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Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution

Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3′ splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that...

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Autores principales: Bradley, Robert K., Merkin, Jason, Lambert, Nicole J., Burge, Christopher B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250501/
https://www.ncbi.nlm.nih.gov/pubmed/22235189
http://dx.doi.org/10.1371/journal.pbio.1001229
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author Bradley, Robert K.
Merkin, Jason
Lambert, Nicole J.
Burge, Christopher B.
author_facet Bradley, Robert K.
Merkin, Jason
Lambert, Nicole J.
Burge, Christopher B.
author_sort Bradley, Robert K.
collection PubMed
description Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3′ splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue-specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ∼15-fold increase in the frequency of three base pair gaps at 3′ splice sites relative to nearby exon positions in both mammals and in Drosophila. Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exon boundaries in rodents, and a model involving point mutations that create, destroy, or alter NAGNAGs can explain both the increased frequency and biased codon composition of gained/lost sequence observed at the beginnings of exons. This study shows that NAGNAG alternative splicing generates widespread differences between the proteomes of mammalian tissues, and suggests that the evolutionary trajectories of mammalian proteins are strongly biased by the locations and phases of the introns that interrupt coding sequences.
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spelling pubmed-32505012012-01-10 Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution Bradley, Robert K. Merkin, Jason Lambert, Nicole J. Burge, Christopher B. PLoS Biol Research Article Thousands of human genes contain introns ending in NAGNAG (N any nucleotide), where both NAGs can function as 3′ splice sites, yielding isoforms that differ by inclusion/exclusion of three bases. However, few models exist for how such splicing might be regulated, and some studies have concluded that NAGNAG splicing is purely stochastic and nonfunctional. Here, we used deep RNA-Seq data from 16 human and eight mouse tissues to analyze the regulation and evolution of NAGNAG splicing. Using both biological and technical replicates to estimate false discovery rates, we estimate that at least 25% of alternatively spliced NAGNAGs undergo tissue-specific regulation in mammals, and alternative splicing of strongly tissue-specific NAGNAGs was 10 times as likely to be conserved between species as was splicing of non-tissue-specific events, implying selective maintenance. Preferential use of the distal NAG was associated with distinct sequence features, including a more distal location of the branch point and presence of a pyrimidine immediately before the first NAG, and alteration of these features in a splicing reporter shifted splicing away from the distal site. Strikingly, alignments of orthologous exons revealed a ∼15-fold increase in the frequency of three base pair gaps at 3′ splice sites relative to nearby exon positions in both mammals and in Drosophila. Alternative splicing of NAGNAGs in human was associated with dramatically increased frequency of exon length changes at orthologous exon boundaries in rodents, and a model involving point mutations that create, destroy, or alter NAGNAGs can explain both the increased frequency and biased codon composition of gained/lost sequence observed at the beginnings of exons. This study shows that NAGNAG alternative splicing generates widespread differences between the proteomes of mammalian tissues, and suggests that the evolutionary trajectories of mammalian proteins are strongly biased by the locations and phases of the introns that interrupt coding sequences. Public Library of Science 2012-01-03 /pmc/articles/PMC3250501/ /pubmed/22235189 http://dx.doi.org/10.1371/journal.pbio.1001229 Text en Bradley et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bradley, Robert K.
Merkin, Jason
Lambert, Nicole J.
Burge, Christopher B.
Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title_full Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title_fullStr Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title_full_unstemmed Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title_short Alternative Splicing of RNA Triplets Is Often Regulated and Accelerates Proteome Evolution
title_sort alternative splicing of rna triplets is often regulated and accelerates proteome evolution
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250501/
https://www.ncbi.nlm.nih.gov/pubmed/22235189
http://dx.doi.org/10.1371/journal.pbio.1001229
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