Structural Biology Sheds Light on the Puzzle of Genomic ORFans

Genomic ORFans are orphan open reading frames (ORFs) with no significant sequence similarity to other ORFs. ORFans comprise 20–30% of the ORFs of most completely sequenced genomes. Because nothing can be learnt about ORFans via sequence homology, the functions and evolutionary origins of ORFans remain a mystery. Furthermore, because relatively few ORFans have been experimentally characterized, it has been suggested that most ORFans are not likely to correspond to functional, expressed proteins, but rather to spurious ORFs, pseudo-genes or to rapidly evolving proteins with non-essential roles. As a snapshot view of current ORFan structural studies, we searched for ORFans among proteins whose three-dimensional structures have been recently determined. We find that functional and structural studies of ORFans are not as underemphasized as previously suggested. These recently determined structures correspond to ORFans from all Kingdoms of life, and include proteins that have previously been functionally characterized, as well as structural genomics targets of unknown function labeled as “hypothetical proteins”. This suggests that many of the ORFans in the databases are likely to correspond to expressed, functional (and even essential) proteins. Furthermore, the recently determined structures include examples of the various types of ORFans, suggesting that the functions and evolutionary origins of ORFans are diverse. Although this survey sheds some light on the ORFan mystery, further experimental studies are required to gain a better understanding of the role and origins of the tens of thousands of ORFans awaiting characterization.