Genetic Co-Occurrence Network across Sequenced Microbes

The phenotype of any organism on earth is, in large part, the consequence of interplay between numerous gene products encoded in the genome, and such interplay between gene products affects the evolutionary fate of the genome itself through the resulting phenotype. In this regard, contemporary genomes can be used as molecular records that reveal associations of various genes working in their natural lifestyles. By analyzing thousands of orthologs across ∼600 bacterial species, we constructed a map of gene-gene co-occurrence across much of the sequenced biome. If genes preferentially co-occur in the same organisms, they were called herein correlogs; in the opposite case, called anti-correlogs. To quantify correlogy and anti-correlogy, we alleviated the contribution of indirect correlations between genes by adapting ideas developed for reverse engineering of transcriptional regulatory networks. Resultant correlogous associations are highly enriched for physically interacting proteins and for co-expressed transcripts, clearly differentiating a subgroup of functionally-obligatory protein interactions from conditional or transient interactions. Other biochemical and phylogenetic properties were also found to be reflected in correlogous and anti-correlogous relationships. Additionally, our study elucidates the global organization of the gene association map, in which various modules of correlogous genes are strikingly interconnected by anti-correlogous crosstalk between the modules. We then demonstrate the effectiveness of such associations along different domains of life and environmental microbial communities. These phylogenetic profiling approaches infer functional coupling of genes regardless of mechanistic details, and may be useful to guide exogenous gene import in synthetic biology. Author Summary: Genes in organisms have a number of interactions with one another in their biological contexts. For example, proteins produced from one gene may interact with other proteins produced from another gene to perform together a particular biological task, and such pairs of cooperative genes may often reside together in the same organisms. We analyzed thousands of genes across ∼600 bacterial species, and found genes with favored co-occurrence in the same organisms (termed correlogs) or disfavored co-occurrence (termed anti-correlogs). These co-occurrence patterns are significantly reflective of actual biochemical interplays between genes, and distinct cliques of correlogous genes are seamlessly interrelated through anti-correlogous links between the cliques. The ‘sociology’ of genes inferred by this approach provides useful information on how to engineer a cell, such as for production of a desired byproduct. For example, an important gene in cellobiose digestion for biofuel production, bglB, is suggested to function better in a cell factory when co-activated with another gene rhaM, the correlogous partner we found in our analysis.