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Small open reading frames: a comparative genetics approach to validation

Open reading frames (ORFs) with fewer than 100 codons are generally not annotated in genomes, although bona fide genes of that size are known. Newer biochemical studies have suggested that thousands of small protein-coding ORFs (smORFs) may exist in the human genome, but the true number and the biol...

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Autores principales: Jain, Niyati, Richter, Felix, Adzhubei, Ivan, Sharp, Andrew J., Gelb, Bruce D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152738/
https://www.ncbi.nlm.nih.gov/pubmed/37127568
http://dx.doi.org/10.1186/s12864-023-09311-7
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author Jain, Niyati
Richter, Felix
Adzhubei, Ivan
Sharp, Andrew J.
Gelb, Bruce D.
author_facet Jain, Niyati
Richter, Felix
Adzhubei, Ivan
Sharp, Andrew J.
Gelb, Bruce D.
author_sort Jain, Niyati
collection PubMed
description Open reading frames (ORFs) with fewer than 100 codons are generally not annotated in genomes, although bona fide genes of that size are known. Newer biochemical studies have suggested that thousands of small protein-coding ORFs (smORFs) may exist in the human genome, but the true number and the biological significance of the micropeptides they encode remain uncertain. Here, we used a comparative genomics approach to identify high-confidence smORFs that are likely protein-coding. We identified 3,326 high-confidence smORFs using constraint within human populations and evolutionary conservation as additional lines of evidence. Next, we validated that, as a group, our high-confidence smORFs are conserved at the amino-acid level rather than merely residing in highly conserved non-coding regions. Finally, we found that high-confidence smORFs are enriched among disease-associated variants from GWAS. Overall, our results highlight that smORF-encoded peptides likely have important functional roles in human disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-023-09311-7.
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spelling pubmed-101527382023-05-03 Small open reading frames: a comparative genetics approach to validation Jain, Niyati Richter, Felix Adzhubei, Ivan Sharp, Andrew J. Gelb, Bruce D. BMC Genomics Research Open reading frames (ORFs) with fewer than 100 codons are generally not annotated in genomes, although bona fide genes of that size are known. Newer biochemical studies have suggested that thousands of small protein-coding ORFs (smORFs) may exist in the human genome, but the true number and the biological significance of the micropeptides they encode remain uncertain. Here, we used a comparative genomics approach to identify high-confidence smORFs that are likely protein-coding. We identified 3,326 high-confidence smORFs using constraint within human populations and evolutionary conservation as additional lines of evidence. Next, we validated that, as a group, our high-confidence smORFs are conserved at the amino-acid level rather than merely residing in highly conserved non-coding regions. Finally, we found that high-confidence smORFs are enriched among disease-associated variants from GWAS. Overall, our results highlight that smORF-encoded peptides likely have important functional roles in human disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-023-09311-7. BioMed Central 2023-05-01 /pmc/articles/PMC10152738/ /pubmed/37127568 http://dx.doi.org/10.1186/s12864-023-09311-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jain, Niyati
Richter, Felix
Adzhubei, Ivan
Sharp, Andrew J.
Gelb, Bruce D.
Small open reading frames: a comparative genetics approach to validation
title Small open reading frames: a comparative genetics approach to validation
title_full Small open reading frames: a comparative genetics approach to validation
title_fullStr Small open reading frames: a comparative genetics approach to validation
title_full_unstemmed Small open reading frames: a comparative genetics approach to validation
title_short Small open reading frames: a comparative genetics approach to validation
title_sort small open reading frames: a comparative genetics approach to validation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152738/
https://www.ncbi.nlm.nih.gov/pubmed/37127568
http://dx.doi.org/10.1186/s12864-023-09311-7
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