Abstract
The genome of Mycobacterium tuberculosis (H37Rv) contains 4,019 protein coding genes, of which more than thousand have been categorized as 'hypothetical' implying that for these not even weak functional associations could be identified so far. We here predict reliable functional indications for half of this large hypothetical orfeome: 497 genes can be annotated based on orthology, and another 125 can be linked to interacting proteins via integrated genomic context analysis and literature mining. The assignments include newly identified clusters of interacting proteins, hypothetical genes that are associated to well known pathways and putative disease-relevant targets. All together, we have raised the fraction of the proteome with at least some functional annotation to 88% which should considerably enhance the interpretation of large-scale experiments targeting this medically important organism.