Volume 45 Issue 9, September 2013

Recent evidence has implicated APOBEC3B as a source of mutations in cervical, bladder, lung, head and neck, and breast cancers. APOBEC enzymes normally function in innate immune responses, including those that target retroviruses, suggesting links between mutagenesis, immunity and viral infection in the process of cancer development.

Rett syndrome is caused by mutations in the gene encoding the transcriptional regulator MECP2. A new study demonstrates that cholesterol homeostasis is disrupted in Mecp2 mutant mice and suggests new therapeutic options for this disease.

Candida albicans is a frequent pathogen of immunologically compromised individuals, but it is an even more common commensal of healthy humans, where it resides in the gut in a benign state. A new study shows that a specific commensal form of the fungus is induced in the gut through a developmental program that downregulates virulence factors and induces metabolic functions, enabling it to thrive on the nutrients that are available in the large intestine without damaging its host.

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.

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

Naomi Wray and colleagues report an analysis of genome-wide association data sets from the Psychiatric Genomics Consortium for five psychiatric disorders. They find that common variation explains 17–29% of the variance in liability and provide further support for a shared genetic etiology for these related psychiatric disorders.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Pierre Szepetowski and colleagues report the identification of mutations in GRIN2A in individuals with acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Sarah von Spiczak, Holger Lerche and colleagues identify mutations in GRIN2A that cause idiopathic focal epilepsy with rolandic spikes.

Heather Mefford, Ingrid Scheffer and colleagues report the identification of inherited mutations in GRIN2A that cause epilepsy-aphasia syndromes, which have a characteristic EEG pattern and developmental regression affecting language.

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.

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.

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.

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.

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.