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Henry Sucov and colleagues demonstrate substantial natural variation in the capacity of the mouse heart to regenerate after injury and link this to the prevalence of mononuclear diploid cardiomyocytes. They identify Tnni3k as one gene that contributes to the observed variation and validate its role through mouse knockout and zebrafish overexpression studies.
Gil McVean and colleagues present a new Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to analyze genetic variants against UK Biobank disease phenotypes derived from self-reporting and hospital episode statistics. Their method displays increased power to detect genetic effects over other approaches and identifies novel associations between classical HLA alleles and common immune-mediated diseases.
Kevin Brown and colleagues functionally characterize a melanoma risk locus encompassing PARP1, correlating the risk genotype to PARP1 gene expression levels in melanoma cells. They identify an intronic gene-regulatory variant in PARP1 and find that PARP1 can promote cell proliferation and rescue oncogene-induced senescence, likely through MITF.
Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating the expression of R-spondin1 and Sprouty1, respectively.
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.
Peter Balint-Kurti, Qin Yang and colleagues report that ZmCCoAOMT2, which encodes a caffeoyl-CoA O-methyltransferase, is a gene within the quantitative trait locus qMdr9.02, which confers resistance to southern leaf blight and gray leaf spot. Their findings suggest that resistance might be caused by differences in levels of lignin and other metabolites in the phenylpropanoid pathway.
Sekar Kathiresan and colleagues perform a genome-wide association test for coronary artery disease (CAD) using data from the UK Biobank. They identify 15 new loci and perform phenome-wide association scanning, implicating insulin resistance pathways and transendothelial migration of leukocytes in CAD.
Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.
Hugh Watkins and colleagues meta-analyze data from the UK Biobank along with recent genome-wide association studies for coronary artery disease. They identify 13 new loci that were genome-wide significant and 243 loci at a 5% false discovery rate.
Kumarasamy Thangaraj, David Reich and colleagues identify 81 South Asian groups descended from extreme founder events, including 14 with a census size of over 1 million people, thus providing an opportunity to test for and decrease the burden of recessive genetic diseases in these populations.
Jeff Hasty and colleagues use an endonuclease from S. cerevisiae along with quorum sensing from A. fischeri to produce sustained cycling of DNA plasmid concentration across a colony of E. coli cells. This copy number modulation system enables dynamic regulation of gene circuit elements without the need for specially engineered promoters.
Matthew Robinson, Peter Visscher and colleagues use phenotypic data on 172,000 sibling pairs and phenotypic and SNP data on 150,832 unrelated individuals to estimate the heritability of body mass index across a range of experimental designs. They conclude that substantially larger sample sizes across ages and lifestyle factors will be required to understand the full genetic architecture of this trait.
Terence Capellini, David Kingsley and colleagues use transgenic mice to show that a Gdf5 enhancer (termed GROW1) is required for normal bone length. They suggest that a common variant at the human GROW1 enhancer was under selection in human populations and also contributes to arthritis susceptibility.
Charles Mullighan, Stephen Hunger, Jinghui Zhang and colleagues report a genomic analysis of 264 pediatric and young adult T-lineage acute lymphoblastic leukemia (T-ALL) samples. They identify 106 candidate driver genes, 53 of which have not been described previously in pediatric T-ALL, as well as associations between mutations and disease stage or subtype.
Junko Takita, Seishi Ogawa and colleagues profile 121 cases of pediatric T cell acute lymphoblasic leukemia (T-ALL) and identify recurrent SPI1 (PU.1) gene fusions. They find that these SPI1 fusions correlated with poor survival, retained transcriptional activity and, in a mouse stem cell model, enhanced cell proliferation.
Schahram Akbarian and colleagues report that mutation of the gene encoding the SETDB1 (KMT1E) histone methyltransferase in mouse neurons leads to dissolution of chromosome conformations and a topologically associated domain at the clustered protocadherin locus. They show that SETDB1 prevents excess CTCF binding and is important for maintaining developmentally important higher-order chromatin organization.
Damian Smedley and colleagues report the phenotypic characterization of the first 3,328 genes by the International Mouse Phenotyping Consortium. They develop new mouse models based on genes known to be associated with human mendelian diseases and identify potential disease-associated genes with little or no previous functional annotation.
Jeffrey Barrett, Tarjinder Singh and colleagues present a meta-analysis of rare coding variants and copy number variants in a large collection of schizophrenia cases and controls, combined with de novo mutation data from family trios. They find that rare, damaging variants contribute to risk of schizophrenia both with and without intellectual disability and that there is overlap between genetic risk for schizophrenia and other neurodevelopmental disorders.
Jos Jonkers, Lodewyk Wessels and colleagues use a Sleeping Beauty transposon mutagenesis screen to identify genes required for invasive lobular breast carcinoma formation (ILC) in mice. They find recurrent and mutually exclusive insertions in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, which are implicated in the actin cytoskeleton regulation pathway and have been found to be altered in human ILC breast cancer.
Rogier Versteeg, Johan van Nes and colleagues report that neuroblastomas comprise two cell types, mesenchymal and adrenergic, that have different responses to chemotherapeutic agents in vitro. Using ChIP–seq and expression profiling of pairs of phenotypically divergent isogenic cell lines, they identify candidate transcription factors for regulation of the two cell states.
