Classification and function of small open reading frames

Couso, Juan Pablo; Patraquim, Pedro

doi:10.1038/nrm.2017.58

Cited by 254 publications

(299 citation statements)

References 112 publications

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“…Yet, it is clear it also leads to numerous false negatives, i.e., functional ORFs shorter than 100 codons excluded from annotations (Andrews and Rothnagel 2014;Ma et al 2014;Pauli et al 2014;Couso and Patraquim 2017). Notwithstanding, we could also question the arbitrary cut-off taken by groups studying alternative ORFs.…”

Section: Is Orf Length An Appropriate Filter?mentioning

confidence: 98%

“…Yet, genome annotations, faced with the challenge of distinguishing functional ORFs from random events, do not include alternative ORFs. That is because of a lack of clinical importance and/or experimental evidence for alternative ORFs (Couso and Patraquim 2017). However, this paucity of evidence is largely due to their absence from current annotations (Cheng et al 2011;Ladoukakis et al 2011;Andrews and Rothnagel 2014;Saghatelian and Couso 2015;Couso and Patraquim 2017).…”

Section: The Clinical and Research Need For A Better Annotation Systemmentioning

confidence: 99%

“…The RefSeq database offers some more putative functional annotation (XM_, XP_ annotations), and Ensembl reports to some extent less supported transcripts' annotations (Pruitt et al 2012;Aken et al 2016). Yet, these still rely on overly restrictive criteria (one CDS per transcript, longer than 100 codons) (Chung et al 2007;Galindo et al 2007;Saghatelian and Couso 2015;Pueyo et al 2016a;Couso and Patraquim 2017). While adapting the framework of genome annotations to consider alternative ORFs will more likely yield significant advances, the need for a more flexible annotation for various purposes could be addressed (Fig.…”

Section: On the Importance Of Filtration And Curationmentioning

confidence: 99%

“…These detection methods-ribosome profiling, proteogenomics, and conservation signatures-are revealing this hidden proteome, a novel repertoire for biomarkers and therapeutic strategies (Couso and Patraquim 2017;Karginov et al 2017;Plaza et al 2017). Here, we briefly review functional evidence for the biological roles of alternative proteins.…”

mentioning

confidence: 99%

“…Consequently, three main criteria are implemented to distinguish "true" ORFs from random events: the use of an ATG start codon, a minimum length of 100 codons, and a limit of a single ORF per transcript (Cheng et al 2011;Andrews and Rothnagel 2014;Saghatelian and Couso 2015;Plaza et al 2017). These criteria result in an important underestimation of translated ORFs in the genome (Andrews and Rothnagel 2014;Saghatelian and Couso 2015;Couso and Patraquim 2017;Plaza et al 2017). With functional evidence for previously unannotated ORFs in bacteria (Wadler and Vanderpool 2007;Hemm et al 2008Hemm et al , 2010Storz et al 2014;Lluch-Senar et al 2015;Baek et al 2017), Drosophila (Galindo et al 2007;Kondo et al 2007;Reinhardt et al 2013;Aspden et al 2014;Albuquerque et al 2015;Li et al 2016a;Pueyo et al 2016a), plants (Hanada et al 2013;Juntawong et al 2014;Hsu et al 2016;Hsu and Benfey 2017), and other eukaryotes (Oyama et al 2007;Ingolia et al 2011;Vanderperre et al 2013;Ma et al 2014), genome annotations will need to be revised.…”

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confidence: 99%

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Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

et al. 2018

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Technological advances promise unprecedented opportunities for whole exome sequencing and proteomic analyses of populations. Currently, data from genome and exome sequencing or proteomic studies are searched against reference genome annotations. This provides the foundation for research and clinical screening for genetic causes of pathologies. However, current genome annotations substantially underestimate the proteomic information encoded within a gene. Numerous studies have now demonstrated the expression and function of alternative (mainly small, sometimes overlapping) ORFs within mature gene transcripts. This has important consequences for the correlation of phenotypes and genotypes. Most alternative ORFs are not yet annotated because of a lack of evidence, and this absence from databases precludes their detection by standard proteomic methods, such as mass spectrometry. Here, we demonstrate how current approaches tend to overlook alternative ORFs, hindering the discovery of new genetic drivers and fundamental research. We discuss available tools and techniques to improve identification of proteins from alternative ORFs and finally suggest a novel annotation system to permit a more complete representation of the transcriptomic and proteomic information contained within a gene. Given the crucial challenge of distinguishing functional ORFs from random ones, the suggested pipeline emphasizes both experimental data and conservation signatures. The addition of alternative ORFs in databases will render identification less serendipitous and advance the pace of research and genomic knowledge. This review highlights the urgent medical and research need to incorporate alternative ORFs in current genome annotations and thus permit their inclusion in hypotheses and models, which relate phenotypes and genotypes.

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Section: Is Orf Length An Appropriate Filter?mentioning

confidence: 98%

Section: The Clinical and Research Need For A Better Annotation Systemmentioning

confidence: 99%

Section: On the Importance Of Filtration And Curationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

et al. 2018

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MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

Benayoun

Lee

2019

BioEssays

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Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator.

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Ribosomal Peptides and Small Proteins on the Rise

2019

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Genetically encoded and ribosomally synthesised peptides and small proteins act as important regulators in fundamental cellular processes, including gene expression, development, signalling and metabolism. Moreover, they also play a crucial role in eukaryotic and prokaryotic defence against microorganisms. Extremely diverse in size and structure, they are often subject to extensive post‐translational modification. Recent technological advances are now allowing the analysis of the whole cellular transcriptome and proteome, revealing the presence of hundreds of long‐overlooked alternative and short open reading frames (short ORFs, or sORFs) in mRNA and supposedly noncoding RNAs. However, in many instances the biological roles of their translational products remain to be elucidated. Here we provide an overview on the intriguing structural and functional diversity of ribosomally synthesised peptides and newly discovered peptides and small proteins.

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Classification and function of small open reading frames

Cited by 254 publications

References 112 publications

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

Ribosomal Peptides and Small Proteins on the Rise

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