Genome-wide identification of coding small open reading frames: The unknown transcriptome

The identification of the complete repertoire of functional peptides in a cell is ultimately essential for a systems-wide understanding of its behavior. There have indeed been a plethora of studies purportedly designed to this end. However, these studies in fact routinely overlook a potentially significant portion of their data that might encode for peptides that are smaller than 100 amino acids. This is largely owing to technical reasons associated with the difficulty of distinguishing, with statistical significance, a coding sequence of this length from a non-coding sequence. Recently, a growing number of studies have shown that there are indeed many small open reading frame (sORF) encoded peptides that play important roles in a wide range of different biological processes. As such, there is now significant interest in methodologies that can be used to identify this drastically neglected portion of the cellular proteome. In this review, we introduce the presently known annotated sORFs and describe the new strategies that have been used to determine the coding sORFs, genome-wide.