Genetic Adaptation to High-Sucrose Dietary Stress in Drosophila Melanogaster

Abstract

Metabolic syndrome is an increasingly prevalent, complex disease that affects ~22% of US residents. Symptoms include central obesity, raised blood lipid levels, and hyperglycemia. The leading cause is thought to be the caloric increase of diets. Genetic variation among individuals also influences disease development and how sugar is processed: for energy with ATP, stored through glycogen and lipids, or excreted. Beyond human GWAS studies, Drosophila melanogaster has been used as a model organism to investigate candidate risk genes for metabolic syndrome and to assess gene functions through knock-down experiments. Selection experiments have also been conducted on fruit flies with high-sugar (HS) stressors to assess change in gene expression. Long-term studies have shown that flies can adapt to HS. After 25 generations, while still showing phenotypes associated with metabolic syndrome, flies are healthy as measured by their fecundity. This study utilizes the evolve-and-resequence (E&R) approach, which introduces a selection pressure and sequences the following generations. We sequenced full-genomes of individual fruit flies reared on high-sucrose or control diets at generation 0, 11, and 25. This strategy provides a more dynamic approach of understanding which genes play important roles in protection against metabolic disease. The E&R method also helps narrow the identification of adaptive genes from the larger list of candidates created by other study methods. Of the genes associated with the 100 most significant SNPs when comparing allele frequencies between G0 and G25 (p < 3.06×10-8), the majority, 56.3%, were highly expressed in digestive tissues, and 36.6% were largely expressed in reproductive tissues. We highlight three particularly interesting genes as associated with response to selection: sNPF-R, HHEX, and rtet. sNPF-R regulates feeding behavior. HHEX has been identified in multiple GWAS studies as a risk factor for T2D and is linked with affecting hyperglycemia, insulin sensitivity, and total triglyceride levels. Finally, rtet codes for an intestinal sugar transporter. Together, it is suggestive that fruit flies adapted to high- sucrose diets through changes that involved the insulin pathway, affected the triglyceride synthesis pathway, and decreased sugar absorption levels in their system. This study sets the groundwork for future studies aimed at validating the contribution of these candidates, such as through knockdown experiments or gene expression manipulations.