Reporting all results efficiently: A RARE proposal to open up the file drawer.

While the social sciences have made impressive progress in adopting transparent research practices that facilitate verification, replication, and reuse of materials, the problem of publication bias persists. Bias on the part of peer reviewers and journal editors, as well as the use of outdated research practices by authors, continues to skew literature toward statistically significant effects, many of which may be false positives. To mitigate this bias, we propose a framework to enable authors to report all results efficiently (RARE), with an initial focus on experimental and other prospective empirical social science research that utilizes public study registries. This framework depicts an integrated system that leverages the capacities of existing infrastructure in the form of public registries, institutional review boards, journals, and granting agencies, as well as investigators themselves, to efficiently incentivize full reporting and thereby, improve confidence in social science findings. In addition to increasing access to the results of scientific endeavors, a well-coordinated research ecosystem can prevent scholars from wasting time investigating the same questions in ways that have not worked in the past and reduce wasted funds on the part of granting agencies.

Response of barren-ground caribou to advancing spring phenology.

Phenological shifts are occurring in many ecosystems around the world. The capacity of species to adapt to changing phenology will be critical to their success under climate change scenarios. Failure to adjust migratory and reproductive timing to keep pace with the earlier onset of spring has led to negative demographic effects for populations of species across a variety of taxa. For caribou, there have been concerns that earlier spring green-up on calving areas might not be matched by earlier migration and parturition, potentially leading to a trophic mismatch with nutritional consequences for parturient and lactating caribou cows. However, there is limited evidence supporting these concerns. Here, we investigate the response of barren-ground caribou to changing spring phenology using data from telemetry and satellite imagery. From 2004 to 2016, we found that the average start of green-up on the calving area advanced by 7.25 days, while the start of migration advanced by 13.64 days, the end of migration advanced by 6.02 days, and the date of peak calving advanced by 9.42 days. Despite the advancing onset of green-up, we found no evidence for the development of a trophic mismatch because the advancing green-up coincided with earlier migration and calving by caribou. Changing snow cover on the late winter and migratory ranges was the most supported driver of advancing migratory behavior. The ability of caribou to adjust the timing of migratory and reproductive behavior in response to changing environmental conditions demonstrates the potential resilience of the species to some aspects of climate change.

Phenology and species determine growing-season albedo increase at the altitudinal limit of shrub growth in the sub-Arctic.

Arctic warming is resulting in reduced snow cover and increased shrub growth, both of which have been associated with altered land surface-atmospheric feedback processes involving sensible heat flux, ground heat flux and biogeochemical cycling. Using field measurements, we show that two common Arctic shrub species (Betula glandulosa and Salix pulchra), which are largely responsible for shrub encroachment in tundra, differed markedly in albedo and that albedo of both species increased as growing season progressed when measured at their altitudinal limit. A moveable apparatus was used to repeatedly measure albedo at six precise spots during the summer of 2012, and resampled in 2013. Contrary to the generally accepted view of shrub-covered areas having low albedo in tundra, full-canopy prostrate B. glandulosa had almost the highest albedo of all surfaces measured during the peak of the growing season. The higher midsummer albedo is also evident in localized MODIS albedo aggregated from 2000 to 2013, which displays a similar increase in growing-season albedo. Using our field measurements, we show the ensemble summer increase in tundra albedo counteracts the generalized effect of earlier spring snow melt on surface energy balance by approximately 40%. This summer increase in albedo, when viewed in absolute values, is as large as the difference between the forest and tundra transition. These results indicate that near future (<50 years) changes in growing-season albedo related to Arctic vegetation change are unlikely to be particularly large and might constitute a negative feedback to climate warming in certain circumstances. Future efforts to calculate energy budgets and a sensible heating feedback in the Arctic will require more detailed information about the relative abundance of different ground cover types, particularly shrub species and their respective growth forms and phenology.

Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation.

A remarkable characteristic of the human major histocompatibility complex (MHC) is its extreme genetic diversity, which is maintained by balancing selection. In fact, the MHC complex remains one of the best-known examples of natural selection in humans, with well-established genetic signatures and biological mechanisms for the action of selection. Here, we present genetic and functional evidence that another gene with a fundamental role in MHC class I presentation, endoplasmic reticulum aminopeptidase 2 (ERAP2), has also evolved under balancing selection and contains a variant that affects antigen presentation. Specifically, genetic analyses of six human populations revealed strong and consistent signatures of balancing selection affecting ERAP2. This selection maintains two highly differentiated haplotypes (Haplotype A and Haplotype B), with frequencies 0.44 and 0.56, respectively. We found that ERAP2 expressed from Haplotype B undergoes differential splicing and encodes a truncated protein, leading to nonsense-mediated decay of the mRNA. To investigate the consequences of ERAP2 deficiency on MHC presentation, we correlated surface MHC class I expression with ERAP2 genotypes in primary lymphocytes. Haplotype B homozygotes had lower levels of MHC class I expressed on the surface of B cells, suggesting that naturally occurring ERAP2 deficiency affects MHC presentation and immune response. Interestingly, an ERAP2 paralog, endoplasmic reticulum aminopeptidase 1 (ERAP1), also shows genetic signatures of balancing selection. Together, our findings link the genetic signatures of selection with an effect on splicing and a cellular phenotype. Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection.

Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data.

Demographic models built from genetic data play important roles in illuminating prehistorical events and serving as null models in genome scans for selection. We introduce an inference method based on the joint frequency spectrum of genetic variants within and between populations. For candidate models we numerically compute the expected spectrum using a diffusion approximation to the one-locus, two-allele Wright-Fisher process, involving up to three simultaneous populations. Our approach is a composite likelihood scheme, since linkage between neutral loci alters the variance but not the expectation of the frequency spectrum. We thus use bootstraps incorporating linkage to estimate uncertainties for parameters and significance values for hypothesis tests. Our method can also incorporate selection on single sites, predicting the joint distribution of selected alleles among populations experiencing a bevy of evolutionary forces, including expansions, contractions, migrations, and admixture. We model human expansion out of Africa and the settlement of the New World, using 5 Mb of noncoding DNA resequenced in 68 individuals from 4 populations (YRI, CHB, CEU, and MXL) by the Environmental Genome Project. We infer divergence between West African and Eurasian populations 140 thousand years ago (95% confidence interval: 40-270 kya). This is earlier than other genetic studies, in part because we incorporate migration. We estimate the European (CEU) and East Asian (CHB) divergence time to be 23 kya (95% c.i.: 17-43 kya), long after archeological evidence places modern humans in Europe. Finally, we estimate divergence between East Asians (CHB) and Mexican-Americans (MXL) of 22 kya (95% c.i.: 16.3-26.9 kya), and our analysis yields no evidence for subsequent migration. Furthermore, combining our demographic model with a previously estimated distribution of selective effects among newly arising amino acid mutations accurately predicts the frequency spectrum of nonsynonymous variants across three continental populations (YRI, CHB, CEU).

Vegetation type is an important predictor of the arctic summer land surface energy budget.

Despite the importance of high-latitude surface energy budgets (SEBs) for land-climate interactions in the rapidly changing Arctic, uncertainties in their prediction persist. Here, we harmonize SEB observations across a network of vegetated and glaciated sites at circumpolar scale (1994-2021). Our variance-partitioning analysis identifies vegetation type as an important predictor for SEB-components during Arctic summer (June-August), compared to other SEB-drivers including climate, latitude and permafrost characteristics. Differences among vegetation types can be of similar magnitude as between vegetation and glacier surfaces and are especially high for summer sensible and latent heat fluxes. The timing of SEB-flux summer-regimes (when daily mean values exceed 0 Wm-2) relative to snow-free and -onset dates varies substantially depending on vegetation type, implying vegetation controls on snow-cover and SEB-flux seasonality. Our results indicate complex shifts in surface energy fluxes with land-cover transitions and a lengthening summer season, and highlight the potential for improving future Earth system models via a refined representation of Arctic vegetation types.

Natural selection on protein-coding genes in the human genome.

Comparisons of DNA polymorphism within species to divergence between species enables the discovery of molecular adaptation in evolutionarily constrained genes as well as the differentiation of weak from strong purifying selection. The extent to which weak negative and positive darwinian selection have driven the molecular evolution of different species varies greatly, with some species, such as Drosophila melanogaster, showing strong evidence of pervasive positive selection, and others, such as the selfing weed Arabidopsis thaliana, showing an excess of deleterious variation within local populations. Here we contrast patterns of coding sequence polymorphism identified by direct sequencing of 39 humans for over 11,000 genes to divergence between humans and chimpanzees, and find strong evidence that natural selection has shaped the recent molecular evolution of our species. Our analysis discovered 304 (9.0%) out of 3,377 potentially informative loci showing evidence of rapid amino acid evolution. Furthermore, 813 (13.5%) out of 6,033 potentially informative loci show a paucity of amino acid differences between humans and chimpanzees, indicating weak negative selection and/or balancing selection operating on mutations at these loci. We find that the distribution of negatively and positively selected genes varies greatly among biological processes and molecular functions, and that some classes, such as transcription factors, show an excess of rapidly evolving genes, whereas others, such as cytoskeletal proteins, show an excess of genes with extensive amino acid polymorphism within humans and yet little amino acid divergence between humans and chimpanzees.

Assessing the evolutionary impact of amino acid mutations in the human genome.

Quantifying the distribution of fitness effects among newly arising mutations in the human genome is key to resolving important debates in medical and evolutionary genetics. Here, we present a method for inferring this distribution using Single Nucleotide Polymorphism (SNP) data from a population with non-stationary demographic history (such as that of modern humans). Application of our method to 47,576 coding SNPs found by direct resequencing of 11,404 protein coding-genes in 35 individuals (20 European Americans and 15 African Americans) allows us to assess the relative contribution of demographic and selective effects to patterning amino acid variation in the human genome. We find evidence of an ancient population expansion in the sample with African ancestry and a relatively recent bottleneck in the sample with European ancestry. After accounting for these demographic effects, we find strong evidence for great variability in the selective effects of new amino acid replacing mutations. In both populations, the patterns of variation are consistent with a leptokurtic distribution of selection coefficients (e.g., gamma or log-normal) peaked near neutrality. Specifically, we predict 27-29% of amino acid changing (nonsynonymous) mutations are neutral or nearly neutral (|s|<0.01%), 30-42% are moderately deleterious (0.01%<|s|<1%), and nearly all the remainder are highly deleterious or lethal (|s|>1%). Our results are consistent with 10-20% of amino acid differences between humans and chimpanzees having been fixed by positive selection with the remainder of differences being neutral or nearly neutral. Our analysis also predicts that many of the alleles identified via whole-genome association mapping may be selectively neutral or (formerly) positively selected, implying that deleterious genetic variation affecting disease phenotype may be missed by this widely used approach for mapping genes underlying complex traits.

Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland.

OBJECTIVE: To measure the UK and Ireland incidence of childhood (<15 years) thyrotoxicosis and to describe the presenting features. CONTEXT: Incidence data on thyrotoxicosis in childhood are not available for the UK and Ireland. Recent studies have reported an apparent increase in cases in Europe. DESIGN: A national prospective surveillance study for 12 months from September 2004, co-ordinated by The British Paediatric Surveillance Unit (BPSU). PATIENTS AND MEASUREMENTS: All paediatricians across the UK and Ireland were requested monthly to report new cases. Details of presenting features were then obtained by questionnaire. RESULTS: One hundred ten cases of acquired childhood thyrotoxicosis were identified in the UK and Ireland. The incidence of acquired thyrotoxicosis was 0.9 per 100,000 <15 years olds in the UK and Ireland, (95% CI: 0.8-1.1). Autoimmune thyrotoxicosis accounted for 96% of cases. There was an increasing incidence with age in each sex. Females have a significantly higher incidence than males in the 10- to 14-year age group. A variety of presenting symptoms were reported: weight loss (64%), fatigue/tiredness (54%), change in behaviour' (50%) and heat intolerance (47%). 4.5 % cases were asymptomatic. The commonest signs were goitre (78%) and tremor (58%). There were no cases of thyroid storm. CONCLUSIONS: This national population survey defines the incidence of thyrotoxicosis in children in the UK and Ireland during 2004-2005, which was lower than expected in comparison with other European studies. The survey illustrates contemporary presenting characteristics of the disease.

Localizing recent adaptive evolution in the human genome.

Identifying genomic locations that have experienced selective sweeps is an important first step toward understanding the molecular basis of adaptive evolution. Using statistical methods that account for the confounding effects of population demography, recombination rate variation, and single-nucleotide polymorphism ascertainment, while also providing fine-scale estimates of the position of the selected site, we analyzed a genomic dataset of 1.2 million human single-nucleotide polymorphisms genotyped in African-American, European-American, and Chinese samples. We identify 101 regions of the human genome with very strong evidence (p < 10(-5)) of a recent selective sweep and where our estimate of the position of the selective sweep falls within 100 kb of a known gene. Within these regions, genes of biological interest include genes in pigmentation pathways, components of the dystrophin protein complex, clusters of olfactory receptors, genes involved in nervous system development and function, immune system genes, and heat shock genes. We also observe consistent evidence of selective sweeps in centromeric regions. In general, we find that recent adaptation is strikingly pervasive in the human genome, with as much as 10% of the genome affected by linkage to a selective sweep.

Global dissemination of a single mutation conferring white pericarp in rice.

Here we report that the change from the red seeds of wild rice to the white seeds of cultivated rice (Oryza sativa) resulted from the strong selective sweep of a single mutation, a frame-shift deletion within the Rc gene that is found in 97.9% of white rice varieties today. A second mutation, also within Rc, is present in less than 3% of white accessions surveyed. Haplotype analysis revealed that the predominant mutation originated in the japonica subspecies and crossed both geographic and sterility barriers to move into the indica subspecies. A little less than one Mb of japonica DNA hitchhiked with the rc allele into most indica varieties, suggesting that other linked domestication alleles may have been transferred from japonica to indica along with white pericarp color. Our finding provides evidence of active cultural exchange among ancient farmers over the course of rice domestication coupled with very strong, positive selection for a single white allele in both subspecies of O. sativa.

Genome-wide patterns of nucleotide polymorphism in domesticated rice.

Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i) selectively neutral population bottleneck model, (ii) bottleneck plus migration model, (iii) multiple selective sweeps model, and (iv) bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation.

A Markov chain Monte Carlo approach for joint inference of population structure and inbreeding rates from multilocus genotype data.

Nonrandom mating induces correlations in allelic states within and among loci that can be exploited to understand the genetic structure of natural populations (Wright 1965). For many species, it is of considerable interest to quantify the contribution of two forms of nonrandom mating to patterns of standing genetic variation: inbreeding (mating among relatives) and population substructure (limited dispersal of gametes). Here, we extend the popular Bayesian clustering approach STRUCTURE (Pritchard et al. 2000) for simultaneous inference of inbreeding or selfing rates and population-of-origin classification using multilocus genetic markers. This is accomplished by eliminating the assumption of Hardy-Weinberg equilibrium within clusters and, instead, calculating expected genotype frequencies on the basis of inbreeding or selfing rates. We demonstrate the need for such an extension by showing that selfing leads to spurious signals of population substructure using the standard STRUCTURE algorithm with a bias toward spurious signals of admixture. We gauge the performance of our method using extensive coalescent simulations and demonstrate that our approach can correct for this bias. We also apply our approach to understanding the population structure of the wild relative of domesticated rice, Oryza rufipogon, an important partially selfing grass species. Using a sample of n = 16 individuals sequenced at 111 random loci, we find strong evidence for existence of two subpopulations, which correlates well with geographic location of sampling, and estimate selfing rates for both groups that are consistent with estimates from experimental data (s approximately 0.48-0.70).

Spring warming in Yukon mountains is not amplified by the snow albedo feedback.

Decreasing spring snow cover may amplify Arctic warming through the snow albedo feedback. To examine the impact of snowmelt on increasing temperature we used a 5,000 m elevation gradient in Yukon, Canada, extending from valley-bottom conifer forests, through middle elevation tundra, to high elevation icefields, to compare validated downscaled reanalysis air temperature patterns across elevational bands characterized by different patterns of spring snowmelt. From 2000 to 2014 we observed surface warming of 0.01 °C/a·1,000 m in May (0.14 °C/a at 1,000 m to 0.19 °C/a at 5,000 m), and uniform cooling of 0.09 °C/a in June at all elevations. May temperature trends across elevationally dependent land cover types were highly correlated with each other despite large variations in albedo and snow cover trends. Furthermore, a clear dependency of infrared skin temperature on snow cover mediated albedo decline was observed in tundra, but this was insufficient to influence average diurnal air temperature. We observed negative June temperature trends which we attribute to increasing daytime cloud cover because albedo and snow cover trends were unchanging. We conclude that 8-day and monthly averaged Spring air temperature trends are responding to a synoptic external forcing that is much stronger than the snow albedo feedback in sub-Arctic mountains.

Long-term outcome of thyrotoxicosis in childhood and adolescence in the west of Scotland: the case for long-term antithyroid treatment and the importance of initial counselling.

BACKGROUND: Thyrotoxicosis is both rarer and more severe in children than in adults, rendering management difficult and often unsatisfactory. OBJECTIVE: To ascertain outcome in a geographically defined area of Scotland between 1989 and 2014. METHOD: Retrospective case note review with follow-up questionnaire to family doctors for patients with Graves' disease and Hashimoto's thyroiditis. RESULTS: Sixty-six patients (58 females:8 males) comprising 53 with Graves' disease and 13 with Hashimoto's thyroiditis were diagnosed at median 10.4 (2.9-15.8) years and followed up for 11.8 (2.6-30.2) years. Antithyroid drug (ATD) therapy was stopped electively in 35 patients after 4.5 (1.5-8.6) years, resulting in remission in 10/13 Hashimoto's thyroiditis and 10/22 Graves' disease. Side effects occurred in 12 patients receiving carbimazole, six of whom changed to propylthiouracil; no adverse events occurred in the latter patients.Second-line therapy was given to 37 patients (34 with Graves' disease), comprising radioiodine (22) at 15.6 (9.3-24.4) years for relapse (6), poor control/adherence (14) or electively (2); and surgery (16) at 12 (6.4-21.3) years for relapse (4), poor control/adherence (5) and electively (7). Adherence problems with thyroxine replacement were reported in 10/33 patients in adulthood. CONCLUSIONS: Hashimoto's thyroiditis should be distinguished from Graves' disease at diagnosis since the prognosis for remission is better. Remission rates for Graves' disease are low (10/53 patients), time to remission variable and adherence with both ATD and thyroxine replacement often problematic. We recommend (a) the giving of long-term ATD rather than a fixed course of treatment in GD and (b) meticulous and realistic counselling of families from the time of diagnosis onwards.

Moss Mediates the Influence of Shrub Species on Soil Properties and Processes in Alpine Tundra.

In tundra ecosystems, bryophytes influence soil processes directly and indirectly through interactions with overstory shrub species. We experimentally manipulated moss cover and measured seasonal soil properties and processes under two species of deciduous shrubs with contrasting canopy structures, Salix planifolia pulchra and Betula glandulosa-nana complex. Soil properties (seasonal temperature, moisture and C:N ratios) and processes (seasonal litter decomposition and soil respiration) were measured over twelve months. Shrub species identity had the largest influence on summer soil temperatures and soil respiration rates, which were higher under Salix canopies. Mosses were associated with lower soil moisture irrespective of shrub identity, but modulated the effects of shrubs on winter soil temperatures and soil C:N ratios so that moss cover reduced differences in soil winter temperatures between shrub species and reduced C:N ratios under Betula but not under Salix canopies. Our results suggest a central role of mosses in mediating soil properties and processes, with their influence depending on shrub species identity. Such species-dependent effects need to be accounted for when forecasting vegetation dynamics under ongoing environmental changes.

Changing Arctic snow cover: A review of recent developments and assessment of future needs for observations, modelling, and impacts.

Snow is a critically important and rapidly changing feature of the Arctic. However, snow-cover and snowpack conditions change through time pose challenges for measuring and prediction of snow. Plausible scenarios of how Arctic snow cover will respond to changing Arctic climate are important for impact assessments and adaptation strategies. Although much progress has been made in understanding and predicting snow-cover changes and their multiple consequences, many uncertainties remain. In this paper, we review advances in snow monitoring and modelling, and the impact of snow changes on ecosystems and society in Arctic regions. Interdisciplinary activities are required to resolve the current limitations on measuring and modelling snow characteristics through the cold season and at different spatial scales to assure human well-being, economic stability, and improve the ability to predict manage and adapt to natural hazards in the Arctic region.

Population genetics of polymorphism and divergence for diploid selection models with arbitrary dominance.

We develop a Poisson random-field model of polymorphism and divergence that allows arbitrary dominance relations in a diploid context. This model provides a maximum-likelihood framework for estimating both selection and dominance parameters of new mutations using information on the frequency spectrum of sequence polymorphisms. This is the first DNA sequence-based estimator of the dominance parameter. Our model also leads to a likelihood-ratio test for distinguishing nongenic from genic selection; simulations indicate that this test is quite powerful when a large number of segregating sites are available. We also use simulations to explore the bias in selection parameter estimates caused by unacknowledged dominance relations. When inference is based on the frequency spectrum of polymorphisms, genic selection estimates of the selection parameter can be very strongly biased even for minor deviations from the genic selection model. Surprisingly, however, when inference is based on polymorphism and divergence (McDonald-Kreitman) data, genic selection estimates of the selection parameter are nearly unbiased, even for completely dominant or recessive mutations. Further, we find that weak overdominant selection can increase, rather than decrease, the substitution rate relative to levels of polymorphism. This nonintuitive result has major implications for the interpretation of several popular tests of neutrality.

Reaction-diffusion models of within-feather pigmentation patterning.

Feathers are complex, branched keratin structures that exhibit a diversity of pigmentation patterns. Feather pigments are transferred into developing feather keratinocytes from pigment cells that migrate into the tubular feather germ from the dermis. Within-feather pigment patterns are determined by differential pigmentation of keratinocytes within independent barb ridges during feather development. Little is known about the molecular mechanisms that determine which keratinocytes receive pigment. We apply reaction-diffusion models to the growth of within-feather pigment patterns based on a realistic model of feather growth. These models accurately simulate the growth of a diversity of the within-feather pigmentation patterns found in real feathers, including a central patch, a 'hollow' central patch, concentric central patches, bars, chevrons, a central circular spot, rows of paired spots, and arrays of offset dots. The models can also simulate the complex transitions between distinct pigmentation patterns among feathers observed in real avian plumages, including transitions from bars to chevrons, bars to paired dots, and bars to arrays of dots. The congruence between the developmental dynamics of the simulated and observed feather patterns indicates that the reaction-diffusion models provide a realistic and accurate description of the determination of pigment pattern within avian feather follicles. The models support the hypothesis that within-feather pigmentation patterning is determined by antagonistic interactions among molecular expression gradients within the tubular follicle and feather germ.