Standardized annotation of translated open reading frames

Mudge, Jonathan M.; Ruiz-Orera, Jorge; Prensner, John R.; Brunet, Marie-Christine; Calvet, Ferriol; Jungreis, Irwin; Gonzalez, Jose M.; Magrane, Michele; Martínez, Thomas F.; Schulz, Jana Felicitas; Yang, Yu; Albà, Mar; Aspden, Julie L.; Baranov, Pavel V.; Bazzini, Ariel; Bruford, Elspeth A.; Martı́n, Marı́a Jesús; Calviello, Lorenzo; Carvunis, Anne‐Ruxandra; Chen, Jin; Couso, Juan Pablo; Deutsch, Eric W.; Flicek, Paul; Frankish, Adam; Gerstein, Mark; Hübner, Norbert; Ingolia, Nicholas T.; Kellis, M; Menschaert, Gerben; Moritz, Robert L.; Ohler, Uwe; Roucou, Xavier; Saghatelian, Alan; Weissman, Jonathan S.; Heesch, Sebastiaan van

doi:10.1038/s41587-022-01369-0

Cited by 148 publications

(192 citation statements)

References 31 publications

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“…In summary, thousands of ORFs have eluded reference annotations as recently shown by ribosome profiling and proteogenomics studies [ 6 , 10 , 21 , 22 ]. OpenVar integrates such non-canonical ORFs in the analysis of genomic variants, unveiling new research avenues to understand the genotype–phenotype relationships.…”

Section: Discussionmentioning

confidence: 99%

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OpenVar: functional annotation of variants in non-canonical open reading frames

Brunet

Leblanc²,

Roucou³

2022

Cell Biosci

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Background Recent technological advances have revealed thousands of functional open reading frames (ORF) that have eluded reference genome annotations. These overlooked ORFs are found throughout the genome, in any reading frame of transcripts, mature or non-coding, and can overlap annotated ORFs in a different reading frame. The exploration of these novel ORFs in genomic datasets and of their role in genetic traits is hindered by a lack of software. Results Here, we present OpenVar, a genomic variant annotator that mends that gap and fosters meaningful discoveries. To illustrate the potential of OpenVar, we analysed all variants within SynMicDB, a database of cancer-associated synonymous mutations. By including non-canonical ORFs in the analysis, OpenVar yields a 33.6-fold, 13.8-fold and 8.3-fold increase in high impact variants over Annovar, SnpEff and VEP respectively. We highlighted an overlapping non-canonical ORF in the HEY2 gene where variants significantly clustered. Conclusions OpenVar integrates non-canonical ORFs in the analysis of genomic variants, unveiling new research avenues to better understand the genotype–phenotype relationships.

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Section: Discussionmentioning

confidence: 99%

“…Yet, these annotations are used worldwide in fundamental and clinical research, providing the necessary dictionary to read a genome. Now aware that thousands of functional alternative ORFs have eluded annotation [3][4][5][6], we need to assess their role in diseases [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

OpenVar: functional annotation of variants in non-canonical open reading frames

Brunet

Leblanc²,

Roucou³

2022

Cell Biosci

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“…We reviewed data from ribosome profiling and mass spectroscopy upstream of TICs used to translate the main protein from annotated genes [13]. Of note, ribosome profiling can predict TIC location on a large scale, while mass spectroscopy can confirm whether such TICs indeed induce measurable protein [14]. Although there are limitations to both methods of TIC identification [13,15,16], cross-verification by the two techniques is valuable.…”

Section: Canonical Tics That Translate the Main Protein As Well As Up...mentioning

confidence: 99%

Kozak Similarity Score Algorithm Identifies Alternative Translation Initiation Codons Implicated in Cancers

Gleason¹,

Ghadge²,

Sonobe³

et al. 2022

Preprint

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Ribosome profiling and mass spectroscopy have identified canonical and noncanonical translation initiation codons (TICs) that are upstream of the main translation initiation site and used to translate oncogenic proteins. Here, we use a Kozak Similarity Score algorithm to find that nearly all of these TICs have flanking nucleotides closely matching the Kozak sequence. Remarkably, the nucleotides flanking alternative noncanonical TICs are frequently closer to the Kozak sequence than the nucleotides flanking TICs used to translate the gene’s main protein. Of note, the 5’ untranslated region (5‘UTR) of cancer-associated genes with an upstream TIC tend to be significantly longer than the same region in genes not associated with cancer. The presence of a longer than typical 5’UTR increases the likelihood of ribosome binding to upstream noncanonical TICs, and may be a distinguishing feature of a number of genes overexpressed in cancer. Noncanonical TICs that are located in the 5’UTR, although thought disadvantageous and suppressed by evolution, may translate oncogenic proteins because of their flanking nucleotides

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“…1997), are theoretically a poor target for EMS mutagenesis, and are often ignored in proteomic screens. Consequently, there is growing interest in this class of protein-coding gene as a potentially rich source of novel bioactive peptides (M udge et al . 2022).…”

Section: Introductionmentioning

confidence: 99%

“…For example, smORFs are underrepresented in genome annotations (BASRAI et al 1997), are theoretically a poor target for EMS mutagenesis, and are often ignored in proteomic screens. Consequently, there is growing interest in this class of protein-coding gene as a potentially rich source of novel bioactive peptides (MUDGE et al 2022). A major obstacle in identifying smORFs that encode functionally important peptides is distinguishing them from the enormous number of smORFs present in the genome by chance (e.g.…”

Section: Introductionmentioning

confidence: 99%

Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III inDrosophila

Bosch

Ugur²,

Pichardo‐Casas

et al. 2020

Preprint

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SummaryNaturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two previously uncharacterized peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. We provide evidence that Sloth1/2 are highly expressed in neurons, localize to mitochondria, and form a complex. Double mutant analysis in animals and cell culture revealed that sloth1 and sloth2 are not functionally redundant, and their loss causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of genes.

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Standardized annotation of translated open reading frames

Cited by 148 publications

References 31 publications

OpenVar: functional annotation of variants in non-canonical open reading frames

OpenVar: functional annotation of variants in non-canonical open reading frames

Kozak Similarity Score Algorithm Identifies Alternative Translation Initiation Codons Implicated in Cancers

Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III inDrosophila

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