Generation of a neutral FST baseline for testing local adaptation on gill raker number within and between European whitefish ecotypes in the Baltic Sea basin

Divergent selection at ecologically important traits is thought to be a major factor driving phenotypic differentiation between populations. To elucidate the role of different evolutionary processes shaping the variation in gill raker number of European whitefish (Coregonus lavaretus sensu lato) in the Baltic Sea basin, we assessed the relationships between genetic and phenotypic variation among and within three whitefish ecotypes (sea spawners, river spawners and lake spawners). To generate expected neutral distribution of F_ST and to evaluate whether highly variable microsatellite loci resulted in deflated F_ST estimates compared to less variable markers, we performed population genetic simulations under finite island and hierarchical island models. The genetic divergence observed among (F_CT = 0.010) and within (F_ST = 0.014–0.041) ecotypes was rather low. The divergence in gill raker number, however, was substantially higher between sea and river spawners compared to observed microsatellite data and simulated neutral baseline (P_CT > F_CT). This suggests that the differences in gill raker number between sea and river spawners are likely driven by divergent natural selection. We also found strong support for divergent selection on gill raker number among different populations of sea spawners (P_ST > F_ST), most likely caused by highly variable habitat use and diverse diet. The putative role of divergent selection within lake spawners initially inferred from empirical microsatellite data was not supported by simulated F_ST distributions. This work provides a first formal test of divergent selection on gill raker number in Baltic whitefish, and demonstrates the usefulness of population genetic simulations to generate informative neutral baselines for P_ST–F_ST analyses helping to disentangle the effects of stochastic evolutionary processes from natural selection.     

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10⁻¹⁵) and controls (OR = 0.53, p = 2×10⁻⁵). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10⁻⁵). The German dataset confirmed these findings (OR = 0.54, p = 1×10⁻⁴ and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.     

Natural Polymorphisms in Tap2 Influence Negative Selection and CD4∶CD8 Lineage Commitment in the Rat

Genetic variation in the major histocompatibility complex (MHC) affects CD4∶CD8 lineage commitment and MHC expression. However, the contribution of specific genes in this gene-dense region has not yet been resolved. Nor has it been established whether the same genes regulate MHC expression and T cell selection. Here, we assessed the impact of natural genetic variation on MHC expression and CD4∶CD8 lineage commitment using two genetic models in the rat. First, we mapped Quantitative Trait Loci (QTLs) associated with variation in MHC class I and II protein expression and the CD4∶CD8 T cell ratio in outbred Heterogeneous Stock rats. We identified 10 QTLs across the genome and found that QTLs for the individual traits colocalized within a region spanning the MHC. To identify the genes underlying these overlapping QTLs, we generated a large panel of MHC-recombinant congenic strains, and refined the QTLs to two adjacent intervals of ∼0.25 Mb in the MHC-I and II regions, respectively. An interaction between these intervals affected MHC class I expression as well as negative selection and lineage commitment of CD8 single-positive (SP) thymocytes. We mapped this effect to the transporter associated with antigen processing 2 (Tap2) in the MHC-II region and the classical MHC class I gene(s) (RT1-A) in the MHC-I region. This interaction was revealed by a recombination between RT1-A and Tap2, which occurred in 0.2% of the rats. Variants of Tap2 have previously been shown to influence the antigenicity of MHC class I molecules by altering the MHC class I ligandome. Our results show that a restricted peptide repertoire on MHC class I molecules leads to reduced negative selection of CD8SP cells. To our knowledge, this is the first study showing how a recombination between natural alleles of genes in the MHC influences lineage commitment of T cells.     

Fullerene Nucleating Agents: A Route Towards Thermally Stable Photovoltaic Blends

The bulk‐heterojunction nanostructure of non‐crystalline polymer:fullerene blends has the tendency to rapidly coarsen when heated above its glass transition temperature, which represents an important degradation mechanism. We demonstrate that fullerene nucleating agents can be used to thermally arrest the nanostructure of photovoltaic blends that comprise a non‐crystalline thiophene‐quinoxaline copolymer and the widely used fullerene derivative [6,6]‐phenyl‐C₆₁‐butyric acid methyl ester (PCBM). To this end, C₆₀ fullerene is employed to efficiently nucleate PCBM crystallization. Sub‐micrometer‐sized fullerene crystals are formed when as little as 2 wt% C₆₀ with respect to PCBM is added to the blend. These reach an average size of only 200 nanometers upon introduction of more than 8 wt% C₆₀. Solar cells based on C₆₀‐nucleated blends indicate significantly improved thermal stability of the bulk‐heterojunction nanostructure even after annealing at an elevated temperature of 130 °C, which lies above the glass transition temperature of the blend. Moreover, we find that various other compounds, including C₇₀ fullerene, single‐walled carbon nanotubes, and sodium benzoate, as well as a number of commercial nucleating agents—commonly used to clarify isotactic polypropylene—permit to control crystallization of the fullerene phase.     

The H-Phosphonate Method for Constructing Phosphodiester Linkages. A Progress Report

Abstract

Ongoing research into the potential of the H-phosphonate method for synthesising oligonucleotides is discussed. Examples include the synthesis of an artificial Haemophilus influenzae antigen and also efforts to extend the method into the automated solid support synthesis of long RNA oligomers.     

Synthesis and Cardiac Pharmacology of 2-(AR)Alkoxyadenosines

Abstract

Certain relatively large 2-(ar)alkoxy substituents selectively raise the agonist potency of adenosine at the A₂ receptor of coronary artery while lowering activity at the A₁ receptor of AV node.     

Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1×10⁻⁵) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (λ = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n _cases = 91, n _controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0×10⁻⁹), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p_raw = 3.1×10⁻⁷, p_genome = 0.03). The total associated region was defined as a ∼1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ∼209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.     

Evasion of CO2 from streams – The dominant component of the carbon export through the aquatic conduit in a boreal landscape

Evasion of gaseous carbon (C) from streams is often poorly quantified in landscape C budgets. Even though the potential importance of the capillary network of streams as C conduits across the land–water–atmosphere interfaces is sometimes mentioned, low‐order streams are often left out of budget estimates due to being poorly characterized in terms of gas exchange and even areal surface coverage. We show that evasion of C is greater than all the total dissolved C (both organic and inorganic) exported downstream in the waters of a boreal landscape. In this study evasion of carbon dioxide (CO₂) from running waters within a 67 km² boreal catchment was studied. During a 4 year period (2006–2009) 13 streams were sampled on 104 different occasions for dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC). From a locally determined model of gas exchange properties, we estimated the daily CO₂ evasion with a high‐resolution (5 × 5 m) grid‐based stream evasion model comprising the entire ~100 km stream network. Despite the low areal coverage of stream surface, the evasion of CO₂ from the stream network constituted 53% (5.0 (±1.8) g C m^?2 yr^?1) of the entire stream C flux (9.6 (±2.4) g C m^?2 yr^?1) (lateral as DIC, DOC, and vertical as CO₂). In addition, 72% of the total CO₂ loss took place already in the first‐ and second‐order streams. This study demonstrates the importance of including CO₂ evasion from low‐order boreal streams into landscape C budgets as it more than doubled the magnitude of the aquatic conduit for C from this landscape. Neglecting this term will consequently result in an overestimation of the terrestrial C sink strength in the boreal landscape.