New insights into the evolutionary features of viral overlapping genes by discriminant analysis

Pavesi, Angelo

doi:10.1016/j.virol.2020.03.007

Cited by 31 publications

(80 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ORF3d comprises 58 codons (including STOP) near the beginning of ORF3a ( Table 1 ), making it longer than the known genes ORF7b (44 codons) and ORF10 (39 codons) ( Supplementary file 1 ). ORF3d was discovered independently by Chan et al, 2020 as ‘ ORF3b ’ and Pavesi, 2020 as ‘hypothetical protein’. Due to this naming ambiguity and its location within ORF3a , ORF3d has subsequently been conflated with the previously documented ORF3b in multiple studies (e.g.…”

Section: Resultsmentioning

confidence: 99%

Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

Nelson

Ardern

Goldberg

et al. 2020

eLife

View full text Add to dashboard Cite

Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics, but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.

show abstract

Section: Resultsmentioning

confidence: 99%

Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

Nelson

Ardern

Goldberg

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…According to previous research reports, angiotensin converting enzyme 2 (ACE2), which is highly expressed in lung and heart, is a functional receptors for severe acute respiratory syndrome coronavirus (SARS-CoV), and is likely to play a critical role in infection of the myocardium [13] , [14] . SARS-CoV-2 may have the same mechanism of infection as SARS-COV because the viruses are highly homologous in genome [15] , [16] , [17] . At the same time, recent studies have demonstrated that ACE2 has a high binding affinity with spike protein of SARS-CoV-2 [18] , [19] , [20] .…”

Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19

Deng

Ying

et al. 2020

Clinica Chimica Acta

View full text Add to dashboard Cite

show abstract

“…Previous studies proposed four ORFs overlapping 3a 6,[8][9][10][11][12][13] : 3c (41 codons), 3d (57 codons), 3b (22 codons, a truncated ortholog of SARS-CoV ORF3b), and a subset of 3d (33 codons). ORF3c was proposed using synonymous constraint across 6 closely-related strains 8 and a broader set of Sarbecoviruses 9 , although on its own such evidence could also stem from other overlapping functional elements (and is abundant in SARS-CoV-2 even outside dual-coding regions), and using ribosome…”

Section: Orf3c Is a Novel Functional Proteinmentioning

confidence: 99%

“…The paper introducing SARS-CoV-2 also shows 3b (which overlaps 3a in SARS-CoV but is truncated in SARS-CoV-2, with several in-frame stop codons) 1 . Other publications [5][6][7][8][9][10][11][12][13] include different subsets, use different names, or propose additional ORFs (including 3c and 3d overlapping 3a). NCBI annotates SARS-CoV (NC_004718.3) orthologs of 3a, 6, 7a, 7b, and 9b, but 8 is split into 8a and 8b, 3b is included, and neither 9c nor 10 are included.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes

Jungreis

Sealfon

Kellis

2020

Preprint

View full text Add to dashboard Cite

Despite its overwhelming clinical importance for understanding and mitigating the COVID-19 pandemic, the protein-coding gene content of the SARS-CoV-2 genome remains unresolved, with the function and even protein-coding status of many hypothetical proteins unknown and often conflicting among different annotations, thus hindering efforts for systematic dissection of its biology and the impact of recent mutations. Comparative genomics is a powerful approach for distinguishing protein-coding versus non-coding functional elements, based on their characteristic patterns of change, which we previously used to annotate protein-coding genes in human, fly, and other species. Here, we use comparative genomics to provide a high-confidence set of SARS-CoV-2 protein-coding genes, to characterize their protein-level and nucleotide-level evolutionary constraint, and to interpret the functional implications for SARS-CoV-2 mutations acquired during the current pandemic. We select 44 complete Sarbecovirus genomes at evolutionary distances well-suited for protein-coding and non-coding element identification, create whole-genome alignments spanning all named and putative genes, and quantify their protein-coding evolutionary signatures using PhyloCSF and their overlapping constraint using FRESCo. We find strong protein-coding signatures for all named genes and for hypothetical ORFs 3a, 6, 7a, 7b, and 8, indicating protein-coding roles, and provide strong evidence of protein-coding status for a recently-proposed alternate-frame novel ORF within 3a. By contrast, ORF10 shows no protein-coding signatures but shows unusually-high nucleotide-level constraint, indicating it has important but non-coding functions, and ORF14 and SARS-CoV-1 ORF3b, which overlap other genes, lack evolutionary signatures expected for dual-coding regions, indicating they do not produce functional proteins. ORF9b has ambiguous protein-coding signatures, preventing us from resolving its protein-coding status. ORF8 shows extremely fast nucleotide-level evolution, lacks a known function, and was deactivated in SARS-CoV-1, but shows clear signatures indicating protein-coding function worthy of further investigation given its rapid evolution and potential role in replication. SARS-CoV-2 mutations are preferentially excluded from evolutionarily-constrained amino acid residues and synonymously-constrained nucleotides, indicating purifying constraint acting at both coding and non-coding levels. In contrast, we find a conserved region in the nucleocapsid that is enriched for recent mutations, which could indicate a selective signal, and find that several spike-protein mutations previously identified as candidates for increased transmission and several mutations in isolates found to generate higher viral load in-vitro disrupt otherwise-perfectly-conserved amino-acids, consistent with adaptations for human-to-human transmission.

show abstract

New insights into the evolutionary features of viral overlapping genes by discriminant analysis

Cited by 31 publications

References 81 publications

Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

The diagnostic and prognostic role of myocardial injury biomarkers in hospitalized patients with COVID-19

SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes

Contact Info

Product

Resources

About