Last major update of page content: (see log): April 21, 2006 11:35

 


Computational modeling of the Plasmodium falciparum interactome
reveals protein function on a genome-wide scale


Shailesh V. Date* and Christian J. Stoeckert, Jr
Center for Bioinformatics, Department of Genetics,
School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.

*Please address all correspondence to:

Companion website | Version 1.0

Abstract

Many thousands of proteins encoded by the genome of Plasmodium falciparum, the causal organism of the deadliest form of human malaria, are of unknown function. It is of utmost importance that these proteins be characterized if we are to develop combative strategies against malaria based on the biology of the parasite. In an attempt to infer protein function on a genome-wide scale, we computationally modeled the P. falciparum interactome, elucidating local and global functional relationships between gene products. The resulting interaction network, reconstructed by integrating in silico and experimental functional genomics data within a Bayesian framework, covers ~68% of the parasite genome and provides functional inferences for more than 2000 uncharacterized proteins, based on their associations. Network reconstruction involved the use of a novel strategy, where we incorporated continuously updated, uniform reference priors in our Bayesian model. This method for generating interaction maps is thus also well suited for application to other genomes, where pre-existing interactome knowledge is sparse. Additionally, we superimposed this map on genomes of three apicomplexan pathogens Plasmodium yoelii, Toxoplasma gondii, and Cryptosporidium parvum describing relationships between these organisms based on retained functional linkages. This comparison provided a glimpse of the highly evolved nature of P. falciparum; for instance, a deficit of nearly 26% in terms of predicted interactions is observed against P. yoelii, because of missing ortholog partners in pairs of functionally linked proteins.

[Supplemental material is available online at www.genome.org and results from this study are available for download from http://cbil.upenn.edu/plasmoMAP/.]



Dynamic queries

  • Generate a data set of any desired cutoff ( example: All links in HB3 >= 20 )
    • Strain (threshold min|max):
      HB3 (2.006|9435.360)  
      3D7 (3.001|4093.949)  
      Dd2 (4.046|3202.211)  

      Threshold greater than or equal to   

      [the result will be a comma-separated file (csv) that you can import into microsoft excel]




  • Get interacting partners for a protein (example: PFC0290w in HB3 )
    • Protein name (only PlasmoDB IDs):

      Strain (threshold min|max):
      HB3 (2.006|9435.360)  
      3D7 (3.001|4093.949)  
      Dd2 (4.046|3202.211)  

      Threshold greater than or equal to

      Output type: HTML    TXT   




    Download data (all files are gzipped)

    Note: Viewing LGL files requires LGLView, a java application that will run on any computer that has java installed. To download the viewer, go to:
    http://bioinformatics.icmb.utexas.edu/lgl/index.html#viewing

    Please follow the instructions described on the LGLView page regarding the required SUN Java version. The network files are extremely large, and it will be best to run LGLView on machines with 1GB or more RAM.

    Please refer to: Adai AT, Date SV, Wieland S, Marcotte EM (2004) LGL: creating a map of protein function with an algorithm for visualizing very large biological networks. J Mol Biol 340: 179-90.


    P. falciparum HB3
     
     
     Raw functional genomics data
     
  • Rosetta stone linkage pairs (with confidence)
  • Phylogenetic profile linkage pairs (with confidence)
  • Expression profile linkage pairs (with confidence)
  • BLAST database (for in silico data)
  • Gold standards (posted May 17, 2006, on request)
  •  
      - Positive set
      - Negative set

  • Rosetta stone fusion details (posted Feb 28, 2008, on request)

  •  
     
     Interaction map of P. falciparum
     
  • All pairs with final likelihood scores
  • LGL files:
  •  
      - .lgl file
      - .coords file
  • Connections
  •  
      - All proteins (human readable file)
      - Unknown proteins with known proteins
      - Unknown proteins with uknown proteins
  • List of KEGG pathways with more than 2 components
  • Function summary by KEGG annotation
  •  
      - All categories
      - Top 3 categories
  • Function summary by GO annotation
  •  
      - All categories
      - Top 3 categories
     
     
     High Confidence subset
     
  • LGL files:
  •  
      - .lgl file
      - .coords file
  • Connections
  •  
      - All proteins (human readable file)
      - Unknown proteins with known proteins
      - Unknown proteins with uknown proteins
  • List of KEGG pathways with more than 2 components
  •  
     
     Linkage detection in other apicomplexa
     
  • Linkages detected in P. falciparum only
  • Linkages detected in P. falciparum and C. parvum
  • Linkages detected in P. falciparum and T. gondii
  • Linkages detected in P. falciparum and P. yoelii
  • Linkages detected in all four apicomplexan species
  •  
     
     Links generated from filtered input
     
    Profiles of proteins that are expressed only in the sporozoite or gametocyte stage (and not in the erythrocytic stages), based on measurements by Le Roch et al. (2003), were excluded from our input data set of IDC profiles. Likelihood scores were then recalculated for all remaining pairs. This filtered set is available for download below.
  • Linkages with filtered input data
  •  
     
    P. falciparum 3D7
     
     
     Functional linkages
     
  • Connections
  •  
      - All proteins (human readable file)
     
     
     Links generated from filtered input
     
    Profiles of proteins that are expressed only in the sporozoite or gametocyte stage (and not in the erythrocytic stages), based on measurements by Le Roch et al. (2003), were excluded from our input data set of IDC profiles. Likelihood scores were then recalculated for all remaining pairs. This filtered set is available for download below.
  • Linkages with filtered input data
  •  
     
    P. falciparum Dd2
     
     
     Functional linkages
     
  • Connections
  •  
      - All proteins (human readable file)
     
     
     Links generated from filtered input
     
    Profiles of proteins that are expressed only in the sporozoite or gametocyte stage (and not in the erythrocytic stages), based on measurements by Le Roch et al. (2003), were excluded from our input data set of IDC profiles. Likelihood scores were then recalculated for all remaining pairs. This filtered set is available for download below.
  • Linkages with filtered input data