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Dec 1, 2007

Investigation of factors affecting prediction of protein-protein interaction networks by phylogenetic profiling. Dec 1, 2007. The problem …… More than 500 Microbial genomes are fully sequence and there is high percent of genes with unknown function. For example: E. coli K12 15%

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Dec 1, 2007

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  1. Investigation of factors affecting prediction of protein-protein interaction networks by phylogenetic profiling Dec 1, 2007

  2. The problem …… More than 500 Microbialgenomes are fully sequence and there is high percent of genes with unknown function. For example: E. coli K12 15% P. aeruginosa45% http://www.genomesonline.org/ X The meaning of protein function C B Y Z A A S P D M N The function of protein A is its action on Substrate to form a Product The function of A is the context of its interactions with other proteins in the cell Post genomic view Biochemical view Eisenberg, D. et. al. Nature 2000

  3. Prediction protein function • Homology based methods (gives partial understanding about protein role) • Simple sequence similarity searches (BLAST) • Profile searches (PSI-BLAST) • Databases of conserved domains (Pfam, SMART) • Prediction from genomic context • Phylogenetic profile • Gene cluster • Gene neighbor • Rosetta Stone • Prediction from high-throughput experimental data • Microarray gene expression data • Protein-protein interaction screens • ...

  4. Phylogenetic Profile Pellegrini et al. PNAS 96, 4285 (1999) Marcotte et al. PNAS 97, 12115 (2000) 1- Select sets of genomes as a reference set • Reference selection? • Does the selection of the reference genomes influence the prediction? • if so? How? • 2- Create phylogenetic profile matrix for target organism: • Do one-against-all BLAST search to identify all homologous target genes in diverse reference organisms. • Reference selection Measure profile similarities • How E-value threshold effects the protein-protein interactions prediction? • Blast E-value threshold (present or absent)

  5. Generate Protein-protein interactions network 3- Measure profile similarities Protein X: 110001111001001110001111 Protein Y: 111000111100000110001111 19 matching bits out of 24 4-Generate protein-protein interactions 2 nodes are connected if the 2 proteins have similar profile) Protein X Protein Y 5- Create clusters from set of protein-protein interactions 6- Visualize network

  6. Measure profile similarities 2 nodes are connected if the 2 proteins have similar profile) Protein X Protein Y Protein X: 110001111001001110001111 Protein Y: 111000111100000110001111 • Inverse homology • Pearson correlation coefficient • Calculate the homology between two genomes: • The ratio of number of homologs of each reference organism j to the number of proteins in the target genome i ( Hi,j) . • Pij =1/( Hi,j) otherwise Pij =0. • Mutual information • MI(X, Y) = H(X) + H(Y) - H(X, Y) • H(Y) = -∑p(i) ln p(i) p(i), (i= 0, 1) as the fraction of genomes in which protein Y in the state i Karimpour-Fard et al. BMC Genomics. 2007;8(1):393

  7. Comparison of different combinations of reference genomes and E-value thresholds using COG Aerobic All Low GC Random sets c) Karimpour-Fard et al. BMC Genomics. 2007;8(1):393 • PPV =TP/(TP+FP) • TP = # predicted pair in the same functional category • FP= # predicted pair that were classified but were not same functional category

  8. Co-evolution can be used to assign function to unstudied genes • Edge color code: • E. coli K12 (green) • E. coli O157 (blue) • Shigella flexneri (black) • S.typhimurium LT2(purple) • P. aeruginosa (mustard) Hypothetical proteins YcgB, YeaH, YeaG are co-conserved across different species. Comparison of sub-graphs across species (CS-CCC) suggested that a previously unstudied S. typhimurium gene, ycgB, is functionally related to yeaH. Experimental data support the hypothesis that both genes are important for antimicrobial peptide resistance. Karimpour-Fard et al. Genome Biology 2007 8:R185

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