Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND:Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS:We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS:We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION:We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING:National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK

Arsenic in the environment

Book synopsis: Up to 200 million people in 70 countries are at risk from drinking water contaminated with arsenic, which is a major cause of chronic debilitating illnesses and fatal cancers. Until recently little was known about the mobility of arsenic, and how redox transformations determined its movement into or out of water supplies. Although human activities contribute to the release of arsenic from minerals, it is now clear that bacteria are responsible for most of the redox transformation of arsenic in the environment. Bacterial oxidation of arsenite (to the less mobile arsenate) has been known since 1918, but it was not until 2000 that a bacterium was shown to gain energy from this process. Since then a wide range of arsenite-oxidizing bacteria have been isolated, including aerobes and anaerobes; heterotrophs and autotrophs; thermophiles, mesophiles and psychrophiles. This book reviews recent advances in the study of such bacteria. After a section on background—geology and health issues—the main body of the book concerns the cellular machinery of arsenite oxidation. It concludes by examining possible applications. Topics treated are: The geology and cycling of arsenic Arsenic and disease Arsenite oxidation: physiology, enzymes, genes, and gene regulation. Community genomics and functioning, and the evolution of arsenite oxidation Microbial arsenite oxidation in bioremediation Biosensors for arsenic in drinking water and industrial effluent

Incongruent weathering of Cd and Zn from mine tailings: a column leaching study

The weathering of discharged mine tailings can contaminate groundwaters, rivers and floodplains with potentially toxic Cd and Zn, depending on tailings mineralogy, storage, dispersal and climatic conditions. The mechanisms of long-term tailings weathering and its influence on waste piles and floodplain environments were assessed by a column leaching experiment that incorporated tailings and soil from Potosí, Bolivia, and modelled 20 cycles of wet and dry season conditions over three calendar years. Chemical analysis of the leachate and column solids, optical mineralogy, XRD, SEM, EPMA, BCR and water-soluble chemical extractions and speciation modelling were carried out to determine the processes responsible for the leaching of Cd, Fe, S and Zn. Over this period, approximately 50 to 95% of the original Cd and 50 to 60% of the Zn were leached from the columns. Large amounts of leached Cd and Zn at the beginning of the experiment are attributed to the dissolution of soluble sulphate minerals present in the original tailings and formed after the first wetting of the columns. The Zn/Cd mass ratios of the tailings and soil, initially 429 and 400, respectively, vary considerably over the course of the experiment. Low values (between 220 and 300) in the early cycles are attributed to preferential weathering of Cd-rich wurtzite [Zn,Fe)S] and sequestration of Zn in preference to Cd in secondary Fe phases forming in the columns. In the middle cycles, dissolution of secondary Fe(OH)3 under low pH (< 3) conditions, and of ferroan (Cd-poor) sphalerite [Zn,Fe)S], releases Zn and raises the Zn/Cd ratio to 550–600 in the tailings-only columns and up to 1500 in the mixed tailings-soil columns. The very high ratios in the latter are also ascribed to the formation of low molecular weight organic ligands that have high affinity for Zn over Cd. In the later column-cycles, Zn/Cd ratios return to near-initial values, due to the weathering of Fe-poor sphalerite and secondary Fe phases, and the declining preference of Zn over Cd in the soil organic acids under the strongly acidic conditions prevailing in the columns. The formation and dissolution of secondary soluble sulphate minerals also play a role in Cd and Zn cycling, especially at the beginning of the experiment

Major and trace metal mobility during weathering of mine tailings: implications for floodplain soils

Mine tailings discharged to river systems have the potential to release significant quantities of major and trace metals to waters and soils when weathered. To provide data on the mechanisms and magnitudes of short- and long-term tailings weathering and its influence on floodplain environments, three calendar year-long column leaching experiments that incorporated tailings from Potosí, Bolivia, and soil from affected downstream floodplains, were carried out. These experiments were designed to model 20 cycles of wet and dry season conditions. Two duplicate columns modeled sub-aerial tailings weathering alone, a third modeled the effects of long-term floodplain tailings contamination and a fourth modeled that of a tailings dam spill on a previously contaminated floodplain. As far as was practical local climatic conditions were modeled. Chemical analysis of the leachate and column solids, optical mineralogy, XRD, SEM, EPMA, BCR and water-soluble chemical extractions and speciation modeling were carried out to determine the processes responsible for the leaching of Al, Ca, Cu, K, Na, Mg, Mn, Sn, Sr and Ti. Over the 20 cycles, the pH declined to a floor of ca. 2 in all columns. Calcium, Cu, Mg, Mn and Na showed significant cumulative losses of up to 100%, 60%, 30%, 95% and 40%, respectively, compared to those of Al, K, Sr, Sn and Ti, which were up to 3%, 1.5%, 5%, 1% and 0.05%, respectively. The high losses are attributed to the dissolution of relatively soluble minerals such as biotite, and oxidation of chalcopyrite and Cu-sulfosalts, while low losses are attributed to the presence of sparingly soluble minerals such as svanbergite, cassiterite and rutile. These results strongly suggest that the release of tailings to floodplains should be limited or prohibited, and that all tailings should be removed from floodplains following dam spills

Future climate and environmental change within the Derwent Valley Mills World Heritage Site

Current news reports are demonstrating the severe impact that extreme climatic events are beginning to have on infrastructure, communities and the wider environment, including historic assets. Both empirical evidence and computer simulation modelling suggest that these problems will be exacerbated under future UK climate scenarios. In addition to the direct impacts of climate change, empirical evidence, particularly from elsewhere in the upland and piedmont regions of the UK, suggests that the legacy of environmental pollution associated with past base-metal mining, which is itself an historic artefact, may well exacerbate the impacts. In the light of potential future climatic change, exacerbated by the environmental impacts of industrial activities, this project has sought to examine the nature of possible environmental and geomorphological landscape transformations along an approximately 24km stretch of the River Derwent, Derbyshire and the potential impact on the globally important historic assets of the Derwent Valley Mills World Heritage Site (DVMWHS) and its designated Buffer Zone (Derwent Valley Mills Partnership 2011, 4). The project has drawn together a range of historical, geomorphological and environmental datasets to assess past landscape change within the valley floor during the last millennium: a timescale encompassing the last two episodes of well-documented major climatic instability (namely the Medieval Warm Period [MWP; c.900-1300] and the Little Ice Age [LIA]; c.1450-1850). This empirical data has been supplemented by numerical modelling of valley floor evolution to identify areas potentially vulnerable to future climate change, with results from both empirical and modelling studies being compared to existing knowledge of historic environment assets amassed in the Derbyshire Historic Environment Record (HER). The outputs of the project have directly informed the developing Research Framework for the Derwent Valley Mills World Heritage Site1 and in particular Theme 10 (Landscape and Environment). It has also built upon points raised in Section 13 (Environmental and Climate Change Issues) of the recently developed Management Plan for the DVMWHS (Derbyshire County Council, 2013). The research outputs of this project provide wider generic lessons for the management of historic assets in the light of future climate change, not only associated with World Heritage Sites but also the historic environment more widely