Cross-phenotype association tests uncover genes mediating nutrient response in Drosophila

Abstract

BackgroundObesity-related diseases are major contributors to morbidity and mortality in the developed world. Molecular diagnostics and targets of therapies to combat nutritional imbalance are urgently needed in the clinic. Invertebrate animals have been a cornerstone of basic research efforts to dissect the genetics of metabolism and nutrient response. We set out to use fruit flies reared on restricted and nutrient-rich diets to identify genes associated with starvation resistance, body mass and composition, in a survey of genetic variation across the Drosophila Genetic Reference Panel (DGRP).ResultsWe measured starvation resistance, body weight and composition in DGRP lines on each of two diets and used several association mapping strategies to harness this panel of phenotypes for molecular insights. We tested DNA sequence variants for a relationship with single metabolic traits and with multiple traits at once, using a scheme for cross-phenotype association mapping; we focused our association tests on homologs of human disease genes and common polymorphisms; and we tested for gene-by-diet interactions. The results revealed gene and gene-by-diet associations between 17 variants and body mass, whole-body triglyceride and glucose content, or starvation resistance. Focused molecular experiments validated the role in body mass of an uncharacterized gene, CG43921 (which we rename heavyweight), and previously unknown functions for the diacylglycerol kinase rdgA, the huntingtin homolog htt, and the ceramide synthase schlank in nutrient-dependent body mass, starvation resistance, and lifespan.ConclusionsOur findings implicate a wealth of gene candidates in fly metabolism and nutrient response, and ascribe novel functions to htt, rdgA, hwt and schlank.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3137-9) contains supplementary material, which is available to authorized users.

Genome-wide analysis reveals distinct genetic mechanisms of diet-dependent lifespan and healthspan inD. melanogaster

“…To determine the effects of genetic variation on DR-mediated changes in lifespan, we reared ∼200 non-virgin females in eight vials from 161 DGRP lines on two dietary conditions that featured a ten-fold variation in dietary yeast. Our DR condition contained 0.5% yeast extract and ad libitum (AL) diet, 5% yeast extract as described previously (4, 77). We observed a broad range in diet-dependent changes in lifespan across the strains, ranging from a 65% reduction in median lifespan from AL to DR to a 12.5-fold increase (Fig.…”

“…Its benefits are widespread, including improved responses in models of cancer (90, 91), neurodegeneration (92), and other age-related disorders (93–95). Despite these reported benefits, enthusiasm for DR has been tempered by the observation that model organisms of different genotypes respond differently to DR (32, 77), with some genotypes even showing a reduced lifespan (31) or worsened health (96). Thus, identifying the mechanisms that promote longevity but not healthspan in response to diet may not provide the most suitable targets for humans.…”

“…We used DGRP release 2 genotypes, and FlyBase R5 coordinates for gene models. As in Nelson et al , 2016 (77), we used only homozygous positions and a minor allele frequency of ≥25% to ensure that the minor allele was represented by many observations at a given polymorphic locus. The collected phenotype and genotype data were used as input into an association test via ordinary least squares regression using the StatsModels module in Python (137).…”

Assessing connectivity despite high diversity in island populations of a malaria mosquito

“…The gene is highly pleiotropic, contributing to signal transduction in the fly visual system [50, 51], but also olfactory [52] and auditory [53] sensory processing. It has been recently implicated in nutritional homeostasis in Drosophila [54] and is known to interact with the TOR pathway [55], which has been identified as a target of ecological adaptation in Drosophila [56, 57] and An. gambiae [58].…”

Starvation resistance is associated with developmentally specified changes in sleep, feeding, and metabolic rate

“…The identification of developmental, metabolic, and behavioral differences in Drosophila populations selected for resistance to starvation suggest that multiple mechanisms likely contribute to the etiology of starvation resistance. Towards this end, association mapping in Drosophila identified a wide range of genes associated with starvation resistance, including those that are known regulators of development, metabolism, and nutrient response (Harbison et al, 2004; Nelson et al, 2016). The complex genetic architecture underlying these traits, and their interrelationship, suggests the evolution of starvation resistance is likely to be highly pleiotropic, and it is possible that distinct mechanisms contribute to starvation resistance in the three replicate populations.…”