Specific mutations are generated in Drosophila homologs of human genes to study phenotypic consequences in vivo. Gene function can be reduced or silenced using CRISPR-Cas9 and RNAi interference, or overexpressed via transgenes. In other words, reverse genetics first observes a gene, then analyzes a phenotype.

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- Reverse genetics
- Forward genetics
- Diagnostic strategy

Genetic tools for Drosophila

Ugur, B., Chen, K., & Bellen, H. J. (2016). Drosophila tools and assays for the study of human diseases. Disease Models & Mechanisms, 9(3), 235–244. https://doi.org/10.1242/dmm.023762

Drosophila tools and assays for the study of human diseases (2016)

Reverse Genetics

In forward genetics, mutations are generated at random, traditionally with ethyl methanesulfonate (EMS). The mutant progeny are then screened for any aberrant phenotype or behavior. Finally, the DNA of mutants displaying a similar phenotype or behavior are sequenced and compared for common polymorphisms. In other words, forward genetics first observes a phenotype, then analyzes a gene.

Forward Genetics

One of the strategies used to identify human disease-causing genes is whole-genome/exome sequencing of patients and their families. However, this strategy has limited statistical power. Through the diagnostic strategy, Drosophila homologs of human disease-causing genes are identified and knocked out via the GAL4-UAS system. If the knockout fly displays a change in phenotype, and expressing wild-type UAS-human-cDNA rescues the aberrant phenotype, then there is evidence that the selected gene causes the associated disease.

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