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Short ORF-encoded peptides and small proteins in eukaryotes have been hiding in the shadow of large proteins for a long time. Recently, improved identifications in MS-based proteomics and ribosome profiling resulted in the detection of large numbers of small proteins. The variety of functions of small proteins is also emerging. It seems to be the right time to reflect on why small proteins remained invisible. In addition to the obvious technical challenge of detecting small proteins, they were mostly forgotten from annotations and they escaped detection because they were not sought. In this review, we identify conventions that need to be revisited, including the assumption that mature mRNAs carry only one coding sequence. The large-scale discovery of small proteins and of their functions will require changing some paradigms and undertaking the annotation of ORFs that are still largely perceived as irrelevant coding information compared to already annotated coding sequences., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Since the completion of the genome sequence of the model eukaryote Saccharomyces cerevisiae, there have been significant advancements in the field of genome annotation, in no small part due to the availability of datasets that make large-scale comparative analyses possible. As a result, since its completion there has been a significant change in annotated ORF size distribution in this first eukaryotic genome, especially in short ORFs (sORFs) predicted to encode polypeptides less than 150 amino acids in length. Due to their small size and the difficulties associated with their study, it is only relatively recently that these genomic features and the sORF-encoded peptides (sPEPs) they encode have become a focus of many researchers. Yet while this class of peptides may seem new and exciting, the study of this part of the proteome is nothing new in S. cerevisiae, a species where the biological importance of sPEPs has been elegantly illustrated over the past 30 years. Here the authors showcase a range of different sORFs found in S. cerevisiae and the diverse biological roles of their encoded sPEPs, and provide an insight into the sORFs found in other fungal species, particularly those pathogenic to humans., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)