ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19

  1. Swarkar Sharma
  2. Inderpal Singh
  3. Shazia Haider
  4. Md. Zubbair Malik
  5. Kalaiarasan Ponnusamy
  6. Ekta Rai

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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single-stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S-protein priming by host cell serine protease TMPRSS2. Recently, COVID19 has been declared pandemic by World Health Organization (WHO) yet high differences in disease outcomes across countries have been seen. We provide evidences to explain these population-level differences. One of the key factors of entry of the virus in host cells presumably is because of differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that a higher expression of ACE2 is facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs), with different frequencies in different populations. We suggest that high expression of ACE2 results in homo-dimerization, proving disadvantageous for TMPRSS2 mediated cleavage of ACE2; whereas, the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of the Virus in host cells. In addition, we suggest that several key host genes, like SLC6A19, ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3 and some other proteases as Cathepsins, might have a critical role. To conclude, understanding population specific differences in these genes may help in developing appropriate management strategies for COVID19 with better therapeutic interventions.

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    SciScore for 10.1101/2020.04.24.050534: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Periodic boundary condition of 10 Angstrom was set using the System Builder Tool of Desmond software(2006).
    Desmond
    suggested: (Desmond, RRID:SCR_014575)
    Structural visualizations and images were traced using pyMOL and VMD (Jacobson et al., 2002) (Humphrey et al., 1996).
    pyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    eQTLs were viewed by GTEx IGV Browser as well as GTEx Locus Browser was used to plot gene specific eQTLs. eQTLs and other gene regulatory information, splice variants, and ESTs were also explored through UCSC genome browser, https://genome.ucsc.edu/ with build GRCh37/hg19.
    UCSC genome browser
    suggested: (UCSC Genome Browser, RRID:SCR_005780)
    Retrieved information was saved in files as well as plotted on UCSC browser as custom tracks.
    UCSC browser
    suggested: None
    HaploReg v4.1 (https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php) was used to annotate effect of noncoding genome variants of regulation motifs.
    HaploReg
    suggested: (HaploReg, RRID:SCR_006796)
    Analyses of Allele frequency distribution of Variants in different population Groups: Genetic data for global population groups was explored through the GnomAD portal at https://gnomad.broadinstitute.org/, as well as dbSNP database of NCBI at https://www.ncbi.nlm.nih.gov/snp.
    https://gnomad.broadinstitute.org/
    suggested: (Genome Aggregation Database, RRID:SCR_014964)
    dbSNP
    suggested: (dbSNP, RRID:SCR_002338)
    EUR: Utah Residents (CEPH) with Northern and Western European Ancestry (CEU), Finnish in Finland (FIN), British in England and Scotland (GBR), Iberian Population in Spain (IBS), Toscani in Italia (TSI).
    CEPH
    suggested: (CEPH2CRI, RRID:SCR_009143)
    LDproxy tools of LDlink 4.0.3 web-based suite (https://ldlink.nci.nih.gov/) was used to map proxy variants in strong LD and with putatively functional role.
    https://ldlink.nci.nih.gov/
    suggested: (LDMatrix, RRID:SCR_017391)
    Pairwise sequence alignment of TMPRSS2 isoforms was carried out by Clustal Omega tool (Sievers et al., 2011).
    Clustal Omega
    suggested: (Clustal Omega, RRID:SCR_001591)
    , Pfam (El-Gebali et al., 2019) and ENSEMBL (Chen et al., 2010), respectively.
    Pfam
    suggested: (Pfam, RRID:SCR_004726)
    ENSEMBL
    suggested: (Ensembl, RRID:SCR_002344)
    Network analysis on SARS-CoV-2 with Human Proteins: We downloaded the SARS-CoV-2 genome (Accession number: MT121215) from the NCBI database.
    NCBI
    suggested: (NCBI, RRID:SCR_006472)
    The protein-protein interaction (PPI) and transcription factor regulation of human proteins were retrieved from GeneMANIA (Warde-Farley et al., 2010) and literature (Barros et al., 2012; David et al., 2010; Maitland et al., 2011; Tumer et al., 2013; Yu et al., 2010; Zhang et al., 2009), respectively.
    GeneMANIA
    suggested: (GeneMANIA, RRID:SCR_005709)
    Further, Hubs were identified using Network analyzer (Assenov et al., 2008), the plugin of Cytoscape v3.2.1.
    Cytoscape
    suggested: (Cytoscape, RRID:SCR_003032)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.04.24.050534v4 on bioRxiv
  3. Version published to 10.1101/2020.04.24.050534v3 on bioRxiv
  4. Version published to 10.1101/2020.04.24.050534v2 on bioRxiv
  5. Version published to 10.1101/2020.04.24.050534v1 on bioRxiv