Gene Structure Evolution of the Short-Chain Dehydrogenase/Reductase (SDR) Family

SDR (Short-chain Dehydrogenases/Reductases) are one of the oldest and heterogeneous superfamily of proteins, whose classification is problematic because of the low percent identity, even within families. To get clearer insights into SDR molecular evolution, we explored the splicing site organization of the 75 human SDR genes across their vertebrate and invertebrate orthologs. We found anomalous gene structures in members of the human SDR7C and SDR42E families that provide clues of retrogene properties and independent evolutionary trajectories from a common invertebrate ancestor. The same analyses revealed that the identity value between human and invertebrate nonallelic variants is not necessarily associated with the homologous gene structure. Accordingly, a revision of the SDR nomenclature is proposed by including the human SDR40C1 and SDR7C gene in the same family

Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer

Background: genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. Methods: we performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. Results: we did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). Conclusions: our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts

mRNA PGC-1α levels in blood samples reliably correlates with its myocardial expression: study in patients undergoing cardiac surgery

et al.[Objective]: Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that has been proposed to play a protective role in mouse models of cardiac ischemia and heart failure, suggesting that PGC-1α could be relevant as a prognostic marker. Our previous studies showed that the estimation of peripheral mRNA PGC-1α expression was feasible and that its induction correlated with the extent of myocardial necrosis and left ventricular remodeling in patients with myocardial infarction. In this study, we sought to determine if the myocardial and peripheral expressions of PGC-1α are well correlated and to analyze the variability of PGC-1α expression depending on the prevalence of some metabolic disorders. [Methods]: This was a cohort of 35 consecutive stable heart failure patients with severe aortic stenosis who underwent an elective aortic valve replacement surgery. mRNA PGC-1α expression was simultaneously determined from myocardial biopsy specimens and blood samples obtained during surgery by quantitative PCR, and a correlation between samples was made using the Kappa index. Patients were divided into two groups according to the detection of baseline expression levels of PGC-1α in blood samples, and comparisons between both groups were made by chi-square test or unpaired Student’s t-test as appropriate. [Results]: Based on myocardial biopsies, we found that mRNA PGC-1α expression in blood samples showed a statistically significant correlation with myocardial expression (Kappa index 0.66, p<0.001). The presence of higher systemic PGC-1α expression was associated with a greater expression of some target genes such as silent information regulator 2 homolog-1 (x-fold expression in blood samples: 4.43±5.22 vs. 1.09±0.14, p=0.044) and better antioxidant status in these patients (concentration of Trolox: 0.40±0.05 vs. 0.34±0.65, p=0.006). [Conclusions]: Most patients with higher peripheral expression also had increased myocardial expression, so we conclude that the non-invasive estimation of mRNA PGC-1α expression from blood samples provides a good approach of the constitutive status of the mitochondrial protection system regulated by PGC-1α and that this could be used as prognostic indicator in cardiovascular disease.Grant from Sociedad Valenciana de Cardiología, 2013 to Óscar Fabregat-Andrés.Peer Reviewe

Population genetics of Copy Number Variants: the case of the Romani population

Much information has been gathered for the Romani population so far, spanning historical, linguistics and genetics research. While whole genome analyses for this population started only recently, most studies using genetic data so far only relied on single nucleotide polymorphisms (SNPs). In this work we address, for the first time, whole genome Copy Number Variant (CNV) markers in the Romani. Using deletions, we reconstruct the relationships of Romani with related populations (Eurasian and South Asian) and highlight differentiation among them. Moreover, increased presence of deletions at Loss of Function (LoF)-intolerant genes in Romani points to a relaxation of natural selection towards putative slightly deleterious variants in the population. Finally, Romani show overrepresentation of such deletions in genes related to nervous system features and, moreover, their linkage disequilibrium with SNPs in previously reported genes of biomedical importance in Romani could suggest a contribution of CNVs and SNPs to phenotypically related outcomes.Mucha información de la población Romaní ha sido recolectada, incluyendo investigación histórica, lingüística y genética. Aunque los análisis de genomas completos en esta población solo empezaron recientemente, hasta ahora la mayoría de los estudios que usan datos genéticos solo usan polimorfismos de nucleótido único (SNPs). Este estudio se dirige, por primera vez, a analizar las variantes del número de copias (CNVs) de genomas completos en los Romaní. Usando las deleciones, reconstruimos las relaciones de los Romaní con las poblaciones relacionadas (Euroasiática y Sudasiática) y destacamos la diferenciación entre ellas. Además, una mayor presencia de deleciones en genes intolerantes a la pérdida de función en los Romaní indica una relajación de la selección natural por aquellas variantes posiblemente deletéreas. Finalmente, los Romaní muestran una sobrerrepresentación de esas deleciones en genes relacionados a características del sistema nervioso y, asimismo, el linkage disequilibrium con SNPs en genes con importancia biomédica previamente analizados en los Romaní podría sugerir una acción sinérgica de CNVs y SNPs en consecuencias fenotípicamente relacionadas

Associazione tra varianti genetiche, percezione gustativa e abitudini alimentari nelle popolazioni umane: una prospettiva evolutiva.

La presente tesi mira ad approfondire l’interpretazione delle basi genetiche del gusto dell'uomo in chiave evolutiva. In particolare, si è indagata l’associazione tra la percezione chimica di alcune sostanze fondamentali contenute nel cibo e la variabilità dei geni di cui è provato il coinvolgimento nella percezione gustativa in alcuni gruppi etnici con marcate differenze nelle loro preferenze alimentari. E’ necessario infatti scomporre la variazione legata alla scelta del cibo nelle sue varie componenti se si vuole ricostruirne i significati evolutivi. I dati genotipici sono stati ottenuti, previo consenso informato dei donatori, attraverso la raccolta di campioni di saliva con un kit apposito (Oragene, Genotek). Il DNA estratto è stato sottoposto ad amplificazione (tecniche multiplex PCR)delle regioni geniche che codificano per i recettori di membrana specifici delle sensazioni dolce, amaro e umami e delle sensazioni chemestetiche (caldo, fresco). L’assegnazione genotipica di un totale di 83 varianti SNPsè stata effettuata tramite la piattaforma Sequenom MassARRAY, che si avvale della tecnica MALDI-TOF (Matrix Assisted Laser Desorption Ionization - Time Of Flight). I dati culturali sono stati raccolti attraverso la somministrazione di un apposito questionario, i dati sensoriali attraverso un test di percezione basato sulla risposta individuale a 7 composti in diversa concentrazione: Glutammato monosodico (MSG) per il gusto umami; Saccarosio per il gusto dolce; Stevioside per il dolce/amaro; Salicina e 6-n-propiltiouracile (PROP) per il gusto amaro; N-etil-p-mentano-carbossiammide (WS-3) e Capsaicina rispettivamente per le sensazioni fresco e piccante. I principali obiettivi dello studio sono stati: 1 - identificare le associazioni genotipo/fenotipo statisticamente significative nei vari gruppi etnici 2 - interpretare tali associazioni alla luce del background demografico, ecologico e culturale del gruppo in questione

A Matter of Taste: Lineage-Specific Loss of Function of Taste Receptor Genes in Vertebrates

Vertebrates can perceive at least five different taste qualities, each of which is thought to have a specific role in the evolution of different species. The avoidance of potentially poisonous foods, which are generally bitter or sour tasting, and the search for more nutritious ones, those with high-fat and high-sugar content, are two of the most well-known examples. The study of taste genes encoding receptors that recognize ligands triggering taste sensations has helped to reconstruct several evolutionary adaptations to dietary changes. In addition, an increasing number of studies have focused on pseudogenes, genomic DNA sequences that have traditionally been considered defunct relatives of functional genes mostly because of the presence of deleterious mutations interrupting their open reading frames. The study of taste receptor pseudogenes has helped to shed light on how the evolutionary history of taste in vertebrates has been the result of a succession of gene gain and loss processes. This dynamic role in evolution has been explained by the “less-is-more” hypothesis, suggesting gene loss as a mechanism of evolutionary change in response to a dietary shift. This mini-review aims at depicting the major lineage-specific loss of function of taste receptor genes in vertebrates, stressing their evolutionary importance and recapitulating signatures of natural selection and their correlations with food habits

Gene Structure Evolution of the Short-Chain Dehydrogenase/Reductase (SDR) Family

SDR (Short-chain Dehydrogenases/Reductases) are one of the oldest and heterogeneous superfamily of proteins, whose classification is problematic because of the low percent identity, even within families. To get clearer insights into SDR molecular evolution, we explored the splicing site organization of the 75 human SDR genes across their vertebrate and invertebrate orthologs. We found anomalous gene structures in members of the human SDR7C and SDR42E families that provide clues of retrogene properties and independent evolutionary trajectories from a common invertebrate ancestor. The same analyses revealed that the identity value between human and invertebrate non-allelic variants is not necessarily associated with the homologous gene structure. Accordingly, a revision of the SDR nomenclature is proposed by including the human SDR40C1 and SDR7C gene in the same family

Symmetries and topological operators, on average

We study Ward identities and selection rules for local correlators in disordered theories where a 0-form global symmetry of a QFT is explicitly broken by a random coupling $h$ but it re-emerges after quenched average. We consider $h$ space-dependent or constant. In both cases we construct the symmetry operator implementing the group action, topological after average. In the first case, relevant in statistical systems with random impurities, such symmetries can be coupled to external backgrounds and can be gauged, like ordinary symmetries in QFTs. We also determine exotic selection rules arising when symmetries emerge after average in the IR, explaining the origin of LogCFTs from symmetry considerations. In the second case, relevant in AdS/CFT to describe the dual boundary theory of certain bulk gravitational theories, the charge operator is not purely codimension-1, it can be defined only on homologically trivial cycles and on connected spaces. Selection rules for average correlators exist, yet such symmetries cannot be coupled to background gauge fields in ordinary ways and cannot be gauged. When the space is disconnected, in each connected component charge violation occurs, as expected from Euclidean wormholes in the bulk theory. Our findings show the obstruction to interpret symmetries emergent after average as gauged in the bulk