Making connections with GO: an integrative approach to highlighting medically relevant Drosophila data

At first glance fruit flies and humans seem very different. But if we look closer we see that they share certain features: limbs, a brain, a heart and much more besides. If we look even more closely we see that this is because we share genes in our DNA. We can use these similarities to study human disease because three quarters of genes associated with human disease are found in fruit flies too. Disrupting genes in fruit flies can tell us how they normally work in humans, how they cause diseases when they are not working well and give us clues about how to we might be able to fix problems caused by the faulty genes. Fruit flies have many advantages for studying disease. For example, we can do many different experiments with flies very quickly, and they get old within weeks, so they are really useful for studying neurodegenerative conditions such as Alzheimer's disease.
Extensive research is carried out using fruit flies by scientists around the world, generating a huge amount of data. It is important that scientists are able to easily and quickly access these data so that they can build on existing knowledge to devise new experiments in their own research. This is where biological databases come in: they have dedicated teams of people (curators) who read the published research papers and enter the information into a computer database. Curators do this by linking scientific terms, taken from special dictionaries, to biological objects such as genes. The aim of our project is to use one such scientific dictionary, called the Gene Ontology, to attach labels to genes that describe what they do and where they do it. We will focus on those fruit fly genes that are equivalent to human genes that are implicated in diseases. This work will be done in the context of gene networks - knowing how genes function together gives a better understanding of how they contribute to our day to day life, and how their disruption leads to disease. Altogether, this project will facilitate the transfer of knowledge gained in fruit flies to the medical community, ultimately helping the development of effective treatments of human diseases.

The aim of this research proposal is to enhance the utility and accessibility of data from Drosophila to the biomedical research community. Our approach will center on the Gene Ontology (GO), a unifying vocabulary for describing the attributes of gene products across species and databases. We will focus our efforts on improving the annotation of pathways and protein complexes relevant to human disease. In parallel, we shall undertake a comprehensive annotation of non-coding RNAs - an important emerging area in human health. Whilst achieving these aims, we will work with the GO consortium to develop the ontology itself and adopt their enhanced annotation framework. Furthermore, in collaboration with FlyBase, we shall present pathways and complex components as easily accessible lists that are highly integrated with all other data in FlyBase. Subsequently, we will enhance these pages by adding graphical models of pathways that will highlight intersections with human disease gene orthologs and those genes studied in Drosophila disease models. Overall, our approach will improve the functional annotation of Drosophila genes related to human disease, and present these data in intuitive and accessible ways to the wider research community to maximise the impact of fly research on biomedical advances.

The proposed research will also have beneficiaries in non-academic sectors and the general public in the UK and abroad. There will be an economic benefit to the pharmaceutical industry. The number of new drugs coming on to the market has declined significantly and traditional in vitro high-throughput screening techniques are failing to yield new therapies. As we gain more understanding of human disease, it is clear that most diseases are multi-factorial; the hopes of 'the-one gene-one-drug' or 'magic bullet' model will not be realized in the majority of cases. The data we collate can be used to inform basic pathway biology in humans. As the data from Next-Generation Sequencing of human genomes enters the clinical arena, we will need good functional annotations to interpret the masses of data to aid the hunt for new therapeutic targets. Drosophila can be used at all stages of the drug-discovery process, from modeling the disease (e.g. Alzheimer's disease, Parkinson's disease, cancers) to an in vivo model for high-throughput screening. Therefore linking gene function data to Drosophila disease models and human disease genes is of great value to such research strategies. Ultimately, this will help bring new drugs to the market and improve the health of the population. With an ageing population there is increased financial pressure on the health service, charities, local government and ultimately the UK taxpayer. The benefits of Drosophila as a model for neurodegenerative and cardiovascular disease will be particularly needed as we head towards an ageing population. We will facilitate this by disseminating the functional annotation of Drosophila gene products by providing our most up-to-date data every 2 months to the GO consortium, the FlyBase database, UniprotKB and RNAcentral. From these sites, the data will be freely available and searchable. All tools for the enhanced searching of Drosophila data are freely available from the FlyBase website.
Drosophila is also an important model for researchers studying insects that seriously impact on human health. There are many disease-causing parasites and viruses borne by insect hosts (vector borne diseases, e.g. sleeping sickness, malaria, dengue). They have a huge medical and economic impact in the developing world and as climate patterns shift, the effects could reach further into Europe and the UK. Globally, insect crop pests have a serious economic impact on agriculture. In the UK it is estimated that the agri-food sector contributes 7% of the economic activity of the nation. With a rise in pesticide resistance and the negative environmental impact of using such technologies, the understanding of Drosophila biology underpins the development of many new strategies to pest control. Functional interpretation of the genomes of disease-carrying insects such as mosquitoes, the Tsetse-fly, and crop pests such as the black fly and the Mediterranean fruit fly, relies heavily on the extensive experimental data available in Drosophila. By making this data freely available, it can be used to annotate the genomes of these closely-related species.