Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Neville, Matthew D.C., Kohze, Robin, Erady, Chaitanya, Meena, Narendra, Hayden, Matthew, Cooper, David N., Mort, Matthew, Prabakaran, Sudhakaran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
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
_version_ 1783645293785382912
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
work_keys_str_mv AT nevillematthewdc aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT kohzerobin aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT eradychaitanya aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT meenanarendra aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT haydenmatthew aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT cooperdavidn aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT mortmatthew aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT prabakaransudhakaran aplatformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT nevillematthewdc platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT kohzerobin platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT eradychaitanya platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT meenanarendra platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT haydenmatthew platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT cooperdavidn platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT mortmatthew platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants
AT prabakaransudhakaran platformforcuratedproductsfromnovelopenreadingframespromptsreinterpretationofdiseasevariants