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Nature Genetics



Publishes the very highest quality research in genetics.



 



Necessary complexity

2017-07-27

This month's research articles span the range of scales of gene-regulatory mechanisms, from a deceptively simple gene therapy vector, via synthetic gene expression circuits, to extremely intricate epigenetic switches. We encourage investigation of synthetic circuits exploring the functions of the 3D genome.



Monogenic immune disorders and severe atopic disease

2017-07-27

Severe allergic disease is common, and few monogenic causes of atopy have been described. A new study that convincingly links severe atopic dermatitis to heterozygous CARD11 mutations with dominant-interfering activity serves as a timely reminder that clinicians should consider the possibility of an underlying monogenic immune disorder when caring for patients suffering from severe allergic disease.



Hacking DNA copy number for circuit engineering

2017-07-27

DNA copy number represents an essential parameter in the dynamics of synthetic gene circuits but typically is not explicitly considered. A new study demonstrates how dynamic control of DNA copy number can serve as an effective strategy to program robust oscillations in gene expression circuits.



The osteoarthritis and height GDF5 locus yields its secrets

2017-07-27

A new study reports molecular characterization of the GDF5 locus, which is associated with osteoarthritis risk and adult height in humans. This study provides evidence of positive selection for short stature at GDF5 in modern humans, as well as in archaic Neandertals and Denisovans.



The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability

2017-06-26

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.



Genotype–covariate interaction effects and the heritability of adult body mass index

2017-07-10

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.



Identification of sequence variants influencing immunoglobulin levels

2017-06-19

Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson and colleagues perform a genome-wide association study for immunoglobulin levels in Icelandic and Swedish cohorts. They find 38 new variants associated with IgA, IgG, IgM or composite immunoglobulin traits and identify candidate genes underlying the regulation of immunoglobulin levels.



Germline hypomorphic CARD11 mutations in severe atopic disease

2017-06-19

Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous CARD11 mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine.



Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk

2017-07-03

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.



The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

2017-07-03

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.



Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma

2017-06-26

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.



Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium

2017-06-26

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.



The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain

2017-07-03

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.



Truncating mutations in RBM12 are associated with psychosis

2017-06-19

Kari Stefansson and colleagues identify a nonsense mutation in RBM12 segregating with psychosis in an extended Icelandic pedigree and an independent frameshift mutation in RBM12 segregating with psychosis in a Finnish family. They further show that carriers of the Icelandic mutation who are unaffected by psychosis exhibit a psychiatric disorder and cognitive test battery profile resembling that of patients with schizophrenia.



Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

2017-06-19

Ralph McGinnis, Valgerdur Steinthorsdottir, Linda Morgan and colleagues perform a genome-wide association study in the offspring of preeclampsia pregnancies and identify variants in the fetal genome near FLT1 that are associated with risk of preeclampsia. FLT1 is known to encode an isoform of placental origin implicated in the pathology of preeclampsia, providing biological support for the association of this locus with preeclampsia risk.



Neuroblastoma is composed of two super-enhancer-associated differentiation states

2017-06-26

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.



Identification of liver-specific enhancer–promoter activity in the 3′ untranslated region of the wild-type AAV2 genome

2017-06-19

Ian Alexander and colleagues characterize a liver-specific enhancer–promoter element that is found in the genome of wild-type adeno-associated virus type 2 (AAV2), from which gene transfer vectors have been derived. They suggest that these sequences could provide a possible link between AAV integration events in the liver and gene dysregulation and pathogenesis.



Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

2017-07-03

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.



Synchronized DNA cycling across a bacterial population

2017-07-10

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.