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 BhattacharyyaiD, Chitrarpita DasiD, Arnab GhoshiD, Animesh Kumar SinghiD, Souvik MukherjeeiD, Partha Pratim MajumderiD, Analabha BasuiD, Nidhan K. BiswasiD
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.
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Abstract summary
Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract
A TMPRSS2 cis-eQTL deletion common in Europe and North America but rare in East Asia is proposed to explain where the D614G SARS-CoV-2 subtype spread fastest.
The spike D614G subtype displaced earlier SARS-CoV-2 subtypes unevenly between continents, and host genetics is one candidate explanation for that geography. Here the pattern is tied to the frequency of a single regulatory deletion controlling TMPRSS2 and MX1 expression, with a protease-based account of why the 614G spike in particular benefits.
Key results
SuggestedThe aspartate-to-glycine substitution at spike position 614 is assessed to add an elastase cleavage site close to the S1-S2 junction.
Sequence assessment of the mutated spike protein; the abstract reports the extra cleavage site but no cleavage assay, score or structural measurement. · Abstract
SuggestedA single-base deletion (delC) at rs35074065, a cis-eQTL of TMPRSS2, is described as very rare in East Asians yet common in Europeans and North Americans, and as raising expression of both TMPRSS2 and the neighbouring MX1.
Allele frequency comparison across population groups plus the reported cis-eQTL effect on TMPRSS2 and MX1; no frequencies, effect sizes, sample sizes or data source are given in the abstract. · Abstract
ClaimedThe authors propose a mechanism in which the delC allele is bound by the activator IRF1 but not the repressor IRF2, so MX1 and TMPRSS2 rise, neutrophil elastase and TMPRSS2 together process the 614G spike, and entry is eased in populations where delC is common.
The variant is said to overlap an IRF1/IRF2 binding site, and the entry and spread steps are presented as a chain of inference; no binding assay, entry experiment or epidemiological model fit is reported. · Abstract
Methods, data and reproducibility
The spike D614G sequence is examined for new serine protease cleavage sites, and this is combined with population allele frequencies, cis-eQTL effects and transcription factor binding annotation at the TMPRSS2 regulatory variant rs35074065 to build a mechanistic account of subtype spread. The abstract does not describe the analyses or their sources in detail.
- SARS-CoV-2 subtypes, including the subtype carrying the spike D614G mutation · SARS-CoV-2 · n = an additional 10 subtypes
- Allele frequencies at rs35074065 in East Asian, European and North American population groups · human
- cis-eQTL effects of rs35074065 on TMPRSS2 and MX1 expression · human
- Transcription factor binding annotation for IRF1 and IRF2 overlapping rs35074065 · human
Limitations (2)
- The route from allele to pandemic geography is argued rather than measured here: the abstract gives no allele frequencies, expression effect sizes, binding assay results, entry experiments or epidemiological model fit. · noted in this summary
- Continental differences in variant frequency are confounded with testing, travel, timing and intervention differences between regions; the abstract does not say how these were separated from the host genotype effect. · noted in this summary
Who should read:Read this if you work on host genetic modifiers of coronavirus entry, TMPRSS2 regulatory variation, or host-genome explanations for regional differences in viral variant frequency.
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