Systems genetics of the Drosophila metabolome.

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.

Gene expression networks in the Drosophila Genetic Reference Panel.

A major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. This question is best addressed in a genetic mapping population in which all molecular polymorphisms are known and for which molecular endophenotypes and complex traits are assessed on the same genotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences and for which phenotypes of many quantitative traits have been evaluated. We mapped expression quantitative trait loci for annotated genes, novel transcribed regions, transposable elements, and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, as well as genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.