Bioinformatics Vol. 19 no. 12 2003
Pages 1524-1530
© 2003 Oxford University Press
Identification of functional links between genes using phylogenetic profiles
1 Department of Biomedical Engineering, USA
2 Bioinformatics Graduate Program,
Boston University, 44 Cummington St., Boston, MA, 02215, USA
Received on November 22, 2002
; revised on February 14, 2003
; accepted on February 15, 2003
Motivation: Genes with identical patterns of occurrence across the phyla tend to function together in the same protein complexes or participate in the same biochemical pathway. However, the requirement that the profiles be identical (i) severely restricts the number of functional links that can be established by such phylogenetic profiling; (ii) limits detection to very strong functional links, failing to capture relations between genes that are not in the same pathway, but nevertheless subserve a common function and (iii) misses relations between analogous genes. Here we present and apply a method for relaxing the restriction, based on the probability that a given arbitrary degree of similarity between two profiles would occur by chance, with no biological pressure. Function is then inferred at any desired level of confidence.
Results: We derive an expression for the probability distribution of a given number of chance co-occurrences of a pair of non-homologous orthologs across a set of genomes. The method is applied to 2905 clusters of orthologous genes (COGs) from 44 fully sequenced microbial genomes representing all three domains of life. Among the results are the following. (1) Of the 51 000 annotated intrapathway gene pairs, 8935 are linked at a level of significance of 0.01. This is over 30-fold greater than the 271 intrapathway pairs obtained at the same confidence level when identical profiles are used. (2) Of the 540 000 interpathway genes pairs, some 65 000 are linked at the 0.01 level of significance, some 12 standard deviations beyond the number expected by chance at this confidence level. We speculate that many of these links involve nearest-neighbor path, and discuss some examples. (3) The difference in the percentage of linked interpathway and intrapathway genes is highly significant, consistent with the intuitive expectation that genes in the same pathway are generally under greater selective pressure than those that are not. (4) The method appears to recover well metabolic networks. This is illustrated by the TCA cycle which is recovered as a highly connected, weighted edge network of 30 of its 31 COGs. (5) The fraction of pairs having a common pathway is a symmetric function of the Hamming distance between their profiles. This finding, that the functional correlation between profiles with near maximum Hamming distance is as large as between profiles with near zero Hamming distance, and as statistically significant, is plausibly explained if the former group represents analogous genes.
Contact: delisi{at}bu.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Tuller, H. Birin, U. Gophna, M. Kupiec, and E. Ruppin Reconstructing ancestral gene content by coevolution Genome Res., January 1, 2010; 20(1): 122 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Uchiyama, T. Higuchi, and M. Kawai MBGD update 2010: toward a comprehensive resource for exploring microbial genome diversity Nucleic Acids Res., January 1, 2010; 38(suppl_1): D361 - D365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Gonzalez and R. Zimmer Assigning functional linkages to proteins using phylogenetic profiles and continuous phenotypes Bioinformatics, May 15, 2008; 24(10): 1257 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. R Kensche, V. van Noort, B. E Dutilh, and M. A Huynen Practical and theoretical advances in predicting the function of a protein by its phylogenetic distribution J R Soc Interface, February 6, 2008; 5(19): 151 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Reddy, B. E. Shakhnovich, D. S. Roberts, S. J. Russek, and C. DeLisi Positional clustering improves computational binding site detection and identifies novel cis-regulatory sites in mammalian GABAA receptor subunit genes Nucleic Acids Res., February 16, 2007; 35(3): e20 - e20. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Gabaldon Computational approaches for the prediction of protein function in the mitochondrion Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1121 - C1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Green and P. D. Karp The outcomes of pathway database computations depend on pathway ontology Nucleic Acids Res., August 7, 2006; 34(13): 3687 - 3697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Campillos, C. von Mering, L. J. Jensen, and P. Bork Identification and analysis of evolutionarily cohesive functional modules in protein networks Genome Res., March 1, 2006; 16(3): 374 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sun, J. Xu, Z. Liu, Q. Liu, A. Zhao, T. Shi, and Y. Li Refined phylogenetic profiles method for predicting protein-protein interactions Bioinformatics, August 15, 2005; 21(16): 3409 - 3415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Green and P. D. Karp Genome annotation errors in pathway databases due to semantic ambiguity in partial EC numbers Nucleic Acids Res., July 20, 2005; 33(13): 4035 - 4039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Bowers, S. J. Cokus, D. Eisenberg, and T. O. Yeates Use of Logic Relationships to Decipher Protein Network Organization Science, December 24, 2004; 306(5705): 2246 - 2249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Karaoz, T. M. Murali, S. Letovsky, Y. Zheng, C. Ding, C. R. Cantor, and S. Kasif Whole-genome annotation by using evidence integration in functional-linkage networks PNAS, March 2, 2004; 101(9): 2888 - 2893. [Abstract] [Full Text] [PDF]
|
|