Investiguen el paper de les metal·lotioneïnes en les Encefalopaties Enpongiformes Transmissibles

Les metal·lotioneïnes (MT) formen part dels mecanismes encefàlics de defensa que actuen en cas d'un procés patològic que afecti el sistema nerviós central. Per això, i per les seves propietats antioxidants, investigadors del CReSA i de la UAB han inoculat, per via intracerebral, una soca d'EETs a ratolins transgènics per intentar comprendre millor la relació que existeix entre les MTs i la patogènia de la tremolor ovina

GStream:improving SNP and CNV coverage on genome-wide association studies

We present GStream, a method that combines genome-wide SNP and CNV genotyping in the Illumina microarray platform with unprecedented accuracy. This new method outperforms previous well-established SNP genotyping software. More importantly, the CNV calling algorithm of GStream dramatically improves the results obtained by previous state-of-the-art methods and yields an accuracy that is close to that obtained by purely CNV-oriented technologies like Comparative Genomic Hybridization (CGH). We demonstrate the superior performance of GStream using microarray data generated from HapMap samples. Using the reference CNV calls generated by the 1000 Genomes Project (1KGP) and well-known studies on whole genome CNV characterization based either on CGH or genotyping microarray technologies, we show that GStream can increase the number of reliably detected variants up to 25% compared to previously developed methods. Furthermore, the increased genome coverage provided by GStream allows the discovery of CNVs in close linkage disequilibrium with SNPs, previously associated with disease risk in published Genome-Wide Association Studies (GWAS). These results could provide important insights into the biological mechanism underlying the detected disease risk association. With GStream, large-scale GWAS will not only benefit from the combined genotyping of SNPs and CNVs at an unprecedented accuracy, but will also take advantage of the computational efficiency of the method.Postprint (published version

CNstream: A method for the identification and genotyping of copy number polymorphisms using Illumina microarrays

<p>Abstract</p> <p>Background</p> <p>Understanding the genetic basis of disease risk in depth requires an exhaustive knowledge of the types of genetic variation. Very recently, Copy Number Variants (CNVs) have received much attention because of their potential implication in common disease susceptibility. Copy Number Polymorphisms (CNPs) are of interest as they segregate at an appreciable frequency in the general population (i.e. > 1%) and are potentially implicated in the genetic basis of common diseases.</p> <p>Results</p> <p>This paper concerns CNstream, a method for whole-genome CNV discovery and genotyping, using Illumina Beadchip arrays. Compared with other methods, a high level of accuracy was achieved by analyzing the measures of each intensity channel separately and combining information from multiple samples. The CNstream method uses heuristics and parametrical statistics to assign a confidence score to each sample at each probe; the sensitivity of the analysis is increased by jointly calling the copy number state over a set of nearby and consecutive probes. The present method has been tested on a real dataset of 575 samples genotyped using Illumina HumanHap 300 Beadchip, and demonstrates a high correlation with the Database of Genomic Variants (DGV). The same set of samples was analyzed with PennCNV, one of the most frequently used copy number inference methods for Illumina platforms. CNstream was able to identify CNP loci that are not detected by PennCNV and it increased the sensitivity over multiple other loci in the genome.</p> <p>Conclusions</p> <p>CNstream is a useful method for the identification and characterization of CNPs using Illumina genotyping microarrays. Compared to the PennCNV method, it has greater sensitivity over multiple CNP loci and allows more powerful statistical analysis in these regions. Therefore, CNstream is a robust CNP analysis tool of use to researchers performing genome-wide association studies (GWAS) on Illumina platforms and aiming to identify CNVs associated with the variables of interest. CNstream has been implemented as an R statistical software package that can work directly from raw intensity files generated from Illumina GWAS projects. The method is available at <url>http://www.urr.cat/cnv/cnstream.html</url>.</p

Central nervous system gene expression changes in a transgenic mouse model for bovine spongiform encephalopathy

Gene expression analysis has proven to be a very useful tool to gain knowledge of the factors involved in the pathogenesis of diseases, particularly in the initial or preclinical stages. With the aim of finding new data on the events occurring in the Central Nervous System in animals affected with Bovine Spongiform Encephalopathy, a comprehensive genome wide gene expression study was conducted at different time points of the disease on mice genetically modified to model the bovine species brain in terms of cellular prion protein. An accurate analysis of the information generated by microarray technique was the key point to assess the biological relevance of the data obtained in terms of Transmissible Spongiform Encephalopathy pathogenesis. Validation of the microarray technique was achieved by RT-PCR confirming the RNA change and immunohistochemistry techniques that verified that expression changes were translated into variable levels of protein for selected genes. Our study reveals changes in the expression of genes, some of them not previously associated with prion diseases, at early stages of the disease previous to the detection of the pathological prion protein, that might have a role in neuronal degeneration and several transcriptional changes showing an important imbalance in the Central Nervous System homeostasis in advanced stages of the disease. Genes whose expression is altered at early stages of the disease should be considered as possible therapeutic targets and potential disease markers in preclinical diagnostic tool development. Genes non-previously related to prion diseases should be taken into consideration for further investigations

El prió de la tremolor ovina atípica no presenta limfotropisme

Dins el marc del programa de vigilància activa de les encefalopaties espongiformes transmissibles (EETs) a Catalunya, el laboratori Priocat del Centre de Recerca en Sanitat Animal (CReSA) ha evidenciat la inexistència de limfotropisme per part de la proteïna resistent associada a la tremolor ovina atípica. Uns resultats que s'extreuen del següent article, on es presenta de forma concomitant una encefalitis vírica -el que implica la formació de fol·licles limfoides a l'encèfal- i una malaltia priònica. Així, mentre els prions de la variant clàssica s'acumulen al teixit limfàtic, els de la variant atípica no ho fan ni tan sols estant presents al cervell.En el marco del programa de vigilancia activa de las encefalopatías espongiformes transmisibles (EETs) de Catalunya, el laboratorio Priocat del Centro de Investigación en Sanidad Animal (CReSA) ha evidenciado la inexistencia de limfotropismo por parte de la proteína resistente asociada al temblor ovino atípico. Unos resultados que se extraen del siguiente artículo, donde se presenta de forma concomitante una encefalitis vírica -lo que implica la formación de folículos linfoides en el encéfalo- y una enfermedad priónica. Así, mientras los priones de la variante clásica se acumulan en el tejido linfático, los de la variante atípica no lo hacen ni siquiera estando presentes en el cerebro.From the active TSE surveillance programme in Catalonia, the Priocat laboratory of animal health research centre (CReSA) has detected a noticeable lack of lymphotropsim as far as scrapie-associated prion protein deposition is concerned. Results described in the paper, where a viral encephalitis -which implies formation of lymphoid follicles in the brain- is concomitant to a prion disease. In the classical strains the prions show a strong affinity for the lymphoid tissue but not in this case, even when follicles are as close as in the same brain

Genetic variation associated with cardiovascular risk in autoimmune diseases

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNF? and IFN? cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity

A deletion at Adamts9-magi1 Locus is associated with psoriatic arthritis risk

Objective: Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. Methods: A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ2 test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). Results: A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3). Conclusions: The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk