Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

Abstract

Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual's risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes' roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

Keywords: AUD; Drosophila; addiction; alcohol abuse; alcohol behavior; fruit fly; gene discovery; genetics; human.

Figure 1

The Gal4-UAS system allows precise control of transgene expression. In this binary system, the yeast transcription factor Gal4 is placed under the control of a specific gene promoter, which limits Gal4 expression to select cell types expressing the driver gene. This transgenic construct is combined with a second transgene that places a desired effector gene downstream of the Gal4-binding upstream activation sequence (UAS). Thus, the expression of the effector gene is under spatial and temporal control of a specific gene promoter. The split-Gal4 system uses an intersectional approach to refine Gal4 expression. The Gal4 activation domain (AD) and DNA-binding domain (DBD) are placed downstream of two different promoters. In cells that express both promoters, the AD and DBD combine to form a functional Gal4 protein, which then binds the UAS and drives transgene expression in a more spatially restricted manner. For example, in brain areas where AD (green region) and DBD (purple region) expression overlap (white neurons), the UAS is expressed.

Figure 2

Assays used to test alcohol-related behaviors in Drosophila. The inebriometer measures sensitivity as a function of loss of postural control by determining the amount of time required for EtOH-exposed flies to “elute” out of a column with interspaced oblique baffles. The “Booze-o-mat” assay employs video tracking of fly postural control and/or movement during vaporized EtOH exposure to determine flies’ naïve alcohol sensitivity. Consumption assays such as the capillary feeder (CAFÉ) and the fluorometric reading assay of preference primed by ethanol (FRAPPÉ) determine flies’ preference for EtOH-containing food compared to control solutions. Different consumption assays permit different temporal resolution.