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Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression of TMPRSS2 and MX1 Genes

View ORCID ProfileChandrika Bhattacharyya, Chitrarpita Das, Arnab Ghosh, Animesh K. Singh, View ORCID ProfileSouvik Mukherjee, View ORCID ProfilePartha P. Majumder, View ORCID ProfileAnalabha Basu, View ORCID ProfileNidhan K. Biswas
doi: https://doi.org/10.1101/2020.05.04.075911
Chandrika Bhattacharyya
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Chitrarpita Das
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Arnab Ghosh
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Animesh K. Singh
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Souvik Mukherjee
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Partha P. Majumder
1National Institute of Biomedical Genomics, Kalyani, India – 741251
2Indian Statistical Institute, Kolkata, India – 700108
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Analabha Basu
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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Nidhan K. Biswas
1National Institute of Biomedical Genomics, Kalyani, India – 741251
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  • For correspondence: nkb1@nibmg.ac.in
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Abstract

COVID-19 pandemic is a major human tragedy. Worldwide, SARS-CoV-2 has already infected over 3 million and has killed about 230,000 people. SARS-CoV-2 originated in China and, within three months, has evolved to an additional 10 subtypes. One particular subtype with a non-silent (Aspartate to Glycine) mutation at 614th position of the Spike protein (D614G) rapidly outcompeted other pre-existing subtypes, including the ancestral. We assessed that D614G mutation generates an additional serine protease (Elastase) cleavage site near the S1-S2 junction of the Spike protein. We also identified that a single nucleotide deletion (delC) at a known variant site (rs35074065) in a cis-eQTL of TMPRSS2, is extremely rare in East Asians but is common in Europeans and North Americans. The delC allele facilitates entry of the 614G subtype into host cells, thus accelerating the spread of 614G subtype in Europe and North America where the delC allele is common. The delC allele at the cis-eQTL locus rs35074065 of TMPRSS2 leads to overexpression of both TMPRSS2 and a nearby gene MX1. The cis-eQTL site, rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.

Competing Interest Statement

The authors have declared no competing interest.

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Posted May 05, 2020.
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Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression of TMPRSS2 and MX1 Genes
Chandrika Bhattacharyya, Chitrarpita Das, Arnab Ghosh, Animesh K. Singh, Souvik Mukherjee, Partha P. Majumder, Analabha Basu, Nidhan K. Biswas
bioRxiv 2020.05.04.075911; doi: https://doi.org/10.1101/2020.05.04.075911
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Global Spread of SARS-CoV-2 Subtype with Spike Protein Mutation D614G is Shaped by Human Genomic Variations that Regulate Expression of TMPRSS2 and MX1 Genes
Chandrika Bhattacharyya, Chitrarpita Das, Arnab Ghosh, Animesh K. Singh, Souvik Mukherjee, Partha P. Majumder, Analabha Basu, Nidhan K. Biswas
bioRxiv 2020.05.04.075911; doi: https://doi.org/10.1101/2020.05.04.075911

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