Comparative analysis of hundreds (soon to be thousands) of genomes is revolutionizing the pace of gene and pathway discovery. We use a subsystems-based approach to mapping the Central Machinery of Life in multiple diverse species. It is based on the encoding and analysis of functional subsystems projected across the entire collection of sequenced genomes. A notion of subsystem, which may be thought of as a generalization of the pathway concept, refers to a group of related functional roles that are jointly involved in a specific biological process (sub-network) or a structural complex. The genes in each species that have a functional variant of a subsystem are thought of as implementing those functional roles.

Subsystem development is a central aspect of a Project to Annotate 1,000 Genomes launched by Fellowship for Interpretation of Genomes (FIG) in 2003. The first steps in this direction are implemented within the framework of the SEED, an open source genomic integration and a set of tools for comparative analysis (http://theseed.uchicago.edu/FIG/index.cgi). A combination of comparative genomics techniques, including genome context analysis, allows us to infer novel functional variants of key subsystems in the Central Machinery of Life and tentatively identify presently unknown (missing) genes involved therein. A power of the approach is illustrated by a focused experimental verification of selected functional predictions.