Prediction of functional modules based on comparative genome analysis and Gene Ontology application

Abstract

We present a computational method for the prediction of functional modules encoded in microbial genomes. In this work, we have also developed a formal measure to quantify the degree of consistency between the predicted and the known modules, and have carried out statistical significance analysis of consistency measures. We first evaluate the functional relationship between two genes from three different perspectives--phylogenetic profile analysis, gene neighborhood analysis and Gene Ontology assignments. We then combine the three different sources of information in the framework of Bayesian inference, and we use the combined information to measure the strength of gene functional relationship. Finally, we apply a threshold-based method to predict functional modules. By applying this method to Escherichia coli K12, we have predicted 185 functional modules. Our predictions are highly consistent with the previously known functional modules in E.coli. The application results have demonstrated that our approach is highly promising for the prediction of functional modules encoded in a microbial genome.

Figure 1

The directed acyclic graph induced from the GO term UDP-N-acetylgalactosamine biosynthesis (GO: 0019277), wherein at the bottommost level is the GO term of interest itself, and at the upper levels are all its ancestors, adapted from QuickGO Go Browser ().

Figure 2

Distribution of S_GO(g_i, g_j) for the positive (circles) and the random (triangles) sets.

Figure 3

Distribution of d(g_i, g_j) for the positive (blue) and the random (red) sets.

Figure 4

Distribution of S_N(g_i, g_j) for the positive (blue) and the random (red) sets.

Figure 5

The normalized C_ombined(g_i, g_j) of both naive Bayesian (red) and Bayesian (blue) inference approaches for both the positive (solid) and the random (dashed) sets.

Figure 6

(a) The number of edges as a function of α; and (b) AHMD values for the known pathways, regulons and operons as functions of α.

Figure 7

Predicted modules consisting of at least three genes obtained by using α = 6.75, where edges of red represent for belonging to the same known pathways, edges of blue represent for belonging to the same known regulons, edges of green represent for belonging to the same known operons, edges of orange represent for transporter unit, edges of purple represent for having similar GO assignments and edges of black represent for having not been experimentally verified.

Figure 8

Predicted module corresponding to the flagellar metabolism pathway, where according to Eco Cyc the genes of blue belong to the same regulon, and the genes of yellow, green and dark red belong to three different operons, respectively.

Figure 9

Predicted modules involving more than one pathways.

Figure 10

Genes are connected mainly because they are conserved neighboring genes along the same strand of DNA.

Figure 11

Predicted modules that have not been experimentally verified.

Figure 12

Predicted modules that hemL (16128147) is involved for different values of α: (a) α = 6.75, (b) α = 5.5 and (c) α = 4.

Figure 12

Predicted modules that hemL (16128147) is involved for different values of α: (a) α = 6.75, (b) α = 5.5 and (c) α = 4.