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How accurate is automated gap filling of metabolic models?

ABSTRACT: BACKGROUND:Reaction gap filling is a computational technique for proposing the addition of reactions to genome-scale metabolic models to permit those models to run correctly. Gap filling completes what are otherwise incomplete models that lack fully connected metabolic networks. The models are incomplete because they are derived from annotated genomes in which not all enzymes have been identified. Here we compare the results of applying an automated likelihood-based gap filler within the Pathway Tools software with the results of manually gap filling the same metabolic model. Both gap-filling exercises were applied to the same genome-derived qualitative metabolic reconstruction for Bifidobacterium longum subsp. longum JCM 1217, and to the same modeling conditions - anaerobic growth under four nutrients producing 53 biomass metabolites. RESULTS:The solution computed by the gap-filling program GenDev contained 12 reactions, but closer examination showed that solution was not minimal; two of the twelve reactions can be removed to yield a set of ten reactions that enable model growth. The manually curated solution contained 13 reactions, eight of which were shared with the 12-reaction computed solution. Thus, GenDev achieved recall of 61.5% and precision of 66.6%. These results suggest that although computational gap fillers are populating metabolic models with significant numbers of correct reactions, automatically gap-filled metabolic models also contain significant numbers of incorrect reactions. CONCLUSIONS:Our conclusion is that manual curation of gap-filler results is needed to obtain high-accuracy models. Many of the differences between the manual and automatic solutions resulted from using expert biological knowledge to direct the choice of reactions within the curated solution, such as reactions specific to the anaerobic lifestyle of B. longum.

SUBMITTER: Karp PD

PROVIDER: S-EPMC6006690 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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How accurate is automated gap filling of metabolic models?

Karp Peter D PD Weaver Daniel D Latendresse Mario M

BMC systems biology 20180619 1

<h4>Background</h4>Reaction gap filling is a computational technique for proposing the addition of reactions to genome-scale metabolic models to permit those models to run correctly. Gap filling completes what are otherwise incomplete models that lack fully connected metabolic networks. The models are incomplete because they are derived from annotated genomes in which not all enzymes have been identified. Here we compare the results of applying an automated likelihood-based gap filler within the ...[more]

PMID: 29914471

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Project description:Genome-scale metabolic models provide a powerful means to harness information from genomes to deepen biological insights. With exponentially increasing sequencing capacity, there is an enormous need for automated reconstruction techniques that can provide more accurate models in a short time frame. Current methods for automated metabolic network reconstruction rely on gene and reaction annotations to build draft metabolic networks and algorithms to fill gaps in these networks. However, automated reconstruction is hampered by database inconsistencies, incorrect annotations, and gap filling largely without considering genomic information. Here we develop an approach for applying genomic information to predict alternative functions for genes and estimate their likelihoods from sequence homology. We show that computed likelihood values were significantly higher for annotations found in manually curated metabolic networks than those that were not. We then apply these alternative functional predictions to estimate reaction likelihoods, which are used in a new gap filling approach called likelihood-based gap filling to predict more genomically consistent solutions. To validate the likelihood-based gap filling approach, we applied it to models where essential pathways were removed, finding that likelihood-based gap filling identified more biologically relevant solutions than parsimony-based gap filling approaches. We also demonstrate that models gap filled using likelihood-based gap filling provide greater coverage and genomic consistency with metabolic gene functions compared to parsimony-based approaches. Interestingly, despite these findings, we found that likelihoods did not significantly affect consistency of gap filled models with Biolog and knockout lethality data. This indicates that the phenotype data alone cannot necessarily be used to discriminate between alternative solutions for gap filling and therefore, that the use of other information is necessary to obtain a more accurate network. All described workflows are implemented as part of the DOE Systems Biology Knowledgebase (KBase) and are publicly available via API or command-line web interface.

Project description:Increasing amounts of sequence data are becoming available for a wide range of non-model organisms. Investigating and modelling the metabolic behaviour of those organisms is highly relevant to understand their biology and ecology. As sequences are often incomplete and poorly annotated, draft networks of their metabolism largely suffer from incompleteness. Appropriate gap-filling methods to identify and add missing reactions are therefore required to address this issue. However, current tools rely on phenotypic or taxonomic information, or are very sensitive to the stoichiometric balance of metabolic reactions, especially concerning the co-factors. This type of information is often not available or at least prone to errors for newly-explored organisms. Here we introduce Meneco, a tool dedicated to the topological gap-filling of genome-scale draft metabolic networks. Meneco reformulates gap-filling as a qualitative combinatorial optimization problem, omitting constraints raised by the stoichiometry of a metabolic network considered in other methods, and solves this problem using Answer Set Programming. Run on several artificial test sets gathering 10,800 degraded Escherichia coli networks Meneco was able to efficiently identify essential reactions missing in networks at high degradation rates, outperforming the stoichiometry-based tools in scalability. To demonstrate the utility of Meneco we applied it to two case studies. Its application to recent metabolic networks reconstructed for the brown algal model Ectocarpus siliculosus and an associated bacterium Candidatus Phaeomarinobacter ectocarpi revealed several candidate metabolic pathways for algal-bacterial interactions. Then Meneco was used to reconstruct, from transcriptomic and metabolomic data, the first metabolic network for the microalga Euglena mutabilis. These two case studies show that Meneco is a versatile tool to complete draft genome-scale metabolic networks produced from heterogeneous data, and to suggest relevant reactions that explain the metabolic capacity of a biological system.

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How accurate is automated gap filling of metabolic models?

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How accurate is automated gap filling of metabolic models?

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