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GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize both dominant and recessive Mendelian disease genes. GeVIR outperforms missense constraint metrics and complements loss-of-function constraint metrics.
Combined genomic and transcriptomic approaches identify the landscape of extrachromosomal circular DNA in neuroblastoma and reveal that extrachromosomal circular DNA is a major source of somatic rearrangements.
Mutations in ADAMTS19 lead to progressive heart valve disease in humans. Analysis of mice lacking Adamts19 highlights the role of a Wnt–Adamts19–Klf2 axis in proper valve function.
N6-methyladenosine (m6A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m6A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.
Combining CRISPRi-FlowFISH to perturb enhancers with an activity-by-contact model to predict complex connections allows systematic mapping of enhancer–gene connections in a given cell type, on the basis of chromatin-state measurements.
Genome-wide analysis of venous thromboembolism identifies 22 new risk loci and facilitates construction of a polygenic risk score. Comparison to arterial vascular disease highlights shared pathophysiology and potential therapeutic strategies.
Genome-wide analyses identify variants near HDAC9 associated with abdominal aortic calcification and other cardiovascular phenotypes. Functional work shows that HDAC9 promotes an osteogenic vascular smooth muscle cell phenotype, enhancing calcification and reducing contractility.
Mapping long-range chromatin interactions in 27 human cell/tissue types identifies candidate target genes of 70,329 putative regulatory elements. Further analysis suggests potential regulatory function for 27,325 noncoding variants associated with 2,117 traits and diseases.
Genomic analysis of 906 Clostridium difficile strains shows that this enteropathogen is undergoing speciation, which is linked to the selection of genes involved in sporulation and in the metabolism of simple dietary sugars.
A mutation in RAS oncogene family-like 3 (RABL3) is discovered in a family with multiple cases of pancreatic cancer. Zebrafish modeling and biochemical approaches suggest that truncated RABL3 elevates KRAS activity via accelerated prenylation.
Long-read sequencing identifies a GGC repeat expansion in NOTCH2NLC that is associated with neuronal intranuclear inclusion disease, a progressive neurodegenerative disorder. The expansion results in abnormal anti-sense transcripts that could contribute to disease pathogenesis.
Genome-wide analyses identify eight independent loci associated with anorexia nervosa. Genetic correlations implicate both psychiatric and metabolic components in the etiology of this disorder, even after adjusting for the effects of common variants associated with body mass index.
A genetics-led translational approach integrating functional genomic predictors, knowledge of network connectivity and immune ontologies defines the drug target prioritization landscape for 30 immune traits at the gene and pathway level.
Analysis of whole-exome sequencing data from 2,343 individuals with autism spectrum disorder compared to 5,852 unaffected individuals demonstrates an excess of biallelic, autosomal mutations for both loss-of-function and damaging missense variants.
Genetic studies using map-based cloning, gene editing, RNA interference, haplotyping and association analyses identify a deletion in TaHRC as a key determinant of Fhb1-mediated resistance to Fusarium head blight in wheat.
Genetic mapping and functional studies show that mutation of a histidine-rich calcium-binding-protein gene at the Fhb1 locus confers resistance to Fusarium head blight in wheat. Notably, transgenic plants expressing the R allele show enhanced resistance to infection.
Phosphorylation of histone H3.3 at serine 31 by CHK1 is shown to stimulate activity of the acetyltransferase p300 in trans. Depletion of histone H3.3 in embryonic stem cells reduces enhancer acetylation during differentiation.
The authors generate Dux cluster knockout mouse lines and find that embryos can survive to adulthood. Transcriptome profiling of the mutant embryos indicates minimal effects on zygotic genome activation.
The authors present a new genomic prediction method for maize germplasm evaluation under genotype × environment interaction, in which genotype × environment interaction of grain yield components is modeled as genotypic sensitivity to environmental drivers.