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Comparative genomics identifies key genes and miRNAs that may be used as a strategy to control and treatment of COVID-19

Abolfazl Bahrami

Department of Animal Science, University college of Agriculture and Natural Resources, University of Tehran, Karaj, Islamic Republic of Iran

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Maryam Bakherad

Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

DOI: 10.15761/TiM.1000253

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Abstract

The novel coronavirus SARS-CoV-2 (COVID-19) is a member of the family Coronaviridae and contains ssRNA genome. The emergency of COVID-19 has caused global threatened and panic health security. In order to detect common regions and genes of the Severe acute respiratory syndrome-associated coronavirus 2, we collected the whole genome of all viruses available in databases for this family (55 complete genomes), and made comparative genomic analyses with the collected data. We performed an interactomics approach to identify miRNAs that could be affected in some regions of the whole virus genome. As well as, protein structure modeling was used for modeling of related sequence. Cladogram revealed Bat coronavirus, MERS-related coronavirus, SARS-related coronavirus and SARS coronavirus 2 are closely related. The most important genes involved in the disease were RELA in virus genome and ACE 2 receptors and CLEC 4M genes in the host genome. RELA gene was suppressed by hsa-miR-516b-3p, hsa-miR-3529-3p and hsa-miR-6749-3p, ACE2 receptor was suppressed by hsa-miR-23b-5p and hsa-miR-769-5p, and finally, hsa-miR-4462 and hsa-miR-5187-5p suppressed CLEC4M gene. Therefore, our results will help to control and treat COVID-19 and revealed new insight into the vaccine design and miRNA therapy.

Key words

COVID-19, comparative genomics, miRNA, miRNA therapy, interactomics

Introduction

The outbreak of person-to-person transmissible and atypical caused by the COVID-19 has caused global concern. There have been more than 1,200,000 approved cases of this disease in the world, as of April 7, 2020. According to the World Health Organization, 16-21% of people with the virus have become ill with a 2-3% mortality rate [1]. Therefore, it is crucial to identify an effective method as early as possible for vaccine design and treatment procedures.

Although some studies have reported clinical characteristics of SARS, MERS and SARS2 [2-5] genomic comparison of complete genome features and suggested treatments for COVID-19 has not been reported yet. The Severe acute respiratory syndrome coronavirus 2 is the seventh member of enveloped RNA coronaviruses [6-8]. A typical coronaviruses family contains four main structural proteins: S (spike protein), M (membrane protein), E (envelope protein), and N (nucleocapsid protein), respectively [9].

Besides, the interactomics approach and miRNA-gene analyses have mostly been used as complementary approaches for extracting biological information from omics layers and increased awareness of the complex disease [10].

Most studies considered neither non-coding region nor the detection of genomic regions associated with COVID-19, which is an important aspect of vaccine design and treatment patients. Therefore, this study aims to demonstrate how new genomic scale comparison and new approaches can provide new insights into the procedures that govern the emergence and evolution of coronaviruses and how to treat related diseases. In doing, so we make general statements about the nature of ssRNA virus evolution and highlight some of the key evolutionary mechanisms. As a sidebar, this work showed the increasingly important role played by comparative genomics and applying the interactomics approach in the study of COVID-19.

Workflow

All of the used software, databases, online/offline tools are listed in Table 1.

Table 1. Software, databases, online/offline tools, generally explanations and website addresses

Software name

Explanations

Accession web Address

 

 

Viral genome browser

The viral genome browser includes 9240 complete genomes. The header part lists taxonomy groups. The genome table lists species and reference genomes (RefSeqs) within a selected taxonomy group.

https://www.ncbi.nlm.nih.gov/genome/viruses

 

Gene Expression Omnibus

GEO is a public functional genomics data repository. Tools are provided to help users query and download experiments and curated gene expression profiles.

https://www.ncbi.nlm.nih.gov/geo

 

 

Functional Annotation Tools

Gene annotation involves the process of taking the raw DNA sequence produced by the genome-sequencing projects and adding layers of analysis and interpretation necessary to extracting biologically significant information and placing such derived details into context.

https://david.ncifcrf.gov

 

Multiple Sequence Alignment (MSA)

MSA is generally the alignment of three or more biological sequences (protein or nucleic acid) of similar length. From the output, homology can be inferred and the evolutionary relationships between the sequences studied.

www.ebi.ac.uk/Tools/msa

 

Phylogenetic Tree

This tool provides access to phylogenetic tree generation methods from the ClustalW2 package.

www.ebi.ac.uk/Tools/phylogeny

 

 

CoGe

CoGe is a platform for performing Comparative Genomics research. It provides an open-ended network of interconnected tools to manage, analyze, and visualize next-gen data.

genomevolution.org/coge

 

BLASTn,p,x

The Basic Local Alignment Search Tool (BLAST) finds regions of local similarity between sequences.

blast.ncbi.nlm.nih.gov/Blast.cgi

 

 

 

Protein modeling

The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for relevant model organisms and experimental structure information for all sequences in UniProtKB.

swissmodel.expasy.org/interactive#sequence

HHPred

Homology detection and structure prediction by HMM-HMM comparison

toolkit.tuebingen.mpg.de/tools/hhpred

Literature Mining

It allows researchers to explore a network of gene and protein interactions based on published scientific literature.

www.ihop-net.org/UniPub/iHOP

 

 

 

miRWalk 2.0 and 3.0

The platform integrates information from different miRNA-target databases, including validated information and prediction datasets: MiRWalk, miRDB, miRMap, miRNAMap, MicroT4, miRanda, miRBridge, PICTAR2, RNAhybrid, Targetscan, PITA and RNA22.

zmf.umm.uni-heidelberg.de/apps/zmf/mirwalk2/index.html

Results and discussion

Structure and comparative genomics of the family Coronaviridae complete genomes were performed based on related complete genome. For this purpose, all published data related to the whole-genome of viruses were collected; a total of 55 complete genomes were used for the next step of the analysis. One of the most important goals of comparative genomics is finding differences between various strains and the use of these differences for the next goals such as the identification of genes and miRNAs. We have identified a total of 459 miRNAs that suppress RELA, ACE2 receptor and CLEC4M genes but we have only reported gene-specific miRNAs and this study one of the first studies in the field of molecular therapeutic specially treatment of COVID-19. miRNAs that suppress these genes were listed as supplementary Table 1. We have performed based on virus RNA sequences and observed high homology (>99%) between nsp1 or leader protein with RELA or p56 gene, as well as, protein homology detection and modeling confirmed mentioned gene. Also, ACE2 receptor and CLEC4M genes were related to S protein or Spike glycoprotein that spike protein S1 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection. Binding to human ACE2 receptor and CLEC4M genes and internalization of the virus into the endosomes of the host cell induces conformational changes in the S glycoprotein. Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes. Spike protein S2 mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein (www.uniprot.org) (supplementary Table 2).

The miRNAs pair with genes or mRNAs to induce gene or mRNA translational repression and degradation [11]. The various molecular procedures at the mRNA destabilization and heart of miRNA-directed translational repression, that include inhibition of translation initiation and poly(A) shortening, are reviewed elsewhere [12]. Within a region of the 3'-UTR (3'-untranslated region) of the RELA, ACE2 receptor and CLEC4M genes in COVID-19 disease were suppressed by mentioned miRNAs.

miRNAs are critical for normal animal growth and are involved in a difference of biological pathways [13]. Expression of miRNAs is associated with many human diseases [14,15]. As well as, miRNAs are secreted into extracellular fluids. Extracellular miRNAs have been widely reported as potential biomarkers for different biological process and they also serve as signaling molecules to mediate cell-cell communications [16].

Phylogenetic analyses of complete genome sequence data have revealed that Bat coronavirus, Middle East respiratory syndrome-related coronavirus, Severe acute respiratory syndrome-related coronavirus and Severe acute respiratory syndrome coronavirus 2 were closely related (Figure 1). This comparison dedicates that the origin of the virus could be held in common and the same strategies can be used to treat them. In addition, by Focusing on the genome structure of these four strains revealed little differences. The most similarity was between the Severe acute respiratory syndrome-related coronavirus and Severe acute respiratory syndrome coronavirus 2 genomes (Supplementary Figure 1). Multiple sequences alignment (MSA) also confirmed this statement (Figure 2).

Figure 1. Cladogramof the family Coronaviridae complete genomes were reconstructed by Clustal Omega using 55 sequences with the best fitting evolutionary model. Subsequently, the tree was purged from the most similar sequences and midpoint rooted. GenBank accession numbers for all viruses are shown.

Figure 2. Multiple sequence alignments (MSAs) of the sequenses combination using Bat coronavirus, Middle East respiratory syndrome-related coronavirus, Severe acute respiratory syndrome-related coronavirus and Severe acute respiratory syndrome coronavirus 2 by LASTZ

Another important aspect of comparative genomics is the comparison of mutation rates and changes in protein structure. So, we studied the protein structure changes, and also evaluated the homology between the different parts of the virus protein with the relevant databases (Figure 3). Protein orf1ab divided into 18 parts that involved: bases 266-805 encode nsp1 and produce leader protein. This protein has high homology with p65 protein. Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene. Gene expression regulation by RELA is fundamental for controlling many important procedures, including immune responses, apoptosis, inflammatory, cell proliferation and development [17]. Up-regulation of this gene related to many cancers and activation has been found to be correlated with cancer development [18]. Using miRNAs that suppressed this gene can disrupt the replication of the virus. In this regard, we identified three miRNAs that increasing the blood concentration of these miRNAs that can suppress the activity of the RELA gene. hsa-miR-516b-3p, hsa-miR-3529-3p and hsa-miR-6749-3p suppressed mentioned gene. Therefore, could be used as a drug that paralyzing for the virus. Bases 806-2719 encode nsp2 and this protein may play a key role in the modulation of host cell survival signaling pathway by interacting with host PHB1 and PHB2. PHB1 and PHB2 belong to the prohibition domain family, and both exist in different cellular compartments such as cell membrane, nucleus and the mitochondria. Many studies have reported differential expression of the PHB1 and PHB2 in cancers. Furthermore, studies confirmed that PHB1 and PHB2 are involved in the biological procedures of tumorigenesis, including metastasis, apoptosis and cell proliferation [19]. Bases 2720-8554, 2720-8554, 2720-8554, 2720-8554 and 2720-8554 that encode nsp3, ADP-ribose-1"-monophosphatase, Replicase polyprotein 1ab, nsp3 and Replicase polyprotein 1ab, respectively. These regions are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, it participates together with nsp4 in the assembly of virally induced cytoplasmic double-membrane vesicles necessary for viral replication. Bases 8555-10054 encode nsp4 and produce RNA-directed RNA polymerase.

Figure 3. Protein structure modeling for Severe acute respiratory syndrome coronavirus 2 by ExPASy tools

Bases 10055-10972 encode SARS-CoV-2 (2019-nCoV) main protease and produce 3C-like proteinase. Bases 11843-12091, 12092-12685 and 12686-13024 encode nsp7, Replicase polyprotein 1ab and ssRNA-binding protein, respectively. Bases 13025-13441encode nsp10 that known as growth-factor-like protein (GFL). This part plays an essential role in viral mRNAs cap methylation. Bases 13025-13441 encode nsp12 and produce RNA-dependent RNA polymerase. Bases 16237-18039 encode nsp13 and produce helicase. Bases 18040-19620 encode 3'-to-5' exonuclease. 3'-to-5' exonuclease processing two different activities: an N7-guanine methyltransferase activity and an exoribonuclease activity acting on both dsRNA and ssRNA. Bases 19621-20658 encode NSP15 Endoribonuclease (Mn(2+)-dependent, uridylate-specific enzyme). Bases 20659-21552 encode putative 2'-o-methyl transferase. Bases 21563-25384 that encode spike glycoprotein, this protein attach the virion to the cell membrane by interacting with the host receptor, initiating the infection.

The finding that SARS-2-S exploits ACE2 for entry, which was also reported [20]. However, ACE2 expression is not limited to the lung, and extrapulmonary spread of SARS-CoV in ACE2+ tissues were reported [21]. Thus, increasing the blood concentration of these miRNAs can suppress the activity of these genes and prevented the virus from progressing. ACE2 receptor was suppressed by hsa-miR-23b-5p and hsa-miR-769-5p, and, hsa-miR-4462 and hsa-miR-5187-5p suppressed CLEC4M gene. Bases 25393-26220, 26245-26472, 26523-27191, 27202-27387, 27394-27759, 27756-27887 and 27894-28259 that encode ORF3a, E, M, orf6, ORF7a, ORF7b and ORF8 proteins, respectively. Bases 28274-29533 encode N protein and produce nucleocapsid phosphoprotein, and finally, bases 29558-29674 encode ORF10 protein. Therefore, the most important genes are RELA, ACE2 receptor and CLEC4M gene. By suppressing these genes, can hope to get treatment for this disease. One of the strategies used to treat cancer is to utilize non-coding RNAs such as miRNAs. In other words, systems biology and the interactomics approach are a systemic level approach to study an all-around understanding of complicated biological systems outside the molecular-level scale [22]. Instead of analyzing individual components or aspects of the organism, such as a cell nucleus or metabolism, systems biologists focus on all aspects and the interactions between them as part of one system such as using the gene-miRNA approach. Therefore, this method of considering miRNA–gene interactome will help to clarify the complicated biological procedures for this disease. microRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally by interfering with the translation of one or more target genes. The dysregulation of miRNAs contributes to the pathogenesis of all types of cancer.

The recent decade has witnessed a substantial improvement of miRNA replacement therapy. This approach aims to restore disease suppressor miRNA function in some cells using miRNA expression plasmids or synthetic miRNA mimics. Recent advances in miRNA replacement therapy for the treatment of cancer and its advantages were reported [23]. The fact that various miRNA replacement therapies are currently in the clinical trial shows the great potential of this approach to treat disease. In the same direction, we applied miRNA databases for identifying miRNAs that suppress motioned genes. We believe that the mentioned approach could treat COVID-19, however, further experimental tests are needed. Therefore, this study could enhance the identification of biological mechanisms and respective candidate genes, and also, useful in disease therapy.

Declarations

Data availability statement

All datasets generated for this study are included in the article/supplementary material.

Ethics statement

Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements.

Declaration of interests

The author declares that they have no competing interests.

Funding

Not applicable.

Acknowledgements

I would like to thank Prof. Reza Miraie-Ashtiani and Prof. Mostafa Sadeghi for providing critical feedback and reagents, Fatemeh Marandi for technical assistance and the University of Tehran, Department of Animal Science. I also thank the anonymous editor and reviewers for their constructive feedback which significantly improved the quality of our analysis.

View Supplementary Data

References

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  3. Wang D, Hu B, Hu C, Zhu F, Liu X, et al. (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323: 1061-1069.
  4. Ren J, Zhang AH, Wang XJ (2020) Traditional Chinese medicine for COVID-19 treatment. Pharmacol Res 10: 47-43.
  5. Al-Baadani AM, Elzein FE, Alhemyadi SA, Khan OA, Albenmousa AH, et al. (2019) Characteristics and outcome of viral pneumonia caused by influenza and Middle East respiratory syndrome-coronavirus infections: A 4-year experience from a tertiary care center. Ann Thorac Med 14: 179-185. [Crossref]
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Editorial Information

Editor-in-Chief

Ying-Fu Chen
Kaohsiung Medical University, Taiwan

Article Type

Research Article

Publication history

Received date: July 31, 2020
Accepted date: August 24, 2020
Published date: August 28, 2020

Copyright

©2020 Bahrami A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Bahrami A, Bakherad M (2020) Comparative genomics identifies key genes and miRNAs that may be used as a strategy to control and treatment of COVID-19. Trends Med 20: DOI: 10.15761/TiM.1000253

Corresponding author

A. Bahrami

Department of Animal Science, University of Tehran, Karaj, I.R. Iran

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1. Cladogramof the family Coronaviridae complete genomes were reconstructed by Clustal Omega using 55 sequences with the best fitting evolutionary model. Subsequently, the tree was purged from the most similar sequences and midpoint rooted. GenBank accession numbers for all viruses are shown.

Figure 2. Multiple sequence alignments (MSAs) of the sequenses combination using Bat coronavirus, Middle East respiratory syndrome-related coronavirus, Severe acute respiratory syndrome-related coronavirus and Severe acute respiratory syndrome coronavirus 2 by LASTZ

Figure 3. Protein structure modeling for Severe acute respiratory syndrome coronavirus 2 by ExPASy tools

Supplemantary Figure 1. Protein domains of the family Coronaviridae was reconstructed for Bat Coronavirus, MERS, SARS and COVID-19 by NCBI genome viewer

Table 1. Software, databases, online/offline tools, generally explanations and website addresses

Software name

Explanations

Accession web Address

 

 

Viral genome browser

The viral genome browser includes 9240 complete genomes. The header part lists taxonomy groups. The genome table lists species and reference genomes (RefSeqs) within a selected taxonomy group.

https://www.ncbi.nlm.nih.gov/genome/viruses

 

Gene Expression Omnibus

GEO is a public functional genomics data repository. Tools are provided to help users query and download experiments and curated gene expression profiles.

https://www.ncbi.nlm.nih.gov/geo

 

 

Functional Annotation Tools

Gene annotation involves the process of taking the raw DNA sequence produced by the genome-sequencing projects and adding layers of analysis and interpretation necessary to extracting biologically significant information and placing such derived details into context.

https://david.ncifcrf.gov

 

Multiple Sequence Alignment (MSA)

MSA is generally the alignment of three or more biological sequences (protein or nucleic acid) of similar length. From the output, homology can be inferred and the evolutionary relationships between the sequences studied.

www.ebi.ac.uk/Tools/msa

 

Phylogenetic Tree

This tool provides access to phylogenetic tree generation methods from the ClustalW2 package.

www.ebi.ac.uk/Tools/phylogeny

 

 

CoGe

CoGe is a platform for performing Comparative Genomics research. It provides an open-ended network of interconnected tools to manage, analyze, and visualize next-gen data.

genomevolution.org/coge

 

BLASTn,p,x

The Basic Local Alignment Search Tool (BLAST) finds regions of local similarity between sequences.

blast.ncbi.nlm.nih.gov/Blast.cgi

 

 

 

Protein modeling

The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for relevant model organisms and experimental structure information for all sequences in UniProtKB.

swissmodel.expasy.org/interactive#sequence

HHPred

Homology detection and structure prediction by HMM-HMM comparison

toolkit.tuebingen.mpg.de/tools/hhpred

Literature Mining

It allows researchers to explore a network of gene and protein interactions based on published scientific literature.

www.ihop-net.org/UniPub/iHOP

 

 

 

miRWalk 2.0 and 3.0

The platform integrates information from different miRNA-target databases, including validated information and prediction datasets: MiRWalk, miRDB, miRMap, miRNAMap, MicroT4, miRanda, miRBridge, PICTAR2, RNAhybrid, Targetscan, PITA and RNA22.

zmf.umm.uni-heidelberg.de/apps/zmf/mirwalk2/index.html

Gene miRNA
RELA hsa-miR-516b-3p
RELA hsa-miR-516a-3p
RELA hsa-miR-4773
RELA hsa-miR-3529-3p
RELA hsa-miR-6749-3p
RELA hsa-miR-6792-3p
RELA hsa-miR-4691-5p
RELA hsa-miR-7162-5p
RELA hsa-miR-3161
RELA hsa-miR-599
RELA hsa-miR-6077
RELA hsa-miR-1236-3p
RELA hsa-miR-3134
RELA hsa-miR-1303
RELA hsa-miR-8082
RELA hsa-miR-6720-5p
RELA hsa-miR-4534
RELA hsa-miR-6866-5p
RELA hsa-miR-6512-3p
RELA hsa-miR-373-3p
RELA hsa-miR-877-5p
RELA hsa-miR-124-3p
RELA hsa-miR-6849-3p
RELA hsa-miR-7-5p
RELA hsa-miR-6859-5p
RELA hsa-miR-7-5p
RELA hsa-miR-3916
RELA hsa-miR-3125
RELA hsa-miR-7-5p
RELA hsa-miR-324-5p
RELA hsa-miR-7-5p
RELA hsa-miR-30e-5p
RELA hsa-miR-96-5p
RELA hsa-miR-320a
RELA hsa-miR-1261
RELA hsa-miR-8064
RELA hsa-miR-8064
RELA hsa-miR-335-5p
RELA hsa-miR-34a-5p
RELA hsa-miR-6884-5p
RELA hsa-miR-27b-3p
RELA hsa-miR-4465
RELA hsa-miR-548f-3p
RELA hsa-miR-6823-3p
RELA hsa-miR-550a-5p
RELA hsa-miR-485-5p
RELA hsa-miR-155-5p
RELA hsa-miR-4666a-3p
RELA hsa-miR-548ar-3p
RELA hsa-miR-2114-3p
RELA hsa-miR-106b-3p
RELA hsa-miR-27a-3p
RELA hsa-miR-2467-5p
RELA hsa-miR-7849-3p
RELA hsa-miR-548az-3p
RELA hsa-miR-134-3p
RELA hsa-miR-93-3p
RELA hsa-miR-27b-3p
RELA hsa-miR-3975
RELA hsa-miR-1185-2-3p
RELA hsa-miR-5007-3p
RELA hsa-miR-7114-5p
RELA hsa-miR-615-3p
RELA hsa-miR-19a-3p
RELA hsa-miR-4774-5p
RELA hsa-miR-1185-1-3p
RELA hsa-miR-590-3p
RELA hsa-miR-6755-3p
RELA hsa-miR-130b-5p
RELA hsa-miR-18a-3p
RELA hsa-miR-19b-3p
RELA hsa-miR-4490
RELA hsa-miR-4789-5p
RELA hsa-miR-302f
RELA hsa-miR-302a-5p
RELA hsa-miR-6849-3p
RELA hsa-miR-193b-3p
RELA hsa-miR-6772-3p
RELA hsa-miR-6824-3p
RELA hsa-let-7a-3p
RELA hsa-let-7f-2-3p
RELA hsa-miR-4639-5p
RELA hsa-miR-1279
RELA hsa-miR-6877-3p
RELA hsa-miR-423-3p
RELA hsa-miR-6780a-3p
RELA hsa-miR-6764-3p
RELA hsa-let-7b-3p
RELA hsa-miR-101-3p
RELA hsa-miR-4775
RELA hsa-miR-892c-3p
RELA hsa-miR-6819-3p
RELA hsa-miR-331-3p
RELA hsa-miR-6509-3p
RELA hsa-miR-1273g-3p
RELA hsa-let-7f-1-3p
RELA hsa-miR-4272
RELA hsa-miR-384
RELA hsa-miR-4676-3p
RELA hsa-miR-4700-3p
RELA hsa-miR-378a-3p
RELA hsa-miR-4795-3p
RELA hsa-miR-181a-2-3p
RELA hsa-miR-26a-5p
RELA hsa-miR-5697
RELA hsa-miR-3685
RELA hsa-miR-452-5p
RELA hsa-miR-320a
RELA hsa-miR-4477a
RELA hsa-miR-8063
RELA hsa-miR-26b-5p
RELA hsa-miR-144-3p
RELA hsa-miR-4652-3p
RELA hsa-miR-5582-3p
RELA hsa-miR-199a-5p
RELA hsa-miR-186-5p
RELA hsa-miR-4448
RELA hsa-miR-21-5p
RELA hsa-miR-126-5p
RELA hsa-miR-32-3p
RELA hsa-miR-192-5p
RELA hsa-miR-4743-3p
RELA hsa-miR-149-5p
RELA hsa-miR-4268
RELA hsa-miR-944
RELA hsa-miR-98-3p
RELA hsa-miR-215-5p
RELA hsa-miR-6720-5p
RELA hsa-miR-125b-5p
RELA hsa-miR-6797-3p
RELA hsa-miR-7-2-3p
RELA hsa-miR-381-3p
RELA hsa-miR-548a-3p
RELA hsa-miR-6512-3p
RELA hsa-miR-183-5p
RELA hsa-miR-6076
RELA hsa-miR-7-1-3p
RELA hsa-miR-300
RELA hsa-miR-606
RELA hsa-miR-2682-3p
RELA hsa-miR-197-3p
RELA hsa-miR-3188
RELA hsa-miR-27a-3p
RELA hsa-miR-1297
RELA hsa-miR-548e-3p
RELA hsa-miR-6781-3p
RELA hsa-miR-877-3p
RELA hsa-let-7b-5p
ACE2 hsa-miR-23b-5p
ACE2 hsa-miR-30c-1-3p
ACE2 hsa-miR-769-5p
ACE2 hsa-miR-1183
ACE2 hsa-miR-1911-3p
ACE2 hsa-miR-514b-5p
ACE2 hsa-miR-4697-3p
ACE2 hsa-miR-2113
ACE2 hsa-miR-761
ACE2 hsa-miR-3684
ACE2 hsa-miR-5002-5p
ACE2 hsa-miR-6760-5p
ACE2 hsa-miR-12136
ACE2 hsa-miR-4685-3p
ACE2 hsa-miR-21-3p
ACE2 hsa-miR-92a-3p
ACE2 hsa-miR-99a-3p
ACE2 hsa-miR-199a-5p
ACE2 hsa-miR-187-3p
ACE2 hsa-miR-212-5p
ACE2 hsa-miR-130a-5p
ACE2 hsa-miR-125a-3p
ACE2 hsa-miR-125b-2-3p
ACE2 hsa-miR-154-5p
ACE2 hsa-miR-320a-3p
ACE2 hsa-miR-106b-3p
ACE2 hsa-miR-30e-5p
ACE2 hsa-miR-365a-5p
ACE2 hsa-miR-330-5p
ACE2 hsa-miR-331-5p
ACE2 hsa-miR-423-3p
ACE2 hsa-miR-433-3p
ACE2 hsa-miR-487a-5p
ACE2 hsa-miR-490-3p
ACE2 hsa-miR-493-3p
ACE2 hsa-miR-526b-5p
ACE2 hsa-miR-518c-5p
ACE2 hsa-miR-501-5p
ACE2 hsa-miR-504-3p
ACE2 hsa-miR-513a-5p
ACE2 hsa-miR-589-3p
ACE2 hsa-miR-593-5p
ACE2 hsa-miR-607
ACE2 hsa-miR-608
ACE2 hsa-miR-610
ACE2 hsa-miR-614
ACE2 hsa-miR-615-5p
ACE2 hsa-miR-618
ACE2 hsa-miR-632
ACE2 hsa-miR-635
ACE2 hsa-miR-637
ACE2 hsa-miR-639
ACE2 hsa-miR-642a-3p
ACE2 hsa-miR-647
ACE2 hsa-miR-648
ACE2 hsa-miR-661
ACE2 hsa-miR-659-5p
ACE2 hsa-miR-659-3p
ACE2 hsa-miR-421
ACE2 hsa-miR-671-3p
ACE2 hsa-miR-320c
ACE2 hsa-miR-769-3p
ACE2 hsa-miR-887-5p
ACE2 hsa-miR-873-3p
ACE2 hsa-miR-216b-3p
ACE2 hsa-miR-942-5p
ACE2 hsa-miR-1225-5p
ACE2 hsa-miR-1229-5p
ACE2 hsa-miR-1202
ACE2 hsa-miR-1285-3p
ACE2 hsa-miR-1294
ACE2 hsa-miR-1268a
ACE2 hsa-miR-513b-5p
ACE2 hsa-miR-1321
ACE2 hsa-miR-1321
ACE2 hsa-miR-1909-5p
ACE2 hsa-miR-1909-3p
ACE2 hsa-miR-1910-5p
ACE2 hsa-miR-1912-3p
ACE2 hsa-miR-2115-3p
ACE2 hsa-miR-2276-5p
ACE2 hsa-miR-2278
ACE2 hsa-miR-3121-5p
ACE2 hsa-miR-3130-3p
ACE2 hsa-miR-3187-5p
ACE2 hsa-miR-3197
ACE2 hsa-miR-4319
ACE2 hsa-miR-4259
ACE2 hsa-miR-4265
ACE2 hsa-miR-4265
ACE2 hsa-miR-4280
ACE2 hsa-miR-4292
ACE2 hsa-miR-3611
ACE2 hsa-miR-3615
ACE2 hsa-miR-3622b-5p
ACE2 hsa-miR-3682-5p
ACE2 hsa-miR-3689a-3p
ACE2 hsa-miR-3937
ACE2 hsa-miR-3940-5p
ACE2 hsa-miR-3940-3p
ACE2 hsa-miR-550b-3p
ACE2 hsa-miR-1268b
ACE2 hsa-miR-4427
ACE2 hsa-miR-4448
ACE2 hsa-miR-4481
ACE2 hsa-miR-4505
ACE2 hsa-miR-4506
ACE2 hsa-miR-4508
ACE2 hsa-miR-4514
ACE2 hsa-miR-4520-5p
ACE2 hsa-miR-4525
ACE2 hsa-miR-4525
ACE2 hsa-miR-3960
ACE2 hsa-miR-4634
ACE2 hsa-miR-4644
ACE2 hsa-miR-4654
ACE2 hsa-miR-4664-5p
ACE2 hsa-miR-4665-5p
ACE2 hsa-miR-4677-3p
ACE2 hsa-miR-4682
ACE2 hsa-miR-4683
ACE2 hsa-miR-4684-3p
ACE2 hsa-miR-4693-3p
ACE2 hsa-miR-4708-5p
ACE2 hsa-miR-4713-3p
ACE2 hsa-miR-4717-3p
ACE2 hsa-miR-4742-3p
ACE2 hsa-miR-4756-5p
ACE2 hsa-miR-4757-5p
ACE2 hsa-miR-4773
ACE2 hsa-miR-4436b-5p
ACE2 hsa-miR-4783-5p
ACE2 hsa-miR-4783-3p
ACE2 hsa-miR-4790-3p
ACE2 hsa-miR-5008-5p
ACE2 hsa-miR-5088-5p
ACE2 hsa-miR-5571-3p
ACE2 hsa-miR-5587-3p
ACE2 hsa-miR-5589-5p
ACE2 hsa-miR-6070
ACE2 hsa-miR-6085
ACE2 hsa-miR-6501-5p
ACE2 hsa-miR-6501-3p
ACE2 hsa-miR-6735-3p
ACE2 hsa-miR-6743-5p
ACE2 hsa-miR-6744-5p
ACE2 hsa-miR-6749-5p
ACE2 hsa-miR-6750-5p
ACE2 hsa-miR-6751-5p
ACE2 hsa-miR-6762-5p
ACE2 hsa-miR-6769a-5p
ACE2 hsa-miR-6771-5p
ACE2 hsa-miR-6776-5p
ACE2 hsa-miR-6783-3p
ACE2 hsa-miR-6798-5p
ACE2 hsa-miR-6803-5p
ACE2 hsa-miR-6805-5p
ACE2 hsa-miR-6817-3p
ACE2 hsa-miR-6825-5p
ACE2 hsa-miR-6828-3p
ACE2 hsa-miR-6828-3p
ACE2 hsa-miR-6834-5p
ACE2 hsa-miR-6841-5p
ACE2 hsa-miR-6841-3p
ACE2 hsa-miR-6850-5p
ACE2 hsa-miR-6856-3p
ACE2 hsa-miR-6862-5p
ACE2 hsa-miR-6868-5p
ACE2 hsa-miR-6870-5p
ACE2 hsa-miR-6871-5p
ACE2 hsa-miR-6877-3p
ACE2 hsa-miR-6888-5p
ACE2 hsa-miR-6895-5p
ACE2 hsa-miR-7849-3p
ACE2 hsa-miR-8052
ACE2 hsa-miR-1843
ACE2 hsa-miR-10397-5p
ACE2 hsa-miR-10399-3p
ACE2 hsa-miR-11181-3p
ACE2 hsa-miR-9851-3p
ACE2 hsa-miR-12115
ACE2 hsa-miR-12119
ACE2 hsa-miR-12120
ACE2 hsa-miR-12129
CLEC4M hsa-miR-4462
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4462
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4462
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-4701-3p
CLEC4M hsa-miR-5187-5p
CLEC4M hsa-miR-525-5p
CLEC4M hsa-miR-557
CLEC4M hsa-miR-551b-5p
CLEC4M hsa-miR-744-5p
CLEC4M hsa-miR-921
CLEC4M hsa-miR-1292-3p
CLEC4M hsa-miR-4259
CLEC4M hsa-miR-3940-5p
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-6894-3p
CLEC4M hsa-miR-7851-3p
CLEC4M hsa-miR-525-5p
CLEC4M hsa-miR-557
CLEC4M hsa-miR-551b-5p
CLEC4M hsa-miR-744-5p
CLEC4M hsa-miR-921
CLEC4M hsa-miR-1292-3p
CLEC4M hsa-miR-4259
CLEC4M hsa-miR-3940-5p
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6726-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-6894-3p
CLEC4M hsa-miR-7851-3p
CLEC4M hsa-miR-150-3p
CLEC4M hsa-miR-652-5p
CLEC4M hsa-miR-4456
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-525-5p
CLEC4M hsa-miR-557
CLEC4M hsa-miR-551b-5p
CLEC4M hsa-miR-744-5p
CLEC4M hsa-miR-921
CLEC4M hsa-miR-1292-3p
CLEC4M hsa-miR-3157-5p
CLEC4M hsa-miR-4259
CLEC4M hsa-miR-3940-5p
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-5572
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-6794-5p
CLEC4M hsa-miR-6894-3p
CLEC4M hsa-miR-7851-3p
CLEC4M hsa-miR-150-3p
CLEC4M hsa-miR-652-5p
CLEC4M hsa-miR-4456
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-6794-5p
CLEC4M hsa-miR-150-3p
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-150-3p
CLEC4M hsa-miR-4456
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-150-3p
CLEC4M hsa-miR-652-5p
CLEC4M hsa-miR-4456
CLEC4M hsa-miR-4753-5p
CLEC4M hsa-miR-6760-5p
CLEC4M hsa-miR-6794-5p
CLEC4M hsa-miR-34a-3p
CLEC4M hsa-miR-34a-3p
CLEC4M hsa-miR-34a-3p
CLEC4M hsa-miR-1908-3p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-5008-5p
CLEC4M hsa-miR-1908-3p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-5008-5p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-1908-3p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-5008-5p
CLEC4M hsa-miR-10526-3p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-10526-3p
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-4730
CLEC4M hsa-miR-10526-3p
CLEC4M hsa-miR-338-5p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-6872-3p
CLEC4M hsa-miR-6529-5p
CLEC4M hsa-miR-338-5p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-6872-3p
CLEC4M hsa-miR-6529-5p
CLEC4M hsa-miR-1238-3p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-4745-3p
CLEC4M hsa-miR-6872-3p
CLEC4M hsa-miR-338-5p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-6872-3p
CLEC4M hsa-miR-6529-5p
CLEC4M hsa-miR-1238-3p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-4745-3p
CLEC4M hsa-miR-6872-3p
CLEC4M hsa-miR-1238-3p
CLEC4M hsa-miR-1275
CLEC4M hsa-miR-4745-3p
CLEC4M hsa-miR-6872-3p

Model No

1

2

3-1

3-2

3-3

3-4

3-5

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

nt Seq

266-805

806..2719

2720..8554

2720..8554

2720..8554

2720..8554

2720..8554

8555..10054

10055..10972

11843..12091

12092..12685

12686..13024

13025..13441

13025..13441

16237..18039

18040..19620

19621..20658

20659..21552

21563..25384

25393..26220

26245..26472

26523..27191

27202..27387

27394..27759

27756..27887

27894..28259

28274..29533

29558..29674

AA Seq

1-180

1..638

1..1945

1..1945

1..1945

1..1945

1..1945

1-500

1..306

1..83

1-198

1-113

1-139

1..932

1..601

1..527

1..346

1..298

1..1273

1..275

1..75

1..222

1..61

1..121

1..43

1..121

1..419

Model Seq

13-127

524-637

1-107

207-373

413-676

746-1059

1089-1203

411-499

1-302

1-83

2-192

3-113

1-131

117-919

1-596

1-525

1-345

3-292

27-1146

8-65

gene

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

orf1ab

S

ORF3a

E

M

orf6

ORF7a

ORF7b

ORF8

N

ORF10

product1

leader protein

nsp2

nsp3

ADP-ribose-1"-monophosphatase

nsp3

nsp3

nsp3

nsp4

SARS-CoV-2 (2019-nCoV) main protease

nsp7

nsp8

nsp9

nsp10

nsp12

nsp13

3'-to-5' exonuclease

NSP15 Endoribonuclease

PUTATIVE 2'-O-METHYL TRANSFERASE

Spike glycoprotein

Envelope small membrane protein

structural protein

ORF7a protein

nadarad

ORF8 protein

nucleocapsid phosphoprotein

nadarad

product2

nsp1

.

Replicase polyprotein 1ab

.

Replicase polyprotein 1ab

RNA-directed RNA polymerase

3C-like proteinase

Replicase polyprotein 1ab

ssRNA-binding protein

known as growth-factor-like

RNA-dependent RNA polymerase

helicase

Guanine-N7 methyltransferase

homolog

p65

.

                     protein (GFL)

View Supplementary Data