Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.     

Lunar activity from recent gas release

Samples of material returned from the Moon have established that widespread lunar volcanism ceased about 3.2 Gyr ago. Crater statistics and degradation models indicate that last-gasp eruptions of thin basalt flows continued until less than 1.0 Gyr ago, but the Moon is now considered to be unaffected by internal processes today, other than weak tidally driven moonquakes and young fault systems. It is therefore widely assumed that only impact craters have reshaped the lunar landscape over the past billion years. Here we report that patches of the lunar regolith in the Ina structure were recently removed. The preservation state of relief, the number of superimposed small craters, and the 'freshness' (spectral maturity) of the regolith together indicate that features within this structure must be as young as 10 Myr, and perhaps are still forming today. We propose that these features result from recent, episodic out-gassing from deep within the Moon. Such out-gassing probably contributed to the radiogenic gases detected during past lunar missions. Future monitoring (including Earth-based observations) should reveal the composition of the gas, yielding important clues to volatiles archived at great depth over the past 4-4.5 Gyr.     

Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration

We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically interpreted translocations and inversions. We confirm that the recently described phenomenon of 'chromothripsis' (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline, where it can resolve to a relatively balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign copy-number variants (CNVs). We compared these results to experimentally generated DNA breakage-repair by sequencing seven transgenic animals, revealing extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion was the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations.     

Towards sustainability in world fisheries

Fisheries have rarely been 'sustainable'. Rather, fishing has induced serial depletions, long masked by improved technology, geographic expansion and exploitation of previously spurned species lower in the food web. With global catches declining since the late 1980s, continuation of present trends will lead to supply shortfall, for which aquaculture cannot be expected to compensate, and may well exacerbate. Reducing fishing capacity to appropriate levels will require strong reductions of subsidies. Zoning the oceans into unfished marine reserves and areas with limited levels of fishing effort would allow sustainable fisheries, based on resources embedded in functional, diverse ecosystems.     

Measures of effectiveness in medical research: Reporting both absolute and relative measures

Biomedical research, especially pharmaceutical research, has been criticised for engaging in practices that lead to over-estimations of the effectiveness of medical treatments. A central issue concerns the reporting of absolute and relative measures of medical effectiveness. In this paper we critically examine proposals made by Jacob Stegenga to (a) give priority to the reporting of absolute measures over relative measures, and (b) downgrade the measures of effectiveness (effect sizes) of the treatments tested in clinical trials (Stegenga, 2015a). After exposing significant flaws in a central case study used by Stegenga to bolster his first proposal (a), we go on to argue that neither of these proposals is defensible (a or b). We defend the practice, in line with the New England Journal of Medicine, of reporting both absolute and relative measures whenever feasible.     

Amyloid and the origin of life: self-replicating catalytic amyloids as prebiotic informational and protometabolic entities

A crucial stage in the origin of life was the emergence of the first molecular entity that was able to replicate, transmit information, and evolve on the early Earth. The amyloid world hypothesis posits that in the pre-RNA era, information processing was based on catalytic amyloids. The self-assembly of short peptides into β-sheet amyloid conformers leads to extraordinary structural stability and novel multifunctionality that cannot be achieved by the corresponding nonaggregated peptides. The new functions include self-replication, catalytic activities, and information transfer. The environmentally sensitive template-assisted replication cycles generate a variety of amyloid polymorphs on which evolutive forces can act, and the fibrillar assemblies can serve as scaffolds for the amyloids themselves and for ribonucleotides proteins and lipids. The role of amyloid in the putative transition process from an amyloid world to an amyloid–RNA–protein world is not limited to scaffolding and protection: the interactions between amyloid, RNA, and protein are both complex and cooperative, and the amyloid assemblages can function as protometabolic entities catalyzing the formation of simple metabolite precursors. The emergence of a pristine amyloid-based in-put sensitive, chiroselective, and error correcting information-processing system, and the evolvement of mutualistic networks were, arguably, of essential importance in the dynamic processes that led to increased complexity, organization, compartmentalization, and, eventually, the origin of life.