Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies

Summary: Genevar (GENe Expression VARiation) is a database and Java tool designed to integrate multiple datasets, and provides analysis and visualization of associations between sequence variation and gene expression. Genevar allows researchers to investigate expression quantitative trait loci (eQTL) associations within a gene locus of interest in real time. The database and application can be installed on a standard computer in database mode and, in addition, on a server to share discoveries among affiliations or the broader community over the Internet via web services protocols

Thioxoethenylidene (CCS) as a bridging ligand

The reaction of [Mo(≡CBr)(CO)2(Tp*)] (Tp* = hydrotris(3,5-dimethylpyrazol-1-yl)borate) with [Fe2(μ-SLi)2(CO)6] affords, inter alia, the unsymmetrical binuclear thioxoethenylidene complex [Mo2(μ,σ(C):η2(C′S)-CCS)(CO)4(Tp*)2], which may be more directly obtained from [Mo(≡CBr)(CO)2(Tp*)] and Li2S. The reaction presumably proceeds via the intermediacy of the bis(alkylidynyl)thioether complex S{C≡Mo(CO)2(Tp*)}2, which was, however, not directly observed but explored computationally and found to lie 78.6 kJ mol–1 higher in energy than the final thioxoethenylidene product. Computational interrogation of the molecules [M2(μ-C2S)(CO)2(Tp*)2] (M = Mo, W, Re, Os) reveals three plausible coordination modes for a thioxoethenylidene bridge which involve a progressive strengthening of the C–C bond and weakening of the M–C and M–S bonds, as might be expected from simple effective atomic number considerations.This work was supported by the Australian Research Council (DP130102598 and DP110101611)

Ligand Rotation in [Ar(R)N]\u3csub\u3e3\u3c/sub\u3eM-N\u3csub\u3e2\u3c/sub\u3e-M′[N(R)Ar]\u3csub\u3e3\u3c/sub\u3e (M, M′ = Mo\u3csup\u3eIII\u3c/sup\u3e, Nb\u3csup\u3eIII\u3c/sup\u3e; R = \u3csup\u3ei\u3c/sup\u3ePr and \u3csup\u3et\u3c/sup\u3eBu) Dimers

Earlier calculations on the model N2-bridged dimer (µ-N2)-{Mo[NH2]3}2 revealed that ligand rotation away from a trigonal arrangement around the metal centres was energetically favourable resulting in a reversal of the singlet and triplet energies such that the singlet state was stabilized 13 kJ mol−1 below the D3d triplet structure. These calculations, however, ignored the steric bulk of the amide ligands N(R)Ar (R = iPr and tBu, Ar = 3,5-C6H3Me2) which may prevent or limit the extent of ligand rotation. In order to investigate the consequences of steric crowding, density functional calculations using QM/MM techniques have been performed on the MoIIIMoIII and MoIIINbIII intermediate dimer complexes (µ-N2)-{Mo[N(R)Ar]3}2 and [Ar(R)N]3Mo-(µ-N2)-Nb[N(R)Ar]3 formed when threecoordinate Mo[N(R)Ar]3 and Nb[N(R)Ar]3 react with dinitrogen. The calculations indicate that ligand rotation away from a trigonal arrangement is energetically favourable for all of the ligands investigated and that the distortion is largely electronic in origin. However, the steric constraints of the bulky amide groups do play a role in determining the final orientation of the ligands, in particular, whether the ligands are rotated at one or both metal centres of the dimer. Analogous to the model system, QM/MM calculations predict a singlet ground state for the (µ-N2)-{Mo[N(R)Ar]3}2 dimers, a result which is seemingly at odds with the experimental triplet ground state found for the related (µ-N2)-{Mo[N(tBu)Ph]3}2 system. However, QM/MM calculations on the (µ-N2)-{Mo[N(tBu)Ph]3}2 dimer reveal that the singlet–triplet gap is nearly 20 kJ mol−1 smaller and therefore this complex is expected to exhibit very different magnetic behaviour to the (µ-N2)-{Mo[N(R)Ar]3}2 system

Rationalizing the Different Products in the Reaction of N\u3csub\u3e2\u3c/sub\u3e with Three-coordinate MoL\u3csub\u3e3\u3c/sub\u3e Complexes

The reaction of N2 with three-coordinate MoL3 complexes is known to give rise to different products, N–MoL3, L3Mo–N–MoL3 or Mo2L6, depending on the nature of the ligand L. The energetics of the different reaction pathways are compared for L = NH2, NMe2, N(iPr)Ar and N(tBu)Ar (Ar = 3,5-C6H3Me2) using density functional methods in order to rationalize the experimental results. Overall, the exothermicity of each reaction pathway decreases as the ligand size increases, largely due to the increased steric crowding in the products compared to reactants. In the absence of steric strain, the formation of the metal–metal bonded dimer, Mo2L6, is the most exothermic pathway but this reaction shows the greatest sensitivity to ligand size varying from significantly exothermic, −403 kJ mol−1 for L = NMe2, to endothermic, +78 kJ mol−1 for L = N(tBu)Ar. For all four ligands, formation of N–MoL3via cleavage of the N2 bridged dimer intermediate, L3Mo–N–N–MoL3, is strongly exothermic. However, in the presence of excess reactant MoL3, formation of the single atom-bridged complex L3Mo–N–MoL3 from N–MoL3 + MoL3 is both thermodynamically and kinetically favoured for L = NMe2 and N(iPr)Ar, in agreement with experiment. In the case of L = N(tBu)Ar, the greater steric bulk of the tBu group results in a much less exothermic reaction and a calculated barrier of 66 kJ mol−1 to formation of the L3Mo–N–MoL3 dimer. Consequently, for this ligand, the energetically and kinetically favoured product, consistent with the experimental data, is the nitride complex L3Mo–N

Test chamber investigation of the volatilization from source materials of brominated flame retardants and their subsequent deposition to indoor dust

Numerous studies have reported elevated concentrations of brominated flame retardants (BFRs) in dust from indoor micro-environments. Limited information is available, however, on the pathways via which BFRs in source materials transfer to indoor dust. The most likely hypothesized pathways are (a) volatilization from the source with subsequent partitioning to dust, (b) abrasion of the treated product, transferring microscopic fibers or particles to the dust (c) direct uptake to dust via contact between source and dust. This study reports the development and application of an in-house test chamber for investigating BFR volatilization from source materials and subsequent partitioning to dust. The performance of the chamber was evaluated against that of a commercially available chamber, and inherent issues with such chambers were investigated, such as loss due to sorption of BFRs to chamber surfaces (so-called sink effects). The partitioning of polybrominated diphenyl ethers to dust, post-volatilization from an artificial source was demonstrated, while analysis in the test chamber of a fabric curtain treated with the hexabromocyclododecane formulation, resulted in dust concentrations exceeding substantially those detected in the dust pre-experiment. These results provide the first experimental evidence of BFR volatilization followed by deposition to dust

A roadmap for China to peak carbon dioxide emissions and achieve a 20% share of non-fossil fuels in primary energy by 2030

As part of its Paris Agreement commitment, China pledged to peak carbon dioxide (CO2) emissions around 2030, striving to peak earlier, and to increase the non-fossil share of primary energy to 20% by 2030. Yet by the end of 2017, China emitted 28% of the world's energy-related CO2 emissions, 76% of which were from coal use. How China can reinvent its energy economy cost-effectively while still achieving its commitments was the focus of a three-year joint research project completed in September 2016. Overall, this analysis found that if China follows a pathway in which it aggressively adopts all cost-effective energy efficiency and CO2 emission reduction technologies while also aggressively moving away from fossil fuels to renewable and other non-fossil resources, it is possible to not only meet its Paris Agreement Nationally Determined Contribution (NDC) commitments, but also to reduce its 2050 CO2 emissions to a level that is 42% below the country's 2010 CO2 emissions. While numerous barriers exist that will need to be addressed through effective policies and programs in order to realize these potential energy use and emissions reductions, there are also significant local environmental (e.g., air quality), national and global environmental (e.g., mitigation of climate change), human health, and other unquantified benefits that will be realized if this pathway is pursued in China

Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence

Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations

Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations

The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r2) or historical (D'). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits. We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect. We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).