Novel Regulators of Sugar-dependent Food Consumption in Drosophila melanogaster

Diet and genetic background interact to influence food consumption, yet the genetic basis of diet-dependent feeding behavior remains poorly understood. Here, we used genome-wide association analysis (GWAS) to investigate the genetic regulation of sugar-dependent food consumption in Drosophila melanogaster. Food intake was quantified in 176 lines of the Drosophila Genetic Reference Panel (DGRP) using the Con-Ex (Consumption-Excretion) assay on low- and high-sugar foods. Flies showed compensatory feeding, consuming more low-sugar food than high-sugar food, and this behavior was largely maintained across genotypes. Additionally, the magnitude and overall consumption varied several-fold among lines, with broad-sense heritability of 0.53 to 0.66 across sexes and diets. Association analysis across six sex- and diet-specific phenotypes identified 161 variants mapping to 118 candidate genes, which shared almost no loci between dietary conditions, indicating that consumption on the two foods is largely under separate genetic control. RNAi knockdown of candidate genes identified CG42673 and Tmtc2, whose knockdown increased consumption across sexes and diets and was reproduced in independent experiments. Together, these findings show that natural genetic variation contributes substantially to diet-dependent feeding and identify candidate regulators of sugar-based food consumption in Drosophila.