De novo mutations revealed by whole-exome sequencing are strongly associated with autism

Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.     

Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis

Polycyclic polyether natural products have fascinated chemists and biologists alike owing to their useful biological activity, highly complex structure and intriguing biosynthetic mechanisms. Following the original proposal for the polyepoxide origin of lasalocid and isolasalocid and the experimental determination of the origins of the oxygen and carbon atoms of both lasalocid and monensin, a unified stereochemical model for the biosynthesis of polyether ionophore antibiotics was proposed. The model was based on a cascade of nucleophilic ring closures of postulated polyepoxide substrates generated by stereospecific oxidation of all-trans polyene polyketide intermediates. Shortly thereafter, a related model was proposed for the biogenesis of marine ladder toxins, involving a series of nominally disfavoured anti-Baldwin, endo-tet epoxide-ring-opening reactions. Recently, we identified Lsd19 from the Streptomyces lasaliensis gene cluster as the epoxide hydrolase responsible for the epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A. Here we report the X-ray crystal structure of Lsd19 in complex with its substrate and product analogue to provide the first atomic structure-to our knowledge-of a natural enzyme capable of catalysing the disfavoured epoxide-opening cyclic ether formation. On the basis of our structural and computational studies, we propose a general mechanism for the enzymatic catalysis of polyether natural product biosynthesis.     

Inland thinning of West Antarctic Ice Sheet steered along subglacial rifts

Current ice loss from the West Antarctic Ice Sheet (WAIS) accounts for about ten per cent of observed global sea-level rise. Losses are dominated by dynamic thinning, in which forcings by oceanic or atmospheric perturbations to the ice margin lead to an accelerated thinning of ice along the coastline. Although central to improving projections of future ice-sheet contributions to global sea-level rise, the incorporation of dynamic thinning into models has been restricted by lack of knowledge of basal topography and subglacial geology so that the rate and ultimate extent of potential WAIS retreat remains difficult to quantify. Here we report the discovery of a subglacial basin under Ferrigno Ice Stream up to 1.5?kilometres deep that connects the ice-sheet interior to the Bellingshausen Sea margin, and whose existence profoundly affects ice loss. We use a suite of ice-penetrating radar, magnetic and gravity measurements to propose a rift origin for the basin in association with the wider development of the West Antarctic rift system. The Ferrigno rift, overdeepened by glacial erosion, is a conduit which fed a major palaeo-ice stream on the adjacent continental shelf during glacial maxima. The palaeo-ice stream, in turn, eroded the 'Belgica' trough, which today routes warm open-ocean water back to the ice front to reinforce dynamic thinning. We show that dynamic thinning from both the Bellingshausen and Amundsen Sea region is being steered back to the ice-sheet interior along rift basins. We conclude that rift basins that cut across the WAIS margin can rapidly transmit coastally perturbed change inland, thereby promoting ice-sheet instability.     

Possible tropical lakes on Titan from observations of dark terrain

Titan has clouds, rain and lakes--like Earth--but composed of methane rather than water. Unlike Earth, most of the condensable methane (the equivalent of 5?m depth globally averaged) lies in the atmosphere. Liquid detected on the surface (about 2?m deep) has been found by radar images only poleward of 50° latitude, while dune fields pervade the tropics. General circulation models explain this dichotomy, predicting that methane efficiently migrates to the poles from these lower latitudes. Here we report an analysis of near-infrared spectral images of the region between 20°?N and 20°?S latitude. The data reveal that the lowest fluxes in seven wavelength bands that probe Titan's surface occur in an oval region of about 60?×?40?km(2), which has been observed repeatedly since 2004. Radiative transfer analyses demonstrate that the resulting spectrum is consistent with a black surface, indicative of liquid methane on the surface. Enduring low-latitude lakes are best explained as supplied by subterranean sources (within the last 10,000 years), which may be responsible for Titan's methane, the continual photochemical depletion of which furnishes Titan's organic chemistry.