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Regulatory features aid interpretation of 3’UTR Variants

Our ability to determine the clinical impact of variants in 3’ untranslated regions (UTRs) of genes remains poor. We provide a thorough analysis of 3’UTR variants from several datasets. Variants in putative regulatory elements including RNA-binding protein motifs, eCLIP peaks, and microRNA sites are...

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Autores principales: Romo, Lindsay, Findlay, Scott D., Burge, Christopher B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418266/
https://www.ncbi.nlm.nih.gov/pubmed/37577470
http://dx.doi.org/10.1101/2023.08.01.551549
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author Romo, Lindsay
Findlay, Scott D.
Burge, Christopher B.
author_facet Romo, Lindsay
Findlay, Scott D.
Burge, Christopher B.
author_sort Romo, Lindsay
collection PubMed
description Our ability to determine the clinical impact of variants in 3’ untranslated regions (UTRs) of genes remains poor. We provide a thorough analysis of 3’UTR variants from several datasets. Variants in putative regulatory elements including RNA-binding protein motifs, eCLIP peaks, and microRNA sites are up to 16 times more likely than other variants to have gene expression and phenotype associations. Heterozygous variants in regulatory motifs result in allele-specific protein binding in cell lines and allele-specific gene expression differences in population studies. In addition, variants in shared regions of alternatively polyadenylated isoforms and those proximal to polyA sites are more likely to affect gene expression and phenotype. Finally, pathogenic 3’UTR variants in ClinVar are 20 times more likely than benign variants to fall in a regulatory site. We incorporated these findings into RegVar, a software tool that interprets regulatory elements and annotations for any 3’UTR variant, and predicts whether the variant is likely to affect gene expression or phenotype. This tool will help prioritize variants for experimental studies and identify pathogenic variants in patients.
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spelling pubmed-104182662023-08-12 Regulatory features aid interpretation of 3’UTR Variants Romo, Lindsay Findlay, Scott D. Burge, Christopher B. bioRxiv Article Our ability to determine the clinical impact of variants in 3’ untranslated regions (UTRs) of genes remains poor. We provide a thorough analysis of 3’UTR variants from several datasets. Variants in putative regulatory elements including RNA-binding protein motifs, eCLIP peaks, and microRNA sites are up to 16 times more likely than other variants to have gene expression and phenotype associations. Heterozygous variants in regulatory motifs result in allele-specific protein binding in cell lines and allele-specific gene expression differences in population studies. In addition, variants in shared regions of alternatively polyadenylated isoforms and those proximal to polyA sites are more likely to affect gene expression and phenotype. Finally, pathogenic 3’UTR variants in ClinVar are 20 times more likely than benign variants to fall in a regulatory site. We incorporated these findings into RegVar, a software tool that interprets regulatory elements and annotations for any 3’UTR variant, and predicts whether the variant is likely to affect gene expression or phenotype. This tool will help prioritize variants for experimental studies and identify pathogenic variants in patients. Cold Spring Harbor Laboratory 2023-08-02 /pmc/articles/PMC10418266/ /pubmed/37577470 http://dx.doi.org/10.1101/2023.08.01.551549 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Romo, Lindsay
Findlay, Scott D.
Burge, Christopher B.
Regulatory features aid interpretation of 3’UTR Variants
title Regulatory features aid interpretation of 3’UTR Variants
title_full Regulatory features aid interpretation of 3’UTR Variants
title_fullStr Regulatory features aid interpretation of 3’UTR Variants
title_full_unstemmed Regulatory features aid interpretation of 3’UTR Variants
title_short Regulatory features aid interpretation of 3’UTR Variants
title_sort regulatory features aid interpretation of 3’utr variants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418266/
https://www.ncbi.nlm.nih.gov/pubmed/37577470
http://dx.doi.org/10.1101/2023.08.01.551549
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