Analysis of nested alternate open reading frames and their encoded proteins. Issue 4 (19th October 2022)

• Record Type: Journal Article
• Authors: Vasu, Kommireddy; Khan, Debjit; Ramachandiran, Iyappan; Blankenberg, Daniel; Fox, Paul L
• Is Part Of: NAR genomics and bioinformatics. Volume 4:Issue 4(2022)
• Publication Date: 2022-10-19
• Subjects: Genomics -- Periodicals; Bioinformatics -- Periodicals; 572.8
• DOI: 10.1093/nargab/lqac076
• Languages: English
• ISSNs: 2631-9268

Abstract

Abstract: Transcriptional and post-transcriptional mechanisms diversify the proteome beyond gene number, while maintaining a sequence relationship between original and altered proteins. A new mechanism breaks this paradigm, generating novel proteins by translating alternative open reading frames (Alt-ORFs) within canonical host mRNAs. Uniquely, 'alt-proteins' lack sequence homology with host ORF-derived proteins. We show global amino acid frequencies, and consequent biochemical characteristics of Alt-ORFs nested within host ORFs (nAlt-ORFs), are genetically-driven, and predicted by summation of frequencies of hundreds of encompassing host codon-pairs. Analysis of 101 human nAlt-ORFs of length ≥150 codons confirms the theoretical predictions, revealing an extraordinarily high median isoelectric point (pI) of 11.68, due to anomalous charged amino acid levels. Also, nAlt-ORF proteins exhibit a >2-fold preference for reading frame 2 versus 3, predicted mitochondrial and nuclear localization, and elevated codon adaptation index indicative of natural selection. Our results provide a theoretical and conceptual framework for exploration of these largely unannotated, but potentially significant, alternative ORFs and their encoded proteins.