Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.

Gene expression kinetics of Exaiptasia pallida innate immune response to Vibrio parahaemolyticus infection.

BACKGROUND: Recent sequencing projects on early-diverging metazoans such as cnidarians, have unveiled a rich innate immunity gene repertoire; however, little is known about immunity gene regulation in the host's early response against marine bacterial pathogens over time. Here, we used RNA-seq on the sea anemone Exaiptasia pallida (Ep) strain CC7 as a model to depict the innate immune response during the onset of infection with the marine pathogenic bacteria Vibrio parahaemolyticus (Vp) clinical strain O3:K6, and lipopolysaccharides (LPS) exposure. Pairwise and time series analyses identified the genes responsive to infection as well as the kinetics of innate immune genes over time. Comparisons between the responses to live Vp and purified LPS was then performed. RESULTS: Gene expression and functional analyses detected hundreds to thousands of genes responsive to the Vp infection after 1, 3, 6 and 12 h, including a few shared with the response to LPS. Our results bring to light the first indications that non-canonical cytoplasmic pattern recognition receptors (PRRs) such as NOD-like and RIG-I-like receptor homologs take part in the immune response of Ep. Over-expression of several members of the lectin-complement pathways in parallel with novel transmembrane and Ig containing ficolins (CniFLs) suggest an active defense against the pathogen. Although lacking typical Toll-like receptors (TLRs), Ep activates a TLR-like pathway including the up-regulation of MyD88, TRAF6, NF-κB and AP-1 genes, which are not induced under LPS treatment and therefore suggest an alternative ligand-to-PRR trigger. Two cytokine-dependent pathways involving Tumor necrosis factor receptors (TNFRs) and several other potential downstream signaling genes likely lead to inflammation and/or apoptosis. Finally, both the extrinsic and intrinsic apoptotic pathways were strongly supported by over-expression of effector and executioner genes. CONCLUSIONS: To our knowledge, this pioneering study is first to follow the kinetics of the innate immune response in a cnidarian during the onset of infection with a bacterial pathogen. Overall, our findings reveal the involvement of both novel immune gene candidates such as NLRs, RLRs and CniFLs, and previously identified TLR-like and apoptotic pathways in anthozoan innate immunity with a large amount of transcript-level evidence.