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Systems genetics of the Drosophila metabolome.

ABSTRACT: How effects of DNA sequence variants are transmitted through intermediate endophenotypes to modulate organismal traits remains a central question in quantitative genetics. This problem can be addressed through a systems approach in a population in which genetic polymorphisms, gene expression traits, metabolites, and complex phenotypes can be evaluated on the same genotypes. Here, we focused on the metabolome, which represents the most proximal link between genetic variation and organismal phenotype, and quantified metabolite levels in 40 lines of the Drosophila melanogaster Genetic Reference Panel. We identified sex-specific modules of genetically correlated metabolites and constructed networks that integrate DNA sequence variation and variation in gene expression with variation in metabolites and organismal traits, including starvation stress resistance and male aggression. Finally, we asked to what extent SNPs and metabolites can predict trait phenotypes and generated trait- and sex-specific prediction models that provide novel insights about the metabolomic underpinnings of complex phenotypes.

SUBMITTER: Zhou S

PROVIDER: S-EPMC7111526 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Systems genetics of the <i>Drosophila</i> metabolome.

Zhou Shanshan S Morgante Fabio F Geisz Matthew S MS Ma Junwu J Anholt Robert R H RRH Mackay Trudy F C TFC

Genome research 20191106 3

How effects of DNA sequence variants are transmitted through intermediate endophenotypes to modulate organismal traits remains a central question in quantitative genetics. This problem can be addressed through a systems approach in a population in which genetic polymorphisms, gene expression traits, metabolites, and complex phenotypes can be evaluated on the same genotypes. Here, we focused on the metabolome, which represents the most proximal link between genetic variation and organismal phenot ...[more]

PMID: 31694867

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Project description:BackgroundObesity and phenotypic traits associated with this condition exhibit significant heritability in natural populations of most organisms. While a number of genes and genetic pathways have been implicated to play a role in obesity associated traits, the genetic architecture that underlies the natural variation in these traits is largely unknown. Here, we used 40 wild-derived inbred lines of Drosophila melanogaster to quantify genetic variation in body weight, the content of three major metabolites (glycogen, triacylglycerol, and glycerol) associated with obesity, and metabolic rate in young flies. We chose these lines because they were previously screened for variation in whole-genome transcript abundance and in several adult life-history traits, including longevity, resistance to starvation stress, chill-coma recovery, mating behavior, and competitive fitness. This enabled us not only to identify candidate genes and transcriptional networks that might explain variation for energy metabolism traits, but also to investigate the genetic interrelationships among energy metabolism, behavioral, and life-history traits that have evolved in natural populations.ResultsWe found significant genetically based variation in all traits. Using a genome-wide association screen for single feature polymorphisms and quantitative trait transcripts, we identified 337, 211, 237, 553, and 152 novel candidate genes associated with body weight, glycogen content, triacylglycerol storage, glycerol levels, and metabolic rate, respectively. Weighted gene co-expression analyses grouped transcripts associated with each trait in significant modules of co-expressed genes and we interpreted these modules in terms of their gene enrichment based on Gene Ontology analysis. Comparison of gene co-expression modules for traits in this study with previously determined modules for life-history traits identified significant modular pleiotropy between glycogen content, body weight, competitive fitness, and starvation resistance.ConclusionsCombining a large phenotypic dataset with information on variation in genome wide transcriptional profiles has provided insight into the complex genetic architecture underlying natural variation in traits that have been associated with obesity. Our findings suggest that understanding the maintenance of genetic variation in metabolic traits in natural populations may require that we understand more fully the degree to which these traits are genetically correlated with other traits, especially those directly affecting fitness.

Dataset Information

Systems genetics of the Drosophila metabolome.

Publications

Systems genetics of the <i>Drosophila</i> metabolome.

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