Articles in 2012

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic target is identified in most of the samples studied.

A description is given of the ENCODE consortium’s efforts to examine the principles of human transcriptional regulatory networks; the results are integrated with other genomic information to form a hierarchical meta-network where different levels have distinct properties.

DNase I footprinting in 41 cell and tissue types reveals millions of short sequence elements encoding an expansive repertoire of conserved recognition sequences for DNA-binding proteins.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

An extensive map of human DNase I hypersensitive sites, markers of regulatory DNA, in 125 diverse cell and tissue types is described; integration of this information with other ENCODE-generated data sets identifies new relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns.

A description is given of the ENCODE effort to provide a complete catalogue of primary and processed RNAs found either in specific subcellular compartments or throughout the cell, revealing that three-quarters of the human genome can be transcribed, and providing a wealth of information on the range and levels of expression, localization, processing fates and modifications of known and previously unannotated RNAs.

Whether a single group of stem cells or multiple populations contribute to the homeostasis of the interfollicular epidermis is controversial; here the authors use lineage tracing and mathematical modelling to show that the progenitors that maintain mouse epidermis are underpinned by slow-cycling stem cells that become mobilized on injury.

A free-electron laser provides a sufficiently intense source of X-rays to allow X-ray and optical wave mixing, here demonstrated by measuring the induced charge density and associated microscopic fields in single-crystal diamond.

A detailed reconstruction of the calcium carbonate compensation depth—at which calcium carbonate is dissolved—in the equatorial Pacific Ocean over the past 53 million years shows that it tracks ocean cooling, increasing as the ocean cools.

This study shows that nematodes without a germ line re-allocate resources to the soma, resulting in elevated proteasome activity, clearance of damaged proteins and increased longevity; this activity is associated with the increased expression of rpn-6 mediated by the transcription factor DAF-16.

Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.

Haploinsufficiency of the gene SCN1A (SCN1A^+/−) causes Dravet’s syndrome in humans, a form of epilepsy with autistic features; this paper shows that Scn1a^+/− mice have the same symptoms, and that social behaviours can be improved by pharmacological treatment with clonazepam.

Treatment of young mice with low levels of antibiotics results in increases in adiposity and causes both a change in the composition of the intestinal microbial community and an alteration in the activity of microbial metabolic pathways, leading to increased short-chain fatty acid production.

This study develops a wide-ranging index to assess the many factors that contribute to the health and benefits of the oceans, and the scores for all costal nations are assessed.

The ‘collateral’ homozygous deletion of essential redundant housekeeping genes in cancer genomes is shown to confer therapeutic vulnerability on cancer cells with the deletion, without affecting genomically intact normal non-cancerous cells, suggesting new therapeutic opportunities.

Using techniques by analogy with parity–time symmetry allows a combination of optical gain and loss in large-scale synthetic lattices, which can lead, for example, to such a lattice being invisible when viewed from one side.

Use of a two-way optical system to activate subclasses of inhibitory neurons, while simultaneously monitoring responses in target cells within cortical circuits in vivo, reveals that parvalbumin-expressing and somatostatin-expressing neurons exert distinct effects on cellular responses across the network.

Acid-sensing ion channels (ASICs) are voltage-independent ion channels that participate in a broad range of biological processes, including nociception and mechanosensation; here X-ray crystal structures of the complexes of chicken ASIC1a with psalmotoxin, a peptide toxin from tarantula, indicate that toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore.

This study presents the crystal structure of a RING-type E3 ligase bound to ubiquitin-loaded E2; the structure reveals how ubiquitin binding to E2 leads to changes in the catalytic site, priming it for catalysis by the E3 enzyme.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.