Genome-wide analysis in Drosophila reveals diet-by-gene interactions and uncovers diet-responsive genes

Francis, Deanne, Ghazanfar, Shila, Havula, Essi, Krycer, James R., Strbenac, Dario, Senior, Alistair, Minard, Annabel Y., Geddes, Thomas, Nelson, Marin E., Weiss, Fiona, Stöckli, Jacqueline, Yang, Jean Y.H., and James, David E. (2021) Genome-wide analysis in Drosophila reveals diet-by-gene interactions and uncovers diet-responsive genes. G3: Genes, Genomes, Genetics, 11 (10). jkab171.

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Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual's genotype. Here, we sought to understand how such gene-diet interactions influenced nutrient storage and utilization, a major determinant of metabolic disease. We subjected 178 inbred strains from the Drosophila genetic reference panel (DGRP) to diets varying in sugar, fat, and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilization that can be robustly measured. Diet influenced the starvation resistance of most strains, but the effect varied markedly between strains such that some displayed better survival on a high carbohydrate diet (HCD) compared to a high-fat diet while others had opposing responses, illustrating a considerable gene x diet interaction. This demonstrates that genetics plays a major role in diet responses. Furthermore, heritability analysis revealed that the greatest genetic variability arose from diets either high in sugar or high in protein. To uncover the genetic variants that contribute to the heterogeneity in starvation resistance, we mapped 566 diet-responsive SNPs in 293 genes, 174 of which have human orthologs. Using whole-body knockdown, we identified two genes that were required for glucose tolerance, storage, and utilization. Strikingly, flies in which the expression of one of these genes, CG4607 a putative homolog of a mammalian glucose transporter, was reduced at the whole-body level, displayed lethality on a HCD. This study provides evidence that there is a strong interplay between diet and genetics in governing survival in response to starvation, a surrogate measure of nutrient storage efficiency and obesity. It is likely that a similar principle applies to higher organisms thus supporting the case for nutrigenomics as an important health strategy.

Item ID: 70061
Item Type: Article (Research - C1)
ISSN: 2160-1836
Keywords: DGRP, Diet-gene interactions, Glucose transport, Multivariate analysis, Starvation
Copyright Information: VC The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact
Funders: National Health and Medical Research Council of Australia (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC NT1086851, ARD DE180101520
Date Deposited: 27 Apr 2022 01:45
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