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A platform for curated products from novel open reading frames prompts reinterpretation of disease variants
Recent evidence from proteomics and deep massively parallel sequencing studies have revealed that eukaryotic genomes contain substantial numbers of as-yet-uncharacterized open reading frames (ORFs). We define these uncharacterized ORFs as novel ORFs (nORFs). nORFs in humans are mostly under 100 codo...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849405/ https://www.ncbi.nlm.nih.gov/pubmed/33468550 http://dx.doi.org/10.1101/gr.263202.120 |
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author | Neville, Matthew D.C. Kohze, Robin Erady, Chaitanya Meena, Narendra Hayden, Matthew Cooper, David N. Mort, Matthew Prabakaran, Sudhakaran |
author_facet | Neville, Matthew D.C. Kohze, Robin Erady, Chaitanya Meena, Narendra Hayden, Matthew Cooper, David N. Mort, Matthew Prabakaran, Sudhakaran |
author_sort | Neville, Matthew D.C. |
collection | PubMed |
description | Recent evidence from proteomics and deep massively parallel sequencing studies have revealed that eukaryotic genomes contain substantial numbers of as-yet-uncharacterized open reading frames (ORFs). We define these uncharacterized ORFs as novel ORFs (nORFs). nORFs in humans are mostly under 100 codons and are found in diverse regions of the genome, including in long noncoding RNAs, pseudogenes, 3′ UTRs, 5′ UTRs, and alternative reading frames of canonical protein coding exons. There is therefore a pressing need to evaluate the potential functional importance of these unannotated transcripts and proteins in biological pathways and human disease on a larger scale, rather than one at a time. In this study, we outline the creation of a valuable nORFs data set with experimental evidence of translation for the community, use measures of heritability and selection that reveal signals for functional importance, and show the potential implications for functional interpretation of genetic variants in nORFs. Our results indicate that some variants that were previously classified as being benign or of uncertain significance may have to be reinterpreted. |
format | Online Article Text |
id | pubmed-7849405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-78494052021-08-01 A platform for curated products from novel open reading frames prompts reinterpretation of disease variants Neville, Matthew D.C. Kohze, Robin Erady, Chaitanya Meena, Narendra Hayden, Matthew Cooper, David N. Mort, Matthew Prabakaran, Sudhakaran Genome Res Resource Recent evidence from proteomics and deep massively parallel sequencing studies have revealed that eukaryotic genomes contain substantial numbers of as-yet-uncharacterized open reading frames (ORFs). We define these uncharacterized ORFs as novel ORFs (nORFs). nORFs in humans are mostly under 100 codons and are found in diverse regions of the genome, including in long noncoding RNAs, pseudogenes, 3′ UTRs, 5′ UTRs, and alternative reading frames of canonical protein coding exons. There is therefore a pressing need to evaluate the potential functional importance of these unannotated transcripts and proteins in biological pathways and human disease on a larger scale, rather than one at a time. In this study, we outline the creation of a valuable nORFs data set with experimental evidence of translation for the community, use measures of heritability and selection that reveal signals for functional importance, and show the potential implications for functional interpretation of genetic variants in nORFs. Our results indicate that some variants that were previously classified as being benign or of uncertain significance may have to be reinterpreted. Cold Spring Harbor Laboratory Press 2021-02 /pmc/articles/PMC7849405/ /pubmed/33468550 http://dx.doi.org/10.1101/gr.263202.120 Text en © 2021 Neville 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 | Resource Neville, Matthew D.C. Kohze, Robin Erady, Chaitanya Meena, Narendra Hayden, Matthew Cooper, David N. Mort, Matthew Prabakaran, Sudhakaran A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title | A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title_full | A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title_fullStr | A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title_full_unstemmed | A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title_short | A platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
title_sort | platform for curated products from novel open reading frames prompts reinterpretation of disease variants |
topic | Resource |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849405/ https://www.ncbi.nlm.nih.gov/pubmed/33468550 http://dx.doi.org/10.1101/gr.263202.120 |
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