424 nature neuroscience • volume 3 no 5 • may 2000

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The complete sequencing of theDrosophila genome1,2 is a spectacularachievement in its own right, as well asbeing a prelude to the much largerhuman genome, whose completion nowseems imminent. With these hugegenomic and microarray data sets ener-gizing much of biology and human dis-ease research, how can the neurosciencecommunity participate in this windfall?What benefits will flow from the genomeprojects of Drosophila, Homo and Mus,with their ancillary and potent dot.combioinformatics, genes on a chip and cut-ting-edge proteomics? Here we discusssome issues that have arisen from theDrosophila genome project, and in par-ticular the implications for neuroscience.

A private company, Celera Genomics,headed by J. Craig Venter, and a consor-tium of University laboratories, coordi-nated by Gerald Rubin, pooled theirresources and were able to sequence theentire euchromatin portion of the flygenome—about 120 megabases—in afew months. To convert the rawsequence information into biologicalknowledge, Celera hosted a two-week‘annotation jamboree’ (more appropri-ately termed a ‘data feeding frenzy’), inwhich scientists from all over theworld—including one of us(G.L.G.M.)—gathered to examine thedata. It can sometimes be difficult topersuade scientists to work together, butin this case the process was autocatalyt-ic. A potpourri of bioinformaticists, purecomputer gurus, protein chemists, sta-tisticians, medical practitioners, neuro-biologists, molecular biologists,transgenic experts, cell biologists andevolutionists, as well as some old-fash-ioned ‘fly pushers’, developed an inten-sity and commitment that was totallyspontaneous. As a result of this effort, a

There are some gene families that arelarger in flies; for example, Drosophilahas 30 glutamate receptor subunits,compared to 10 in C. elegans. Drosophi-la also has various genes that are notrepresented in C. elegans. Among theseare voltage-activated sodium channels,of which there are two in flies (and atleast eight in mammals), but which donot occur in C. elegans, whose neuronsdo not generate sodium spikes.

The molecular machinery of exocy-tosis and endocytosis is broadly con-served between Drosophila andmammals. There are many conservedvesicular trafficking proteins, and acommon pattern is to find onesequence in flies and three or fourhomologs in mammals. One exceptionis the synaptotagmin family; with eightmembers in flies, this is the largestfamily of vesicular proteins. The endo-cytotic molecules dynamin, clathrin,amphiphysin and synaptojanin are allpresent in Drosophila, as are the vesic-ular transporters for glutamate,dopamine, serotonin, GABA andacetylcholine.

The picture is less clear when wecome to the structural organization ofthe synapse. A number of proteins foundat mammalian active zones, such as bas-soon, aczonin and piccolo, have noDrosophila counterparts. Conversely,flies have a number of proteins withunique combinations of C2, PDZ, zinc-

huge amount of data has been freely andrapidly disseminated for the scientificcommunity to evaluate (www.celera.comand www.fruitfly.org).

Drosophila has about 14,000 genes, ascompared to about 18,000 in Caenorhab-ditis elegans and an estimated 80,000 inhumans2. At least a third of Drosophilatranscripts are alternatively spliced, sothe predicted number of proteins encod-ed by this genome is over 20,000. The14,000 fly genes can be classified intoabout 8000 families: some have only asingle member, whereas others have beenduplicated many times. For example,there is only a single homolog of theAlzheimer’s precursor protein gene(APPL), whereas one family of trypsin-like (S1) peptidases contains 199 mem-bers. Moreover, the majority of fly geneshave human counterparts, and it isbecoming increasingly apparent that thevertebrate genome arose from the ampli-fication of a core set of genes not muchlarger than that of the fly.

The fly is the most neurobiologicallycomplex organism to be sequenced todate, with about 250,000 neurons, as com-pared to 302 in C. elegans. Yet there is noindication so far of a corresponding dif-ference in the complexity of the twogenomes, and indeed many families ofneurobiologically important moleculeshave fewer members in flies1–3 than inworms4. For example, Drosophila hasabout 30 potassium channels, comparedto the 90 known in C. elegans, 11 nicotinicreceptor subunit genes compared to 42 inC. elegans, and 12 GABAA/glycine-likereceptor subunit genes, compared to 37in C. elegans. Of particular interest are theG-protein-coupled receptors (GPCRs),many of which are important drug targetsin humans; there are about 1,100 GPCRsin C. elegans (and at least 700 in humans),whereas the fly has only 160 or there-abouts. Some of these fly genes arehomologs of metabotropic glutamate,adenosine, GABA, dopamine, serotoninand muscarinic acetylcholine receptors,whereas 57 are thought to be olfactoryreceptors (Fig. 1)—again, many fewerthan the 1000 or so present in C. elegans.

Deus ex genomixGeorge L. Gabor Miklos and Ryszard Maleszka

The full sequence of the Drosophila genome is now available. Acomparison with other genomes promises to yield many newinsights into how genes control neural development and function.

George L. Gabor Miklos is at GenetixXpressProprietary Limited, 78 Pacific Road, PalmBeach, Sydney, NSW, 2108, Australia. RyszardMaleszka is at the Australian NationalUniversity, Canberra, ACT, 0200, Australia.email: genetixxpress@ozemail.com.au ormaleszka@rsbs.anu.edu.au

Fig. 1. Adult Drosophila maxillary palp, inwhich odorant receptor neurons (red) arevisualized with lacZ under the control of anodorant receptor promotor (DOR104).Courtesy of Leslie Vosshall, ColumbiaUniversity.

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nature neuroscience • volume 3 no 5 • may 2000 425

finger and proline-rich domains.Whether all of these molecules are local-ized to synapses remains to be deter-mined, but one intriguing possibility isthat these genomic differences mayreflect differences in synaptic organiza-tion between phyla.

The development of neural circuitryis of course a vastly complex process,and many of its components—notablythe control of neuronal morphology andthe formation of specific synaptic con-nections—are still very poorly under-stood at the molecular level. Oneimportant factor, however, is cell adhe-sion5, which is known to affect neuriteoutgrowth and may also be important inestablishing synaptic connectivity.Among the adhesion molecules, it isnoteworthy that the fly has only 3 clas-sic cadherins compared to the 20 or sofound in vertebrates; moreover, it com-pletely lacks protocadherins, whereasvertebrates have three gene clustersencoding over 50 of these molecules.The fly is also missing reelin, a ligand forparticular protocadherins of vertebratesthat has been implicated in neuronalmigration.

What about human neurological dis-ease genes? Flies were already known tohave counterparts of genes such as Notch,Presenilin and Lis1 (the gene affected inMiller-Dieker lissencephaly). The genomeproject has now revealed many others,including fly homologs of parkin (juve-nile Parkinson’s disease), tau (fronto-tem-poral dementia with Parkinsonism) andneuroserpin (familial encephalopathy).

The humanized flyThe completion of this phase of the flygenome project means that entirely new

Quo vadis?As Table 1 starkly illustrates, there is lit-tle relationship between total gene num-ber, neuron number, morphology andbehavioral capacities of diverse organismsin different phyla12–15. One can speculatethat gene numbers may reflect the num-ber of neuronal cell types rather than thetotal number of neurons, but the fact isthat we do not know, and such specula-tions merely highlight our ignorance ofbiological complexity and how it isinstantiated. The discrepancies suggest,however, that it will be fruitful to com-pare related species for which small dif-ferences in their genomes lead to largedifferences in their brains and behaviors.One such pair will be Drosophila and thehoney bee Apis mellifera, whose richbehavioral repertoire makes it an idealmodel for comparative studies15, and forwhich an EST (expressed sequence tag)project is already underway.

In conclusion, two salient lessonsemerge from the fly genome project;first, large-scale corporate–academicinteractions can deliver the goods, andsecond, the era of non-transgenic analy-sis of single genes, single neurons, sin-gle networks and single organisms, all inglorious isolation, is largely headed forobsolescence. In its place is the newglobal scale on which biological researchwill operate.

1. Adams, M. D. et al. Science 287, 2185–2195(2000).

2. Rubin, G. M. et al. Science 287, 2204–2215(2000).

3. Littleton, J. T. & Ganetsky, B. Neuron (in press).

4. Bargmann, C. I. Science 282, 2028–2033(1998).

5. Hynes, R. O. Trends Cell Biol. 9, M33 (1999).

6. Feany, M. B. & Bender, W. W. Nature 404,394–398 (2000).

7. Karlin, S. & Burge, C. Proc. Natl. Acad. Sci.USA 93, 1560–1565 (1996).

8. Marsh, J. L. et al. Hum. Mol. Genet. 9, 13–25(2000).

9. Warrick, J. M. et al. Nat. Genet. 23, 425–428(1999).

10. Kazemi-Esfarjani, P. & Benzer, S. Science 287,1837–1840 (2000).

11. Maleszka, R., de Couet, H. G. & Miklos, G. L. G.Proc. Natl. Acad. Sci. USA 95, 3731–3736(1998).

12. Miklos, G. L. G. J. Neurobiol. 24, 842–890(1993).

13. Miklos, G. L. G. Daedalus 127, 197–216(1998).

14. Heisenberg, M., Heusipp, M. & Wanke, C. J. Neurosci. 15, 1951–1960 (1995).

15. Robinson, G. E., Fahrbach, S. E. & Winston,M. L. BioEssays 19, 1099–1108 (1997).

types of experiments can be executedwith great accuracy, one class being theplacement of human genes into flies.This should allow for a rapid evaluationof the generic network components thatcontribute to a human disease. Forexample, the expression of normal andmutant forms of human α-synuclein inDrosophila causes a phenotype thatresembles human Parkinson’s disease6.The flies exhibit a parallel time courseof dopaminergic cell degeneration, theformation of inclusions and locomotordysfunction. Similarly, proteins withabnormally expanded polyglutaminerepeats that cause nuclear inclusionsand neurodegeneration in humans havea similar effect in fly neurons7,8. Mostimportantly, this neurodegeneration canbe completely suppressed9,10, forinstance by co-expression of the humanheat shock protein hsp-90 and thehuman spinocerebellar ataxia 3 protein,allowing the use of genetic screens tohunt for other suppressor genes.Drosophila, with its powerful array ofgenetic technologies, is currently themost practical organism for discoveringthe components of such gene networks,both for disease genes and for othermolecules of interest. It is important tobear in mind, however, the need forcaution when extrapolating data acrossphyla. Although related molecules mayhave similar functions at the molecularlevel, inferences about function are like-ly to become increasingly unreliable asone moves from the molecular to thecellular to the systems level11–13. Anobvious synergy will accrue if the infor-mation from transgenic flies is evaluat-ed and used in parallel with transgenicmice.

Table 1. Estimated numbers of genes and neurons for selected metazoa.

Organism Number of genes Number of neuronsFly 14,000 250,000Nematode worm 18,000 302*Honey bee 14,000 1 millionMiniature wasp (14,000)** 5,000Octopus 40,000*** 150 millionMiniature salamander (80,000) **** 300,000Mouse 80,000 40 millionWhale/elephant 80,000 200,000 millionHuman 80,000 85,000 million

Species names can be found in refs. 12, 13; values in parenthesis are approximations based on com-parison to other species in same phylum. *Lacks a centralized brain; **based on estimates of a mini-mum genome size in insects being of the order of 100 Mb; ***based on reassociation kinetic databut with excellent controls to mammalian genomes; ****based on extrapolations from reassociationdata within the amphibia.

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