Volume 45 Issue 11, November 2013

Genes encoding subunits of the SWI/SNF chromatin-remodeling complex constitute, collectively, one of the most frequently mutated targets in cancer. Although mutations in SWI/SNF genes are uncommon in prostate cancer, a new study shows that SChLAP1, a long noncoding RNA frequently expressed in aggressive prostate tumors, drives cancer by directly disrupting SNF5, a core subunit of the SWI/SNF complex.

The significance of epigenomic aberrations in cancer development has been underscored by the discovery of mutations in key chromatin modifiers, most notably in hematological malignancies. A new study of pediatric acute lymphoblastic leukemia (ALL) demonstrates the usefulness of mapping global epigenetic signatures and applying these data in a framework to identify and characterize underlying somatic genetic alterations in human cancers.

A new study shows that a specific mutation in SCN11A, which encodes the Na_v1.9 voltage-gated sodium channel, underlies a human disorder characterized by insensitivity to pain. This finding provides fresh insights into human pain perception and suggests a new avenue for the development of analgesic drugs.

Cristen Willer and colleagues report genome-wide association analyses for blood lipid levels in 188,578 individuals. They identify 62 loci newly associated with blood lipid levels, refine the association signals at 12 loci and examine associations with cardiovascular and metabolic traits.

Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity.

Seishi Ogawa and colleagues report the landscape of somatic mutations in Down syndrome–related myeloid disorders. They identify recurrent mutations in multiple cohesin components, CTCF and epigenetic regulators in Down syndrome–related acute megakaryoblastic leukemia.

Magdalena Götz, Stephen Robertson and colleagues show that biallelic mutations in DCHS1 and FAT4 cause a multisystem disorder that includes periventricular neuronal heterotopia. They further show that reducing expression of Dchs1 and Fat4 in mouse embryonic neuroepithelium causes an increase in progenitor cell numbers and reduced neuronal differentiation, resulting in heterotopic accumulation of cells below the neuronal layers in the neocortex.

Marco Sandri, Helge Amthor, Stefano Piccolo and colleagues show that BMP signaling is a key positive regulator of muscle hypertrophy. They further show that inhibiting BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin knockout mice and exacerbates the effects of denervation and fasting.

James Lupski and colleagues report a high-resolution analysis of 67 breakpoint junctions in 31 unrelated individuals with MECP2 duplication syndrome. They find that ~52% of genomic rearrangements in these individuals represent complex events in which the sequences flanking the breakpoints acquire additional changes, including small insertions, deletions and point mutations, likely resulting from error-prone DNA polymerase activity.

Ian Henderson and colleagues report fine-scale mapping and characterization of recombination rates in Arabidopsis thaliana. They find an enrichment of recombination hot spots overlapping transcription start and termination sites, as well as that hot spot–associated promoter regions show elevated levels of chromatin marks, including high H2A.Z, high H3K4me3 and low nucleosome density.

Alexander van Oudenaarden and colleagues analyze the temporal dynamics of the Caenorhabditis elegans transcriptome, reporting that ~2,000 genes show periodic expression oscillations in synchrony with progression through larval stages. They characterize the expression dynamics of the microRNA lin-4 and its target lin-14 and suggest that a microRNA-mediated feed-forward circuit is required for efficient dampening of expression oscillations to maintain the temporal gradient of the microRNA target.

Sekar Kathiresan and colleagues examine 185 common variants using a modified mendelian randomization approach and provide evidence supporting a causal role of triglyceride-rich lipoproteins in the development of coronary artery disease.

The International Multiple Sclerosis Genetics Consortium reports the discovery of 48 new susceptibility variants for multiple sclerosis through targeted follow-up of immune-related loci. They also report fine mapping of association signals at established susceptibility loci and provide insights into the immune system processes underlying this disease.

Jing Wang, Fengchun Zhang and colleagues report the results of a genome-wide association study of primary Sjögren's syndrome, a common autoimmune disease. They confirm associations in the STAT4, TNFAIP3 and HLA regions and identify a new susceptibility locus in the GTF2I region at 7q11.23.

Johanna Seddon, Soumya Raychaudhuri and colleagues report the identification of rare variants in C3, CFI and C9 associated with risk of advanced age-related macular degeneration.

Patrick Sulem, Kari Stefansson and colleagues report the identification of a rare nonsynonymous variant in the C3 gene, encoding complement factor 3, that is associated with age-related macular degeneration.

Goncalo Abecasis and colleagues report identification of a rare coding variant in the complement 3 gene that is associated with age-related macular degeneration.

David Altshuler and colleagues sequenced seven genes for maturity-onset diabetes of the young (MODY), a dominant Mendelian disorder, in 4,003 individuals drawn from three population-based cohorts. They find ~2% of individuals unselected for phenotype carry low frequency variants in one of these MODY genes, predicted as likely to be pathogenic; however most of these individuals remain asymptomatic through middle age.

Frank Stegmeier, Levi Garraway and colleagues apply a targeted mass spectrometry approach that measures level of histone modifications and identify a recurrent p.E1099K variant in NSD2 in acute lymphoblastic leukemia. When ectopically expressed in a cancer cell line, this variant promotes transformation.

Arul Chinnaiyan and colleagues report that the long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers and predicts poor outcome. Mechanistically, they show that SChLAP1 promotes invasiveness and metastasis and antagonizes the functions of the SWI/SNF chromatin-remodeling complex.

Ingo Kurth and colleagues show that a specific de novo missense mutation in SCN11A results in an inability to experience pain. They further show that mutant channels display higher activity at resting voltages, causing sustained depolarization of pain receptors, impaired generation of action potentials and aberrant synaptic transmission.

Christian Schaaf, Manuel Gonzalez-Garay and colleagues report the identification of four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the imprinted domain linked to Prader-Willi syndrome (PWS). The four individuals have PWS or PWS-related phenotypes, and all have autism.