Drosophila as a Model for Human Diseases


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.


Amir RE, Van den Veyver IB, Wan M and Tran CQ (1999) Rett syndrome is caused by mutations in X‐linked MECP2, encoding methyl‐CpG‐binding protein 2. Nature Genetics 23: 185–188.

Bellen HJ, Levis RW, He Y, et al. (2011) The Drosophila gene disruption project: progress using transposons with distinctive site specificities. Genetics 188: 731–743.

Bellen HJ and Yamamoto S (2015) Morgan's legacy: fruit flies and the functional annotation of conserved genes. Cell 163: 12–14.

Bier E and Bodmer R (2004) Drosophila, an emerging model for cardiac disease. Gene 342: 1–11.

Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nature Reviews Genetics 6: 9–23.

Broer L, Koudstaal PJ, Amin N, et al. (2011) Association of heat shock proteins with Parkinson's disease. European Journal of Epidemiology 26: 933–935.

Bryantsev AL, Baker PW, Lovato TL, Jaramillo MS and Cripps RM (2012) Differential requirements for myocyte enhancer factor‐2 during adult myogenesis in Drosophila. Developmental Biology 361: 191–207.

Caussinus E, Kanca O and Affolter M (2013) Protein knockouts in living eukaryotes using deGradFP and green fluorescent protein fusion targets. Current Protocols in Protein Science 73: Unit 30.2.

Chao HT, Davids M, Burke E, et al. (2017) A syndromic neurodevelopmental disorder caused by de novo variants in EBF3. The American Journal of Human Genetics 100: 128–137.

Chintapalli VR, Wang J and Dow J (2007) Using FlyAtlas to identify better Drosophila melanogaster models of human disease. Nature Genetics 39: 715.

Chow CY and Reiter LT (2017) Etiology of human genetic disease on the fly. Trends in Genetics 33: 391–398.

Coffee RL, Tessier CR, Woodruff EA and Broadie K (2010) Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P. Disease Models & Mechanisms 3: 471–485.

de la Cova C, Abril M, Bellosta P, Gallant P and Johnston LA (2004) Drosophila myc regulates organ size by inducing cell competition. Cell 117: 107–116.

Cronin SJF, Nehme NT, Limmer S, et al. (2009) Genome‐wide RNAi screen identifies genes involved in intestinal pathogenic bacterial infection. Science 325: 340–343.

Cukier HN, Perez AM, Collins AL, et al. (2008) Genetic modifiers of MeCP2 function in Drosophila. PLoS Genetics 4: e1000179.

Diao F, Ironfield H, Luan H, et al. (2015) Plug‐and‐play genetic access to Drosophila cell types using exchangeable exon cassettes. Cell Reports 10: 1410–1421.

Feany MB and Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404: 394–398.

Ferdousy F, Bodeen W, Summers K, et al. (2011) Drosophila Ube3a regulates monoamine synthesis by increasing GTP cyclohydrolase I activity via a non‐ubiquitin ligase mechanism. Neurobiology of Disease 41: 669–677.

Fernandez‐Funez P, Nino‐Rosales ML and de Gouyon B (2000) Identification of genes that modify ataxin‐1‐induced neurodegeneration. Nature 408: 101.

Fillip Port SLB (2016) Augmenting CRISPR applications in Drosophila with tRNA‐flanked Cas9 and Cpf1 sgRNAs. Nature Methods 13: 852–854.

Fischer C, Trautman EP, Crawford JM and Stabb EV (2017) Metabolite exchange between microbiome members produces compounds that influence Drosophila behavior. eLife 6: e18855.

Gantz VM, Jasinskiene N, Tatarenkova O, et al. (2015) Highly efficient Cas9‐mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. Proceedings of the National Academy of Sciences of the United States of America 112: E6736–E6743.

Guichard A, Park JM, Cruz‐Moreno B, Karin M and Bier E (2006) Anthrax lethal factor and edema factor act on conserved targets in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 103: 3244–3249.

Guichard A, McGillivray SM and Cruz‐Moreno B (2010) Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst. Nature 467: 854.

Han Z, Yi P, Li X and Olson EN (2006) Hand, an evolutionarily conserved bHLH transcription factor required for Drosophila cardiogenesis and hematopoiesis. Development 133: 1175–1182.

Iijima K, Liu HP, Chiang AS, et al. (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 101: 6623–6628.

Johnston DS (2002) The art and design of genetic screens: Drosophila melanogaster. Nature Reviews Genetics 3: 176.

Kishino T, Lalande M and Wagstaff J (1997) UBE3A/E6‐AP mutations cause Angelman syndrome. Nature Genetics 15: 70–73.

Kwon C, Han Z, Olson EN and Srivastava D (2005) MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proceedings of the National Academy of Sciences of the United States of America 102: 18986–18991.

Lemaitre B and Hoffmann J (2007) The host defense of Drosophila melanogaster. Annual Review of Immunology 25: 697–743.

Lenz S, Karsten P, Schulz JB and Voigt A (2013) Drosophila as a screening tool to study human neurodegenerative diseases. Journal of Neurochemistry 127: 453–460.

Lin MT and Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787.

Lu B and Vogel H (2009) Drosophila models of neurodegenerative diseases. Annual Review of Pathological 4: 315–342.

Marcogliese PC, Abuaish S, Kabbach G, et al. (2017) LRRK2(I2020T) functional genetic interactors that modify eye degeneration and dopaminergic cell loss in Drosophila. Human Molecular Genetics 26: 1247–1257.

Martin I, Dawson VL and Dawson TM (2011) Recent advances in the genetics of Parkinson's disease. Annual Review of Genomics and Human Genetics 12: 301–325.

McGurk L, Berson A and Bonini NM (2015) Drosophila as an in vivo model for human neurodegenerative disease. Genetics 201: 377–402.

Nedelsky NB, Pennuto M, Smith RB, et al. (2010) Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron 67: 936–952.

Nishimura M, Ocorr K, Bodmer R and Cartry J (2011) Drosophila as a model to study cardiac aging. Experimental Gerontology 46: 326–330.

Ocorr K, Akasaka T and Bodmer R (2007) Age‐related cardiac disease model of Drosophila. Mechanisms of Ageing and Development 128: 112–116.

Pagliarini RA and Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302: 1227–1231.

Ranganayakulu G, Zhao B, Dokidis A, et al. (1995) A series of mutations in the D‐MEF2 transcription factor reveal multiple functions in larval and adult myogenesis in Drosophila. Developmental Biology 171: 169–181.

Rousseaux MW, de Haro M, Lasagna‐Reeves CA, et al. (2016) TRIM28 regulates the nuclear accumulation and toxicity of both alpha‐synuclein and tau. eLife 5. pii: e19809.

Shulman JM, Imboywa S and Giagtzoglou N (2013) Functional screening in Drosophila identifies Alzheimer's disease susceptibility genes and implicates Tau‐mediated mechanisms. Human Molecular Genetics 23: 870–877.

Southall TD, Elliott DA and Brand AH (2008) The GAL4 system: a versatile toolkit for gene expression in Drosophila. Cold Spring Harbor Protocols 2008: 49.

Sun YM, Wang J, Qiu XB, et al. (2016) A HAND2 loss‐of‐function mutation causes familial ventricular septal defect and pulmonary stenosis. G3 (Bethesda, Md.) 6: 987–992.

Ugur B, Chen K and Bellen HJ (2016) Drosophila tools and assays for the study of human diseases. Disease Models & Mechanisms 9: 235–244.

Uhlirova M and Bohmann D (2006) JNK‐ and Fos‐regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO Journal 25: 5294–5304.

del Valle Rodríguez A, Didiano D and Desplan C (2012) Power tools for gene expression and clonal analysis in Drosophila. Nature Methods 9: 7–55.

Venken KJT, Simpson JH and Bellen HJ (2011) Genetic manipulation of genes and cells in the nervous system of the fruit fly. Neuron 72: 202–230.

Vidal M and Cagan RL (2006) Drosophila models for cancer research. Current Opinion in Genetics & Development 16: 10–16.

Wang L, Fan C, Topol SE, Topol EJ and Wang Q (2003) Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 302: 1578–1581.

Wolf MJ, Amrein H, Izatt JA, et al. (2006) Drosophila as a model for the identification of genes causing adult human heart disease. Proceedings of the National Academy of Sciences of the United States of America 103: 1394–1399.

Wu Y, Bolduc FV, Bell K, et al. (2008) A Drosophila model for Angelman syndrome. Proceedings of the National Academy of Sciences of the United States of America 105: 12399–12404.

Yamamoto S, Jaiswal M, Charng WL, et al. (2014) A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases. Cell 159: 200–214.

Yasunaga A, Hanna SL, Li J, et al. (2014) Genome‐wide RNAi screen identifies broadly‐acting host factors that inhibit arbovirus infection. PLoS Pathogens 10: e1003914.

Yoon WH, Sandoval H, Nagarkar‐Jaiswal S, et al. (2017) Loss of nardilysin, a mitochondrial co‐chaperone for α‐ketoglutarate dehydrogenase, promotes mTORC1 activation and neurodegeneration. Neuron 93: 115–131.

Further Reading

Bangi E (2013) Drosophila at the intersection of infection, inflammation, and cancer. Frontiers in Cellular and Infection Microbiology 3: 103.

Bassett AR and Liu JL (2014) CRISPR/Cas9 and genome editing in Drosophila. Journal of Genetics and Genomics 41: 7–19.

Bellen HJ, Levis RW, Liao G, et al. (2004) The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila genes. Genetics 167: 761–781.

Buchon N, Silverman N and Cherry S (2014) Immunity in Drosophila melanogaster – from microbial recognition to whole‐organism physiology. Nature Reviews Immunology 14: 796–810.

Gratz SJ, Cummings AM, Nguyen JN, et al. (2013a) Genome engineering of Drosophila with the CRISPR RNA‐guided cas9 nuclease. Genetics 194: 1029–1035.

Gratz SJ, Wildonger J, Harrison MM and O'Connor‐Giles KM (2013b) CRISPR/cas9‐mediated genome engineering and the promise of designer flies on demand. Fly 7: 249–255.

Reiter LT (2006) Drosophila as a model for human diseases. In: eLS. Chichester: John Wiley & Sons, Ltd.

Ocorr K, Vogler G and Bodmer R (2014) Methods to assess Drosophila heart development, function and aging. Methods 68: 265–272.

Pandey UB, Nichols CD and Barker EL (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Nature Reviews. Cancer 13: 172.

Pick L (2017) Fly Models of Human Diseases, vol. 121. Cambridge, MA: Academic Press.

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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]