Rare variants contribute disproportionately to quantitative trait variation in yeast.

How variants with different frequencies contribute to trait variation is a central question in genetics. We use a unique model system to disentangle the contributions of common and rare variants to quantitative traits. We generated ~14,000 progeny from crosses among 16 diverse yeast strains and identified thousands of quantitative trait loci (QTLs) for 38 traits. We combined our results with sequencing data for 1011 yeast isolates to show that rare variants make a disproportionate contribution to trait variation. Evolutionary analyses revealed that this contribution is driven by rare variants that arose recently, and that negative selection has shaped the relationship between variant frequency and effect size. We leveraged the structure of the crosses to resolve hundreds of QTLs to single genes. These results refine our understanding of trait variation at the population level and suggest that studies of rare variants are a fertile ground for discovery of genetic effects

Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p

Automated conjecturing II : chomp and reasoned game play

We demonstrate the use of a program that generates conjectures about positions of the combinatorial game Chomp—explanations of why certain moves are bad. These could be used in the design of a Chomp-playing program that gives reasons for its moves. We prove one of these Chomp conjectures—demonstrating that our conjecturing program can produce genuine Chomp knowledge. The conjectures are generated by a general purpose conjecturing program that was previously and successfully used to generate mathematical conjectures. Our program is initialized with Chomp invariants and example game boards—the conjectures take the form of invariant-relation statements interpreted to be true for all board positions of a certain kind. The conjectures describe a theory of Chomp positions. The program uses limited, natural input and suggests how theories generated on-the-fly might be used in a variety of situations where decisions—based on reasons—are required

Analysis of the giant genomes of Fritillaria (Liliaceae) indicates that a lack of DNA removal characterizes extreme expansions in genome size.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Plants exhibit an extraordinary range of genome sizes, varying by > 2000-fold between the smallest and largest recorded values. In the absence of polyploidy, changes in the amount of repetitive DNA (transposable elements and tandem repeats) are primarily responsible for genome size differences between species. However, there is ongoing debate regarding the relative importance of amplification of repetitive DNA versus its deletion in governing genome size. Using data from 454 sequencing, we analysed the most repetitive fraction of some of the largest known genomes for diploid plant species, from members of Fritillaria. We revealed that genomic expansion has not resulted from the recent massive amplification of just a handful of repeat families, as shown in species with smaller genomes. Instead, the bulk of these immense genomes is composed of highly heterogeneous, relatively low-abundance repeat-derived DNA, supporting a scenario where amplified repeats continually accumulate due to infrequent DNA removal. Our results indicate that a lack of deletion and low turnover of repetitive DNA are major contributors to the evolution of extremely large genomes and show that their size cannot simply be accounted for by the activity of a small number of high-abundance repeat families.Thiswork was supported by the Natural Environment ResearchCouncil (grant no. NE/G017 24/1), the Czech Science Fou nda-tion (grant no. P501/12/G090), the AVCR (grant no.RVO:60077344) and a Beatriu de Pinos postdoctoral fellowshipto J.P. (grant no. 2011-A-00292; Catalan Government-E.U. 7thF.P.)

Patterns of Ecosystem Structure and Wildfire Carbon Combustion Across Six Ecoregions of the North American Boreal Forest

Increases in fire frequency, extent, and severity are expected to strongly impact the structure and function of boreal forest ecosystems. An important function of the boreal forest is its ability to sequester and store carbon (C). Increasing disturbance from wildfires, emitting large amounts of C to the atmosphere, may create a positive feedback to climate warming. Variation in ecosystem structure and function throughout the boreal forest is important for predicting the effects of climate warming and changing fire regimes on C dynamics. In this study, we compiled data on soil characteristics, stand structure, pre-fire C pools, C loss from fire, and the potential drivers of these C metrics from 527 sites distributed across six ecoregions of North America’s western boreal forests. We assessed structural and functional differences between these fire-prone ecoregions using data from 417 recently burned sites (2004–2015) and estimated ecoregion-specific relationships between soil characteristics and depth from 167 of these sites plus an additional 110 sites (27 burned, 83 unburned). We found that northern boreal ecoregions were generally older, stored and emitted proportionally more belowground than aboveground C, and exhibited lower rates of C accumulation over time than southern ecoregions. We present ecoregion-specific estimates of depth-wise soil characteristics that are important for predicting C combustion from fire. As climate continues to warm and disturbance from wildfires increases, the C dynamics of these fire-prone ecoregions are likely to change with significant implications for the global C cycle and its feedbacks to climate change

Linear and nonlinear effects of temperature and precipitation on ecosystem properties in tidal saline wetlands

Climate greatly influences the structure and functioning of tidal saline wetland ecosystems. However, there is a need to better quantify the effects of climatic drivers on ecosystem properties, particularly near climate-sensitive ecological transition zones. Here, we used climate- and literature-derived ecological data from tidal saline wetlands to test hypotheses regarding the influence of climatic drivers (i.e., temperature and precipitation regimes) on the following six ecosystem properties: canopy height, biomass, productivity, decomposition, soil carbon density, and soil carbon accumulation. Our analyses quantify and elucidate linear and nonlinear effects of climatic drivers. We quantified positive linear relationships between temperature and above-ground productivity and strong positive nonlinear (sigmoidal) relationships between (1) temperature and above-ground biomass and canopy height and (2) precipitation and canopy height. Near temperature-controlled mangrove range limits, small changes in temperature are expected to trigger comparatively large changes in biomass and canopy height, as mangrove forests grow, expand, and, in some cases, replace salt marshes. However, within these same transition zones, temperature- induced changes in productivity are expected to be comparatively small. Interestingly, despite the significant above-ground height, biomass, and productivity relationships across the tropical–temperate mangrove–marsh transition zone, the relationships between temperature and soil carbon density or soil carbon accumulation were not significant. Our literature review identifies several ecosystem properties and many regions of the world for which there are insufficient data to fully evaluate the influence of climatic drivers, and the identified data gaps can be used by scientists to guide future research. Our analyses indicate that near precipitation-controlled transition zones, small changes in precipitation are expected to trigger comparatively large changes in canopy height. However, there are scant data to evaluate the influence of precipitation on other ecosystem properties. There is a need for more decomposition data across climatic gradients, and to advance understanding of the influence of changes in precipitation and freshwater availability, additional ecological data are needed from tidal saline wetlands in arid climates. Collectively, our results can help scientists and managers better anticipate the linear and nonlinear ecological consequences of climate change for coastal wetlands

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1)

OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075

Physical restraint in residential child care : the experiences of young people and residential workers

There have long been concerns about the use of physical restraint in residential care. This paper presents the findings of a qualitative study which explores the experiences of children, young people and residential workers about physical restraint. The research identifies the dilemmas and ambiguities for both staff and young people, and participants discuss the situations where they feel physical restraint is appropriate as well as their concerns about unjustified or painful restraints. They describe the negative emotions involved in restraint but also those situations where, through positive relationships and trust, restraint can help young people through unsafe situations

Climate and plant controls on soil organic matter in coastal wetlands

Coastal wetlands are among the most productive and carbon‐rich ecosystems on Earth. Long‐term carbon storage in coastal wetlands occurs primarily belowground as soil organic matter (SOM). In addition to serving as a carbon sink, SOM influences wetland ecosystem structure, function, and stability. To anticipate and mitigate the effects of climate change, there is a need to advance understanding of environmental controls on wetland SOM. Here, we investigated the influence of four soil formation factors: climate, biota, parent materials, and topography. Along the northern Gulf of Mexico, we collected wetland plant and soil data across elevation and zonation gradients within 10 estuaries that span broad temperature and precipitation gradients. Our results highlight the importance of climate–plant controls and indicate that the influence of elevation is scale and location dependent. Coastal wetland plants are sensitive to climate change; small changes in temperature or precipitation can transform coastal wetland plant communities. Across the region, SOM was greatest in mangrove forests and in salt marshes dominated by graminoid plants. SOM was lower in salt flats that lacked vascular plants and in salt marshes dominated by succulent plants. We quantified strong relationships between precipitation, salinity, plant productivity, and SOM. Low precipitation leads to high salinity, which limits plant productivity and appears to constrain SOM accumulation. Our analyses use data from the Gulf of Mexico, but our results can be related to coastal wetlands across the globe and provide a foundation for predicting the ecological effects of future reductions in precipitation and freshwater availability. Coastal wetlands provide many ecosystem services that are SOM dependent and highly vulnerable to climate change. Collectively, our results indicate that future changes in SOM and plant productivity, regulated by cascading effects of precipitation on freshwater availability and salinity, could impact wetland stability and affect the supply of some wetland ecosystem services