Design and evaluation of a panel os single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.

Decay of linkage disequilibrium within genes across HGDP-CEPH human samples: most population isolates do not show increased LD

Background: It is well known that the pattern of linkage disequilibrium varies between human populations, with remarkable geographical stratification. Indirect association studies routinely exploit linkage disequilibrium around genes, particularly in isolated populations where it is assumed to be higher. Here, we explore both the amount and the decay of linkage disequilibrium with physical distance along 211 gene regions, most of them related to complex diseases, across 39 HGDP-CEPH population samples, focusing particularly on the populations defined as isolates. Within each gene region and population we use r2 between all possible single nucleotide polymorphism (SNP) pairs as a measure of linkage disequilibrium and focus on the proportion of SNP pairs with r2 greater than 0.8.Results: Although the average r2 was found to be significantly different both between and within continental regions, a much higher proportion of r2 variance could be attributed to differences between continental regions (2.8% vs. 0.5%, respectively). Similarly, while the proportion of SNP pairs with r2 > 0.8 was significantly different across continents for all distance classes, it was generally much more homogenous within continents, except in the case of Africa and the Americas. The only isolated populations with consistently higher LD in all distance classes with respect to their continent are the Kalash (Central South Asia) and the Surui (America). Moreover, isolated populations showed only slightly higher proportions of SNP pairs with r2 > 0.8 per gene region than non-isolated populations in the same continent. Thus, the number of SNPs in isolated populations that need to be genotyped may be only slightly less than in non-isolates. Conclusion: The "isolated population" label by itself does not guarantee a greater genotyping efficiency in association studies, and properties other than increased linkage disequilibrium may make these populations interesting in genetic epidemiology.

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Background: Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results: This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC.Conclusion: This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

OSIRISv1.2: a named entity recognition system for sequence variants of genes in biomedical literature

Background: Single Nucleotide Polymorphisms, among other type of sequence variants, constitute key elements in genetic epidemiology and pharmacogenomics. While sequence data about genetic variation is found at databases such as dbSNP, clues about the functional and phenotypic consequences of the variations are generally found in biomedical literature. The identification of the relevant documents and the extraction of the information from them are hampered by the large size of literature databases and the lack of widely accepted standard notation for biomedical entities. Thus, automatic systems for the identification of citations of allelic variants of genes in biomedical texts are required. Results: Our group has previously reported the development of OSIRIS, a system aimed at the retrieval of literature about allelic variants of genes http://ibi.imim.es/osirisform.html. Here we describe the development of a new version of OSIRIS (OSIRISv1.2, http://ibi.imim.es/OSIRISv1.2.html webcite) which incorporates a new entity recognition module and is built on top of a local mirror of the MEDLINE collection and HgenetInfoDB: a database that collects data on human gene sequence variations. The new entity recognition module is based on a pattern-based search algorithm for the identification of variation terms in the texts and their mapping to dbSNP identifiers. The performance of OSIRISv1.2 was evaluated on a manually annotated corpus, resulting in 99% precision, 82% recall, and an F-score of 0.89. As an example, the application of the system for collecting literature citations for the allelic variants of genes related to the diseases intracranial aneurysm and breast cancer is presented. Conclusion: OSIRISv1.2 can be used to link literature references to dbSNP database entries with high accuracy, and therefore is suitable for collecting current knowledge on gene sequence variations and supporting the functional annotation of variation databases. The application of OSIRISv1.2 in combination with controlled vocabularies like MeSH provides a way to identify associations of biomedical interest, such as those that relate SNPs with diseases.

Camiños denominativos cara a un mesmo concepto

Neste artigo presentamos unha revisión teórica sobre o concepto especializado e a relación que mantén coa variación. Nós defendemos que existe un grao de motivación importante na denominación terminolóxica e que, a través dela, se fan visibles uns trazos semánticos determinados, achegándonos así unha visión particular do concepto. Por último facemos unha proposta de análise da variación terminolóxica consistnete en recompilar as diferentes variantes e analizar o contenido semántico expresado na denominación. Os exemplos foron tirados dun corpus de textos bilingüe francés-galego sobre o marisqueo.

Variación denominativa y biunivocidad en el lenguaje de las matemáticas

A veces se ha sugerido una relación entre la variación (sinonimia o polisemia) y el campo temático, y parece necesaria la tarea de verificar la presencia de la variación en diferentes campos del conocimiento. En este artículo si toma como area de trabajo uno de los campos considerado menos variado por excelencia. El lenguaje de las matemáticas se considera preciso, conciso y muy formalizado; se afirma que los términos matemáticos son biunívocos y que esta característica sirve para evitar las ambigüedades lingüísticas y para asegurar la eficacia comunicativa. Nuestros objectivos son analizar algunos términos matemáticos en textos especializados y probar que también estan sujetos a variación denominativa. Los ejemplos se analizan desde el punto de vista formal y semántico, y se indagan también las causas que provocan la variación.

L' Anàlisi estilística per atribuir l'autoria

Aquest treball proposa un nou mètode per la comparació forense de textos escrits en les xarxes socials mitjançant l’anàlisi estilística. Es basa en l’anàlisi de cinc autors en què es van definir les variables estilístiques i es va determinar el seu poder discriminant tant en la variació intra-escriptor com inter-escriptor.

El Reto de la traducción: la transferencia del puzzle lingüístico de Andrea Camilleri al castellano y al catalán

El presente estudio versa sobre las problemáticas derivadas de la traducción, al castellano y al catalán, del divertido pastiche lingüístico del escritor siciliano Andrea Camilleri. Para indagar el problema, hemos escogido las novelas Il birraio di Preston (1995) e Il cane di terracotta (1995), como muestra significativa de los dos géneros cultivados por nuestro autor, respectivamente la novela policial y la novela histórica. Se trata de textos que ponen al traductor frente a la empresa seductora y, a la vez, titánica de encontrar en su lengua una forma de devolver acertadamente la “sicilianidad” y el mosaico de dialectos italianos: para los teóricos y los traductores el lenguaje no estándar representa un reto que pone frente a problemáticas todavía no resueltas. Con este estudio descriptivo nos proponemos arrojar luz sobre este complejo asunto y tratar de indicar unas posibles pautas a seguir para el que quiera continuar con esta dialéctica.

Anàlisi del títol d’anticossos anti-achr i la seva correlació clínica en pacients amb miastenia gravis seropositiva

Els anticossos contra el receptor de l’acetilcolina representen el principal mecanisme patogènic en la Miastènia Gravis, però la seva utilitat com a biomarcador durant el seguiment de la malaltia és desconeguda. S’ha realitzat un estudi retrospectiu amb 77 pacients que disposen de múltiples determinacions en el títol d’anticossos, relacionant-los amb l’estat clínic de cada moment. L’anàlisi demostra una correlació significativa entre la variació dels Ac i l’evolució clínica intrapacient, tant al llarg de la malaltia com en les fluctuacions clíniques. Per tant, la determinació seriada d’anticossos representa una mida dels canvis clínics i pot ser d’utilitat en el seguiment d’aquests pacients.

Medida de acoplamientos dipolares residuales en moléculas orgánicas

En aquest treball es descriu la preparació i l’ús d’un gel comprimit de polimetilmetacrilat (PMMA) com a mitjà d’alineament anisotròpic necessari per a la mesura de constants d’acoplament dipolars residuals (RDCs) mitjançant espectroscopia de Resonància Magnètica Nuclear (RMN). S’ha estudiat la variació del grau d’ordre del mitjà en funció de la seva compressió axial i s’han implementat diferentes versions de l’experiment HSQC amb la intenció de determinar quins mètodes són els més idonis per a la mesura de RDCs en termes de sensibilitat, resolució i precissió. El mètode s’ha aplicat en l’estudi conformacional de l’ibuprofen.

Anàlisi multivariada craniomètrica de les poblacions catalano-balears del passat

S'ha portat a terme una analisi estadística de les dades craniometriques de les principals poblacions catalano-balears del passat, des de J'Edat del Bronze fins a l'Edat Mitjana, i posteriorment s'han integrat les poblacions en un context peninsular més ampli. S'han analitzalles relacions entre poblacions per mitja d'un analisi d'agrupament (cluster), emprant els algoritmes UPGMA i del "veí més proper" i la distancia euclídea al quadrat. Així mateix, s'ha realitzat un re-mostreig (bootstrap) per comprovar la robustes de les agrupacions obtingudes i un test de Mantel per comprovar el grau de concordan~a entre les poblacions femenines i masculines. Els resultats mostren que, a nivell peninsular, els Bascos són la població més diferenciada de la resta des d'un punt de vista morfologic, la qual cosa pot estar relacionada amb una major antiguitat d'aquesta població, potser present des de temps pre-neolítics. La segona font de variació peninsular la constitueixen dues poblacions amb possibles influencies foranies d'origen africa: jueus i musulmans. La resta de poblacions, incloent-hi les de Mallorca, són notablement homogenies a pesar de la seva heterogene'itat cultural, temporal i geogràtfica. Finalment, es conclou que no hi ha cap analisi estadística que objectivament recolzi I'existencia deIs tipus racials tradicionalmcnt descrits a la Península Iberica, i que responen a una visió tipologica i estatica de la diversitat humana.

Testing for hysteresis in unemployment in OECD countries: new evidence using stationarity panel tests with breaks

This paper tests hysteresis effects in unemployment using panel data for 19 OECD countries covering the period 1956-2001. The tests exploit the cross-section variations of the series, and additionally, allow for a diferent number of endogenous breakpoints in the unemployment series. The critical values are simulated based on our specific panel sizes and time periods. The findings stress the importance of accounting for exogenous shocks in the series and give support to the natural-rate hypothesis of unemployment for the majority of the countries analyzed

Aggregate shocks or vertical tax interdependence? Evidende from gasoline and cigarettes

[cat] Besley i Rosen -1998- van ser els primers autors en estimar empíricament la rellevància de les externalitats impositives verticals. Aquests autors varen fer-ho per al cas dels impostos sobre la benzina i el tabac, en concret, per al cas dels EEUU. Ara bé, no varen tenir en compte les diferències en el nivell de vida entre Estats: àrees amb un nivell elevat paguen menys en termes reals que àrees amb un nivell de vida baix, doncs l'impost unitari sobre la benzina o sobre el tabac no difereix d'acord amb l'Estat on l'impost s'aplica. En conseqüència, proposem que la competència impositiva vertical sigui estimada deflactant totes les variables monetàries utilitzant l'anomenat "House Price Index (HPI)", el qual està disponible al nivell dels Estats. Això genera una variable impositiva federal expressada en termes reals i que presenta variació entre Estats. Aquesta estratègia empírica ens permet diferenciar entre la interdependència vertical entre els tipus impositius federals i els estatals de shocks agregats al llarg del temps, utilitzant dades per als EEUU durant el període 1975 a 2006 per a benzina i tabac. Trobem una nivell significatiu de competència impositiva horitzontal, la qual és més elevada en el cas del tabac, però en cap cas reacció impositiva vertical. Els resultats són robustos al període analitzat.

Testing for hysteresis in unemployment in OECD countries: new evidence using stationarity panel tests with breaks

This paper tests hysteresis effects in unemployment using panel data for 19 OECD countries covering the period 1956-2001. The tests exploit the cross-section variations of the series, and additionally, allow for a diferent number of endogenous breakpoints in the unemployment series. The critical values are simulated based on our specific panel sizes and time periods. The findings stress the importance of accounting for exogenous shocks in the series and give support to the natural-rate hypothesis of unemployment for the majority of the countries analyzed