Inter-Species Rescue of Mutant Phenotype—The Standard for Genetic Analysis of Human Genetic Disorders in Drosophila melanogaster Model

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.

Hyperpolarization Induced by Lipopolysaccharides but Not by Chloroform Is Inhibited by Doxapram, an Inhibitor of Two-P-Domain K+ Channel (K2P)

“…Potentially, doxapram might even serve as a modulator to help alleviate the action of some forms anesthetics if they aid in blocking the same channels. Drosophila , as a model, have immensely served in advancing the understanding of biological systems and currently serve a role in clinically relevant research [ 21 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

Drosophila melanogaster as a versatile model organism to study genetic epilepsies: An overview

“…Drosophila as a model organism offers one of the most extensive genetic toolkits available ( Senturk and Bellen, 2018 ) and a nervous system that allows to investigate complex behavior ( Ecovoiu et al, 2022 ). A high conservation rate for human disease-associated genes of ~75% makes it an attractive model to study genetic variants found in humans ( Takai et al, 2020 ).…”

“…To understand the effect of a variant on the phenotype, a rescue experiment can be performed ( Ecovoiu et al, 2022 ). Here, a disease-related phenotype is alleviated by reintroducing a functional allele.…”

Mimicking Human EED Variants in Drosophila: A Promising Strategy to Analyse Human EED Variant Function

“…Numerous studies have documented the utility of such a mimetic approach to demonstrate a human variant's functional impact and inform disease mechanism. [7][8][9][10] Indeed, recent work showed the utility of such a mimetic approach by identifying a gain of function impact for a rare human EZH1 variant in the context of an identical amino acid change in the orthologous E(z) fly gene a fly model. 11 Here, we demonstrate that known pathogenic (P) and LB EED variants faithfully recapitulate their relative function when mimicked in the esc gene, allowing for successful calibration of an assay to test EED VoUS.…”