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.
Highlights
Obesity-related diseases are major contributors to morbidity and mortality in the developed world
As expected [32,33,34,35,36], on average DR treatment was associated with an increase in all traits except wet body mass, which decreased in DR flies relative to AL flies (Additional file 1: Figure S1)
Common variants associated with metabolic traits As an additional strategy to improve mapping power in the Drosophila Genetic Reference Panel (DGRP), we developed a scheme for analysis of polymorphisms at which the minor allele was very common
Summary
Obesity-related diseases are major contributors to morbidity and mortality in the developed world. Against a backdrop of landmark advances in dissections of the basic biology of metabolism [2], geneticists continue to search for novel genes that modulate body composition and diet responses, as potential targets for drug development. Alongside its use in gene discovery, GWAS reveals the genetic architecture of natural variation in a trait of interest These strengths have motivated previous studies focused on metabolic rate and body size and composition in the fly, yielding a number of intriguing candidate genes and polymorphisms [16, 18,19,20,21,22]
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