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Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Martin Farrall and colleagues report the results of a large genome-wide association meta-analysis of coronary artery disease based on 1000 Genomes imputation. They identify ten new risk loci and show that susceptibility to this disease is largely determined by common SNPs with small effect sizes.
Jen Jen Yeh and colleagues apply statistical methods to separate tumor, stroma and normal tissue gene expression signatures from pancreatic ductal adenocarcinoma expression profiling data sets. They identify and validate two tumor-specific and two stroma-specific subtypes, which are associated with different clinical outcomes.
Sarah Elderkin and colleagues show that PRC1 acts as a master regulator of genome architecture in mouse embryonic stem cells by organizing genes in three-dimensional interaction networks. They find that the strongest spatial network is composed of the four Hox clusters and key early developmental transcription factor genes, and they propose that selective release of genes from this spatial network underlies cell fate specification during embryonic development.
Jian Yang and colleagues present a method, GREML-LDMS, to estimate heritability for complex human traits using whole-genome sequencing data or imputation with the 1000 Genomes Project reference panel. Using the heritability estimates from GREML-LDMS, they find that there is negligible missing heritability for human height and BMI.
Laurent Frantz and colleagues report an analysis of 103 whole genomes from European and Asian wild boars and domestic pigs. They find evidence in support of a complex domestication model with gene flow from wild populations counteracted by recurrent artificial selection for traits important for domestication.
Christian Dina, Nabila Bouatia-Naji, Xavier Jeunemaitre and colleagues from the Leducq Transatlantic MITRAL Network report the results of a genome-wide association study of nonsyndromic mitral valve prolapse. They identify six susceptibility loci and provide functional evidence implicating LMCD1 and TNS1 as genes influencing mitral valve development.
Wei Li, Qianben Wang and colleagues analyze genome-wide epigenetic patterns in tumor and normal tissues and find that broad H3K4me3 peaks are associated with increased transcription elongation and are enriched at tumor-suppressor genes. They demonstrate that this epigenetic mark may be used to identify new candidate tumor-suppressor genes.
Kornelia Polyak, Franziska Michor and colleagues report a novel method, STAR-FISH, for combined in situ single-cell analysis of point mutations and copy number alterations in archived tissue samples. They apply STAR-FISH to clinically relevant PIK3CA mutations and HER2 amplifications and observe associations between intratumoral diversity and clinical outcome.
Jessica Zucman-Rossi and colleagues identify clonal integrations of adeno-associated virus type 2 (AAV2) in hepatocellular carcinomas. These AAV2 integrations occurred within known cancer driver genes, suggesting a pathogenic role of AAV2 in these patients.
Roderic GuigĂł, Montserrat Corominas and colleagues find that histone marks associated with active chromatin are absent from genes with high expression during specific developmental stages in both Drosophila melanogaster and Caenorhabditis elegans. They observe similar patterns for genes with high levels of transcriptional variation across mammalian tissues and cell types.
Soumya Raychaudhuri, Paul de Bakker and colleagues test the non-additive disease contributions of classical HLA alleles to five common autoimmune diseases. In four of the five diseases, they observe highly significant non-additive dominance and interaction effects.
Paul Khavari and colleagues report genomic analyses of cutaneous T cell lymphomas. They identify recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of tumors and show that expression of a recurrent TNFR2 mutant in T cells leads to enhanced non-canonical NF-ÎşB signaling that is sensitive to the proteasome inhibitor bortezomib.
Dmitry Gordenin and colleagues use a yeast reporter strain to identify distinct mutagenic signatures for the cytosine deaminases APOBEC3A and APOBEC3B. They find that cancer samples with APOBEC3A-like mutation signatures have greater than tenfold more APOBEC signature mutations than those with APOBEC3B-like signatures.
Hae Kyung Im and colleagues report a method for predicting gene expression perturbations from genotype data after training on reference transcriptome data sets. Association of predicted gene expression with disease traits identifies known and new candidate disease genes.
Tatsuhiro Shibata and colleagues molecularly characterize 260 biliary tract cancer samples by a combination of exome and transcriptome sequencing. They find genomic alterations that could potentially be therapeutic targets.
Colin Ross and colleagues report the results of a genome-wide association study of anthracycline-induced cardiotoxicity in children treated for cancer. They identify a nonsynonymous coding variant in RARG associated with roughly fivefold higher risk of developing this severe adverse drug reaction.
Matthew Law, Mark Iles and colleagues report the results of a large-scale genome-wide meta-analysis of cutaneous malignant melanoma. They confirm previously reported association signals and identify five new susceptibility loci, with associated variants mapping within putative melanocyte regulatory elements.
Steve Brown and colleagues report an analysis of 20 phenotyping tests, including 413 data parameters, across 449 mutant mouse alleles. They identify widespread pleiotropy and assign putative functions to genes that lacked previous phenotypic annotation.