Thousands of human non-AUG extended proteoforms lack evidence of evolutionary selection among mammals

• Published in: Nature communications Vol. 13; no. 1; p. 7910
• Main Authors: Fedorova, Alla D., Kiniry, Stephen J., Andreev, Dmitry E., Mudge, Jonathan M., Baranov, Pavel V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/114/2184; 631/114/2785; 631/181/735; 631/337/574; 631/45/612/1248; Algorithms; Animals; Codon - genetics; Codon - metabolism; Codons; Datasets; Evolution; Genomic analysis; Genomics; Humanities and Social Sciences; Humans; Mammals; Mammals - genetics; Mammals - metabolism; multidisciplinary; Open Reading Frames - genetics; Phylogenetics; Phylogeny; Protein Biosynthesis; Proteins; Proteins - metabolism; Ribosomes - metabolism; Science; Science (multidisciplinary); Sequences
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35595-6

The synthesis of most proteins begins at AUG codons, yet a small number of non-AUG initiated proteoforms are also known. Here we analyse a large number of publicly available Ribo-seq datasets to identify novel, previously uncharacterised non-AUG proteoforms using Trips-Viz implementation of a novel algorithm for detecting translated ORFs. In parallel we analyse genomic alignment of 120 mammals to identify evidence of protein coding evolution in sequences encoding potential extensions. Unexpectedly we find that the number of non-AUG proteoforms identified with ribosome profiling data greatly exceeds those with strong phylogenetic support suggesting their recent evolution. Our study argues that the protein coding potential of human genome greatly exceeds that detectable through comparative genomics and exposes the existence of multiple proteins encoded by the same genomic loci. Analysis of a large number of Ribo-seq datasets and genomic alignments led to detection of novel non-AUG proteoforms. Unexpectedly the number of non-AUG proteoforms identified with Ribo-seq greatly exceeds those with strong phylogenetic support.