Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

Meta-analyses of European populations has successfully identified genetic variants in over 150 loci associated with lipid levels, but results from additional ethnicities remain limited. Previously, we reported two novel lipid loci identified in a sample of 7,657 African Americans using a gene-centric array including 50,000 SNPs in 2,100 candidate genes. Initial discovery and follow-up of signals with P < 10⁻⁵ in additional African American samples confirmed CD36 and ICAM1. Using an additional 8,244 African American female samples from the Women’s Health Initiative SNP Health Association Resource genome-wide association study dataset, we further examined the previous meta-analyses results by attempting to replicate 20 additional putative lipid signals with P < 10⁻⁴. Replication confirmed rs868213, located in a splice donor region of exocyst complex component 3-like 1 (EXOC3L1) as a novel signal for HDL (additive allelic effect β = 0.02; P = 1.4 × 10⁻⁸; meta-analyses of discovery and replication). EXOC3L1 is strongly expressed in vascular endothelium and forms part of the exocyst complex, a key facilitator of the trafficking of lipid receptors. Increasing sample sizes for genetic studies in nonEuropean populations will continue to improve our understanding of lipid metabolism.     

Why replication is important in landscape genetics: American black bear in the Rocky Mountains

We investigated how landscape features influence gene flow of black bears by testing the relative support for 36 alternative landscape resistance hypotheses, including isolation by distance (IBD) in each of 12 study areas in the north central U.S. Rocky Mountains. The study areas all contained the same basic elements, but differed in extent of forest fragmentation, altitude, variation in elevation and road coverage. In all but one of the study areas, isolation by landscape resistance was more supported than IBD suggesting gene flow is likely influenced by elevation, forest cover, and roads. However, the landscape features influencing gene flow varied among study areas. Using subsets of loci usually gave models with the very similar landscape features influencing gene flow as with all loci, suggesting the landscape features influencing gene flow were correctly identified. To test if the cause of the variability of supported landscape features in study areas resulted from landscape differences among study areas, we conducted a limiting factor analysis. We found that features were supported in landscape models only when the features were highly variable. This is perhaps not surprising but suggests an important cautionary note - that if landscape features are not found to influence gene flow, researchers should not automatically conclude that the features are unimportant to the species' movement and gene flow. Failure to investigate multiple study areas that have a range of variability in landscape features could cause misleading inferences about which landscape features generally limit gene flow. This could lead to potentially erroneous identification of corridors and barriers if models are transferred between areas with different landscape characteristics.     

What makes species unique? The contribution of proteins with obscure features

Background  

Proteins with obscure features (POFs), which lack currently defined motifs or domains, represent between 18% and 38% of a typical eukaryotic proteome. To evaluate the contribution of this class of proteins to the diversity of eukaryotes, we performed a comparative analysis of the predicted proteomes derived from 10 different sequenced genomes, including budding and fission yeast, worm, fly, mosquito, Arabidopsis, rice, mouse, rat, and human.     

Binding of an Indenoisoquinoline to the Topoisomerase-DNA Complex Induces Reduction of Linker Mobility and Strengthening of Protein-DNA Interaction

Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect.     

Crystal structure of an archaeal pentameric riboflavin synthase in complex with a substrate analog inhibitor: stereochemical implications

Whereas eubacterial and eukaryotic riboflavin synthases form homotrimers, archaeal riboflavin synthases from Methanocaldococcus jannaschii and Methanothermobacter thermoautrophicus are homopentamers with sequence similarity to the 6,7-dimethyl-8-ribityllumazine synthase catalyzing the penultimate step in riboflavin biosynthesis. Recently it could be shown that the complex dismutation reaction catalyzed by the pentameric M. jannaschii riboflavin synthase generates riboflavin with the same regiochemistry as observed for trimeric riboflavin synthases. Here we present crystal structures of the pentameric riboflavin synthase from M. jannaschii and its complex with the substrate analog inhibitor, 6,7-dioxo-8-ribityllumazine. The complex structure shows five active sites located between adjacent monomers of the pentamer. Each active site can accommodate two substrate analog molecules in anti-parallel orientation. The topology of the two bound ligands at the active site is well in line with the known stereochemistry of a pentacyclic adduct of 6,7-dimethyl-8-ribityllumazine that has been shown to serve as a kinetically competent intermediate. The pentacyclic intermediates of trimeric and pentameric riboflavin synthases are diastereomers.     

Conformations in solution of angiotensin II, and its 1-7 and 1-6 fragments.

High-resolution proton spectra at 620 MHz of human angiotensin II (1-8), angiotensin II (1-7), and angiotensin II (1-6) have been obtained in aqueous solution at acidic pH, and in dimethylsulfoxide solution. Complete chemical shift assignments for all three angiotensin peptides were made based on two-dimensional (2D) correlated spectroscopy and 2D-CA-MELSPIN spectra. Based on the measured values of 3JHNCH, the pattern of observed transverse Overhauser effects, and side-chain coupling constants, it is concluded that all three analogues exist in H2O or DMSO-d6 as a mixture of conformers that is largely extended, with negligible content of folded structures, such as beta-turns, gamma-turns, or helix content. The results fit well with those of Nikiforovich et al.