Organisms in the Study of Development and Disease

“…In addition, several signaling systems have been implicated in axonal pathfinding and synapse formation, including by the Netrin, Round About (Robo), Semaphorin, Neuroglian, and BMP-mediated pathways. Diseasecausing mutations have been identified in components of nearly all of these major signaling pathway categories (Reiter et al, 2001). Consistent with the high degree of evolutionary conservation between vertebrate and invertebrate genetic systems, many human diseases associated with mutations in signal-transduction pathways lead to developmental disorders, as illustrated by the diseases covered in this volume.…”

“…In the course of discussing these points, we review the compelling evidence that developmentally important genes have been phylogenetically conserved and the likelihood that developmental disorders in humans will often involve genes controlling similar morphogenetic processes in vertebrates and invertebrates. A systematic analysis of human disease gene homologs in Drosophila supports this view since 75% of human disease genes are structurally related to genes present in Drosophila and more than a third of these human genes are highly related to their fruit fly counterparts (Bernards and Hariharan, 2001;Reiter et al, 2001;Chien et al, 2002).…”

“…Unicellular organisms such as yeast (Saccharomyces) (Foury, 1997) and the facultatively colonial slime mold (Dictyostelium) (Firtel and Chung, 2000;Chung et al, 2001) can be used to analyze phenomena that involve important basic eukaryotic cell functions, such as metabolism, regulation of the cell cycle, membrane targeting and dynamics, protein folding, and DNA repair. Simple invertebrate systems such as Drosophila (Bernards and Hariharan, 2001;Reiter et al, 2001;Chien et al, 2002) or Caenorhabditis elegans (Aboobaker and Blaxter, 2000;Culetto and Sattelle, 2000) are excellent models for examining the coordinated actions of genes that function as components of a common molecular machine such as a signal-transduction pathway or a complex of physically interacting proteins. These proteins may or may not have highly related sequences in yeast, but if so, the value of the invertebrate system would be most pronounced if the human disease condition involved a tissue-specific requirement for the protein in question (e.g.. metabolic disorders resulting in neurological phenotypes).…”

“…One notable trend among diseases associated with mutations in components of signaling pathways is that defects in extracellular components such as ligands or in ligand-specific receptor subunits often result in limited developmental defects while mutations in more downstream intracellular components, which mediate the action of many ligands, often result in cancer (Reiter et al, 2001). For example, in the BMP pathway, mutations affecting the human BMP2/4 ligand and BMP5/7-specific type I receptor lead to morphological defects such as brachydactyly and hereditary hemoragic telangiectasia, whereas mutations in the shared BMP2 type II receptor or the signal transducer SMAD4 cause cancer (Table 3-4).…”