Prediction of a deletion copy number variant by a dense SNP panel

<p>Abstract</p> <p>Background</p> <p>A newly recognized type of genetic variation, Copy Number Variation (CNV), is detected in mammalian genomes, e.g. the cattle genome. This form of variation can potentially cause phenotypic variation. Our objective was to determine whether dense SNP (single nucleotide polymorphisms) panels can capture the genetic variation due to a simple bi-allelic CNV, with the prospect of including the effect of such structural variations into genomic predictions.</p> <p>Methods</p> <p>A deletion type CNV on bovine chromosome 6 was predicted from its neighboring SNP with a multiple regression model. Our dataset consisted of CNV genotypes of 1,682 cows, along with 100 surrounding SNP genotypes. A prediction model was fitted considering 10 to 100 surrounding SNP and the accuracy obtained directly from the model was confirmed by cross-validation.</p> <p>Results and conclusions</p> <p>The accuracy of prediction increased with an increasing number of SNP in the model and the predicted accuracies were similar to those obtained by cross-validation. A substantial increase in accuracy was observed when the number of SNP increased from 10 to 50 but thereafter the increase was smaller, reaching the highest accuracy (0.94) with 100 surrounding SNP. Thus, we conclude that the genotype of a deletion type CNV and its putative QTL effect can be predicted with a maximum accuracy of 0.94 from surrounding SNP. This high prediction accuracy suggests that genetic variation due to simple deletion CNV is well captured by dense SNP panels. Since genomic selection relies on the availability of a dense marker panel with markers in close linkage disequilibrium to the QTL in order to predict their genetic values, we also discuss opportunities for genomic selection to predict the effects of CNV by dense SNP panels, when CNV cause variation in quantitative traits.</p

Sphagnum bleaching:Bicarbonate ‘toxicity’ and tolerance for seven Sphagnum species

Growth and functioning of Sphagnum mosses are closely linked to water level and chemistry. Sphagnum mosses occur in wet, generally acidic conditions, and when buffered, alkaline water is known to negatively impact Sphagnum. The effects of time, dose and species-specific responses of buffered, alkaline water on Sphagnum are largely unknown. We investigated the effects of bicarbonate and calcium on the survival, growth and physiological functioning of seven Sphagnum species occurring in contrasting environments, from raised bogs to (rich) fens. Mosses were submerged in different concentrations of bicarbonate and calcium solutions for 10 weeks under climate-controlled circumstances. After 2 weeks, all species exposed to the high bicarbonate treatment (2.0 mM) showed severe potassium leakage and swift discoloration. In contrast, species showed differential responses to the intermediate bicarbonate treatment (0.8 mM), some with a later onset of potassium leakage. S. squarrosum, S. teres & S. contortum generally persisted the longest, with all species dying after 6 to 10 weeks. Calcium alone, in contrast, negatively affected S. squarrosum, S. teres & S. contortum, causing discoloration and potassium leakage. Our study shows enrichment with bicarbonate, but not calcium, is detrimental for most Sphagnum species tested. A mechanistic model was developed that is consistent with dose and duration dependence and the species specificity. Future conservation and restoration measures for Sphagnum-dominated habitats and Sphagnum farming (cultivation, production and harvest of Sphagnum moss biomass) should limit flooding with bicarbonate-rich waters while investigating new management options, like acidifying surface waters to lower bicarbonate levels

Thermal Particle Creation in Cosmological Spacetimes: A Stochastic Approach

The stochastic method based on the influence functional formalism introduced in an earlier paper to treat particle creation in near-uniformly accelerated detectors and collapsing masses is applied here to treat thermal and near-thermal radiance in certain types of cosmological expansions. It is indicated how the appearance of thermal radiance in different cosmological spacetimes and in the two apparently distinct classes of black hole and cosmological spacetimes can be understood under a unifying conceptual and methodological framework.Comment: 17 pages, revtex (aps, eqsecnum), submitted to PRD, April 199

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

Background: Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes. Methods: Wfs1KO mice were generated by homologous recombination. Both Wfs1KO and wild type (wt) male mice were mated with wt female mice. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analysed. Serum testosterone and FSH concentrations were also measured. Results: The pregnancy rate in wt females mated with Wfs1KO males was significantly lower than in the control group (15% vs. 32%; p < 0.05), but there was no significant difference in litter size. Analysis of male fertility showed that, in the Wfs1KO group, eight males out of 13 had pups whereas in the control group all 13 males had at least one litter. Sperm motility was not affected in Wfs1KO mice, but Wfs1KO males had less proximal bent tails (14.4 +/- 1.2% vs. 21.5 +/- 1.3 p < 0.05) and less abnormal sperm heads (22.8 +/- 1.8 vs. 31.5 +/- 3.5, p < 0.05) than wt males. Testes histology revealed significantly reduced number of spermatogonia (23.9 +/- 4.9 vs. 38.1 +/- 2.8; p < 0.05) and Sertoli cells (6.4 +/- 0.5 vs. 9.2 +/- 1.0; p < 0.05) in Wfs1KO mice. Serum testosterone and FSH concentrations did not differ between the two groups. Conclusion: The impaired fertility of Wfs1KO male mice is most likely due to changes in sperm morphology and reduced number of spermatogenic cells. The exact mechanism through which the Wfs1 gene influences sperm morphology needs to be clarified in further studies

BEC Collapse and Dynamical Squeezing of Vacuum Fluctuations

We analyze the phenomena of Bose Novae, as described by Donley et al [Nature 412, 295 (2001)], by focusing on the behavior of excitations or fluctuations above the condensate, as driven by the dynamics of the condensate (rather than the dynamics of the condensate alone or the kinetics of the atoms). The dynamics of the condensate squeezes and amplifies the quantum excitations, mixing the positive and negative frequency components of their wave functions thereby creating particles which appear as bursts and jets. By analyzing the changing amplitude and particle content of these excitations, our simple physical picture (based on a test field approximation) explains well the overall features of the Bose Novae phenomena and provide excellent quantitative fits with experimental data on several aspects, such as the scaling behavior of the collapse time and the amount of particles in the jet. The predictions of the bursts at this level of approximation is less than satisfactory but may be improved on by including the backreaction of the excitations on the condensate. The mechanism behind the dominant effect -- parametric amplification of vacuum fluctuations and freezing of modes outside of horizon -- is similar to that of cosmological particle creation and structure formation in a rapid quench (which is fundamentally different from Hawking radiation in black holes). This shows that BEC dynamics is a promising venue for doing `laboratory cosmology'.Comment: Latex 36 pages, 6 figure

Polymorphisms in the interleukin-10 gene cluster are possibly involved in the increased risk for major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD.</p> <p>Methods</p> <p>Case-control association study was performed with seven SNPs from the <it>IL10 </it>gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited.</p> <p>Results</p> <p>None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the <it>IL10 </it>gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (<it>IL20 </it>and <it>IL24 </it>genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097).</p> <p>Conclusion</p> <p>Our study established increased risk for MDD related to the <it>IL20 </it>and <it>IL24 </it>haplotype and suggests that cytokines may contribute to the pathogenesis of MDD. Since none of the block 2 SNPs were individually associated with MDD, it is possible that other polymorphisms linked to them contribute to the disease susceptibility. Future studies are needed to confirm the results and to find the possible functional explanation.</p

Correlation Entropy of an Interacting Quantum Field and H-theorem for the O(N) Model

Following the paradigm of Boltzmann-BBGKY we propose a correlation entropy (of the nth order) for an interacting quantum field, obtained by `slaving' (truncation with causal factorization) of the higher (n+1 th) order correlation functions in the Schwinger-Dyson system of equations. This renders an otherwise closed system effectively open where dissipation arises. The concept of correlation entropy is useful for addressing issues related to thermalization. As a small yet important step in that direction we prove an H-theorem for the correlation entropy of a quantum mechanical O(N) model with a Closed Time Path Two Particle Irreducible Effective Action at the level of Next-to-Leading-Order large N approximation. This model may be regarded as a field theory in $0$ space dimensions.Comment: 22 page

Entropy and Uncertainty of Squeezed Quantum Open Systems

We define the entropy S and uncertainty function of a squeezed system interacting with a thermal bath, and study how they change in time by following the evolution of the reduced density matrix in the influence functional formalism. As examples, we calculate the entropy of two exactly solvable squeezed systems: an inverted harmonic oscillator and a scalar field mode evolving in an inflationary universe. For the inverted oscillator with weak coupling to the bath, at both high and low temperatures, $S\to r$, where r is the squeeze parameter. In the de Sitter case, at high temperatures, $S\to (1-c)r$ where $c = \gamma_0/H$, $\gamma_0$ being the coupling to the bath and H the Hubble constant. These three cases confirm previous results based on more ad hoc prescriptions for calculating entropy. But at low temperatures, the de Sitter entropy $S\to (1/2-c)r$ is noticeably different. This result, obtained from a more rigorous approach, shows that factors usually ignored by the conventional approaches, i.e., the nature of the environment and the coupling strength betwen the system and the environment, are important.Comment: 36 pages, epsfig, 2 in-text figures include

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients