Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Altered Hydrology of the Missouri River and its Effects on Floodplain Forest Ecosystems

It is generally expected that construction and operation of a floodplain protection project will alter a river system's hydrologic regimen, but this altered regimen also has been suspected of having major, long-term effects on the natural dynamics of riparian ecosystems that remain in gaps between large reservoirs. This study confirms that hypothesis by documenting some of those impacts in an area between Garrison Dam and Oahe Reservoir on the Missouri River in south-central North Dakota. Specifically, it examines post-dam changes in river meandering rate, floodplain forest composition, tree population structure, and tree growth rate

Characterization of seawater intrusion using 2D electrical imaging

We have investigated the potential of 2D electrical imaging for the characterization of seawater intrusion using field data from a site in Almeria, SE Spain. Numerical simulations have been run for several scenarios, with a hydrogeological model reflecting the local site conditions. The simulations showed that only the lower salt concentrations of the seawater-freshwater transition zone could be recovered, due to the loss of resolution with depth. We quantified this capability in terms of the cumulative sensitivity associated with the measurement setup and showed that the mismatch between the targeted and imaged parameter values occurs from a certain sensitivity threshold. Similarly, heterogeneity may only be determined accurately if located in an adequately sensitive area. At the field site, we identified seawater intrusion at the scale of a few kilometres down to a hundred metres. Borehole logs show a remarkable correlation with the image obtained from surface data but indicate that the electrically derived mass fraction of pure seawater could not be recovered due to the discrepancy between the in-situ and laboratory-derived petrophysical relationships. Surface-to-hole inversion results suggest that the laterally varying resolution pattern associated with such a setup dominates the image characteristics compared to the laterally more homogeneous resolution pattern of surface only inversion results and hence, surface-to-hole images are not easily interpretable in terms of larger-scale features. Our results indicate that electrical imaging can be used to constrain seawater intrusion models if image appraisal tools are appropriately used to quantify the spatial variation of sensitivity and resolution. The most crucial limitation is probably the apparent non-stationarity of the petrophysical relationship during the imaging process

Expression, Purification, and Applications of the Recombinant Lectin PVL from Psathyrella velutina Specific for Terminal N-Acetyl-Glucosamine

International audienceThe lectin PVL from the mushroom Psathyrella velutina is the founding member of novel family of fungal lectins. It adopts a seven bladed β-propeller presenting six binding sites specific for the recognition of non-reducing terminal N-acetyl-glucosamine (GlcNAc). The latest can be mainly found in glycoconjugates presenting truncated glycans where aberrant β-GlcNAc terminated glycans represent tumor markers. It can also be found in O-GlcNAcylated proteins where disruption of the O-GlcNAcylation homeostasis is associated with many physiopathological states. The recombinant PVL lectin proved to be a very powerful tool for labelling terminal GlcNAc antigens displayed by extracellular glycoconjugates but also by O-GlcNAcylated proteins found in the cytoplasm and nucleus. This chapter will describe how to produce and purify recombinant PVL and several applications for rPVL as probe for the detection of terminal O-GlcNAc