Natural variation in the regulation of neurodevelopmental genes modifies flight performance inDrosophila
Authors: Spierer Adam N. , Mossman Jim A. , Smith Samuel Pattillo , Crawford Lorin , Ramachandran Sohini , Rand David M. 
Published: May 2020

AbstractThe winged insects of the orderDipteraare colloquially named for their most recognizable phenotype: flight. These insects rely on flight for a number of important life history traits, like dispersal, foraging, and courtship. Despite the importance of flight, relatively little is known about the genetic architecture of variation for flight performance. Accordingly, we sought to uncover the genetic modifiers of flight using a measure of flies’ reaction and response to an abrupt drop in a vertical flight column. We conducted an association study using 197 of theDrosophilaGenetic Reference Panel (DGRP) lines, and identified a combination of additive and marginal variants, epistatic interactions, whole genes, and enrichment across interaction networks. We functionally validated 13 of these candidate genes’ (Adgf-A/Adgf-A2/CG32181, bru1, CadN, CG11073, CG15236, CG9766, CREG, Dscam4, form3, fry, Lasp/CG9692, Pde6, Snoo) contribution to flight, two of which (fryandSnoo) also validate a whole gene analysis we introduce for the DGRP:PEGASUS_flies. Overall, our results suggest modifiers of muscle and wing morphology, and peripheral and central nervous system assembly and function are all important for flight performance. Additionally, we identifiedppk23, an Acid Sensing Ion Channel (ASIC) homolog, as an important hub for epistatic interactions. These results represent a snapshot of the genetic modifiers affecting drop-response flight performance inDrosophila, with implications for other insects. It also draws connections between genetic modifiers of performance and BMP signaling and ASICs as targets for treating neurodegeneration and neurodysfunction.Author summaryInsect flight is a widely recognizable phenotype of winged insects, hence the name: flies. While fruit flies, orDrosophila melanogaster, are a genetically tractable model, flight performance is a highly integrative phenotype, making it challenging to comprehensively identify the genetic modifiers that contribute to its genetic architecture. Accordingly, we screened 197 Drosophila Genetic Reference Panel lines for their ability to react and respond to an abrupt drop. Using several computational tools, we successfully identified several additive, marginal, and epistatic variants, as well as whole genes and altered sub-networks of gene-gene and protein-protein interaction networks, demonstrating the benefits of using multiple methodologies to elucidate the genetic architecture of complex traits more generally. Many of these significant genes and variants mapped to regions of the genome that affect development of sensory and motor neurons, wing and muscle development, and regulation of transcription factors. We also introduce PEGASUS_flies, aDrosophila-adapted version of the PEGASUS platform first used in human studies, to infer gene-level significance of association based on the distribution of individual variantP-values. Our results contribute to the debate over the relative importance of individual, additive factors and epistatic, or higher order, interactions, in the mapping of genotype to phenotype.