Abstract
Drosophila melanogaster (the fruit fly) is arguably a superstar of genetics, an astonishing versatile experimental model which fueled no less than six Nobel prizes in medicine. Nowadays, an evolving research endeavor is to simulate and investigate human genetic diseases in the powerful D. melanogaster platform. Such a translational experimental strategy is expected to allow scientists not only to understand the molecular mechanisms of the respective disorders but also to alleviate or even cure them. In this regard, functional gene orthology should be initially confirmed in vivo by transferring human or vertebrate orthologous transgenes in specific mutant backgrounds of D. melanogaster. If such a transgene rescues, at least partially, the mutant phenotype, then it qualifies as a strong candidate for modeling the respective genetic disorder in the fruit fly. Herein, we review various examples of inter-species rescue of relevant mutant phenotypes of the fruit fly and discuss how these results recommend several human genes as candidates to study and validate genetic variants associated with human diseases. We also consider that a wider implementation of this evolutionist exploratory approach as a standard for the medicine of genetic disorders would allow this particular field of human health to advance at a faster pace.
Highlights
Advances in animal model-based research markedly increased our understanding of molecular mechanisms that regulate physiological and pathological processes
Interdisciplinary research teaming up experts in genetics, bioinformatics, genomics and other medical domains strongly relies on D. melanogaster to model both mechanisms and treatment attempts of several impacting human genetic disorder (hGD), such as neurological and cardiac disorders, cancers and infectious diseases
Data emerging from functional complementation assays are very valuable for understanding the contribution of mutations associated with a genetic disorder in the context of an individual genetic background
Summary
Advances in animal model-based research markedly increased our understanding of molecular mechanisms that regulate physiological and pathological processes. A crucial rescue assay for modelling a human genetic disorder (hGD) in D. melanogaster is the functional complementation (heterologous rescue) of an appropriate mutant fruit fly strain by the orthologous human or mammalian transgene associated with the respective hGD. Whichever experimental alternatives are to be considered in practice, either individually or overlapping, a key step is to perform preliminary inter-specific phenotype rescue experiments, namely, to check if the wild-type copy of hGOI is able to functionally compensate a mutant allele of the orthologous dGOI. 2022, 23, 2613 generation and analysis of relevant mutant alleles in D. melanogaster, delivery of the orthologous human cDNA into the appropriate fruit fly mutant background by means of effective molecular constructs and checking for partial or complete rescue phenotype of the transgenic fruit flies. We argue that preliminary experiments of mutant phenotype rescue should be the paradigm for any relevant genetic analysis of hGDs on the D. melanogaster model
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