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A chemo-centric view of human health and disease.

ABSTRACT: Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here we consider thousands of chemicals and analyse the relationship of their structures with adverse and therapeutic responses. Our study includes molecules related to the aetiology of 934 health-threatening conditions and used to treat 835 diseases. We first identify chemical moieties that could be independently associated with each phenotypic effect. Using these fragments, we build accurate predictors for approximately 400 clinical phenotypes, finding many privileged and liable structures. Finally, we connect two diseases if they relate to similar chemical structures. The resulting networks of human conditions are able to predict disease comorbidities, as well as identifying potential drug side effects and opportunities for drug repositioning, and show a remarkable coincidence with clinical observations.

SUBMITTER: Duran-Frigola M

PROVIDER: S-EPMC4338530 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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A chemo-centric view of human health and disease.

Duran-Frigola Miquel M Rossell David D Aloy Patrick P

Nature communications 20141201

Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here we consider thousands of chemicals and analyse the relationship of their structures with adverse and therapeutic responses. Our study includes molecules related to the aetiology of 934 health-threatening conditions and used to treat 835 diseases. We first identify chemical moieties that coul ...[more]

PMID: 25435099

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Project description:BackgroundGenome-scale metabolic models are important tools in systems biology. They permit the in-silico prediction of cellular phenotypes via mathematical optimisation procedures, most importantly flux balance analysis. Current studies on metabolic models mostly consider reaction fluxes in isolation. Based on a recently proposed metabolite-centric approach, we here describe a set of methods that enable the analysis and interpretation of flux distributions in an integrated metabolite-centric view. We demonstrate how this framework can be used for the refinement of genome-scale metabolic models.ResultsWe applied the metabolite-centric view developed here to the most recent metabolic reconstruction of Escherichia coli. By compiling the balance sheets of a small number of currency metabolites, we were able to fully characterise the energy metabolism as predicted by the model and to identify a possibility for model refinement in NADPH metabolism. Selected branch points were examined in detail in order to demonstrate how a metabolite-centric view allows identifying functional roles of metabolites. Fructose 6-phosphate aldolase and the sedoheptulose bisphosphate bypass were identified as enzymatic reactions that can carry high fluxes in the model but are unlikely to exhibit significant activity in vivo. Performing a metabolite essentiality analysis, unconstrained import and export of iron ions could be identified as potentially problematic for the quality of model predictions.ConclusionsThe system-wide analysis of split ratios and branch points allows a much deeper insight into the metabolic network than reaction-centric analyses. Extending an earlier metabolite-centric approach, the methods introduced here establish an integrated metabolite-centric framework for the interpretation of flux distributions in genome-scale metabolic networks that can complement the classical reaction-centric framework. Analysing fluxes and their metabolic context simultaneously opens the door to systems biological interpretations that are not apparent from isolated reaction fluxes. Particularly powerful demonstrations of this are the analyses of the complete metabolic contexts of energy metabolism and the folate-dependent one-carbon pool presented in this work. Finally, a metabolite-centric view on flux distributions can guide the refinement of metabolic reconstructions for specific growth scenarios.

Project description:Both climatic and edaphic conditions determine plant distribution, however many species distribution models do not include edaphic variables especially over large geographical extent. Using an exceptional database of vegetation plots (n?=?4839) covering an extent of ?55,000 km2, we tested whether the inclusion of fine scale edaphic variables would improve model predictions of plant distribution compared to models using only climate predictors. We also tested how well these edaphic variables could predict distribution on their own, to evaluate the assumption that at large extents, distribution is governed largely by climate. We also hypothesized that the relative contribution of edaphic and climatic data would vary among species depending on their growth forms and biogeographical attributes within the study area. We modelled 128 native plant species from diverse taxa using four statistical model types and three sets of abiotic predictors: climate, edaphic, and edaphic-climate. Model predictive accuracy and variable importance were compared among these models and for species' characteristics describing growth form, range boundaries within the study area, and prevalence. For many species both the climate-only and edaphic-only models performed well, however the edaphic-climate models generally performed best. The three sets of predictors differed in the spatial information provided about habitat suitability, with climate models able to distinguish range edges, but edaphic models able to better distinguish within-range variation. Model predictive accuracy was generally lower for species without a range boundary within the study area and for common species, but these effects were buffered by including both edaphic and climatic predictors. The relative importance of edaphic and climatic variables varied with growth forms, with trees being more related to climate whereas lower growth forms were more related to edaphic conditions. Our study identifies the potential for non-climate aspects of the environment to pose a constraint to range expansion under climate change.

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A chemo-centric view of human health and disease.

Publications

A chemo-centric view of human health and disease.

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