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A platform for curated products from novel Open Reading Frames (nORFs) prompts reinterpretation of disease variants

Neville, Matthew D.C., Kohze, Robin, Erady, Chaitanya, Meena, Narendra, Hayden, Matthew, Cooper, David N., Mort, Matthew and Prabakaran, Sudhakaran 2021. A platform for curated products from novel Open Reading Frames (nORFs) prompts reinterpretation of disease variants. Genome Research 31 (2) , pp. 327-336. 10.1101/gr.263202.120

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: Cambridge Enterprise Limited, Indian Institute of Science Education and Research, and International Centre for Genetic Engineering and Biotechnology have filed patent applications related to the work described here. The title of the patent application is "TREATMENT OF DISEASES ASSOCIATED WITH VARIANT NOVEL OPEN READING FRAMES". The U.S. Provisional Application was filed on December 9, 2020, Application No. 63/123,454.
Publisher: Cold Spring Harbor Laboratory Press
ISSN: 1088-9051
Date of First Compliant Deposit: 4 December 2020
Date of Acceptance: 24 November 2020
Last Modified: 15 May 2022 14:38

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