Identification des gènes modifiant l'âge d'apparition du glaucome primaire à angle-ouvert dans une famille canadienne-française fondatrice.

Le glaucome est un groupe hétérogène de maladies qui sont caractérisées par l'apoptose des cellules ganglionnaires de la rétine et la dégénérescence progressive du nerf optique. Il s’agit de la première cause de cécité irréversible, qui touche environ 60 millions de personnes dans le monde. Sa forme la plus commune est le glaucome à angle ouvert (GAO), un trouble polygénique causé principalement par une prédisposition génétique, en interaction avec d'autres facteurs de risque tels que l'âge et la pression intraoculaire élevée (PIO). Le GAO est une maladie génétique complexe, bien que certaines formes sévères sont autosomiques dominantes. Dix-sept loci ont été liés à la maladie et acceptés par la « Human Genome Organisation » (HUGO) et cinq gènes ont été identifiés à ces loci (MYOC, OPTN, WDR36, NTF4, ASB10). Récemment, des études d’association sur l’ensemble du génome ont identifié plus de 20 facteurs de risque fréquents, avec des effets relativement faibles. Depuis plus de 50 ans, notre équipe étudie 749 membres de la grande famille canadienne-française CA où la mutation MYOCK423E cause une forme autosomale dominante de GAO dont l’âge de début est fortement variable. Premièrement, il a été montré que cette variabilité de l’âge de début de l'hypertension intraoculaire possède une importante composante génétique causée par au moins un gène modificateur. Ce modificateur interagit avec la mutation primaire et altère la sévérité du glaucome chez les porteurs de MYOCK423E. Un gène modificateur candidat WDR36 a été génotypé dans 2 grandes familles CA et BV. Les porteurs de variations non-synonymes de WDR36 ainsi que de MYOCK423E de la famille CA ont montré une tendance à développer la maladie plus jeune. Un outil de forage de données a été développé pour représenter des informations connues relatives à la maladie et faciliter la priorisation des gènes candidats. Cet outil a été appliqué avec succès à la dépression bipolaire et au glaucome. La suite du projet consiste à finaliser un balayage de génome sur la famille CA et à séquencer les loci afin d’identifier les variations modificatrices du glaucome. Éventuellement, ces variations permettront d’identifier les individus dont le glaucome risque d’être plus agressif.Glaucoma, which is a group of ocular disorders, is characterized by optic nerve atrophy following progressive loss of retinal ganglion cells. It is the leading cause of blindness worldwide which is affecting an estimated 60 million people worldwide. Open angle glaucoma (OAG), the common form of glaucoma, is a polygenic disorder caused mainly by genetic predisposition, in interaction with other risk factors such as age and elevated intraocular pressure (IOP). OAG is a complex genetic disease, although some severe forms are simply autosomal dominant. Seventeen loci were shown to be associated with the disease and are reported by the «Human Genome Organisation» HUGO and five genes have been identified in those loci (MYOC, OPTN, WDR36, NTF4, ASB10). Recently, genome-wide association studies have found more than 20 frequent risk factors with relatively small effects. For more than 50 years, our team have been studying the CA family, a large French-Canadian pedigree (749 people), in which autosomal OAG is caused by the MYOCK423E mutation which is characterised by variable age at onset. It has been demonstrated that the variability of the age at beginning of ocular hypertension has an important genetic component caused by at least one modifier gene. A potential modifier gene, WDR36, has been genotyped in families CA and BV. In the CA family, carriers of non-synonymous WDR36 variations which are also carriers of MYOCK423E, have shown a tendency to develop the disease younger. This modifier interacts with the primary mutation and alters the severity of glaucoma for MYOCK423E mutation carriers. A data-mining tool has been developed to generate graphical diagram of a disease causal model and facilitate the prioritization of the candidate genes. It has been successfully used for bipolar disorder and glaucoma. The next step for this project is to finalize a genome scan of the CA family and to sequence loci with the goal of identifying glaucoma modifier variations. Those variations could potentially allow identification of the individuals for whom glaucoma could be far more aggressive

Accurate and robust inference of genetic ancestry from cancer-derived molecular data across genomic platforms

Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we develop a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Testing our approach for three representative cancer types, and across three molecular profiling modalities, we demonstrate that global, continental-level ancestry of the patient can be inferred with high accuracy, as quantified by its agreement with the golden standard of the ancestry derived from matching cancer-free molecular data. Our study demonstrates that vast amounts of existing cancer-derived molecular data potentially are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients’ self-identification by ancestry

Genetic ancestry inference from cancer-derived molecular data across genomic and transcriptomic platforms

Genetic ancestry-oriented cancer research requires the ability to perform accurate and robust genetic ancestry inference from existing cancer-derived data, including whole exome sequencing, transcriptome sequencing, and targeted gene panels, very often in the absence of matching cancer-free genomic data. Here we examined the feasibility and accuracy of computational inference of genetic ancestry relying exclusively on cancer-derived data. A data synthesis framework was developed to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. The data synthesis framework is applicable to multiple profiling platforms, making it possible to assess the performance of inference specifically for a given molecular profile and separately for each continental-level ancestry; this ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. The inference procedure was demonstrated to be accurate and robust in a wide range of sequencing depths. Testing of the approach in four representative cancer types and across three molecular profiling modalities showed that continental-level ancestry of patients can be inferred with high accuracy, as quantified by its agreement with the gold standard of deriving ancestry from matching cancer-free molecular data. This study demonstrates that vast amounts of existing cancer-derived molecular data are potentially amenable to ancestry-oriented studies of the disease without requiring matching cancer-free genomes or patient self-reported ancestry

Insights into the role of the berry-specific ethylene responsive factor VviERF045

During grape ripening, numerous transcriptional and metabolic changes are required in order to obtain colored, sweet, and flavored berries. There is evidence that ethylene, together with other signals, plays an important role in triggering the onset of ripening. Here, we report the functional characterization of a berry-specific Ethylene Responsive Factor (ERF), VviERF045, which is induced just before véraison and peaks at ripening. Phylogenetic analysis revealed it is close to the SHINE clade of ERFs, factors involved in the regulation of wax biosynthesis and cuticle morphology. Transgenic grapevines lines overexpressing VviERF045 were obtained, in vitro propagated, phenotypically characterized, and analyzed for the content of specific classes of metabolites. The effect of VviERF045 was correlated with the level of transgene expression, with highexpressing lines showing stunted growth, discolored and smaller leaves, and a lower level of chlorophylls and carotenoids. One line with intermediate expression, L15, was characterized at the transcriptomic level and showed 573 differentially expressed genes compared to wild type plants. Microscopy and gene expression analyses point toward a major role of VviERF045 in epidermis patterning by acting on waxes and cuticle. They also indicate that VviERF045 affects phenolic secondary metabolism and induces a reaction resembling a plant immune response with modulation of receptor likekinases and pathogen related genes. These results suggest also a possible role of this transcription factor in berry ripening, likely related to changes in epidermis and cuticle of the berry, cell expansion, a decrease in photosynthetic capacity, and the activation of several defense related genes as well as from the phenylpropanoid metabolism. All these processes occur in the berry during ripening.CL was supported by the Marie Curie FP7-PEOPLE-2011-CIG action program- [Graperipe project n. 303907]. Network activities have been supported by COST1106 action.Leida, C.; Dal Rì, A.; Dalla Costa, L.; Gómez Jiménez, MD.; Pompili, V.; Sonego, P.; Engelen, K.... (2016). Insights into the role of the berry-specific ethylene responsive factor VviERF045. Frontiers in Plant Science. 7(1793):1-17. https://doi.org/10.3389/fpls.2016.01793S1177179

Le Chemin de l’Univers.

Le « Chemin de l’Univers » est une exposition permanente composée de 27 panneaux / posters qui présenteront différents objets observés et/ou détectés dans l’Univers. Ces objets seront décrits successivement, selon leur distance croissante par rapport à la Terre. Les panneaux seront installés sur la commune de La Couyère (Ille-et-Vilaine, France)

PITX2 Is Involved in Stress Response in Cultured Human Trabecular Meshwork Cells through Regulation of SLC13A3

The development of glaucoma in patients with Axenfeld-Rieger syndrome may be a distinct consequence of PITX2 mutation separate from the congenital structural defects that manifest in the anterior segment. The authors investigated a target gene of PITX2 regulation that may account for late-onset glaucoma due to oxidative stress