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  • Review Article
  • Published:

Emerging evidence for functional peptides encoded by short open reading frames

Nature Reviews Genetics volume 15, pages 193–204 (2014)Cite this article

Subjects

An Erratum to this article was published on 04 March 2014

This article has been updated

Key Points

  • Short open reading frames (sORFs) of ∼100 codons in length are common and are distributed throughout the genome, but not all sORFs are biologically relevant.

  • sORFs are found on non-coding RNAs and within the 5′ leader and 3′ trailer regions of mRNAs. They can also overlap with the main protein-coding sequence of mRNAs.

  • The identification of sORFs that are translatable and that are likely to encode short peptides remains a major challenge. Three complementary approaches that are typically used to discover functional sORFs are bioinformatics, transcriptomics and proteomics.

  • Bioinformatic studies have identified a large pool of potentially translatable sORFs on the basis of sequence characteristics such as degree of conservation, coding potential and context of the initiation codon.

  • Global ribosome profiling has provided evidence of ribosome engagement at the start codon of many sORFs in various species, including yeast, insects, plants and mammals.

  • Proteomic studies using mass spectrometry on size-fractionated whole-cell lysates have identified several short peptides encoded by sORFs (sPEPs) in human tissues and cell lines.

  • Functional sPEPs have been identified in insects, plants and mammals, but only a small number of them have been fully characterized.

Abstract

Short open reading frames (sORFs) are a common feature of all genomes, but their coding potential has mostly been disregarded, partly because of the difficulty in determining whether these sequences are translated. Recent innovations in computing, proteomics and high-throughput analyses of translation start sites have begun to address this challenge and have identified hundreds of putative coding sORFs. The translation of some of these has been confirmed, although the contribution of their peptide products to cellular functions remains largely unknown. This Review examines this hitherto overlooked component of the proteome and considers potential roles for sORF-encoded peptides.

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Figure 1: Leaky scanning and re-initiation.
Figure 2: The Tal peptides and regulation of Ovo in Drosophila melanogaster.
Figure 3: Example of a 'peptoswitch'.

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Change history

  • 04 March 2014

    In Table 2 (page 200) of the above article, the gene “RanGAP” was corrected to “SclA and SclB”, where Scl refers to the Sarcolamban gene in Drosophila melanogaster. The corresponding footnote was also corrected. The article has been corrected online. The editors apologize for this error.

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Acknowledgements

This work was supported by a grant to J.A.R. from the Australian National Health and Medical Research Council (ID631551).

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  1. School of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, 4072, Queensland, Australia

    Shea J. Andrews & Joseph A. Rothnagel

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  1. Shea J. Andrews
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Correspondence to Joseph A. Rothnagel.

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PowerPoint slides

Glossary

Short open reading frames

(sORFs). Open reading frames that are usually <100 codons in length but that can also be longer.

Coding DNA sequence

(CDS). An open reading frame (ORF) that encodes a verified protein product.The CDS is typically the first ORF identified and characterized on an mRNA. It defines the end of the 5′ leader and the start of the 3′ trailer sequences.

Ka/Ks test

A ratio that compares the number of nonsynonymous substitutions per nonsynonymous site with the number of synonymous substitutions per synonymous site.

Transcription activator-like effector nucleases

(TALENs). Engineered enzymes that permit precise editing of genomes and that can be used to make specific sequence changes in model organisms such as Arabidopsis thaliana, zebrafish and mice.

Microproteins

Negative regulators of multiprotein complexes. In this case, micro refers to the mechanism of action of these proteins rather than to their sizes.

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Andrews, S., Rothnagel, J. Emerging evidence for functional peptides encoded by short open reading frames. Nat Rev Genet 15, 193–204 (2014). https://doi.org/10.1038/nrg3520

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