Late Fetal Blood Transcriptomic Approach To Get Insight Into Biology Related To Birth Survival

In recent decades, improvement of prolificacy and body composition has been accompanied by a substantial increase in the mortality of piglets before weaning. The most critical period is the perinatal period, mostly during the first 24-48 hours following birth. The maturity of piglets, defined as the state of full development for survival at birth, is an important determinant of early mortality. The objective of our project is to take advantage of current knowledge about two pig breeds, Large White (LW) pigs selected for prolificacy and body composition and Meishan (MS) pigs being more robust. Maturity of several tissues and metabolite profiles of various fluids are analyzed on the fetuses (LW, MS and reciprocal F1) at day 90 or 110 of gestation (birth at day 114). Here we presented the transcriptomic analysis done on total blood samples (N=63). We did two different statistical analyses, a supervised one to reveal differential pathways for the interaction between gestational stages and genotypes and an unsupervised analysis (hclust and differential analyses) to identify potential predictors of a lesser maturity at birth. All p-values were adjusted with a Bonferroni correction < 1%. The 265 genes differential for the interaction (Bonferroni 1%) in blood samples revealed many genes for mitochondrial ATP synthesis, transcriptional regulation, and response to hypoxia (overexpressed in LW at day 110 of gestation)

Progeny-testing of full-sibs IBD in a SSC2 QTL region highlights epistatic interactions for fatness traits in pigs

<p>Abstract</p> <p>Background</p> <p>Many QTL have been detected in pigs, but very few of them have been fine-mapped up to the causal mutation. On SSC2, the <it>IGF2</it>-intron3-G3072A mutation has been described as the causative polymorphism for a QTL underlying muscle mass and backfat deposition, but further studies have demonstrated that at least one additional QTL should segregate downstream of this mutation. A marker-assisted backcrossing design was set up in order to confirm the segregation of this second locus, reduce its confidence interval and better understand its mode of segregation.</p> <p>Results</p> <p>Five recombinant full-sibs, with genotype G/G at the <it>IGF2 </it>mutation, were progeny-tested. Only two of them displayed significant QTL for fatness traits although four inherited the same paternal and maternal chromosomes, thus exhibiting the same haplotypic contrast in the QTL region. The hypothesis of an interaction with another region in the genome was proposed to explain these discrepancies and after a genome scan, four different regions were retained as potential interacting regions with the SSC2 QTL. A candidate interacting region on SSC13 was confirmed by the analysis of an F2 pedigree, and in the backcross pedigree one haplotype in this region was found to mask the SSC2 QTL effect.</p> <p>Conclusions</p> <p>Assuming the hypothesis of interactions with other chromosomal regions, the QTL could be unambiguously mapped to a 30 cM region delimited by recombination points. The marker-assisted backcrossing design was successfully used to confirm the segregation of a QTL on SSC2 and, because full-sibs that inherited the same alleles from their two parents were analysed, the detection of epistatic interactions could be performed between alleles and not between breeds as usually done with the traditional Line-Cross model. Additional analyses of other recombinant sires should provide more information to further improve the fine-mapping of this locus, and confirm or deny the interaction identified between chromosomes 2 and 13.</p

Comprehensive transcriptome analysis of mouse embryonic stem cell adipogenesis unravels new processes of adipocyte development

International audienceBACKGROUND: The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. RESULTS: Here we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps. CONCLUSIONS: This study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays

Identification of QTL with effects on intramuscular fat content and fatty acid composition in a Duroc × Large White cross

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Comparing the intestinal transcriptome of Meishan and Large White piglets during late fetal development reveals genes involved in glucose and lipid metabolism and immunity as valuable clues of intestinal maturity

Background: Maturity of intestinal functions is critical for neonatal health and survival, but comprehensive description of mechanisms underlying intestinal maturation that occur during late gestation still remain poorly characterized. The aim of this study was to investigate biological processes specifically involved in intestinal maturation by comparing fetal jejunal transcriptomes of two representative porcine breeds (Large White, LW; Meishan, MS) with contrasting neonatal vitality and maturity, at two key time points during late gestation (gestational days 90 and 110). MS and LW sows inseminated with mixed semen (from breed LW and MS) gave birth to both purebred and crossbred fetuses. We hypothesized that part of the differences in neonatal maturity between the two breeds results from distinct developmental profiles of the fetal intestine during late gestation. Reciprocal crossed fetuses were used to analyze the effect of parental genome. Transcriptomic data and 23 phenotypic variables known to be associated with maturity trait were integrated using multivariate analysis with expectation of identifying relevant genes-phenotypic variable relationships involved in intestinal maturation. Results: A moderate maternal genotype effect, but no paternal genotype effect, was observed on offspring intestinal maturation. Four hundred and four differentially expressed probes, corresponding to 274 differentially expressed genes (DEGs), more specifically involved in the maturation process were further studied. In day 110-MS fetuses, Ingenuity® functional enrichment analysis revealed that 46% of DEGs were involved in glucose and lipid metabolism, cell proliferation, vasculogenesis and hormone synthesis compared to day 90-MS fetuses. Expression of genes involved in immune pathways including phagocytosis, inflammation and defense processes was changed in day 110-LW compared to day 90-LW fetuses (corresponding to 13% of DEGs). The transcriptional regulator PPARGC1A was predicted to be an important regulator of differentially expressed genes in MS. Fetal blood fructose level, intestinal lactase activity and villous height were the best predicted phenotypic variables with probes mostly involved in lipid metabolism, carbohydrate metabolism and cellular movement biological pathways. [b]Conclusions[/b]: Collectively, our findings indicate that the neonatal maturity of pig intestine may rely on functional development of glucose and lipid metabolisms, immune phagocyte differentiation and inflammatory pathways. This process may partially be governed by PPARGC1A

Review. Divergent selection for residual feed intake in the growing pig

To view supplementary material for this article, please visit https:/doi.org/10.1017/S175173111600286XThis review summarizes the results from the INRA (Institut National de la Recherche Agronomique) divergent selection experiment on residual feed intake (RFI) in growing Large White pigs during nine generations of selection. It discusses the remaining challenges and perspectives for the improvement of feed efficiency in growing pigs. The impacts on growing pigs raised under standard conditions and in alternative situations such as heat stress, inflammatory challenges or lactation have been studied. After nine generations of selection, the divergent selection for RFI led to highly significant ( P<0.001) line differences for RFI (−165 g/day in the low RFI (LRFI) line compared with high RFI line) and daily feed intake (−270 g/day). Low responses wereobserved on growth rate (−12.8 g/day, P <0.05) and body composition (+0.9mm backfat thickness, P = 0.57; −2.64% lean meat content, P<0.001) with a marked response on feed conversion ratio (−0.32 kg feed/kg gain, P<0.001). Reduced ultimate pH and increased lightness of the meat ( P<0.001) were observed in LRFI pigs with minor impact on the sensory quality of the meat. These changes in meat quality were associated with changes of the muscular energy metabolism. Reduced maintenance energy requirements (−10% after five generations of selection) and activity (−21% of time standing after six generations of selection) of LRFI pigs greatly contributed to the gain in energy efficiency. However, the impact of selection for RFI on the protein metabolism of the pig remains unclear. Digestibility of energy and nutrients was not affected by selection, neither for pigs fed conventional diets nor for pigs fed high-fibre diets. A significant improvement of digestive efficiency could likely be achieved by selecting pigs on fibre diets. No convincing genetic or blood biomarker has been identified for explaining the differences in RFI, suggesting that pigs have various ways to achieve an efficient use of feed. No deleterious impact of the selection on the sow reproduction performance was observed. The resource allocation theory states that low RFI may reduce the ability to cope with stressors,via the reduction of a buffer compartment dedicated to responses to stress. None of the experiments focussed on the response of pigs to stress or challenges could confirm this theory. Understanding the relationships between RFI and responses to stress and energy demanding processes, as such immunity and lactation, remains a major challenge for a better understanding of the underlying biological mechanisms of the trait and to reconcile the experimental results with the resource allocation theory

The FunGenES Database: A Genomics Resource for Mouse Embryonic Stem Cell Differentiation

Embryonic stem (ES) cells have high self-renewal capacity and the potential to differentiate into a large variety of cell types. To investigate gene networks operating in pluripotent ES cells and their derivatives, the “Functional Genomics in Embryonic Stem Cells” consortium (FunGenES) has analyzed the transcriptome of mouse ES cells in eleven diverse settings representing sixty-seven experimental conditions. To better illustrate gene expression profiles in mouse ES cells, we have organized the results in an interactive database with a number of features and tools. Specifically, we have generated clusters of transcripts that behave the same way under the entire spectrum of the sixty-seven experimental conditions; we have assembled genes in groups according to their time of expression during successive days of ES cell differentiation; we have included expression profiles of specific gene classes such as transcription regulatory factors and Expressed Sequence Tags; transcripts have been arranged in “Expression Waves” and juxtaposed to genes with opposite or complementary expression patterns; we have designed search engines to display the expression profile of any transcript during ES cell differentiation; gene expression data have been organized in animated graphs of KEGG signaling and metabolic pathways; and finally, we have incorporated advanced functional annotations for individual genes or gene clusters of interest and links to microarray and genomic resources. The FunGenES database provides a comprehensive resource for studies into the biology of ES cells

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Prescriptions hors-AMM : comment en pratique les identifier, les encadrer, informer et les suivre ?

À la suite de l’affaire Médiator, et de la loi de sécurité sanitaire de décembre 2011, la prescription hors-autorisation de mise sur le marché (AMM) est une réelle préoccupation partagée par tous les acteurs de santé. Le hors-AMM au sens le plus strict est défini par toutes les prescriptions qui ne correspondent pas au résumé des caractéristiques du produit (RCP), en particulier celles qui sont en dehors des indications et des posologies définies par l’AMM, pour des raisons évidentes de sécurité. Les raisons de la prescription hors-AMM sont diverses, conscientes comme inconscientes, elles ont pour objectif de répondre d’une part aux besoins médicaux non couverts, à ceux des populations peu ou pas étudiées dans les essais mais chez lesquelles une extrapolation de l’AMM est raisonnable (prescriptions de bon sens), et d’autre part à des besoins de santé publique urgents (baclofène, femmes enceintes et médicaments du virus de l’immunodéficience humaine…). Toutes ces prescriptions mériteraient d’être étudiées en vue d’une AMM. Par contre, il existe des prescriptions hors-AMM qu’il faut limiter voire sanctionner quand il s’agit de prescriptions compassionnelles, de complaisance et/ou ne reposant sur aucun fondement scientifique. Les prescriptions hors-AMM ne sont pas faciles à dépister car si le prescripteur est tenu d’écrire la mention « hors-AMM » sur son ordonnance lorsqu’il se livre à ce type de prescription, force est de constater qu’en pratique il ne le fait qu’exceptionnellement. Les pharmaciens qui délivrent le médicament tout comme les caisses d’assurance maladie qui le remboursent, n’ont pas accès au diagnostic (ou l’indication visée) ; il faut donc, pour les identifier, avoir recours au croisement des bases de données à notre disposition (pharmacovigilance, programme de médicalisation des systèmes d’information [PMSI], livret thérapeutique hospitalier, échantillon généraliste des bénéficaires de l’Assurance maladie [EGB] ou système national d’information inter régions [SNIIRAM], données de ventes, d’études de marché…). Le dossier patient informatisé partagé par tous résoudra possiblement cette problématique. Le dispositif de recommandation temporaire d’utilisation (RTU) proposé par la loi de sécurité du médicament ne répondra à cette problématique qu’en partie pour les molécules récemment commercialisées (extension d’indication). Ce dispositif dérogatoire et transitoire autorisera une prescription hors-AMM reconnue, possiblement remboursée et surveillée pendant 3 ans. Ces RTU concerneront la faible partie du « hors-AMM » qui dispose de preuves d’une balance bénéfice-risque positive (AMM conditionnelle anciennement protocole thérapeutique temporaire [PTT]) mais ceci est loin de viser la majorité des prescriptions hors-AMM. De ce fait et afin d’améliorer le bon usage des médicaments, il apparait important de proposer un système d’encadrement de tout le « hors-AMM » à l’aide d’une commission dédiée : la commission du « hors-AMM » qui permettra de conduire à des recommandations d’utilisation (RU) ou non