PERSPECTIVE N ATU RE G EN ETI C S | VOLUME 39 | NUMBER 6 | JUNE 2007 715 Using FlyAtlas to identify better Drosophila melanogaster models of human disease Venkateswara R Chintapalli, Jing Wang & Julian A T Dow FlyAtlas, a new online resource, provides the most comprehensive view yet of expression in multiple tissues of Drosophila melanogaster. Meta-analysis of the data shows that a significant fraction of the genome is expressed with great tissue specificity in the adult, demonstrating the need for the functional genomic community to embrace a wide range of functional phenotypes. Well-known developmental genes are often reused in surprising tissues in the adult, suggesting new functions. The homologs of many human genetic disease loci show selective expression in the Drosophila tissues analogous to the affected human tissues, providing a useful filter for potential candidate genes. Additionally, the contributions of each tissue to the whole-fly array signal can be calculated, demonstrating the limitations of whole-organism approaches to functional genomics and allowing modeling of a simple tissue fractionation procedure that should improve detection of weak or tissue- specific signals. Experimental reverse genetics is a powerful tool for understanding novel genes, a key goal of functional genomics 1,2 , both for basic science and for the understanding of human disease 3,4 . Simple genetic models have vital roles in this endeavor because of the relative ease, power and cost of their reverse genetic techniques 2,5 compared with mouse. The announcement of the Drosophila genome was accompanied by prediction of its utility in understanding human genetic disease, and this optimism was accom- panied by the formation—and subsequent closure or refocusing—of several companies. Now, a more prosaic approach pertains. The case for Drosophila as a model of human disease is based on a gene-by-gene argu- ment, and the powerful genetics associated with this tiny fly is starting to produce useful insights. It has also proved possible to ‘humanize’ the fly by introducing human genes of interest and studying them in an organotypic context that can prove more informative than studies in cell culture. However, recent data suggest that to study novel genes by reverse genet- ics (that is, studying gene function by generating mutants and study- ing the phenotypes), the Drosophila community may need to broaden its focus. It has long been realized that functional genomics demands functional phenotypes, whereas most model organisms were adopted for studies of development. The mismatch between the range of functions of an organism’s genes and the range of phenotypes available in that organ- ism has been termed the ‘phenotype gap’ 6–8 . The utility of Drosophila in studies of development is beyond dispute, but it is salutary to note that perhaps a third of a million researcher-years spent studying Drosophila (predominantly its development) had led to the identification of only 20% of its genes 8 before the release of the genome sequence 9 . So if most of the genes encoded by the Drosophila genome are not primarily devel- opmental in function, where should one seek phenotypes for the rest? Drosophila research in the UK has been helped by the Investigating Gene Function (IGF) initiative of the Biotechnology and Biological Sciences Research Council (BBSRC), which has invested £4 million ($6 million) in infrastructure for microarrays, proteomics and novel mutant collections. As part of this initiative, the UK Drosophila Affymetrix Microarray Facility has provided 1,000 arrays, as well as processing and analysis, free of charge to over 50 projects from the UK (http://www. mblab.gla.ac.uk/igf). As a service to the community, we have produced FlyAtlas (http://flyatlas.org), a microarray-based atlas of gene expression in multiple adult tissues. As well as providing some clear messages about the utility of whole-fly arrays, the database also helps delineate the phe- notype gap by identifying those tissues in which specific genes of interest (and thus, the homologs of human disease genes) can be studied. The online data set thus provides an instant entrée into the field, not just for Drosophilists but also for scientists who can identify a likely homolog in the fly, regardless of the organism they use. Venkateswara R. Chintapalli, Jing Wang and Julian A.T. Dow are in the Division of Molecular Genetics, University of Glasgow, Glasgow G11 6NU, UK. e-mail: j.a.t.dow@bio.gla.ac.uk Published online 29 May 2007; doi:10.1038/ng2049 100 80 60 40 20 0 Brain Head Crop Midgut Tubule Hindgut Testis Ovary Accessory gland Whole fly Detected at least once Detected every time Percentage of total probe sets Figure 1 Drosophila tissues typically express around half the computed transcriptome. For each tissue, the number of probe sets giving at least one ‘present’ call is shown, together with those meeting the stricter criterion of giving four present calls out of four chips. © 2007 Nature Publishing Group http://www.nature.com/naturegenetics