Phylogenetic Profiling for Probing the Modular Architecture of the Human Genome

Information about functional connections between genes can be derived from patterns of coupled loss of their homologs across multiple species. This comparative approach, termed phylogenetic profiling, has been successfully used to infer genetic interactions in bacteria and eukaryotes. Rapid progress in sequencing eukaryotic species has enabled the recent phylogenetic profiling of the human genome, resulting in systematic functional predictions for uncharacterized human genes. Importantly, groups of co-evolving genes reveal widespread modularity in the underlying genetic network, facilitating experimental analyses in human cells as well as comparative studies of conserved functional modules across species. This strategy is particularly successful in identifying novel metabolic proteins and components of multi-protein complexes. The targeted sequencing of additional key eukaryotes and the incorporation of improved methods to generate and compare phylogenetic profiles will further boost the predictive power and utility of this evolutionary approach to the functional analysis of gene interaction networks.