Drosophila Orthologues to Human Disease Genes: An Update on Progress
Introduction
The goal of this chapter is to present to a broader view of the state of human disease modeling in Drosophila melanogaster and to outline new directions in the study of the genetic basis of human disorders in flies. The Drosophila classical genetics powerhouse in combination with rapidly developing genomic and postgenomic tools accelerates the identification and characterization of gene networks. Because the molecular mechanisms controlling a variety of physiological pathways are largely conserved between flies and humans, flies are quite useful in modeling a variety of human diseases. These include nervous system disorders, cancer, immune responses, elements of the cardiovascular system, and many more (1). In addition, Drosophila genetic tools can also be used to study systems that are not evolutionally conserved or common between flies and humans. In fact, fly genetics has been applied to the dissection of certain basic metabolic pathways in human organs that are not even present or undeveloped in flies. Due to obvious anatomical differences, the humble fruit fly certainly will never compete with mammalian models in every aspect of human diseases research, but a century of fly genetics should not be underestimated. As a genetic model organism, Drosophila has much to offer human disease researchers in terms of genetic screening power, a wide variety of molecular tools, multiple stock centers packed with a variety of allele, transgene, and deficiency collections and at the same time, any fly geneticist will tell you that they offer an elegant simplicity that drives basic research discoveries even in inexperienced student investigators.
Section snippets
Neurological Disease
In terms of modeling human genetic disease in Drosophila, neurological diseases have been the most lucrative [reviewed in (2., 3.)]. This is not surprising considering a significant level of sequence and function conservation of nervous system genes and pathways that are directly relevant to human neurological disease [links between human disease and fly genes can be found using the Homophila database at http://homophila.sdsc.edu; (1., 4.)]. Although the basic processes of neurogenesis,
Drosophila in Cancer Research
The major functional components of the cell cycle and metabolic and signaling pathways leading to cancer are highly conserved between fruit flies and humans. Drosophila is quite useful in modeling cancer or at least simple morphological aspects of cancer such as cell division, apoptosis, or cell migration [reviewed in (42., 43., 44., 45., 46., 47.)]. It should also be noted that the fruit fly has a glorious past serving in studies on the delineation of signaling pathways involved in
Tumorigenesis, Neuroprotection, and Fortitude: The Hypoxic Response in Drosophila
Oxygen deprivation, or hypoxia, and the cellular mechanisms that can regulate hypoxia are key factors in the pathogenesis of cancer, stroke, and familial inherited disorders such as those that occur in Von Hippel-Lindau syndrome (OMIM #193300) [reviewed in (85., 86., 87.)]. For example, localized hypoxic effects play a central role in limiting tumor growth and may also be involved in blunting the actions of important chemotherapies [reviewed in (88., 89.)]. Oxygen deprivation causes devastating
Blood, Immune Response, and Infectious Disease
Innate immunity is a phylogenetically ancient protection mechanism. It serves as the first line of defense against infection by foreign pathogens. Evolutionary conservation of biochemical pathways involved in innate immunity make Drosophila a powerful model to study the prototypical immune response.
Flies, just like humans, also suffer from infectious disease. A fly could not survive without mechanisms to constantly defend itself against pathogens in its native environment. Despite the fact that
Future Candidates
There are a large number of Drosophila genes that would potentially contribute to unraveling the basic biology of human disorders. Sequence comparison databases are regularly updated and integrated into a more synergistic view of the model system. A current list of Drosophila genes that are homologues to human disease genes to an e-value of <10−100 is presented in Table I.
In conclusion, ongoing research on Drosophila models is very valuable and promising. A number of genes have been identified
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