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.

Royal Jelly (RJ) is a product made by honey bee workers and is required for queen differentiation and accompanying changes in queen body size, development time, lifespan and reproductive output relative to workers. Previous studies have reported similar changes in Drosophila melanogaster in response to RJ. Here, we quantified viability, development time, body size, productivity, lifespan and genome wide transcript abundance of D. melanogaster reared on standard culture medium supplemented with increasing concentrations of RJ. We found that lower concentrations of RJ do induce significant differences in body size in both sexes; higher concentrations reduce size, increase mortality, shorten lifespan and reduce productivity. Increased concentrations of RJ also consistently lengthened development time in both sexes. RJ is associated with changes in expression of 1,581 probe sets assessed using Affymetrix Drosophila 2.0 microarrays, which were enriched for genes associated with metabolism and amino acid degradation. The transcriptional changes are consistent with alterations in cellular processes to cope with excess nutrients provided by RJ, including biosynthesis and detoxification, which might contribute to accelerated senescence and reduced lifespan.

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.

Background Older individuals with inflammatory bowel disease (IBD) require ongoing medications. We aimed to describe 1) medication use in older and younger IBD patients and 2) medication associations with patient reported outcomes (PRO’s) in older patients. Methods We conducted cross-sectional and longitudinal analyses within CCFA Partners internet-based cohort of patients with self-reported IBD. We assessed medication use by disease sub-type and age. We used bivariate analyses to 1) compare medication use in older and younger patients and 2) determine associations between continued steroid use and PRO’s in older patients. Results We included 5382 participants with IBD; 1004 were older (≥ age 60). Older patients with Crohn’s disease (CD) had lower anti-tumor necrosis factor alpha (anti-TNF) use at baseline (29.1% vs 44.3%, p<0.001), comparable steroid use (16.0% vs. 16.5%, p=0.77), and higher aminosalicylate use (40.3% vs. 33.9%, p=0.003) versus younger patients. Older ulcerative colitis (UC) patients had similar anti-TNF use (16.0% vs. 19.2%, p=0.16), lower steroid use (9.6% vs. 15.4%, p=0.004) and higher aminosalicylate use (73.8% vs. 68.2%, p=0.04) at baseline. In longitudinal analyses, older CD patients had higher continued steroid use (11.6% vs. 7.8%, p=0.002); which was associated with worsened anxiety (p=0.02), sleep (p=0.01), and fatigue (p=0.001) versus non-use. Older CD patients on steroids, versus anti-TNF or immunomodulators, had increased depression (p=0.04) and anxiety (p=0.03). Conclusions Medication utilization differs in older patients with IBD. Older CD patients have higher continued steroid use; associated with worsened PRO’s. As in younger IBD populations; continued steroid use should be limited in older patients.