Volume 500 Issue 7463


Subject to question p.377

Even when conducting clinical trials to study widely used therapies, researchers must ensure that they disclose the full risks to patients.

doi: 10.1038/500377a


News Features

Egg engineers p.392

In a technical tour de force, Japanese researchers created eggs and sperm in the laboratory. Now, scientists have to determine how to use those cells safely — and ethically.

doi: 10.1038/500392a

News & Views

Electric defence p.404

Herbivory and mechanical wounding in plants have been shown to elicit electrical signals — mediated by two glutamate-receptor-like proteins — that induce defence responses at local and distant sites. See Letter p.422

doi: 10.1038/500404a

Twinkling stars p.405

A correlation between stellar brightness variations and the gravitational acceleration at a star's surface has been observed that allows this acceleration to be measured with a precision of better than 25%. See Letter p.427

doi: 10.1038/500405a

Programming genomes with light p.406

The combination of two techniques — optogenetics and genome editing using engineered nucleases — now provides a general means for the light-controlled regulation of any gene of interest. See Letter p.472

doi: 10.1038/500406a

A solid triple point p.408

The observation of a triple point of coexistence between two insulating phases and a conducting phase in vanadium dioxide reveals physics that may help to unravel the role of electronic correlations in this material. See Letter p.431

doi: 10.1038/500408a

Sweet enticements to move p.409

The formation of new blood vessels from pre-existing ones is a carefully orchestrated dance. A study reveals that the metabolism of sugar by glycolysis contributes to its regulation.

doi: 10.1038/nature12549

Abundant equals nested p.411

How ecological network structures are influenced by species coexistence, community stability and perturbations is a topic of debate. It seems that one overlooked correlate of nested structures is species abundances. See Letter p.449

doi: 10.1038/500411a

A gut feeling for isolation p.412

The far-reaching effects of the relationship between an animal and its resident gut microorganisms are becoming ever clearer. New findings suggest it can even create barriers that keep species separate.

doi: 10.1038/500412a


Signatures of mutational processes in human cancer p.415

An analysis of mutations from over 7,000 cancers of diverse origins reveals the diversity of mutational processes underlying the development of cancer; more than 20 distinct mutational signatures are described, some of which are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are specific to individual tumour types.

doi: 10.1038/nature12477


An observational correlation between stellar brightness variations and surface gravity p.427

Surface gravity is a basic stellar property, but it is difficult to measure accurately, with typical uncertainties of 25 to 50 per cent if measured spectroscopically and 90 to 150 per cent if measured photometrically. Asteroseismology measures gravity with an uncertainty of about 2 per cent but is restricted to relatively small samples of bright stars, most of which are giants. The availability of high-precision measurements of brightness variations for more than 150,000 stars provides an opportunity to investigate whether the variations can be used to determine surface gravities. The Fourier power of granulation on a star’s surface correlates physically with surface gravity: if brightness variations on timescales of hours arise from granulation, then such variations should correlate with surface gravity. Here we report an analysis of archival data that reveals an observational correlation between surface gravity and root mean squared brightness variations on timescales of less than eight hours for stars with temperatures of 4,500 to 6,750 kelvin, log surface gravities of 2.5 to 4.5 (cgs units) and overall brightness variations of less than three parts per thousand. A straightforward observation of optical brightness variations therefore allows a determination of the surface gravity with a precision of better than 25 per cent for inactive Sun-like stars at main-sequence to giant stages of evolution.

doi: 10.1038/nature12419

Measurement of a solid-state triple point at the metal–insulator transition in VO2 p.431

First-order phase transitions in solids are notoriously challenging to study. The combination of change in unit cell shape, long range of elastic distortion and flow of latent heat leads to large energy barriers resulting in domain structure, hysteresis and cracking. The situation is worse near a triple point, where more than two phases are involved. The well-known metal–insulator transition in vanadium dioxide, a popular candidate for ultrafast optical and electrical switching applications, is a case in point. Even though VO2 is one of the simplest strongly correlated materials, experimental difficulties posed by the first-order nature of the metal–insulator transition as well as the involvement of at least two competing insulating phases have led to persistent controversy about its nature. Here we show that studying single-crystal VO2 nanobeams in a purpose-built nanomechanical strain apparatus allows investigation of this prototypical phase transition with unprecedented control and precision. Our results include the striking finding that the triple point of the metallic phase and two insulating phases is at the transition temperature, Ttr = Tc, which we determine to be 65.0 ± 0.1 °C. The findings have profound implications for the mechanism of the metal–insulator transition in VO2, but they also demonstrate the importance of this approach for mastering phase transitions in many other strongly correlated materials, such as manganites and iron-based superconductors.

doi: 10.1038/nature12425

The role of spin in the kinetic control of recombination in organic photovoltaics p.435

In biological complexes, cascade structures promote the spatial separation of photogenerated electrons and holes, preventing their recombination. In contrast, the photogenerated excitons in organic photovoltaic cells are dissociated at a single donor–acceptor heterojunction formed within a de-mixed blend of the donor and acceptor semiconductors. The nanoscale morphology and high charge densities give a high rate of electron–hole encounters, which should in principle result in the formation of spin-triplet excitons, as in organic light-emitting diodes. Although organic photovoltaic cells would have poor quantum efficiencies if every encounter led to recombination, state-of-the-art examples nevertheless demonstrate near-unity quantum efficiency. Here we show that this suppression of recombination arises through the interplay between spin, energetics and delocalization of electronic excitations in organic semiconductors. We use time-resolved spectroscopy to study a series of model high-efficiency polymer–fullerene systems in which the lowest-energy molecular triplet exciton (T1) for the polymer is lower in energy than the intermolecular charge transfer state. We observe the formation of T1 states following bimolecular recombination, indicating that encounters of spin-uncorrelated electrons and holes generate charge transfer states with both spin-singlet (1CT) and spin-triplet (3CT) characters. We show that the formation of triplet excitons can be the main loss mechanism in organic photovoltaic cells. But we also find that, even when energetically favoured, the relaxation of 3CT states to T1 states can be strongly suppressed by wavefunction delocalization, allowing for the dissociation of 3CT states back to free charges, thereby reducing recombination and enhancing device performance. Our results point towards new design rules both for photoconversion systems, enabling the suppression of electron–hole recombination, and for organic light-emitting diodes, avoiding the formation of triplet excitons and enhancing fluorescence efficiency.

doi: 10.1038/nature12339

Onset of deglacial warming in West Antarctica driven by local orbital forcing p.440

The cause of warming in the Southern Hemisphere during the most recent deglaciation remains a matter of debate. Hypotheses for a Northern Hemisphere trigger, through oceanic redistributions of heat, are based in part on the abrupt onset of warming seen in East Antarctic ice cores and dated to 18,000 years ago, which is several thousand years after high-latitude Northern Hemisphere summer insolation intensity began increasing from its minimum, approximately 24,000 years ago. An alternative explanation is that local solar insolation changes cause the Southern Hemisphere to warm independently. Here we present results from a new, annually resolved ice-core record from West Antarctica that reconciles these two views. The records show that 18,000 years ago snow accumulation in West Antarctica began increasing, coincident with increasing carbon dioxide concentrations, warming in East Antarctica and cooling in the Northern Hemisphere associated with an abrupt decrease in Atlantic meridional overturning circulation. However, significant warming in West Antarctica began at least 2,000 years earlier. Circum-Antarctic sea-ice decline, driven by increasing local insolation, is the likely cause of this warming. The marine-influenced West Antarctic records suggest a more active role for the Southern Ocean in the onset of deglaciation than is inferred from ice cores in the East Antarctic interior, which are largely isolated from sea-ice changes.

doi: 10.1038/nature12376

Digit loss in archosaur evolution and the interplay between selection and constraints p.445

Evolution involves interplay between natural selection and developmental constraints. This is seen, for example, when digits are lost from the limbs during evolution. Extant archosaurs (crocodiles and birds) show several instances of digit loss under different selective regimes, and show limbs with one, two, three, four or the ancestral number of five digits. The ‘lost’ digits sometimes persist for millions of years as developmental vestiges. Here we examine digit loss in the Nile crocodile and five birds, using markers of three successive stages of digit development. In two independent lineages under different selection, wing digit I and all its markers disappear. In contrast, hindlimb digit V persists in all species sampled, both as cartilage, and as Sox9- expressing precartilage domains, 250 million years after the adult digit disappeared. There is therefore a mismatch between evolution of the embryonic and adult phenotypes. All limbs, regardless of digit number, showed similar expression of sonic hedgehog (Shh). Even in the one-fingered emu wing, expression of posterior genes Hoxd11 and Hoxd12 was conserved, whereas expression of anterior genes Gli3 and Alx4 was not. We suggest that the persistence of digit V in the embryo may reflect constraints, particularly the conserved posterior gene networks associated with the zone of polarizing activity (ZPA). The more rapid and complete disappearance of digit I may reflect its ZPA-independent specification, and hence, weaker developmental constraints. Interacting with these constraints are selection pressures for limb functions such as flying and perching. This model may help to explain the diverse patterns of digit loss in tetrapods. Our study may also help to understand how selection on adults leads to changes in development.

doi: 10.1038/nature12336

Emergence of structural and dynamical properties of ecological mutualistic networks p.449

Mutualistic networks are formed when the interactions between two classes of species are mutually beneficial. They are important examples of cooperation shaped by evolution. Mutualism between animals and plants has a key role in the organization of ecological communities. Such networks in ecology have generally evolved a nested architecture independent of species composition and latitude; specialist species, with only few mutualistic links, tend to interact with a proper subset of the many mutualistic partners of any of the generalist species. Despite sustained efforts to explain observed network structure on the basis of community-level stability or persistence, such correlative studies have reached minimal consensus. Here we show that nested interaction networks could emerge as a consequence of an optimization principle aimed at maximizing the species abundance in mutualistic communities. Using analytical and numerical approaches, we show that because of the mutualistic interactions, an increase in abundance of a given species results in a corresponding increase in the total number of individuals in the community, and also an increase in the nestedness of the interaction matrix. Indeed, the species abundances and the nestedness of the interaction matrix are correlated by a factor that depends on the strength of the mutualistic interactions. Nestedness and the observed spontaneous emergence of generalist and specialist species occur for several dynamical implementations of the variational principle under stationary conditions. Optimized networks, although remaining stable, tend to be less resilient than their counterparts with randomly assigned interactions. In particular, we show analytically that the abundance of the rarest species is linked directly to the resilience of the community. Our work provides a unifying framework for studying the emergent structural and dynamical properties of ecological mutualistic networks.

doi: 10.1038/nature12438

Genomic evidence for ameiotic evolution in the bdelloid rotifer Adineta vaga OPEN p.453

Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years. Neither male sex organs nor meiosis have ever been observed in these microscopic animals: oocytes are formed through mitotic divisions, with no reduction of chromosome number and no indication of chromosome pairing. However, current evidence does not exclude that they may engage in sex on rare, cryptic occasions. Here we report the genome of a bdelloid rotifer, Adineta vaga (Davis, 1873), and show that its structure is incompatible with conventional meiosis. At gene scale, the genome of A. vaga is tetraploid and comprises both anciently duplicated segments and less divergent allelic regions. However, in contrast to sexual species, the allelic regions are rearranged and sometimes even found on the same chromosome. Such structure does not allow meiotic pairing; instead, we find abundant evidence of gene conversion, which may limit the accumulation of deleterious mutations in the absence of meiosis. Gene families involved in resistance to oxidation, carbohydrate metabolism and defence against transposons are significantly expanded, which may explain why transposable elements cover only 3% of the assembled sequence. Furthermore, 8% of the genes are likely to be of non-metazoan origin and were probably acquired horizontally. This apparent convergence between bdelloids and prokaryotes sheds new light on the evolutionary significance of sex.

doi: 10.1038/nature12326

Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons p.458

Neuromodulatory control by oxytocin is essential to a wide range of social, parental and stress-related behaviours. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels and with genetic alterations of the oxytocin receptor (OXTR). Thirty years ago, Mühlethaler et al. found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron–pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision.

doi: 10.1038/nature12330

Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids p.463

Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2α (cPLA2α), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, α-helically-dominated ‘sandwich’ topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2α release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.

doi: 10.1038/nature12332

The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy p.468

Autophagy is an evolutionarily conserved catabolic process involved in several physiological and pathological processes. Although primarily cytoprotective, autophagy can also contribute to cell death; it is thus important to understand what distinguishes the life or death decision in autophagic cells. Here we report that induction of autophagy is coupled to reduction of histone H4 lysine 16 acetylation (H4K16ac) through downregulation of the histone acetyltransferase hMOF (also called KAT8 or MYST1), and demonstrate that this histone modification regulates the outcome of autophagy. At a genome-wide level, we find that H4K16 deacetylation is associated predominantly with the downregulation of autophagy-related genes. Antagonizing H4K16ac downregulation upon autophagy induction results in the promotion of cell death. Our findings establish that alteration in a specific histone post-translational modification during autophagy affects the transcriptional regulation of autophagy-related genes and initiates a regulatory feedback loop, which serves as a key determinant of survival versus death responses upon autophagy induction.

doi: 10.1038/nature12313

Optical control of mammalian endogenous transcription and epigenetic states p.472

Here the customizable TALE DNA-binding domain was integrated with the light-sensitive cryptochrome 2 protein and its interacting partner (CIB1) from Arabidopsis thaliana, thereby creating an optogenetic two-hybrid system called light-inducible transcriptional effectors (LITEs); the LITE system establishes a novel mode of optogenetic control of endogenous transcription and epigenetic states.

doi: 10.1038/nature12466

Charting a dynamic DNA methylation landscape of the human genome p.477

DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively stable DNA methylation patterns, with 70–80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70–80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.

doi: 10.1038/nature12433

DNA unwinding heterogeneity by RecBCD results from static molecules able to equilibrate p.482

Single-molecule studies can overcome the complications of asynchrony and ensemble-averaging in bulk-phase measurements, provide mechanistic insights into molecular activities, and reveal interesting variations between individual molecules. The application of these techniques to the RecBCD helicase of Escherichia coli has resolved some long-standing discrepancies, and has provided otherwise unattainable mechanistic insights into its enzymatic behaviour. Enigmatically, the DNA unwinding rates of individual enzyme molecules are seen to vary considerably, but the origin of this heterogeneity remains unknown. Here we investigate the physical basis for this behaviour. Although any individual RecBCD molecule unwound DNA at a constant rate for an average of approximately 30,000 steps, we discover that transiently halting a single enzyme–DNA complex by depleting Mg2+-ATP could change the subsequent rates of DNA unwinding by that enzyme after reintroduction to ligand. The proportion of molecules that changed rate increased exponentially with the duration of the interruption, with a half-life of approximately 1 second, suggesting that a conformational change occurred during the time that the molecule was arrested. The velocity after pausing an individual molecule was any velocity found in the starting distribution of the ensemble. We suggest that substrate binding stabilizes the enzyme in one of many equilibrium conformational sub-states that determine the rate-limiting translocation behaviour of each RecBCD molecule. Each stabilized sub-state can persist for the duration (approximately 1 minute) of processive unwinding of a DNA molecule, comprising tens of thousands of catalytic steps, each of which is much faster than the time needed for the conformational change required to alter kinetic behaviour. This ligand-dependent stabilization of rate-defining conformational sub-states results in seemingly static molecule-to-molecule variation in RecBCD helicase activity, but in fact reflects one microstate from the equilibrium ensemble that a single molecule manifests during an individual processive translocation event.

doi: 10.1038/nature12333

Structural basis for molecular recognition of folic acid by folate receptors p.486

Folate receptors (FRα, FRβ and FRγ) are cysteine-rich cell-surface glycoproteins that bind folate with high affinity to mediate cellular uptake of folate. Although expressed at very low levels in most tissues, folate receptors, especially FRα, are expressed at high levels in numerous cancers to meet the folate demand of rapidly dividing cells under low folate conditions. The folate dependency of many tumours has been therapeutically and diagnostically exploited by administration of anti-FRα antibodies, high-affinity antifolates, folate-based imaging agents and folate-conjugated drugs and toxins. To understand how folate binds its receptors, we determined the crystal structure of human FRα in complex with folic acid at 2.8 Å resolution. FRα has a globular structure stabilized by eight disulphide bonds and contains a deep open folate-binding pocket comprised of residues that are conserved in all receptor subtypes. The folate pteroate moiety is buried inside the receptor, whereas its glutamate moiety is solvent-exposed and sticks out of the pocket entrance, allowing it to be conjugated to drugs without adversely affecting FRα binding. The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system.

doi: 10.1038/nature12327