Multiple loci are associated with white blood cell phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.     

Forest ecosystem genomics and adaptation: EVOLTREE conference report

This article is a summary report of the international conference "Forest ecosystem genomics and adaptation" organized by the EVOLTREE Network of Excellence in San Lorenzo de El Escorial (Madrid), Spain, from 9 to 11 June 2010. Main achievements and results of the network are presented for the eight thematic sessions and a stakeholder session. The conference has shown that adaptive responses of trees to biotic or abiotic selection pressures can now be investigated at the gene level for traits of adaptive significance. Candidate genes have been catalogued for phenological and drought-related traits in important tree families (Salicaceae, Fagaceaea and Pinaceae), and their variation in natural populations is being explored. Genomics can now be integrated in ecological research to investigate evolutionary response to climate changes in a wide range of species. New avenues of research were also highlighted as the exploration of gene networks involved in adaptive responses and the combination of experimental and modelling approaches to disentangle components of evolutionary changes triggered by climate change. The main focus of the conference was the adaptation of trees to environmental changes. The conference was organized in eight thematic sessions ranging from genomic approaches aiming at identifying genes of adaptive significance to practical issues regarding mitigation options for combating climate change. A dialogue between scientists and end users took place in the form of an ad hoc stakeholder session. A panel of end users from various forest and policy-making institutions expressed their expectations, and the discussions with the scientists addressed the potential applications of research findings to the management of genetic resources in the context of climate changes. The conference was introduced by two keynote speakers Dr. Pierre Mathy from the European Commission, Directorate General of Research, and Dr. Allen Solomon, former National Program Leader for Global Change, US Forest Service. All the thematic sessions were introduced by high-level invited speakers from the respective fields.     

Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.     

Stereoselective differentiation in the Salt-induced Peptide Formation reaction and its relevance for the origin of life

All living organisms on earth are almost totally made up of biomolecules of only one chiral form. For example, proteins are built almost exclusively of L-amino acids, and sugars are composed of D-saccharides, a fact that is usually referred to as biohomochirality. Its origin is the center of numerous investigations and theories but is not really elucidated yet. The results of experimental investigations of peptide formation in a prebiotically relevant scenario, as described in this paper, give indications on a possible pathway for the synthesis of homochiral L-peptides in the course of the Salt-induced Peptide Formation (SIPF) reaction.     

The role of Glu181 in the photoactivation of rhodopsin

The visual pigment rhodopsin is a prototypical seven transmembrane helical G protein-coupled receptor. Photoisomerization of its protonated Schiff base (PSB) retinylidene chromophore initiates a progression of metastable intermediates. We studied the structural dynamics of receptor activation by FTIR spectroscopy of recombinant pigments. Formation of the active state, Meta II, is characterized by neutralization of the PSB and its counterion Glu113. We focused on testing the hypothesis of a PSB counterion switch from Glu113 to Glu181 during the transition of rhodopsin to the still inactive Meta I photointermediate. Our results, especially from studies of the E181Q mutant, support the view that both Glu113 and Glu181 are deprotonated, forming a complex counterion to the PSB in rhodopsin, and that the function of the primary counterion shifts from Glu113 to Glu181 during the transition to Meta I. The Meta I conformation in the E181Q mutant is less constrained compared with that of wild-type Meta I. In particular, the hydrogen bonded network linking transmembrane helices 1, 2, and 7, adopts a conformation that is already Meta II-like, while other parts of the receptor appear to be in a Meta I-like conformation similar to wild-type. We conclude that Glu181 is responsible, in part, for controlling the extraordinary high pK(a) of the chromophore PSB in the dark state, which very likely decreases upon transition to Meta I in a stepwise weakening of the interaction between PSB and its complex counterion during the course of receptor activation. A model for the specific role in coupling chromophore isomerization to protein conformational changes concomitant with receptor activation is presented.     

Growth and biomass of mycorrhizal mycelia in coniferous forests along short natural nutrient gradients

Hybridization may lead to unique phytochemical expression in plant individuals. Hybrids may express novel combinations or extreme concentrations of secondary metabolites or, in some cases, produce metabolites novel to both parental species. Here we test whether there is evidence for extreme metabolite expression or novelty in F1 hybrids between Senecio aquaticus and Senecio jacobaea. Hybridization is thought to occur frequently within Senecio, and hybridization might facilitate secondary metabolite diversification within this genus. Parental species express different quantities of several classes of compounds known to be involved in antiherbivore defence, including pyrrolizidine alkaloids, chlorogenic acid, flavonoids and benzoquinoids. Hybrids demonstrate differential expression of some metabolites, producing lower concentrations of amino acids, and perhaps flavonoids, than either parental species. Despite evidence for quantitative hybrid novelty in this system, NMR profiling did not detect any novel compounds among the plant groups studied. Metabolomic profiling is a useful technique for identifying qualitative changes in major metabolites according to plant species and/or genotype, but is less useful for identifying small differences between plant groups, or differences in compounds expressed in low concentrations.     

Foxl2 gene and the development of the ovary: a story about goat, mouse, fish and woman

In this review, we describe recent results concerning the genetics of sex determination in mammals. Particularly, we developed the study of the FOXL2 gene and its implication in genetic anomalies in goats (PIS mutation) and humans (BPES). We present the expression of FOXL2 in the ovaries of different species.     

Caspase-8 can be activated by interchain proteolysis without receptor-triggered dimerization during drug-induced apoptosis

Proteases of the caspase family are thought to be activated by proteolytic processing of their inactive zymogens. However, although proteolytic cleavage is sufficient for executioner caspases, a different mechanism has been recently proposed for initiator caspases, such as caspase-8, which are believed to be activated by proximity-induced dimerization. According to this model, dimerization rather than proteolytic processing is considered as the critical event for caspase-8 activation. Such a mechanism would suggest that in the absence of a dimerization platform such as the death-inducing signaling complex, caspase-8 proteolytic cleavage would result in an inactive enzyme. As several studies have described caspase-8 cleavage during mitochondrial apoptosis, we now investigated whether caspase-8 becomes indeed catalytically active in this pathway. Using an in vivo affinity labeling approach, we demonstrate that caspase-8 is activated in etoposide-treated cells in vivo in the absence of the receptor-induced death-inducing signaling complex formation. Furthermore, we show that both caspase-3 and -6 are required for the efficient activation of caspase-8. Our data therefore indicate that interchain cleavage of caspase-8 in the mitochondrial pathway is sufficient to produce an active enzyme even in the absence of receptor-driven procaspase-8 dimerization.