GENETIC ARCHITECTURE OF DROSOPHILA BRAIN CIRCUIT ASYMMETRY

Structural and functional asymmetry between brain hemispheres is a widespread feature across bilaterian animals supporting various aspects of cognition and behavior. In humans, brain asymmetry constitutes a complex trait in which individual phenotypes are determined by the interplay between a multitude of genetic and environmental factors but how they influence interhemispheric circuit formation remains largely unknown.
In Drosophila, circuit lateralization within the Central Complex (CX), a conserved brain structure for insect cognition, allows genetic analysis at single cell resolution. Here, we employed a collection of Drosophila inbred lines to determine the genetic complexity of structural brain asymmetry. While each genotype showed a defined level of CX lateralization, the degree of L/R asymmetry varied among individuals flies and was modulated by developmental temperature. GWAS identified 64 single-nucleotide polymorphisms (SNPs) associated with Drosophila CX lateralization, implicating molecular processes related to cell adhesion, cytoskeletal organization and neuronal activity. Functional validation through targeted knockdown and expression analysis of candidate genes revealed two functional classes: While the cell adhesion molecules Connectin and Fascilin3 are expressed in bilaterally symmetric CX neurons with low impact on circuit asymmetry, the metalloprotease Meltrin and the amino acid transporter Pathetic are required cell-autonomously in asymmetry CX neurons to support lateralized circuit remodeling. Taken together, by recapitulating the genetic complexity and phenotypic variability of human brain lateralization, Drosophila CX asymmetry provides experimental access to decipher common developmental and functional principals of interhemispheric specificity.