Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

diatSOM : un package R pour la biotypologie des communautés de diatomées à l'aide des cartes auto-organisantes

International audienceOwing to the high complexity of diatom community data, there is a special need for methods accounting for complex non-linear gradients. A Kohonen’s self-organizing map (SOM) is a neural network with unsupervised learning. It allows both unbiased classification of the communities and visualization of biological gradients on a two-dimensional plane. However, as with other neural networks, many parameters must be set. A new R-package with a SOM parameterization specifically suited to diatom communities has been developed. Further developments will consist of creating a graphical user interface in order to make this method easier to use for the scientific community

Application of the Self Organizing Map algorithm combined with the Structuring Index to classify stream diatoms communities

[Departement_IRSTEA]GMA [TR1_IRSTEA]12 - MILEAU / ALTERMILIn the field of understanding the relationships between environmental conditions and stream biological assemblages, the aim of the present research was to demonstrate on a pilot data-set the efficiency of using the association of the Self Organizing Map algorithm (Kohonen, 1995) and the Structuring Index (Giraudel, submitted) to classify different ecological conditions and to select the most relevant species (called "structuring species") influencing this typology. Diatoms, water chemistry, stream physical parameters were characterised for 49 reference stations spread over the Adour-Garonne basin (South-Western France). This dataset allowed us to carry on diatom-based stream classification with Self Organizing Maps (SOM), knowing that this methodology has already been successfully used in ecology for community patternising (Foody, 1999 ; Giraudel, 2001 ; Cereghino et al., 2001 ; Brosse et al., 2001), but not yet for benthic algae. The typology obtained was confronted with the corresponding physico-chemical parameters in order to assess relationships between biotic and abiotic descriptors, and then to meet the Water Framework Directive (WFD) requirements concerning stream ecoregional classification. In this way, four main ecoregions were characterised. As SOM enables the observation of each species distribution according to environmental gradients, a specific work has also been led to improve existing ecological profiles (Daget & Godron 1982). This method appeared to be very powerful and promising concerning advances in diatom-based bio-assessment methods. The last part of the work consisted in the selection of relevant diatom species with regards to stream ecotypes. The Structuring Index, a new mathematical tool, allowed us to reach this objective

Application of the Self Organizing Map algorithm combined with the Structuring Index to classify stream diatoms communities

[Departement_IRSTEA]GMA [TR1_IRSTEA]12 - MILEAU / ALTERMILIn the field of understanding the relationships between environmental conditions and stream biological assemblages, the aim of the present research was to demonstrate on a pilot data-set the efficiency of using the association of the Self Organizing Map algorithm (Kohonen, 1995) and the Structuring Index (Giraudel, submitted) to classify different ecological conditions and to select the most relevant species (called "structuring species") influencing this typology. Diatoms, water chemistry, stream physical parameters were characterised for 49 reference stations spread over the Adour-Garonne basin (South-Western France). This dataset allowed us to carry on diatom-based stream classification with Self Organizing Maps (SOM), knowing that this methodology has already been successfully used in ecology for community patternising (Foody, 1999 ; Giraudel, 2001 ; Cereghino et al., 2001 ; Brosse et al., 2001), but not yet for benthic algae. The typology obtained was confronted with the corresponding physico-chemical parameters in order to assess relationships between biotic and abiotic descriptors, and then to meet the Water Framework Directive (WFD) requirements concerning stream ecoregional classification. In this way, four main ecoregions were characterised. As SOM enables the observation of each species distribution according to environmental gradients, a specific work has also been led to improve existing ecological profiles (Daget & Godron 1982). This method appeared to be very powerful and promising concerning advances in diatom-based bio-assessment methods. The last part of the work consisted in the selection of relevant diatom species with regards to stream ecotypes. The Structuring Index, a new mathematical tool, allowed us to reach this objective

An easy-to-use package for ordination of diatom assemblages using Self-Organizing Kohonen Maps

International audienceFrom about fifteen years, diatoms are routinely used for the ecological status assessment of rivers. Nevertheless classically used diatom indexes don't allow a really fine diagnosis of each type of pollution, furthermore they poorly integer temporal or spatial variation in natural conditions. The aim of this work is then to use new biomathematical methods in order to test their relevance towards diagnosis of ecological quality

High production going along with high respiration: impact of biofilm formation for sea-ice biogeochemistry

While representing less than 5% of the total ice cover around Antarctica, landfast sea ice is nevertheless an important habitat known to exhibit high biomass levels at the ocean/ice interface, with particulate organic carbon (POC) concentrations easily reaching 2000 μmol C L–1 during spring bloom. Surprisingly, together with the POC increase in bottom ice, fieldwork measurements performed in East Antarctica (Adélie Land 2011, McMurdo Sound 2012, Prydz Bay 2015) of nitrate and phosphate concentrations report a simultaneous increase with concentrations exceeding those of underlying seawater, suggesting an intense remineralization and nitrification processes within the ice. This goes against the classic view of nutrients being consumed during the growth season and regenerated after the height of the bloom. Regardless of the high nitrate levels available in the ice, increasing total nitrogen concentrations also suggest still more nitrogen from the underlying seawater was brought into the ice. Results of a NPZD-model indicates that a second nutrient pool, in addition to the brine pool, is essential to successfully model and reproduce field observations. The presence of a biofilm attached to the ice walls could act as a water-retaining substrate forming microenvironments with chemical gradients within the brine channels. The effect of biofilm on nitrogen dynamics (concentration and isotopic composition) in sea ice will be discussed as well as potential implications for other parameters (phosphate, carbon, oxygen). This calls for the integration of the biofilm concept into the current view of sea-ice biogeochemistry

Use of unsupervised neural networks for ecoregional zoning of hydrosystems through diatom communities: case study of Adour-Garonne watershed (France)

[Departement_IRSTEA]MA [TR1_IRSTEA]QSA / DYNAQInternational audienceKnowing that diatoms are good indicators of stream ecological conditions, the aim of our research program was to test on a pilot data-set the interest and efficiency of using a Self-Organizing Map (SOM) as an ordination technique to determine and to classify types of river ecosystems. Such neural networks have already been successfully used for other aquatic communities patterning. Diatoms, water chemistry and stream morpho-dynamical parameters were characterised for 49 non impacted sampling stations spread over the Adour-Garonne watershed (South-Western France). Combining the SOM to the Structuring Index we selected in a second step the most relevant species (called "structuring species") influencing this typology. In this way, three main homogeneous regions were characterised, as regards to diatom communities and abiotic parameters, allowing us to meet the Water Framework Directive requirements concerning stream ecoregional classification

Distribution and biogeochemical behaviour of iron in the East Antarctic sea ice

We have attempted to evaluate the relative importance, compared to other possible sources, of sea ice in supplying Fe to East Antarctic surface ocean waters. Samples of snow, brine, seawater and sea ice were collected and processed for Fe analysis during the "ARISE in the East" Antarctic cruise during September-October 2003 (64°-65°S/112°-119°E, RV Aurora Australis). Total-dissolvable and dissolved Fe concentrations were measured together with relevant physical, chemical and biological parameters. The most striking feature we observed is that total-dissolvable Fe concentrations in sea ice were up to an order of magnitude higher than those measured in the underlying seawater. Moreover, total-dissolvable Fe in sea ice is more concentrated at cold "winter" type stations than at the warm "spring" ones. This probably results from the enhanced ice permeability as spring arrives, which allows brine drainage within the ice cover and renders exchanges with the water column possible. During the melting period, iron inputs to surface waters from sea ice may represent as much as 70% of the estimated daily total flux into surface seawater when taking into account available data on dust deposition, extraterrestrial iron, vertical diffusion and upwelling. Our results highlight the potentially important contribution of pack ice to the Fe biogeochemical cycle in the East Antarctic oceanic Ecosystem