The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report

A High-Resolution Map of Human Evolutionary Constraint Using 29 Mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.National Human Genome Research Institute (U.S.)National Institute of General Medical Sciences (U.S.) (Grant number GM82901)National Science Foundation (U.S.). Postdoctural Fellowship (Award 0905968)National Science Foundation (U.S.). Career (0644282)National Institutes of Health (U.S.) (R01-HG004037)Alfred P. Sloan Foundation.Austrian Science Fund. Erwin Schrodinger Fellowshi

Investigation of cracks in GaN films grown by combined hydride and metal organic vapor-phase epitaxial method

Cracks appeared in GaN epitaxial layers which were grown by a novel method combining metal organic vapor-phase epitaxy (MOCVD) and hydride vapor-phase epitaxy (HVPE) in one chamber. The origin of cracks in a 22-μm thick GaN film was fully investigated by high-resolution X-ray diffraction (XRD), micro-Raman spectra, and scanning electron microscopy (SEM). Many cracks under the surface were first observed by SEM after etching for 10 min. By investigating the cross section of the sample with high-resolution micro-Raman spectra, the distribution of the stress along the depth was determined. From the interface of the film/substrate to the top surface of the film, several turnings were found. A large compressive stress existed at the interface. The stress went down as the detecting area was moved up from the interface to the overlayer, and it was maintained at a large value for a long depth area. Then it went down again, and it finally increased near the top surface. The cross-section of the film was observed after cleaving and etching for 2 min. It was found that the crystal quality of the healed part was nearly the same as the uncracked region. This indicated that cracking occurred in the growth, when the tensile stress accumulated and reached the critical value. Moreover, the cracks would heal because of high lateral growth rate

De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes

Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.</p

SuRFing the genomics wave: an R package for prioritising SNPs by functionality

Identifying functional non-coding variants is one of the greatest unmet challenges in genetics. To help address this, we introduce an R package, SuRFR, which integrates functional annotation and prior biological knowledge to prioritise candidate functional variants. SuRFR is publicly available, modular, flexible, fast, and simple to use. We demonstrate that SuRFR performs with high sensitivity and specificity and provide a widely applicable and scalable benchmarking dataset for model training and validation. Website: http://www.cgem.ed.ac.uk/resources/ ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-014-0079-1) contains supplementary material, which is available to authorized users

The 2024 Outline of Fungi and fungus-like taxa

With the simultaneous growth in interest from the mycological community to discover fungal species and classify them, there is also an important need to assemble all taxonomic information onto common platforms. Fungal classification is facing a rapidly evolving landscape and organizing genera into an appropriate taxonomic hierarchy is central to better structure a unified classification scheme and avoid incorrect taxonomic inferences. With this in mind, the Outlines of Fungi and fungus-like taxa (2020, 2022) were published as an open-source taxonomic scheme to assist mycologists to better understand the taxonomic position of species within the Fungal Kingdom as well as to improve the accuracy and consistency of our taxonomic language. In this paper, the third contribution to the series of Outline of Fungi and fungus-like taxa prepared by the Global Consortium for the Classification of Fungi and fungus-like taxa is published. The former is updated considering our previous reviews and the taxonomic changes based on recent taxonomic work. In addition, it is more comprehensive and derives more input and consensus from a larger number of mycologists worldwide. Apart from listing the position of a particular genus in a taxonomic level, nearly 1000 notes are provided for newly established genera and higher taxa introduced since 2022. The notes section emphasizes on recent findings with corresponding references, discusses background information to support the current taxonomic status and some controversial taxonomic issues are also highlighted. To elicit maximum taxonomic information, notes/taxa are linked to recognized databases such as Index Fungorum, Faces of Fungi, MycoBank and GenBank, Species Fungorum and others. A new feature includes links to Fungalpedia, offering notes in the Compendium of Fungi and fungus-like Organisms. When specific notes are not provided, links are available to webpages and relevant publications for genera or higher taxa to ease data accessibility. Following the recent synonymization of Caulochytriomycota under Chytridiomycota, with Caulochytriomycetes now classified as a class within the latter, based on formally described and currently accepted data, the Fungi comprises 19 Phyla, 83 classes, 1,220 families, 10,685 genera and ca 140,000 species. Of the genera, 39.5% are monotypic and this begs the question whether mycologists split genera unnecessarily or are we going to find other species in these genera as more parts of the world are surveyed? They are 433 speciose genera with more than 50 species. The document also highlights discussion of some important topics including number of genera categorized as incertae sedis status in higher level fungal classification. The number of species at the higher taxonomic level has always been a contentious issue especially when mycologists consider either a lumping or a splitting approach and herein we provide figures. Herein a summary of updates in the outline of Basidiomycota is provided with discussion on whether there are too many genera of Boletales, Ceratobasidiaceae, and speciose genera such as Colletotrichum. Specific case studies deal with Cortinarius, early diverging fungi, Glomeromycota, a diverse early divergent lineage of symbiotic fungi, Eurotiomycetes, marine fungi, Myxomycetes, Phyllosticta, Hymenochaetaceae and Polyporaceae and the longstanding practice of misapplying intercontinental conspecificity. The outline will aid to better stabilize fungal taxonomy and serves as a necessary tool for mycologists and other scientists interested in the classification of the Fungi

Identification and comparative analysis of ncRNAs in human, mouse and zebrafish indicate a conserved role in regulation of genes expressed in brain

ncRNAs(non-coding RNAs), in particular long ncRNAs, represent a significant proportion of the vertebrate transcriptome and probably regulate many biological processes. We used publically available ESTs(Expressed Sequence Tags) from human, mouse and zebrafish and a previously published analysis pipeline to annotate and analyze the vertebrate nonprotein-coding transcriptome. Comparative analysis confirmed some previously described features of intergenic ncRNAs, such as a positionally biased distribution with respect to regulatory or development related protein-coding genes, and weak but clear sequence conservation across species. Significantly, comparative analysis of developmental and regulatory genes proximate to long ncRNAs indicated that the only conserved relationship of these genes to neighbor long ncRNAs was with respect to genes expressed in human brain, suggesting a conserved, ncRNA cis-regulatory network in vertebrate nervous system development. Most of the relationships between long ncRNAs and proximate coding genes were not conserved, providing evidence for the rapid evolution of species-specific gene associated long ncRNAs. We have reconstructed and annotated over 130,000 long ncRNAs in these three species, providing a significantly expanded number of candidates for functional testing by the research community.Zhipeng Qu and David L. Adelso