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

View ORCID ProfileSwarkar Sharma, View ORCID ProfileInderpal Singh, Shazia Haider, View ORCID ProfileMd. Zubbair Malik, View ORCID ProfileKalaiarasan Ponnusamy, Ekta Rai
doi: https://doi.org/10.1101/2020.04.24.050534
Swarkar Sharma
1Human Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
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  • For correspondence: swarkar.sharma@smvdu.ac.in
Inderpal Singh
1Human Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
2Bioinfores Pvt. Ltd., R. S. Pura, Jammu, Jammu and Kashmir, India
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Shazia Haider
3Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Sector-62, Uttar Pradesh, India
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Md. Zubbair Malik
4School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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Kalaiarasan Ponnusamy
5School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
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Ekta Rai
1Human Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
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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.

Competing Interest Statement

Footnotes

  • 1. Made corrections to Ms. 2. divided content into main and supplementary data. 3. Included an additional figure as Figure 1' explaining more in a) and b) The findings for the first time, based on potential structural mechanisms, highlighting with ACE2 homodimerisation only one SARS-CoV2 spike protein can bind and further provides explanation how ACE2 can give protection from severe lung injury in COVID19.

  • https://covid19.who.int/

  • https://gtexportal.org/

  • https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php

  • https://www.proteinatlas.org

  • https://gnomad.broadinstitute.org

  • https://www.ncbi.nlm.nih.gov/snp.

  • https://genome.ucsc.edu/

  • https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes

  • https://www.datawrapper.de/

  • https://ldlink.nci.nih.gov/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 19, 2020.
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ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19
Swarkar Sharma, Inderpal Singh, Shazia Haider, Md. Zubbair Malik, Kalaiarasan Ponnusamy, Ekta Rai
bioRxiv 2020.04.24.050534; doi: https://doi.org/10.1101/2020.04.24.050534
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ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19
Swarkar Sharma, Inderpal Singh, Shazia Haider, Md. Zubbair Malik, Kalaiarasan Ponnusamy, Ekta Rai
bioRxiv 2020.04.24.050534; doi: https://doi.org/10.1101/2020.04.24.050534

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