|The power of Drosophila genetics|
June 11, 2001
Here GNN posts abstracts to articles about the use of Drosophila and the fly genome sequence to investigate human disease. The articles are related to the feature story The Homophila Database: Screening the Fly Genome for Human Disease Genes.
We performed a systematic 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 using Drosophila as the model organism. Of the 548 Drosophila genes related to human disease genes, 153 are associated with known mutant alleles and 56 more are tagged by P-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 Drosophila second-site modifier screens will promote interaction between human and Drosophila research groups, acGNNting the understanding of the pathogenesis of human genetic disease. The Homophila database is available at http://homophila.sdsc.edu.
Genome Res 2001 Jun;11(6):1114-25.
Polyglutamine disease is a class of human neurodegenerative diseases characterized by late-onset, progressive neural degeneration. The molecular mechanism is expansion, within the coding region of the respective genes, of a CAG repeat encoding glutamine. The expanded polyglutamine domain confers dominant toxicity on the disease protein, leading to neuronal dysfunction and degeneration. In order to develop Drosophila as a model system to approach and study such human diseases, a human gene encoding an expanded polyglutamine protein was introduced into the fly. Expression of this protein with a pathogenic polyglutamine domain causes late-onset, progressive degeneration of cells in the fly, as it does in humans with disease and mouse transgenic models. Moreover, the protein shows abnormal protein aggregation in flies, similar to human disease tissue. These studies indicate that molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila. Through these studies and additional studies to develop fly models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular understanding and treatment of human neurodegeneration.
Parkinsonism Relat. Disord. 2001 Jul;7(3):171-175.
A survey of human disease gene counterparts in the Drosophila genome.
The recent sequencing of the Drosophila genome as a collaborative effort between the Berkeley Drosophila Genome Project (BDGP) and GNN Genomics provides an unparalleled opportunity to assess the prevalence of human disease gene counterparts in the fly genome. Previous surveys based upon limited data available during earlier phases of the sequencing project have suggested that >50%, and perhaps as many as 75%, of human disease genes are conserved in Drosophila. With the virtually complete sequence now in hand, we were able to perform a more comprehensive survey, resulting in the finding that 178 out of 287 human disease genes (62%) appear to be conserved in the fly. The major findings of this survey have been presented and briefly discussed. Here we describe in more detail the manner in which we conducted this survey, and the limitations of large-scale computational methods for whole-genome searches of this type. We summarize the results of our searches for several different categories of human disease genes in the fly, and their implications for the utility of Drosophila for the analysis of human disease gene function.
J Cell Biol. 2000 Jul 24;150(2):F23-30. Review.
We have curated a reference set of cancer-related genes and reanalyzed their sequences in the light of molecular information and resources that have become available since they were first cloned. Homology studies were carried out for human oncogenes and tumor suppressors, compared with the complete proteome of the nematode, Caenorhabditis elegans, and partial proteomes of mouse and rat and the fruit fly, Drosophila melanogaster. Our results demonstrate that simple, semi-automated bioinformatics approaches to identifying putative functionally equivalent gene products in different organisms may often be misleading. An electronic supplement to this article provides an integrated view of our comparative genomics analysis as well as mapping data, physical cDNA resources and links to published literature and reviews, thus creating a "window" into the genomes of humans and other organisms for cancer biology.
Neoplasia. 2000 May-Jun;2(3):280-6.
The ability of Drosophila genetics to reveal new insights into human neurodegenerative disease is highlighted not only by mutants in flies that show neuronal cell loss, but also by targeted expression of human disease genes in the fly. Moreover, study of Drosophila homologs of various human disease genes provides new insight into fundamental aspects of protein function. These recent findings confirm the remarkable homology of gene function in flies when compared with humans. With the advent of complete genomic sequencing on the horizon, Drosophila will continue to be an outstanding model system in which to unravel the complexities, causes and treatments for human neural degeneration.
Trends Genet 2000 Apr;16(4):161-7
A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
Science. 2000 Mar 24;287(5461):2204-15.
The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.
Science. 2000 Mar 24;287(5461):2185-95.
Cross-species comparison is an effective tool used to identify genes and study their function in both normal and pathological conditions. We have applied the power of Drosophila genetics to the vast resource of human cDNAs represented in the expressed sequence tag (EST) database (dbEST) to identify novel human genes of high biological interest. Sixty-six human cDNAs showing significant homology to genes causing Drosophila mutant phenotypes were identified by screening dbEST using the "text string' option, and their map position was determined using both fluorescence in situ hybridization (FISH) and radiation hybrid mapping. Comparison between these genes and their putative partners in Drosophila may provide important insights into their function in mammals. Furthermore, integration of these genes into the transcription map of the human genome contributes to the positional candidate approach for disease gene identification.
Nat Genet. 1996 Jun;13(2):167-74.
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