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Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers
Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2004
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514884/ https://www.ncbi.nlm.nih.gov/pubmed/15340491 http://dx.doi.org/10.1371/journal.pbio.0020268 |
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author | Fairbrother, William G Holste, Dirk Burge, Christopher B Sharp, Phillip A |
author_facet | Fairbrother, William G Holste, Dirk Burge, Christopher B Sharp, Phillip A |
author_sort | Fairbrother, William G |
collection | PubMed |
description | Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant elimination reinforces functionality), which can be used to assess the extent of natural selection acting on an oligonucleotide motif or set of motifs predicted to have biological activity. As an application of this approach, we analyzed a set of 238 hexanucleotides previously predicted to have exonic splicing enhancer (ESE) activity in human exons using the relative enhancer and silencer classification by unanimous enrichment (RESCUE)-ESE method. Aligning the single nucleotide polymorphisms (SNPs) from the public human SNP database to the chimpanzee genome allowed inference of the direction of the mutations that created present-day SNPs. Analyzing the set of SNPs that overlap RESCUE-ESE hexamers, we conclude that nearly one-fifth of the mutations that disrupt predicted ESEs have been eliminated by natural selection (odds ratio = 0.82 ± 0.05). This selection is strongest for the predicted ESEs that are located near splice sites. Our results demonstrate a novel approach for quantifying the extent of natural selection acting on candidate functional motifs and also suggest certain features of mutations/SNPs, such as proximity to the splice site and disruption or alteration of predicted ESEs, that should be useful in identifying variants that might cause a biological phenotype. |
format | Text |
id | pubmed-514884 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2004 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-5148842004-08-31 Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers Fairbrother, William G Holste, Dirk Burge, Christopher B Sharp, Phillip A PLoS Biol Research Article Because deleterious alleles arising from mutation are filtered by natural selection, mutations that create such alleles will be underrepresented in the set of common genetic variation existing in a population at any given time. Here, we describe an approach based on this idea called VERIFY (variant elimination reinforces functionality), which can be used to assess the extent of natural selection acting on an oligonucleotide motif or set of motifs predicted to have biological activity. As an application of this approach, we analyzed a set of 238 hexanucleotides previously predicted to have exonic splicing enhancer (ESE) activity in human exons using the relative enhancer and silencer classification by unanimous enrichment (RESCUE)-ESE method. Aligning the single nucleotide polymorphisms (SNPs) from the public human SNP database to the chimpanzee genome allowed inference of the direction of the mutations that created present-day SNPs. Analyzing the set of SNPs that overlap RESCUE-ESE hexamers, we conclude that nearly one-fifth of the mutations that disrupt predicted ESEs have been eliminated by natural selection (odds ratio = 0.82 ± 0.05). This selection is strongest for the predicted ESEs that are located near splice sites. Our results demonstrate a novel approach for quantifying the extent of natural selection acting on candidate functional motifs and also suggest certain features of mutations/SNPs, such as proximity to the splice site and disruption or alteration of predicted ESEs, that should be useful in identifying variants that might cause a biological phenotype. Public Library of Science 2004-09 2004-08-31 /pmc/articles/PMC514884/ /pubmed/15340491 http://dx.doi.org/10.1371/journal.pbio.0020268 Text en Copyright: © Fairbrother 2004 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 Fairbrother, William G Holste, Dirk Burge, Christopher B Sharp, Phillip A Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title | Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title_full | Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title_fullStr | Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title_full_unstemmed | Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title_short | Single Nucleotide Polymorphism–Based Validation of Exonic Splicing Enhancers |
title_sort | single nucleotide polymorphism–based validation of exonic splicing enhancers |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC514884/ https://www.ncbi.nlm.nih.gov/pubmed/15340491 http://dx.doi.org/10.1371/journal.pbio.0020268 |
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