Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimers Disease

The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD

Editorial: Ralstonia solanacearum-Plant Interactions: Plant Defense Responses, Virulence Mechanisms and Signaling Pathways

In the Research Topic Ralstonia solanacearum-Plant Interactions: Plant Defense Responses, Virulence Mechanisms and Signaling Pathways, we aimed to collect manuscripts dealing with not only molecular mechanisms of R. solanacearum virulence and host responses but also development of the disease control system such as the disease-resistance cultivars and microbial inoculants..

A luminescent reporter evidences active expression of Ralstonia solanacearum type III secretion system genes throughout plant infection

Although much is known about the signals that trigger transcription of virulence genes in plant pathogens, their prevalence and timing during infection are still unknown. In this work, we address these questions by analysing expression of the main pathogenicity determinants in the bacterial pathogen Ralstonia solanacearum. We set up a quantitative, non-invasive luminescent reporter to monitor in planta transcription from single promoters in the bacterial chromosome. We show that the new reporter provides a real-time measure of promoter output in vivo – either after re-isolation of pathogens from infected plants or directly in situ – and confirm that the promoter controlling exopolysaccharide (EPS) synthesis is active in bacteria growing in the xylem. We also provide evidence that hrpB, the master regulator of type III secretion system (T3SS) genes, is transcribed in symptomatic plants. Quantitative RT-PCR assays demonstrate that hrpB and type III effector transcripts are abundant at late stages of plant infection, suggesting that their function is required throughout disease. Our results challenge the widespread view in R. solanacearum pathogenicity that the T3SS, and thus injection of effector proteins, is only active to manipulate plant defences at the first stages of infection, and that its expression is turned down when bacteria reach high cell densities and EPS synthesis starts.F. M. held a PhD fellowship from the Fundação para a Ciência e a Tecnologia (RFRH/BD/45850/2008). This work was supported by grants from Comissionat per Universitats i Recerca of the Generalitat de Catalunya (SGR0052 and CONES2010-0030) and from the Ministerio de Ciencia, Tecnología e Innovación of the Spanish Government (HF2008-0021 and AGL2010-21870). S. G. is part of the ‘Laboratoire d’Excellence’ (LABEX) entitled TULIP (ANR-10-LABX-41).Peer reviewe

Multi-organ genome-scale metabolic modeling of tomato plant

International audiencePlant growth relies on a division of physiological roles between organs: assimilation of soil nutrients and water is performed by root while synthesis of organic carbon from CO2 is performed by photosynthetic tissues. The plant saps allow exchanges between the two organs: ascending xylem sap transmits root products and nutrients extracted from the soil to the aerial parts of the plant while descending phloem sap gives organic carbon to the roots. Representing each organ and their respective role is thus important to accurately predict the effect of external (ex: nutrition) or internal (ex: mutations) perturbations on the physiology of the plant. We developed a multi-organ genome-scale metabolic model of tomato plant (Solanum lycopersicum). The model combines networks of leaf, stem and root. Exchanges are performed by xylem and phloem sap. Our model was intensively calibrated with experiments we performed at various scales, gathering physiological data (growth, transpiration) and metabolomics (biomass composition, xylem sap chemistry). This model allowed us to explore the metabolic flux distribution in different organs and to study for the first time the organic composition of sap fluxes. Physiological properties of the organs (growth rates, ratios) allowed to predict key properties of xylem sap, such as the predominance of glutamine, suggesting that these properties are majorly driven by plant physiology. We also used our model to predict plant responses to different perturbations. First, we examined the effects of nitrogen nutrition on growth, and then the impact on metabolic fluxes of reduced mitochondrial citrate synthase activity in a transgenic tomato line. In both cases, the predictions were consistent with experimental studies, showing that our model is accurate and thus a useful tool to decipher how internal or external perturbations impact the whole plant

Multi-organ genome-scale metabolic modeling of tomato plant

International audiencePlant growth relies on a division of physiological roles between organs: assimilation of soil nutrients and water is performed by root while synthesis of organic carbon from CO2 is performed by photosynthetic tissues. The plant saps allow exchanges between the two organs: ascending xylem sap transmits root products and nutrients extracted from the soil to the aerial parts of the plant while descending phloem sap gives organic carbon to the roots. Representing each organ and their respective role is thus important to accurately predict the effect of external (ex: nutrition) or internal (ex: mutations) perturbations on the physiology of the plant. We developed a multi-organ genome-scale metabolic model of tomato plant (Solanum lycopersicum). The model combines networks of leaf, stem and root. Exchanges are performed by xylem and phloem sap. Our model was intensively calibrated with experiments we performed at various scales, gathering physiological data (growth, transpiration) and metabolomics (biomass composition, xylem sap chemistry). This model allowed us to explore the metabolic flux distribution in different organs and to study for the first time the organic composition of sap fluxes. Physiological properties of the organs (growth rates, ratios) allowed to predict key properties of xylem sap, such as the predominance of glutamine, suggesting that these properties are majorly driven by plant physiology. We also used our model to predict plant responses to different perturbations. First, we examined the effects of nitrogen nutrition on growth, and then the impact on metabolic fluxes of reduced mitochondrial citrate synthase activity in a transgenic tomato line. In both cases, the predictions were consistent with experimental studies, showing that our model is accurate and thus a useful tool to decipher how internal or external perturbations impact the whole plant

rpoN1, but not rpoN2, is required for twitching motility, natural competence, growth on nitrate, and virulence of Ralstonia solanacearum

The plant pathogen Ralstonia solanacearum has two genes encoding for the sigma factor sigma(54): rpoN1, located in the chromosome and rpoN2, located in a distinct "megaplasmid" replicon. In this study, individual mutants as well as a double mutant of rpoN were created in R. solanacearum strain GM 11000 in order to determine the extent of functional overlap between these two genes. By virulence assay we observed that rpoN1 is required for virulence whereas rpoN2 is not. In addition rpoN1 controls other important functions such twitching motility, natural transformation and growth on nitrate, unlike rpoN2. The rpoN1 and rpoN2 genes have different expression pattern, the expression of rpoN1 being constitutive whereas rpoN2 expression is induced in minimal medium and in the presence of plant cells. Moreover, the expression of rpoN2 is dependent upon rpoN1 Our work therefore reveals that the two rpoN genes are not functionally redundant in R. solanacearum. A list of potential sigma(54) targets was identified in the R. solanacearum genome and suggests that multiple traits are under the control of these regulators. Based on these findings, we provide a model describing the functional connection between RpoN1 and the PehR pathogenicity regulator and their dual role in the control of several R. solanacearum virulence determinants

Repertoire, unified nomenclature and evolution of the Type III effector gene set in the Ralstonia solanacearum species complex

Background Ralstonia solanacearum is a soil-borne beta-proteobacterium that causes bacterial wilt disease in many food crops and is a major problem for agriculture in intertropical regions. R. solanacearum is a heterogeneous species, both phenotypically and genetically, and is considered as a species complex. Pathogenicity of R. solanacearum relies on the Type III secretion system that injects Type III effector (T3E) proteins into plant cells. T3E collectively perturb host cell processes and modulate plant immunity to enable bacterial infection. Results We provide the catalogue of T3E in the R. solanacearum species complex, as well as candidates in newly sequenced strains. 94 T3E orthologous groups were defined on phylogenetic bases and ordered using a uniform nomenclature. This curated T3E catalog is available on a public website and a bioinformatic pipeline has been designed to rapidly predict T3E genes in newly sequenced strains. Systematical analyses were performed to detect lateral T3E gene transfer events and identify T3E genes under positive selection. Our analyses also pinpoint the RipF translocon proteins as major discriminating determinants among the phylogenetic lineages. Conclusions Establishment of T3E repertoires in strains representatives of the R. solanacearum biodiversity allowed determining a set of 22 T3E present in all the strains but provided no clues on host specificity determinants. The definition of a standardized nomenclature and the optimization of predictive tools will pave the way to understanding how variation of these repertoires is correlated to the diversification of this species complex and how they contribute to the different strain pathotypes.ISSN:1471-216