Research articles

Chiea Chuen Khor, Tin Aung and colleagues report the results of a large genome-wide association study of primary angle closure glaucoma. They identify five new susceptibility loci and provide insights into disease pathogenesis.

Hiroyuki Mano and colleagues report fusions involving DUX4 in 16.4% of Ph-negative adolescent and young adult acute lymphoblastic leukemia (AYA-ALL) cases. Transplantation assays in mice support an oncogenic role for the DUX4-IGH fusion gene, which expresses DUX4 protein with an aberrant C terminus at high levels in patients with AYA-ALL.

Nadav Ahituv, Nicola Illing, Jeff Wall and colleagues sequence the genome of the bat Miniopterus natalensis and perform RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages. Their analyses identify genomic regions that may contribute to bat wing formation.

Bin Zhou and colleagues use genetic labeling in mice to show that endocardial cells of the sinus venosus substantially contribute to the liver vasculature, which thus shares a common developmental origin with coronary arteries. Inhibition of endocardial angiogenesis leads to reduced endocardial contribution to the liver vasculature and to defects in liver organogenesis.

Jian Yang and colleagues propose a method that integrates summary data from GWAS and eQTL studies to identify genes whose expression levels are associated with complex traits because of pleiotropy. They apply the method to five human complex traits and prioritize 126 genes for future functional studies.

Adrian Liston and colleagues use a transgenic mouse model to demonstrate that beta cell failure is a mechanistic commonality in type 1 and type 2 diabetes. They find that the changes in the molecular pathways identified as contributing to beta cell loss are paralleled in human islets from patients with type 2 diabetes.

Elise Robinson, Mark Daly and colleagues present an analysis of genetic data from autism spectrum disorder (ASD) and population-based studies and find evidence for genetic correlations between ASDs and typical variation in social behavior and communication traits. These results may inform genetic models of ASDs and other neuropsychiatric disorders.

James Collins and colleagues explore the role of the bacterial epigenome in antibiotic stress survival. They find that Escherichia coli survival under antibiotic pressure is strongly compromised in the absence of adenine methylation at GATC sites, suggesting that targeting adenine methylation might be a viable approach to enhance antibiotic activity.

Johannes Beckers, Martin Hrabě de Angelis and colleagues use in vitro fertilization to demonstrate epigenetic germline inheritance of acquired metabolic disorders in mice. They show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes.

David Ellinghaus and colleagues report a combined association analysis of five chronic inflammatory diseases. They identify 27 new associations and highlight disease-specific association patterns at shared susceptibility loci.

Thomas Whitington and colleagues present a detailed characterization of gene regulatory mechanisms underlying prostate cancer susceptibility. Their analysis highlights key mechanisms altered by disease-associated SNPs, including widespread disruption of ternary complexes involving AR, FOXA1 and HOXB13.

Sergey Nikolaev, Stylianos Antonarakis and colleagues analyze the genetic architecture of 293 basal cell carcinomas (BCCs) and characterize their mutational landscape. They observe UV signature mutations and identify new driver mutations in MYCN, PTPN14 and LATS1 in BCC.

Bin Han and colleagues present a genome-wide association analysis of grain size and shape in cultivated rice and identify a major locus for grain size encoding the transcription factor OsSPL13. They find that the large-grain allele in tropical japonica cultivars was introgressed from indica varieties during selection for improved grain yield.

Ingo Braasch, John Postlethwait and colleagues report the genome of the spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before genome duplication. Their data provide insights into the evolution of genes involved in immunity, mineralization and development and facilitate the comparison of cis-regulatory elements between teleosts and humans.

Raphael Bueno, Eric Stawiski, Somasekar Seshagiri and colleagues present a comprehensive genomic analysis of malignant pleural mesothelioma. They identify four distinct molecular subtypes using RNA-seq data and highlight recurrent somatic mutations, gene fusions and splicing alterations.

Ozren Bogdanović, Ryan Lister, José Luis Gómez-Skarmeta, Michiel Vermeulen and colleagues report widespread DNA demethylation at developmental enhancers during the phylotypic period in zebrafish, Xenopus and mouse embryos. Their findings suggest a conserved role for Tet proteins and active DNA demethylation in the regulation of phylotypic enhancers.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

David Solit and colleagues report that inactivating CDH1 mutations are found in 84% of plasmacytoid bladder cancer samples tested and are not found in other bladder cancer subtypes. CRISPR/Cas9-mediated knockout of CDH1 in cell lines leads to enhanced cellular migration.

Steven McCarroll and colleagues present a detailed study of copy number variation of exons within the human HP (haptoglobin) gene. They show that HP exons undergo recurring deletions that, together with local SNP variation, influence LDL and total cholesterol levels in human populations.

Andy Dahl and colleagues present a method for imputing missing phenotype data in genetic studies with multiple correlated phenotypes where samples can have any level of relatedness. They apply their method to simulated and real data sets and show that it improves the sensitivity to detect association signals.