Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements

Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h²_median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.     

Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.     

Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment.     

Differential Infectivities among Different Japanese Encephalitis Virus Genotypes in Culex quinquefasciatus Mosquitoes

During the last 20 years, the epidemiology of Japanese encephalitis virus (JEV) has changed significantly in its endemic regions due to the gradual displacement of the previously dominant genotype III (GIII) with clade b of GI (GI-b). Whilst there is only limited genetic difference distinguishing the two GI clades (GI-a and GI-b), GI-b has shown a significantly wider and more rapid dispersal pattern in several regions in Asia than the GI-a clade, which remains restricted in its geographic distribution since its emergence. Although previously published molecular epidemiological evidence has shown distinct phylodynamic patterns, characterization of the two GI clades has only been limited to in vitro studies. In this study, Culex quinquefasciatus, a known competent JEV mosquito vector species, was orally challenged with three JEV strains each representing GI-a, GI-b, and GIII, respectively. Infection and dissemination were determined based on the detection of infectious viruses in homogenized mosquitoes. Detection of JEV RNA in mosquito saliva at 14 days post infection indicated that Cx. quinquefasciatus can be a competent vector species for both GI and GIII strains. Significantly higher infection rates in mosquitoes exposed to the GI-b and GIII strains than the GI-a strain suggest infectivity in arthropod vectors may lead to the selective advantage of previously and currently dominant genotypes. It could thus play a role in enzootic transmission cycles for the maintenance of JEV if this virus were ever to be introduced into North America.     

Coalition Formation by Male Vervet Monkeys (Chlorocebus pygerythrus) in South Africa

Unrelated male primates frequently cohabit in bisexual groups and, despite being reproductive competitors, have been shown to cooperate in ways that are associated with reproductive success. Such coalitions between males are common in some taxa, where they can serve two primary functions – status management and improved mating opportunities – that subserve long‐ and short‐term objectives. Here, we use observational data to provide information on male coalitions in vervet monkeys (Chlorocebus pygerythrus), a guenon with a multimale group structure. We recorded a total of 62 coalitions from two troops across a 10‐mo period at Samara Game Reserve, South Africa. We found that males who were more frequently associated spatially and who had groomed one another were more likely to form coalitions and did so against higher‐ranking opponents. This was not linked to any evidence that coalitionary aggression provided either short‐ or long‐term reproductive benefits for the aggressors and coalitions were not restricted to the mating season. There was little evidence that particular individuals were targeted, reciprocation between partners was not observed, and recent immigrant males were not targeted disproportionately. Our data suggest that within‐group coalition formation between vervet males may represent something close to an ancestral state whereby males form ad hoc coalitions opportunistically, joining an ongoing dyadic contest to target an opponent without facing the possible risks of dyadic contest, such as a greater chance of injury.     

Evolutionary perspectives on human height variation

Human height is a highly variable trait, both within and between populations, has a high heritability, and influences the manner in which people behave and are treated in society. Although we know much about human height, this information has rarely been brought together in a comprehensive, systematic fashion. Here, we present a synthetic review of the literature on human height from an explicit evolutionary perspective, addressing its phylogenetic history, development, and environmental and genetic influences on growth and stature. In addition to presenting evidence to suggest the past action of natural selection on human height, we also assess the evidence that natural and sexual selection continues to act on height in contemporary populations. Although there is clear evidence to suggest that selection acts on height, mainly through life‐history processes but perhaps also directly, it is also apparent that methodological factors reduce the confidence with which such inferences can be drawn, and there remain surprising gaps in our knowledge. The inability to draw firm conclusions about the adaptiveness of such a highly visible and easily measured trait suggests we should show an appropriate degree of caution when dealing with other human traits in evolutionary perspective.     

Using dynamic relative climate impact curves to quantify the climate impact of bioenergy production systems over time

The climate impact of bioenergy is commonly quantified in terms of CO₂ equivalents, using a fixed 100‐year global warming potential as an equivalency metric. This method has been criticized for the inability to appropriately address emissions timing and the focus on a single impact metric, which may lead to inaccurate or incomplete quantification of the climate impact of bioenergy production. In this study, we introduce Dynamic Relative Climate Impact (DRCI) curves, a novel approach to visualize and quantify the climate impact of bioenergy systems over time. The DRCI approach offers the flexibility to analyze system performance for different value judgments regarding the impact category (e.g., emissions, radiative forcing, and temperature change), equivalency metric, and analytical time horizon. The DRCI curves constructed for fourteen bioenergy systems illustrate how value judgments affect the merit order of bioenergy systems, because they alter the importance of one‐time (associated with land use change emissions) versus sustained (associated with carbon debt or foregone sequestration) emission fluxes and short‐ versus long‐lived climate forcers. Best practices for bioenergy production (irrespective of value judgments) include high feedstock yields, high conversion efficiencies, and the application of carbon capture and storage. Furthermore, this study provides examples of production contexts in which the risk of land use change emissions, carbon debt, or foregone sequestration can be mitigated. For example, the risk of indirect land use change emissions can be mitigated by accompanying bioenergy production with increasing agricultural yields. Moreover, production contexts in which the counterfactual scenario yields immediate or additional climate impacts can provide significant climate benefits. This paper is accompanied by an Excel‐based calculation tool to reproduce the calculation steps outlined in this paper and construct DRCI curves for bioenergy systems of choice.