Drosophila as a Model for Human Diseases

Abstract

The fruit fly has long been a powerful organism for high‐throughput in vivo studies in biology and genetics. Studies in Drosophila offer a simple platform, modelling multiple human diseases. With an ever‐expanding genetic toolkit, the fly genome has become increasingly accessible to experimental manipulation. The ectopic expression of human disease genes involved in neurodegenerative and neurodevelopmental disorders have elucidated genetic modifiers that have been revealed to also cause human disease or to be potential drug targets for human neurological disorders. Recently, fly models are being used to study other human pathology such as cancer, infections and cardiovascular disorders. Lastly, ‘humanisation’ strategies to replace endogenous fly genes with their human homologue have begun. This has been particularly beneficial in assessing putative pathogenic variants implicated in rare Mendelian disorders, and thereby aiding diagnosis. In summary, the fly has remained a relevant platform for modelling human disease and elucidating genetic pathways and potential therapeutic targets.

Key Concepts

  • There is a vast, ever‐expanding genetic toolkit for manipulation of genes in the fly.
  • Significant advances have been made to further understanding a wide range of human diseases through studies of fly models.
  • Humanisation via use of the T2A‐GAL4 system along with UAS human cDNA transgenics provide a method to test variants implicated in human disease.
  • Flies can be used to study common neurodegenerative diseases as well as rare Mendelian disorders.
  • Functional testing of putative disease causing variants may still be accomplished in flies even when the phenotype may not overlap with human disease presentation.

Keywords: Drosophila melanogaster; fruit flies; model organisms; neurodegeneration; animal models; neurodevelopment; fly models of human disease; genetic screens; infection models; cardiac disease

Figure 1. Highlights of the Drosophila genetic toolkit. (a) Fly genes have classically been randomly disrupted by mutagens such as EMS (ethyl methanesulfonate). The allele depicted in shows a point mutation indicated by the red asterisks in an exon (orange boxes) of a fly gene. (b) The use of transposable elements (green triangles) such as P‐elements has allowed for gene disruption with a variety of cassettes but is limited by insertional ‘hot‐spots’. (c) GAL4 binding the UAS under control of a tissue‐specific driver may be used to knock down fly genes using RNAi (ribonucleic acid interference). (d) Overexpression of constructs such as cDNA (complementary deoxyribonucleic acid) (i.e. fly, mouse or human) or fluorescent reporters in a tissue‐specific manner. (e) Generation of mitotic clones via FRT recombination has allowed for biological study of essential genes that typically cause lethality by examining homozygous mutant cells in a mostly wild‐type tissue. (f) CRISPR strategies have allowed targeted gene disruption to either make gene knockouts/knock‐in animals or insert any user‐defined cassettes. (g) Intronic insertion between coding exons of a T2A‐GAL4 cassette via CRISPR or MiMIC cassette conversion by RMCE (recombination‐mediated cassette exchange) allows for fly gene loss of function and subsequent ‘humanisation’ and replacement with human cDNA to test for conserved function and potential disease‐associated variants.
Figure 2. Assays for phenotypic characterisation of Drosophila in models of human disease. The diagrams depict only some of the common assays involved in using Drosophila to study human disease. Triangles from the left and clockwise: (1) Suppressor/enhancer screening has been a consistent method for revealing genetic modifiers of toxic gene expression, which has played a predominant role in neurodegenerative disorders. (2) Many neurological disorders present with motor dysfunction and flies can be analysed for climbing or flight defects. In addition, activity monitors that use an infrared beambreak system can be an automated method to measure activity, sleep and circadian rhythms. Not depicted are fly tracking software that can measure a variety movement phenotypes on top of other behaviours after video capture. (3) Electrophysiological recordings by electroretinogram are an easy method for modelling neurotransmission defects in flies. Represented is a stereotypical response after stimulation that can be compared to mutant flies. (4) Particularly in diseases of ageing, lifespan analysis can offer insight if degeneration is occurring. Furthermore, fly mutants can be examined for human disease hallmarks by histological analysis. (5) Owing to the simplicity of the fly immune system, it offers a robust model to examine the conserved function of the immune response upon infection. Typical readouts include survival, phagocytic engulfment of bacteria and colony‐forming assays to measure how well flies clear the infection. (6) Complex neurological behaviours can be modelled in flies. Learning and memory assays can be performed by using a T‐maze. Flies are trained to enter two chambers with two different neutral odours, and then one is then paired with an electric shock. Short‐ and long‐term memory tests can then be conducted to test for avoidance of the chamber with the shock. Lastly, flies may be assessed for their response after mechanical stress.
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Marcogliese, Paul C, and Wangler, Michael F(Jan 2018) Drosophila as a Model for Human Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005578.pub2]