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Evidence for widespread existence of functional novel and non-canonical human transcripts

BACKGROUND: Fraction of functional sequence in the human genome remains a key unresolved question in Biology and the subject of vigorous debate. While a plethora of studies have connected a significant fraction of human DNA to various biochemical processes, the classical definition of function requi...

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Autores principales: Xu, Dongyang, Tang, Lu, Zhou, Junjun, Wang, Fang, Cao, Huifen, Huang, Yu, Kapranov, Philipp
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675921/
https://www.ncbi.nlm.nih.gov/pubmed/38001496
http://dx.doi.org/10.1186/s12915-023-01753-5
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author Xu, Dongyang
Tang, Lu
Zhou, Junjun
Wang, Fang
Cao, Huifen
Huang, Yu
Kapranov, Philipp
author_facet Xu, Dongyang
Tang, Lu
Zhou, Junjun
Wang, Fang
Cao, Huifen
Huang, Yu
Kapranov, Philipp
author_sort Xu, Dongyang
collection PubMed
description BACKGROUND: Fraction of functional sequence in the human genome remains a key unresolved question in Biology and the subject of vigorous debate. While a plethora of studies have connected a significant fraction of human DNA to various biochemical processes, the classical definition of function requires evidence of effects on cellular or organismal fitness that such studies do not provide. Although multiple high-throughput reverse genetics screens have been developed to address this issue, they are limited to annotated genomic elements and suffer from non-specific effects, arguing for a strong need to develop additional functional genomics approaches. RESULTS: In this work, we established a high-throughput lentivirus-based insertional mutagenesis strategy as a forward genetics screen tool in aneuploid cells. Application of this approach to human cell lines in multiple phenotypic screens suggested the presence of many yet uncharacterized functional elements in the human genome, represented at least in part by novel exons of known and novel genes. The novel transcripts containing these exons can be massively, up to thousands-fold, induced by specific stresses, and at least some can represent bi-cistronic protein-coding mRNAs. CONCLUSIONS: Altogether, these results argue that many unannotated and non-canonical human transcripts, including those that appear as aberrant splice products, have biological relevance under specific biological conditions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-023-01753-5.
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spelling pubmed-106759212023-11-24 Evidence for widespread existence of functional novel and non-canonical human transcripts Xu, Dongyang Tang, Lu Zhou, Junjun Wang, Fang Cao, Huifen Huang, Yu Kapranov, Philipp BMC Biol Research Article BACKGROUND: Fraction of functional sequence in the human genome remains a key unresolved question in Biology and the subject of vigorous debate. While a plethora of studies have connected a significant fraction of human DNA to various biochemical processes, the classical definition of function requires evidence of effects on cellular or organismal fitness that such studies do not provide. Although multiple high-throughput reverse genetics screens have been developed to address this issue, they are limited to annotated genomic elements and suffer from non-specific effects, arguing for a strong need to develop additional functional genomics approaches. RESULTS: In this work, we established a high-throughput lentivirus-based insertional mutagenesis strategy as a forward genetics screen tool in aneuploid cells. Application of this approach to human cell lines in multiple phenotypic screens suggested the presence of many yet uncharacterized functional elements in the human genome, represented at least in part by novel exons of known and novel genes. The novel transcripts containing these exons can be massively, up to thousands-fold, induced by specific stresses, and at least some can represent bi-cistronic protein-coding mRNAs. CONCLUSIONS: Altogether, these results argue that many unannotated and non-canonical human transcripts, including those that appear as aberrant splice products, have biological relevance under specific biological conditions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-023-01753-5. BioMed Central 2023-11-24 /pmc/articles/PMC10675921/ /pubmed/38001496 http://dx.doi.org/10.1186/s12915-023-01753-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This 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 Article
Xu, Dongyang
Tang, Lu
Zhou, Junjun
Wang, Fang
Cao, Huifen
Huang, Yu
Kapranov, Philipp
Evidence for widespread existence of functional novel and non-canonical human transcripts
title Evidence for widespread existence of functional novel and non-canonical human transcripts
title_full Evidence for widespread existence of functional novel and non-canonical human transcripts
title_fullStr Evidence for widespread existence of functional novel and non-canonical human transcripts
title_full_unstemmed Evidence for widespread existence of functional novel and non-canonical human transcripts
title_short Evidence for widespread existence of functional novel and non-canonical human transcripts
title_sort evidence for widespread existence of functional novel and non-canonical human transcripts
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675921/
https://www.ncbi.nlm.nih.gov/pubmed/38001496
http://dx.doi.org/10.1186/s12915-023-01753-5
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