Research articles

Anna Lasorella, Raul Rabadan, Antonio Iavarone and colleagues report an integrated analysis of genomic alterations in glioblastoma. They identify and functionally validate several new driver events, including loss-of-function mutations in CTNND2 and recurrent EGFR fusions.

Morris Brown and colleagues identify somatic mutations in ATP1A1 and CACNA1D in aldosterone-producing adenomas with features resembling zonaglomerulosa cells. They further show that the ATP1A1 mutations cause inward leak currents under physiological conditions, whereas the CACNA1D mutations induce a shift of voltage-dependent gating to more negative potentials and suppress channel inactivation.

Christer Betsholtz, Christine Klein, Maria Sobrido and colleagues report the identification of mutations in the gene encoding PDGF-B that cause idiopathic basal ganglia calcification. They also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications.

Yusaku Uga and colleagues show that the gene underlying the rice quantitative trait locus DEEPER ROOTING 1 (DRO1) influences root growth angle and allows plants to maintain high yield performance under drought conditions. They further show that DRO1 is involved in cell elongation in the root tip that causes asymmetric root growth and downward bending of the root in response to gravity.

Richard Lifton and colleagues identify somatic and germline mutations in the CACNA1D calcium channel gene in aldosterone-producing adenomas and primary aldosteronism. Their functional studies show that these mutations result in channel activation at more hyperpolarized membrane potentials, implicating increased Ca²⁺ influx in disease pathogenesis.

Nadav Ahituv and colleagues use a massively parallel reporter assay to test 4,970 synthetic regulatory element sequences, containing patterns of 12 known liver transcription factor binding sites, in mice and in HepG2 cells. They systematically test the impact of binding site copy number, spacing, combination and order on gene expression.

Stefan Somlo and colleagues show that loss of intact cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease (ADPKD). They further show that the severity of cystic disease in these models is directly related to the length of time between the initial loss of polycystins and the subsequent involution of cilia, implicating a cilia-dependent cyst growth–promoting pathway in the pathogenesis of ADPKD.

Suzanne Noble and colleagues show that the passage of Candida albicans through the mammalian gut induces expression of the Wor1 transcription factor, triggering a developmental switch that promotes commensal fitness.

Monica Justice and colleagues performed a genetic suppressor screen in Mecp2-null mice, which recapitulate symptoms of Rett syndrome, a neurological disease with autistic features. They identify a nonsense suppressor mutation in Sqle, which encodes a rate-limiting enzyme in cholesterol synthesis, and show that treatment of Mecp2 mutant mice with statins improves symptoms and increases longevity.

David Page and colleagues report an improved assembly of the human X-chromosome using single haplotype sequencing. They used this assembly to systematically test Ohno's law of X-chromosome conservation by comparison to the mouse X-chromsome and identify 341 X-linked protein coding genes that are not shared between species and therefore violate Ohno's law.

Heymut Omran, Joseph LoTurco and colleagues show that mutations in the dyslexia susceptibility candidate gene DYX1C1 cause primary ciliary dyskinesia. Their functional studies suggest that DYX1C1 is required for the cytoplasmic preassembly of axonemal dynein complexes.

Connie Bezzina, Richard Redon and colleagues show that common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disorder with high risk of sudden cardiac death. The newly discovered loci have a large cumulative effect on disease risk and illustrate how common variants can have a strong impact on predisposition to rare diseases.

Philippe Froguel and colleagues report an analysis of large chromosomal clonal mosaic events in individuals with type 2 diabetes. They find a significant association between CME occurrence and T2D with vascular complications.

Reuben Harris and colleagues report an analysis of gene expression and mutation data for multiple tumor types. They show that the DNA cytosine deaminase APOBEC3B is upregulated and that its preferred target sequence is frequently mutated in many types of cancer

Olivier Voinnet and colleagues characterize the sequence of molecular events underyling the activation, proliferation and eventual silencing of an endogenous retrotransposon in Arabidopsis thaliana. They further show how this transient mobilization causes widespread genome diversification and de novo epiallelism that could serve as sources of selectable and potentially adaptative traits.

Dmitry Gordenin, Gad Getz and colleagues report an analysis of mutation patterns in cancer genomes and find evidence of mutagenesis induced by APOBEC cytidine deaminase enzymes. They find an APOBEC mutagenesis pattern in bladder, cervical, breast, head and neck, and lung cancers, representing 68% of all mutations in some samples.

Thomas Wicker and colleagues report the whole-genome sequencing of four wheat powdery mildew (Blumeria graminis forma specialis tritici) isolates from different geographic regions. Their comparative genomic analysis provides insights into the evolution of powdery mildews, which are obligate biotropic fungal pathogens.

Jaroslaw Maciejewski and colleagues report whole-exome sequencing of 20 cases of myeloid malignancies, with follow up of SETBP1 in 727 further cases of myeloid malignancies. They identify SETBP1 mutations in 52 cases (7.2%).

Seiji Kojima and colleagues report whole-exome sequencing of 13 juvenile myelomonocytic leukemias. They identify RAS pathway mutations in 82 of the 92 total cases analyzed and mutations in SETBP1 or JAK3 in 16 cases.

Mathieu Blanchette and colleagues report whole-genome sequencing of three Brassicaceae species, Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum. They include comparative genomic analysis with 6 additional crucifier genomes, identify and characterize over 90,000 conserved noncoding sequences and provide a map of functional noncoding regions in plant genomes.