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Title: Likelihood-based gene annotations for gap filling and quality assessment in genome-scale metabolic models

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-basedmore » 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.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6]
  1. Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States). Dept. of Chemical and Biomolecular Engineering.
  2. Mayo Clinic, Rochester, MN (United States). Center for Individualized Medicine.
  3. Argonne National Lab. (ANL), Lement, IL (United States). Mathematics and Computer Science Division.
  4. Mayo Clinic, Rochester, MN (United States). Center for Individualized Medicine, Depts. of Surgery and Physiology and Bioengineering.
  5. Univ. of Illinois at Urbana-Champaign, Urbana, IL (United States). Dept. of Chemical and Biomolecular Engineering; Inst. for Systems Biology, Seattle, WA (United States)
  6. Pennsylvania State Univ., University Park, PA (US)
Publication Date:
OSTI Identifier:
1212409
Grant/Contract Number:
FG02-10ER64999; AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 10; Journal Issue: 10; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES genomic databases; metabolic networks; drug metabolism; sequence databases; web-based applications; genome annotation; genetic networks; simulation and modeling