Affiliation:
1. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195, USA
2. Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195, USA
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.
Funder
National Institutes of Health
National Institutes of Diabetes and Digestive Disease
National Institutes of Aging
National Institutes of Neurosciences
Publisher
Oxford University Press (OUP)
Subject
Applied Mathematics,Computer Science Applications,Genetics,Molecular Biology,Structural Biology