SURVEY AND SUMMARY ‘Conserved hypothetical ’ proteins: prioritization of targets for experimental study

Comparative genomics shows that a substantial fraction of the genes in sequenced genomes encodes ‘conserved hypothetical ’ proteins, i.e. those that are found in organisms from several phylogenetic lineagesbuthavenotbeen functionallycharacterized. Here, we briefly discuss recent progress in functional characterization of prokaryotic ‘conserved hypothet-ical ’ proteins and the possible criteria for prioritizing targets for experimental study. Based on these cri-teria, the chief one being wide phyletic spread, we offer two ‘top 10 ’ lists of highly attractive targets. The first list consists of proteins for which biochem-ical activity could be predicted with reasonable con-fidence but the biological function was predicted only in general terms, if at all (‘known unknowns’). The second list includes proteins for which there is no prediction of biochemical activity, even if, for some, general biological clues exist (‘unknown unknowns’). The experimental characterization of these and other ‘conserved hypothetical ’ proteins is expected to reveal new, crucial aspects of microbial biology and could also lead to better functional prediction for medically relevant human homologs