Genomic gene clustering analysis of pathways in eukaryotes

Abstract

Genomic clustering of genes in a pathway is commonly found in prokaryotes due to transcriptional operons, but these are not present in most eukaryotes. Yet, there might be clustering to a lesser extent of pathway members in eukaryotic genomes, that assist coregulation of a set of functionally cooperating genes. We analyzed five sequenced eukaryotic genomes for clustering of genes assigned to the same pathway in the KEGG database. Between 98% and 30% of the analyzed pathways in a genome were found to exhibit significantly higher clustering levels than expected by chance. In descending order by the level of clustering, the genomes studied were Saccharomyces cerevisiae, Homo sapiens, Caenorhabditis elegans, Arabidopsis thaliana, and Drosophila melanogaster. Surprisingly, there is not much agreement between genomes in terms of which pathways are most clustered. Only seven of 69 pathways found in all species were significantly clustered in all five of them. This species-specific pattern of pathway clustering may reflect adaptations or evolutionary events unique to a particular lineage. We note that although operons are common in C. elegans, only 58% of the pathways showed significant clustering, which is less than in human. Virtually all pathways in S. cerevisiae showed significant clustering.

Figure 1.

Clustering results for four pathways, illustrating different levels in clustering score observed among different genomes, pathways, and merged/unmerged data. Pathway 00361 is significantly clustered in all species, whereas the other pathways show varying degrees of clustering. In S. cerevisiae, all but two pathways showed significant clustering (using merged data). Note that the scale of the clustering score is logarithmic.

Figure 2.

Distribution of pathway clustering scores (using merged data). The x-axis represents how much higher from the median the score is in terms of difference between the median and the 3rd quartile. Also shown is the score distribution from randomly chosen pathways (from all organisms) in which the genes were picked randomly from all genes in the particular organism.

Figure 3.

Distribution of genes in pathways with and without significant clustering in A. thaliana. Pathway 00360 has a highly significant clustering score, whereas pathway 03020 does not. Merged data were used. The boxes represent putative loose gene clusters.

Figure 4.

Relationship between clustering score per gene and number of genes in the pathway (merged data).

Figure 5.

Comparison of percent identity in BLAST matches of enzymes with the same EC number to those with different EC numbers, across all organisms and pathways in this study. Less than 0.6% of all pairs with different EC numbers had an identity above 60%.