A fruit fly model of fetal alcohol spectrum disorder reveals a Cyclin E-centric network modifies developmental sensitivity.
Alcohol exposure in utero can lead to a wide range of developmental problems, even causing fetal death in some cases. But since this exposure doesn’t always have the same outcome, is it more likely to be a problem for some than others? Exploring the genetic factors that influence susceptibility to fetal alcohol effects is extremely challenging in humans because both exposure levels and the spectrum of phenotypic outcomes are inherently difficult to quantify. In a report in G3: Genes|Genomes|Genetics, Morozova et al. turned to fruit flies to investigate genes that might be involved in prenatal sensitivity to alcohol.
Alcohol is a familiar hazard to the rotten-fruit-loving fly. However, like humans, fruit flies are susceptible to the effects of too much booze, especially during development. When fly larvae are exposed to alcohol, the outcome can be developmental delays and even death. Morozova et al. looked for genes that influence the developmental response to alcohol by using a population of over 200 wild-derived inbred fly lines called the Drosophila melanogaster Genetic Reference Panel (DGRP). The DGRP lines capture a great deal of genetic diversity while also allowing for replication within a line, and the lines have fully-sequenced, well-annotated genomes. The authors compared the effects of alcohol exposure on viability (how many of the flies survived) and development time (how long it takes for flies to reach adulthood) in the DGRP lines. They also examined how ethanol exposure affected locomotion in a subset of the lines.
Unsurprisingly, ethanol exposure in this experiment increased development time, decreased viability, and impaired locomotion in most of the lines tested. However, there was a lot of variation between lines, and a few lines actually developed faster when reared on ethanol-supplemented food.
The authors performed genome-wide association analyses to identify the genetic variants associated with different sensitivities to alcohol exposure. The genes identified were involved in a wide range of biological processes, including cytoskeleton organization, egg laying, and mitosis regulation. The authors validated the function of a number of these genes using RNAi-mediated knockdown or transposon-tagged mutational insertions.
They then constructed an interaction network using the genes associated with viability and development time, revealing that Cyclin E (CycE) was a highly connected hub gene. Since CycE is associated with cell cycle regulation and is highly expressed in Drosophila ovaries, it makes sense that it might play a key role in determining an organism’s sensitivity to developmental alcohol exposure. Their results may one day help researchers narrow the search for human gene variants that influence fetal sensitivity to this most common of drugs.
A Cyclin E Centered Genetic Network Contributes to Alcohol-Induced Variation in Drosophila Development
Tatiana V. Morozova, Yasmeen Hussain, Lenovia J. McCoy, Eugenea V. Zhirnov, Morgan R. Davis, Victoria A. Pray, Rachel A. Lyman, Laura H. Duncan, Anna McMillen, Aiden Jones, Trudy F. C. Mackay, R. H. Anholt
G3: GENES|GENOMES|GENETICS August 2018 8: 2643-2653;