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A compendium of conserved cleavage and polyadenylation events in mammalian genes

Cleavage and polyadenylation is essential for 3′ end processing of almost all eukaryotic mRNAs. Recent studies have shown widespread alternative cleavage and polyadenylation (APA) events leading to mRNA isoforms with different 3′ UTRs and/or coding sequences. Here, we present a compendium of conserv...

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Autores principales: Wang, Ruijia, Zheng, Dinghai, Yehia, Ghassan, Tian, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169888/
https://www.ncbi.nlm.nih.gov/pubmed/30143597
http://dx.doi.org/10.1101/gr.237826.118
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author Wang, Ruijia
Zheng, Dinghai
Yehia, Ghassan
Tian, Bin
author_facet Wang, Ruijia
Zheng, Dinghai
Yehia, Ghassan
Tian, Bin
author_sort Wang, Ruijia
collection PubMed
description Cleavage and polyadenylation is essential for 3′ end processing of almost all eukaryotic mRNAs. Recent studies have shown widespread alternative cleavage and polyadenylation (APA) events leading to mRNA isoforms with different 3′ UTRs and/or coding sequences. Here, we present a compendium of conserved cleavage and polyadenylation sites (PASs) in mammalian genes, based on approximately 1.2 billion 3′ end sequencing reads from more than 360 human, mouse, and rat samples. We show that ∼80% of mammalian mRNA genes contain at least one conserved PAS, and ∼50% have conserved APA events. PAS conservation generally reduces promiscuous 3′ end processing, stabilizing gene expression levels across species. Conservation of APA correlates with gene age, gene expression features, and gene functions. Genes with certain functions, such as cell morphology, cell proliferation, and mRNA metabolism, are particularly enriched with conserved APA events. Whereas tissue-specific genes typically have a low APA rate, brain-specific genes tend to evolve APA. In addition, we show enrichment of mRNA destabilizing motifs in alternative 3′ UTR sequences, leading to substantial differences in mRNA stability between 3′ UTR isoforms. Using conserved PASs, we reveal sequence motifs surrounding APA sites and a preference of adenosine at the cleavage site. Furthermore, we show that mutations of U-rich motifs around the PAS often accompany APA profile differences between species. Analysis of lncRNA PASs indicates a mechanism of PAS fixation through evolution of A-rich motifs. Taken together, our results present a comprehensive view of PAS evolution in mammals, and a phylogenic perspective on APA functions.
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spelling pubmed-61698882019-04-01 A compendium of conserved cleavage and polyadenylation events in mammalian genes Wang, Ruijia Zheng, Dinghai Yehia, Ghassan Tian, Bin Genome Res Research Cleavage and polyadenylation is essential for 3′ end processing of almost all eukaryotic mRNAs. Recent studies have shown widespread alternative cleavage and polyadenylation (APA) events leading to mRNA isoforms with different 3′ UTRs and/or coding sequences. Here, we present a compendium of conserved cleavage and polyadenylation sites (PASs) in mammalian genes, based on approximately 1.2 billion 3′ end sequencing reads from more than 360 human, mouse, and rat samples. We show that ∼80% of mammalian mRNA genes contain at least one conserved PAS, and ∼50% have conserved APA events. PAS conservation generally reduces promiscuous 3′ end processing, stabilizing gene expression levels across species. Conservation of APA correlates with gene age, gene expression features, and gene functions. Genes with certain functions, such as cell morphology, cell proliferation, and mRNA metabolism, are particularly enriched with conserved APA events. Whereas tissue-specific genes typically have a low APA rate, brain-specific genes tend to evolve APA. In addition, we show enrichment of mRNA destabilizing motifs in alternative 3′ UTR sequences, leading to substantial differences in mRNA stability between 3′ UTR isoforms. Using conserved PASs, we reveal sequence motifs surrounding APA sites and a preference of adenosine at the cleavage site. Furthermore, we show that mutations of U-rich motifs around the PAS often accompany APA profile differences between species. Analysis of lncRNA PASs indicates a mechanism of PAS fixation through evolution of A-rich motifs. Taken together, our results present a comprehensive view of PAS evolution in mammals, and a phylogenic perspective on APA functions. Cold Spring Harbor Laboratory Press 2018-10 /pmc/articles/PMC6169888/ /pubmed/30143597 http://dx.doi.org/10.1101/gr.237826.118 Text en © 2018 Wang et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Wang, Ruijia
Zheng, Dinghai
Yehia, Ghassan
Tian, Bin
A compendium of conserved cleavage and polyadenylation events in mammalian genes
title A compendium of conserved cleavage and polyadenylation events in mammalian genes
title_full A compendium of conserved cleavage and polyadenylation events in mammalian genes
title_fullStr A compendium of conserved cleavage and polyadenylation events in mammalian genes
title_full_unstemmed A compendium of conserved cleavage and polyadenylation events in mammalian genes
title_short A compendium of conserved cleavage and polyadenylation events in mammalian genes
title_sort compendium of conserved cleavage and polyadenylation events in mammalian genes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169888/
https://www.ncbi.nlm.nih.gov/pubmed/30143597
http://dx.doi.org/10.1101/gr.237826.118
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