Flies Invade Human Genetics

DOUBLE WINGS: An ultrabithorax mutant fly has a total duplication of the body segment that carries wings. Recent issues of The American Journal of Human Genetics have featured a newcomer: Drosophila melanogaster. The fruit fly is a frequent star of a series of review articles called "Insights From Model Systems." The insect's appearance in a human genetics journal is a telling sign that this model among model organisms, long used to decipher the general principles of inheritance, has achieved a new status in helping researchers understand human genome information. Researchers of the past studied mutations that alter flies in noticeable ways: eye color, wing shape, or mixed-up parts. Today's "fly people" take a more molecular approach, sequencing genes and proteins, then deciphering how they connect into pathways and networks that enable cells to communicate with each other to build the tissues of a complex organism. Such discoveries increasingly point the way to identifying related functions in humans. And the sequence similarities, called homologies, between many fly and human genes are "stunning and striking," says Thomas C. Kaufman, professor of biology at Indiana University in Bloomington. "Whole pathways in flies are maintained in humans, using the same molecules. Who would have believed 20 years ago that that would be the case. Then, we were just working on peculiar genes in fruit flies," he adds. Drosophila genetics began in the "fly room" at Columbia University shortly after Mendel's laws were rediscovered at the dawn of the twentieth century. Here, Thomas Hunt Morgan, Alfred Sturtevant, and others meticulously assigned visible traits to one of the four fruit fly chromosome types. "Those Drosophila geneticists were visionaries. For 50 years, they played with phenotypes, mapped genes; it is just amazing what they did. Only in the last 10 years has anyone understood the meaning of this," says Thomas Brody, a former geneticist who runs a Web site called The Interactive Fly. The tide began to turn for Drosophila research in the mid-1980s, when the tools of molecular biology probed genes that had been studied with classical breeding experiments for years. A key event was the 1984 discovery of the homeobox (see accompanying article), which is a part of many genes that lay down the fundamental body plan. Over the next few years, as researchers identified homeobox genes in other species, the status of Drosophila research rose. It skyrocketed in 1989 with identification of homeotic genes in a vertebrate. "Previously people had found a homeobox gene here and there, but Robb Krumlauff, at the National Institute of Medical Research in London, found an array of four gene clusters in mouse that were co-sequential with the fly clusters," recalls Kevin Moses, an associate professor of cell biology at Emory University in Atlanta who studies eye development (A. Graham et al., Cell, 57:367-378, 1989). "It took a few years for the homeobox finding to have enough experimental support to convince the masses, but once that came along, it did change the opinions of many, many scientists about the extent of conservation in developmental patterning molecules and pathways," concurs William McGinnis, a professor of molecular biophysics and biochemistry at the University of California, San Diego, who co-discovered the homeobox. Photos courtesy of Robert J. Fleming NOTCH EFFECTS: The top photo above shows a wildDrosophila embryo that has been stained for the developing central nervous system. The lower photo shows an embryo that lacksNotch gene activity at the same stage of development and stained for the same neural marker. Above right, a Drosophila wing is malformed due to inadequate Notch function; in comparison, the lower right wing is normal. Photo courtesy of Krishna Bhat NORMAL AND MUTANT: Most of the genes that control development of the nervous system in a fly also regulate development of the nervous system in other organisms, including humans. Above, the difference is obvious between ventral nervous systems of normal and mutant Drosophila embryos. Since the 1980s, technology has catapulted fly research into the limelight. "Back then, when a gene was discovered in Drosophila that had a homolog in a human, it was wow! Now a researcher feels apologetic if there isn't an homology," observes Geoffrey Duyk, chief scientific officer of Exelixis Pharmaceuticals Inc. in South San Francisco, Calif. Exelixis is a privately held genomics company that studies human genes of clinical interest by scrutinizing corresponding pathways in the fly (S. Bunk, The Scientist, 12[9]:1, April 27, 1998). "The wide-scale availability of sequence databases and the consistent observation of conservation of not only genes, but pathways, has raised the profile of Drosophila genetics within the scientific community," he adds. The Interactive Fly sdb.bio.purdue.edu/fly/aimain/1aahome.htm Flybase (data) flybase.bio.indiana.edu Drosophila virtual library (Internet resource list) ceolas.org/fly/ Flybrain (atlas and database of nervous system) http://flybrain.neurobio.arizona.edu/ FlyView (image database) http://pbio07.uni-muenster.de/Home.html Berkeley Drosophila Genome Project (encyclopedia of sequence data) http://fruitfly.berkeley.edu/ DRES (Drosophila-related expressed sequences) http://www.tigem.it/dros.html Exelixis's isn't the only effort to systematically link fly genes to human genes. Many pharmaceutical and biotech companies are using model organisms to focus their drug development programs, Duyk says. And a group at the Telethon Institute of Genetics and Medicine in Milan is cataloging 150 human cDNAs that are homologous to Drosophila genes (see box for web sites). Before asking the question, "Why flies?", a larger question looms: "Why compare the genes of any species?" "Easy. Evolution isn't going to recruit new genes. It's too much trouble. It's easier to modify the same genes and pathways that are already there. That's why you can take any important human gene and find a counterpart in the fly," says Krishna Bhat, an assistant professor of biology at Emory University who studies the fly nervous system. "Evolution recruited the same molecules, and used them in slightly different ways in different species," he adds. Drosophila has advantages beyond its extensive archive of described and mapped genes. "You can manipulate flies more easily than other organisms. And the nice thing about Drosophila versus vertebrates is that it is simplified--that is, it has one copy of genes," says Robert Fleming, an assistant professor of biology at the University of Rochester who studies signal transduction in development. " Drosophila has 12,000 to 15,000 genes, and humans have 100,000. What accounts for the difference? Some genes in vertebrates are not in invertebrates. Also, there has been gene duplication in the evolution of invertebrates to vertebrates. On average, vertebrates have four homologs for every gene in flies," adds Duyk. Courtesy: R. Turner, Indiana University ANTENNAS TO LEGS: In a fly that inherited a mutant Antennapedia gene, antennae have been transformed into legs. Homeotic genes such as Antennapedia include a region called the homeobox, which is a part of genes in many species, where the body plan is determined. The problem with redundant genes is that "you can knock out one gene, but another may compensate," says Susan Zusman, an assistant professor of biology at the University of Rochester. She studies integrins, which participate in cell adhesion. "Vertebrates have many types of integrins, but Drosophila has only a very few. You can really target a particular integrin and see how it works," she adds. Identifying homologies is an exciting but first step. A bigger challenge, researchers say, is establishing orthologies--similarities in function. The correspondence between what homologous genes do is not often obvious. Here are examples of how certain fly genes compare to their human counterparts. Fertility Genes: The fly genes doublesex, boule, and diaphanous share extensive sequence with human genes that cause male sex reversal, lack of sperm, and premature ovarian failure, respectively (C.S. Raymon et al, Nature 391:691-5, 1998; C.G. Eberhart et al, Nature 381:783-785, 1996; S. Bione et al, Amer. J. of Hum. Gen., 62:533-41, 1998). These correspondences could lead to better understanding of human infertility. "Given the substantial similarities between fly and human spermatogenesis, I suspect that we will identify many more molecular parallels in the next few years," says Steve Wasserman, a professor of molecular biology and oncology at the University of Texas Southwestern Medical Center in Dallas. Notch: A 1968 textbook describes Notch as a gene that when mutant indents a female's wing and kills a male. Today we know that the Notch protein resides in the cell membrane, and responds to incoming signals by controlling the ability of the cell to respond to other signals. This action ultimately sets up cell type boundaries, which sculpt a tissue. Serrate, a gene that signals Notch, has a human version that causes Alagille syndrome. Symptoms include severe itching; characteristic facial features; eye, rib, and heart abnormalities; and absent bile ducts. Ether-a-go-go: "When you use ether to immobilize this mutant, when it comes out of the ether, it jumps like popcorn being popped, it flips right off the microscope stage," explains Harold Dowse, a professor of biology at the University of Maine in Orono. The fly gene ether-a-go-go encodes a potassium channel; when abnormal, it slows the heartbeat. The human homolog, called HERG for human ether-a-go-go related gene, causes long QT syndrome. "This disease is one of the main causes of sudden death in young, otherwise healthy, athletes," from cardiac failure, Dowse adds. Pax-6: Analysis of the fly gene Pax-6 is greatly changing our view of eye evolution. "Every animal group has eyes, even jellyfish. The conventional view is that photoreceptor cells were reinvented 39 times," explains Moses. But the fact that humans inherit a condition called aniridia (absent iris) when their version of Pax-6 is absent or abnormal, argues against that long-held view. Apparently, the basic structure of a visual system based on photoreceptors and pigments dates back to a shared ancestor of Drosophila and humans. As the human genome project nears completion, it's clear that the similarities between flies and people, at the molecular level at least, will continue to mount. Sums up Zusman, "It sounds strange, but more and more, the basic way that flies operate is being found to be very similar to humans. But why should evolution change? It is ideal to be able to study how these things work in a complex organism where the genetics is so easy to manipulate." Ricki Lewis, a freelance science writer based in Scotia, N.Y., is the author of several biology textbooks. She can be reached online at rickilewis@nasw.org. The year 1980, when I earned my Ph.D., was a pivotal time in Drosophila genetics. As the first graduate student in the laboratory of Thomas C. Kaufman at Indiana University in Bloomington, I spent four years inducing mutations in the Antennapedia gene complex, crossing flies to map their genes. But I chose to leave the fly world--largely because I could see no connection between human genetics and insects with legs on their heads. Was I wrong! When I left the lab, the first postdoc arrived, Matt Scott . He and graduate student Amy Weiner delved into the molecular morass of Antennapedia , and by 1994 they had identified the 180-base homeobox in several key genes (M.P. Scott, A.J. Weiner, Procedures of the National Academy of Sciences, 1:4115-19, 1984). At the University of Basel, William McGinnis and Michael Levine , in the lab of Walter Gehring , accomplished the same feat (W. McGinnis et al. Nature 308:428-33, 1984). Homeobox-containing genes affect other genes to set up the basic body plan. Mutations cause one structure to develop as another. Photo: Rich Lannon Ricki Lewis William Bateson first described homeotic mutations in insects and flowers in 1894 (W. Bateson, Materials for the study of variation treated with especial regard to discontinuity in the origin of species, London, Macmillan, 1894), but they remained an oddity. Ninety years later, identifying the homeobox gene gave researchers a probe with which to pull out similar genes in other species. Homeobox-harboring genes were rapidly identified in beetles, frogs, corn, nematodes, and flowering plants. Experiments showing that a homeotic gene from one species can disrupt development when transferred to another testified to the ancient and essential nature of these genes. Today, several Web sites catalog fly-human homologies. One of those Web sites, The Interactive Fly, is the brainchild of someone who, like myself, erroneously dismissed Drosophila research as too basic. Thomas Brody got his Ph.D. in immunology at the University of California at Berkeley in 1970. "I gave up science for the same reason--I couldn't see the logic. I left science 15 years ago, and opened an art gallery in Washington, D.C. Then I started going to NIH seminars, where I noticed that people were really getting excited about the demonstration of the conserved nature of homeobox-containing genes. I realized that there was a great difference now in the outlook," he recalls. That difference meant segueing from studying gene structure to gene function. "In 1970, we didn't have the slightest idea what genes did. For example, back then, a spineless aristapedia fly had the tip of the antenna transforming to leg. The gene turns out to encode a dioxin receptor, with a homolog in vertebrates. What does that mean?" Questions like these led Brody to develop The Interactive Fly. "We can study evolution, how genes change, and how they function in different organisms. The stories revealed in the next 10 years will be amazing," he concludes. --RL

Flies Invade Human Genetics

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