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Analysis of 329,000 individuals in the UK Biobank identifies 116 loci associated with neuroticism. Genes implicated are enriched in neuronal differentiation pathways, and genetic correlations between neuroticism and other mental health traits are elucidated.
A reference-quality genome assembly of a Drosophila melanogaster strain allows for accurate mapping of structural variants through comparative analysis with the existing Drosophila genome. Previously hidden structural variation alters a larger fraction of the genome than SNPs and often affects candidate genes underlying complex traits.
An analysis of single-cell DNA methylome sequencing data from human preimplantation embryos finds evidence for de novo methylation. Methylation reprogramming at this stage is a balance between global demethylation, which is faster in the paternal genome, and focused remethylation.
This study presents a probabilistic framework for inferring negative and positive selection in human cancers that addresses the problem of mutation rate variation. Applying the model to sequencing data from 17 cancer types identifies new significantly mutated genes and detects significant signals of negative selection in many cancer types.
Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.
This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes.
CERES is a new computational method to estimate gene-dependency levels from CRISPR–Cas9 essentiality screens while accounting for copy number effects and variable sgRNA activity. Applying CERES to new genome-scale CRISPR–Cas9 essentiality screen data from 342 cancer cell lines and other published data sets shows that CERES decreases false-positive results and provides consistent estimates of sgRNA activity.
CaVEMaN is a new method that uses whole-genome sequencing and RNA-sequencing data to implicate likely causal variants affecting gene expression. The set of high-confidence causal variants found in multiple tissues is enriched for variants associated with complex traits.
Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.
Ali Shilatifard and colleagues generate Drosophila lines expressing catalytically deficient Trr, which normally deposits H3K4me1 at enhancers. Trr mutants undergo normal development and show minimal changes in gene expression.
Missense mutations affecting lysine 91 in the histone H4 core cause a developmental syndrome marked by growth delay, microcephaly and intellectual disability. These mutations cause genomic instability by interfering with H4K91 ubiquitination, leading to abnormal cell cycle progression and apoptosis during early development.
Robert Graham and colleagues carried out a GWAS meta-analysis for Parkinson's disease (PD) and report 17 new risk loci. Their analyses support a key role for autophagy and lysosomal biology in PD risk.
Stefan Mundlos, Darío Lupiáñez and colleagues investigate CNVs involving the regulatory landscape of IHH (Indian hedgehog), which cause craniosynostosis and synpolydactyly. Using genetic manipulation in mice, they show that Ihh is regulated by at least nine enhancers with individual tissue specificities and that duplications in this region can cause dose-dependent upregulation and also misexpression of Ihh.
Frank Uhlmann and colleagues use chromosome conformation capture (Hi-C) to study mitotic chromosome condensation in the fission yeast Schizosaccharomyces pombe, reporting that small chromatin domains in interphase are replaced by fewer and larger domains in mitosis. They show that condensin sets up longer-range DNA interactions that compact and individualize chromosomes while also restraining local chromatin contacts.
Doris Wagner and colleagues define Polycomb response elements (PREs) that direct the placement of Polycomb repressive complex 2 (PRC2) at developmental genes in Arabidopsis. They identify transcription factor families that bind to PREs, physically interact with and recruit PRC2, and are required for gene silencing in vivo.
Greg Gibson and colleagues integrate summary-level GWAS and eQTL data with RNA-seq data from a cohort of pediatric Crohn's disease and report transcriptional risk scores that identify patients who will progress to complicated disease. Their dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion or protection.
Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt and colleagues report that mutations in OSGEP, TP53RK, TPRKB and LAGE3, genes encoding KEOPS-complex subunits, cause Galloway–Mowat syndrome, a recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Functional studies suggest that the phenotypes result from impaired protein translation, thus leading to endoplasmic reticulum stress and apoptosis.
Adam Rubin, Brook Barajas, Mayra Furlan-Magaril and colleagues studied dynamic chromatin across the genome of differentiating human skin keratinocytes, identifying both stable and reorganizing classes of transcriptional enhancers.
Daniel Gudbjartsson, Kari Stefansson and colleagues assess the effect of variants associated with mean fasting glucose levels on the variance in fasting glucose levels. They find that variants that increase both the levels and variance of fasting glucose increase type 2 diabetes risk, whereas those that increase the levels but reduce the variance do not.
Isabelle Janoueix-Lerosey, Valentina Boeva and colleagues analyze the super-enhancer landscape of 25 neuroblastoma cell lines to define core regulatory circuits controlling gene expression programs. They find and functionally characterize two types of cell identity that contribute to the tumor heterogeneity of neuroblastoma.