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At the 5′ end are two large ORFs, ORF1a and ORF1b, covering more than two-thirds of the genome. SARS-CoV-2 includes the six ORFs that are common to all coronaviruses 3. SARS-CoV-2 NCBI/UniProt genes (blue), unannotated candidate genes and mapped SARS-CoV genes (black, panel b only), frame-specific protein-coding PhyloCSF scores (green), Synonymous Constraint Elements (SCEs) (blue), and phastCons/phyloP nucleotide-level constraint (green/blue/red) across genomic coordinates (x-axis) for entire genome (panel a) and final 4-kb subset (panel b, dashed black box): a strong protein-coding signal in correct frame for each named gene conservation-signal frame-change at programmed frameshift site strong protein-coding signal throughout S despite lack of nucleotide conservation in S1 b unambiguous and frame-specific protein-coding signal for ORFs 3a (despite only partial nucleotide conservation), 7a, 7b, and 8 (despite lack of nucleotide conservation) clear protein-coding signal in first half and last quarter of ORF6 no protein-coding signal for 10 (despite high nucleotide conservation) synonymous constraint (blue) in novel-ORF 3c and confirmed-ORF 9b no synonymous constraint in rejected ORFs 9c, 3b, 3d. Only modestly negative ORF9c/ORF10 scores are artifacts of score compression in high-nucleotide-constraint regions, and substantially drop when nucleotide-conservation-scaled (see Supplementary Fig. Novel ORF3c (purple) clusters with protein-coding. c PhyloCSF score ( x-axis) for all confirmed (green) and rejected (red) ORFs, showing annotated/candidate/novel (labeled) and all AUG-initiated ≥25-codons-long locally maximal ORFs (unlabeled).
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amino-acid-disruptive (red) substitutions, and stop codons (cyan/magenta/yellow) in frame-specific alignments, and additional features. non-coding (right) using evolutionary signatures, including distinct frequencies of amino-acid-preserving (green) vs. b Phylogenetic Codon Substitution Frequencies (PhyloCSF) scores distinguish protein-coding (left) vs. Here we report a high-confidence gene set and evolutionary-history annotations providing valuable resources and insights on SARS-CoV-2 biology, mutations, and evolution.Ī Coronavirus-wide (black font) and species-specific or candidate (blue font) SARS-CoV-2 genes, with confirmed protein-coding (green), rejected (red), or novel protein-coding (purple) classification, using evolutionary and experimental evidence.
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Previously reported RNA-modification sites show no enrichment for conservation. Evolutionary histories of residues disrupted by spike-protein substitutions D614G, N501Y, E484K, and K417N/T provide clues about their biology, and we catalog likely-functional co-inherited mutations. Cross-strain and within-strain evolutionary pressures agree, except for fewer-than-expected within-strain mutations in nsp3 and S1, and more-than-expected in nucleocapsid, which shows a cluster of mutations in a predicted B-cell epitope, suggesting immune-avoidance selection. Mutation analysis suggests ORF8 contributes to within-individual fitness but not person-to-person transmission. Furthermore, we show no other conserved protein-coding genes remain to be discovered. We find strong protein-coding signatures for ORFs 3a, 6, 7a, 7b, 8, 9b, and a novel alternate-frame gene, ORF3c, whereas ORFs 2b, 3d/3d-2, 3b, 9c, and 10 lack protein-coding signatures or convincing experimental evidence of protein-coding function. We select 44 Sarbecovirus genomes at ideally-suited evolutionary distances, and quantify protein-coding evolutionary signatures and overlapping constraint. We use comparative genomics to provide a high-confidence protein-coding gene set, characterize evolutionary constraint, and prioritize functional mutations. Despite its clinical importance, the SARS-CoV-2 gene set remains unresolved, hindering dissection of COVID-19 biology.