Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.

Two novel antibiotic resistance genes, tet(44) and ant(6)-Ib, are located within a transferable pathogenicity island in Campylobacter fetus subsp. fetus

New tetracycline and streptomycin resistance genes, tet(44) and ant(6)-Ib, were identified in Campylobacter fetus subsp. fetus within a transferable pathogenicity island that is typically unique to Campylobacter fetus subsp. venerealis. The 640-amino-acid tetracycline resistance determinant, Tet 44, belongs to a class of proteins that confers resistance to tetracycline and minocycline by ribosomal protection. The 286-amino-acid streptomycin resistance determinant, ANT(6)-Ib, belongs to a family of aminoglycoside nucleotidyltransferases. The resistance phenotypes were demonstrated by gene inactivation and expression.

Temporal and spatial variation of nitrogen transformations in nitrogen-saturated soils of a central Appalachian hardwood forest

We studied temporal and spatial patterns of soil nitrogen (N) dynamics from 1993 to 1995 in three watersheds of Fernow Experimental Forest, W.V.: WS7 (24-year-old, untreated); WS4 (mature, untreated); and WS3 (24-year-old, treated with (NH4)2SO since 1989 at the rate of 35 kg Nha–1year–1). Net nitrification was 141, 114, and115 kg Nha–1year–1, for WS3, WS4, and WS7, respectively, essentially 100% of net N mineralization for all watersheds. Temporal (seasonal) patterns of nitrification were significantly related to soil moisture and ambient temperaturein untreated watersheds only. Spatial patterns of soil water NO3–of WS4 suggest that microenvironmental variabilitylimits rates of N processing in some areas of this N-saturated watershed, in part by ericaceous species in the herbaceous layer. Spatial patterns of soil water NO3–in treated WS3 suggest that later stages of N saturation may result inhigher concentrations with less spatial variability. Spatial variability in soil N variables was lower in treated WS3 versus untreated watersheds. Nitrogen additions have altered the response of N-processing microbes to environmental factors, becoming less sensitive to seasonal changes in soil moisture and temperature. Biotic processes responsible forregulating N dynamics may be compromised in N-saturated forest ecosystems.

Variation in human platelet glycoprotein VI content modulates glycoprotein VI-specific prothrombinase activity

- Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen that figures prominently in signal transduction. An addition to binding to type I and III collagens, GPVI is also bound specifically by collagen-related peptide and convulxin (CVX), a snake venom protein. We developed a quantitative assay of platelet GPVI in which biotin-conjugated CVX binds selectively to GPVI in separated total platelet proteins by a ligand blot procedure. Using this approach, we have documented a 5-fold range in platelet GPVI content among 23 normal healthy subjects. In addition, we have determined that CVX-induced or collagen-related peptide-induced prothrombinase activity is directly proportional to the platelet content of GPVI. A statistically significant correlation was observed at 2 CVX concentrations: 14.7 ng/mL (R(2)=0.854 and P<0.001, n=11) and 22 ng/mL (R(2)=0.776 and P<0.001, n=12). In previous studies, we established a similar range of expression of the integrin collagen receptor alpha(2)beta(1) on platelets of normal subjects. Among 15 donors, there is a direct correlation between platelet alpha(2)beta(1) density and GPVI content (R(2)=0.475 and P=0.004). In view of the well-documented association of GPVI with platelet procoagulant activity, this study suggests that the variation in GPVI content is a potential risk factor that may predispose individuals to hemorrhagic or thromboembolic disorders.

Investigating within-canopy variation of functional traits and cellular structure of sugar maple (Acer saccharum) leaves

Patterns of increasing leaf mass per area (LMA), area-based leaf nitrogen (Narea), and carbon isotope composition (δ13C) with increasing height in the canopy have been attributed to light gradients or hydraulic limitation in tall trees. Theoretical optimal distributions of LMA and Narea that scale with light maximize canopy photosynthesis; however, sub-optimal distributions are often observed due to hydraulic constraints on leaf development. Using observational, experimental, and modeling approaches, we investigated the response of leaf functional traits (LMA, density, thickness, and leaf nitrogen), leaf carbon isotope composition (δ13C), and cellular structure to light availability, height, and leaf water potential (Ψl) in an Acer saccharum forest to tease apart the influence of light and hydraulic limitations. LMA, leaf and palisade layer thickness, and leaf density were greater at greater light availability but similar heights, highlighting the strong control of light on leaf morphology and cellular structure. Experimental shading decreased both LMA and area-based leaf nitrogen (Narea) and revealed that LMA and Narea were more strongly correlated with height earlier in the growing season and with light later in the growing season. The supply of CO2 to leaves at higher heights appeared to be constrained by stomatal sensitivity to vapor pressure deficit (VPD) or midday leaf water potential, as indicated by increasing δ13C and VPD and decreasing midday Ψl with height. Model simulations showed that daily canopy photosynthesis was biased during the early growing season when seasonality was not accounted for, and was biased throughout the growing season when vertical gradients in LMA and Narea were not accounted for. Overall, our results suggest that leaves acclimate to light soon after leaf expansion, through an accumulation of leaf carbon, thickening of palisade layers and increased LMA, and reduction in stomatal sensitivity to Ψl or VPD. This period of light acclimation in leaves appears to optimize leaf function over time, despite height-related constraints early in the growing season. Our results imply that vertical gradients in leaf functional traits and leaf acclimation to light should be incorporated in canopy function models in order to refine estimates of canopy photosynthesis.

Tight Genetic Linkage of Prezygotic Barrier Loci Creates a Multifunctional Speciation Island in Petunia

Most flowering plants depend on animal vectors for pollination and seed dispersal. Differential pollinator preferences lead to premating isolation and thus reduced gene flow between interbreeding plant populations [1, 2, 3 and 4]. Sets of floral traits, adapted to attract specific pollinator guilds, are called pollination syndromes [5]. Shifts in pollination syndromes have occurred surprisingly frequently [6], considering that they must involve coordinated changes in multiple genes affecting multiple floral traits. Although the identification of individual genes specifying single pollination syndrome traits is in progress in many species, little is known about the genetic architecture of coadapted pollination syndrome traits and how they are embedded within the genome [7]. Here we describe the tight genetic linkage of loci specifying five major pollination syndrome traits in the genus Petunia: visible color, UV absorption, floral scent production, pistil length, and stamen length. Comparison with other Solanaceae indicates that, in P. exserta and P. axillaris, loci specifying these floral traits have specifically become clustered into a multifunctional “speciation island��� [ 8 and 9]. Such an arrangement promotes linkage disequilibrium and avoids the dissolution of pollination syndromes by recombination. We suggest that tight genetic linkage provides a mechanism for rapid switches between distinct pollination syndromes in response to changes in pollinator availabilities.

Falkland Island English

This chapter examines some of the grammatical variability and non-standardness found in the English of the Falkland Islands. The Falklands are an archipelago of over 700 islands located in the western South Atlantic Ocean, 480km off the east coast of Argentina. Although the population is small – around 3000 - the islands cover an area of over 12000km2 – slightly larger than Jamaica and half the size of Wales, making them, after Greenland, the most sparsely populated political entity in the world. In political terms, the Falklands are an Overseas Territory of the United Kingdom. In contrast to the rural isolated image that the Falklands perhaps conjure up, the community is, in demographic terms, an urban and diverse one. Over 85% of the population living in the capital Stanley. The 2006 census (Government of the Falkland Islands 2007: 6) shows that 55% of the population were not born on the Islands, with the largest migrant groups coming from the UK, St Helena (another British Overseas Territory, located in the eastern South Atlantic), Chile and Australia. It also highlighted the fact that people born in 62 different countries were resident on the islands at the time (Pascoe and Pepper 2008: 38). By way of a comparison, only Monaco and Andorra, in Europe, have a higher proportion of their populations made up of migrants. In addition to the local Falkland population, there is a large military presence on the islands at the Royal Airforce Base at Mount Pleasant, 50km south-west of Stanley. The Head of State is the monarch of the UK, who is represented on the islands by a governor. The democratically elected 11-member Legislative Assembly is responsible for day-to-day government of the islands. The Falklands are perhaps most famous because of their 74 day occupation by Argentina in 1982. It is not appropriate here to go into detail about the dispute between the UK and Argentina about the sovereignty of the Islands. What is undisputed is that there has been a continuous Anglophone speech community on the islands since the early 1830s, making it one of the most recently developed ‘Inner Circle’ (Kachru 1985) Englishes in the world. This chapter examines the grammatical characteristics of Falkland Island English, drawn from a transcribed corpus of over 500,000 words of informal conversational speech, collected by Andrea Sudbury both in Stanley and in ‘Camp’ (the local name for the rest of the islands) (see Sudbury 2000, 2001 for more details about the methods used in the survey).

Beyond the tree of texts: Building an empirical model of scribal variation through graph analysis of texts and stemmata

Stemmatology, or the reconstruction of the transmission history of texts, is a field that stands particularly to gain from digital methods. Many scholars already take stemmatic approaches that rely heavily on computational analysis of the collated text (e.g. Robinson and O’Hara 1996; Salemans 2000; Heikkilä 2005; Windram et al. 2008 among many others). Although there is great value in computationally assisted stemmatology, providing as it does a reproducible result and allowing access to the relevant methodological process in related fields such as evolutionary biology, computational stemmatics is not without its critics. The current state-of-the-art effectively forces scholars to choose between a preconceived judgment of the significance of textual differences (the Lachmannian or neo-Lachmannian approach, and the weighted phylogenetic approach) or to make no judgment at all (the unweighted phylogenetic approach). Some basis for judgment of the significance of variation is sorely needed for medieval text criticism in particular. By this, we mean that there is a need for a statistical empirical profile of the text-genealogical significance of the different sorts of variation in different sorts of medieval texts. The rules that apply to copies of Greek and Latin classics may not apply to copies of medieval Dutch story collections; the practices of copying authoritative texts such as the Bible will most likely have been different from the practices of copying the Lives of local saints and other commonly adapted texts. It is nevertheless imperative that we have a consistent, flexible, and analytically tractable model for capturing these phenomena of transmission. In this article, we present a computational model that captures most of the phenomena of text variation, and a method for analysis of one or more stemma hypotheses against the variation model. We apply this method to three ‘artificial traditions’ (i.e. texts copied under laboratory conditions by scholars to study the properties of text variation) and four genuine medieval traditions whose transmission history is known or deduced in varying degrees. Although our findings are necessarily limited by the small number of texts at our disposal, we demonstrate here some of the wide variety of calculations that can be made using our model. Certain of our results call sharply into question the utility of excluding ‘trivial’ variation such as orthographic and spelling changes from stemmatic analysis.