After the emergence of SARS-COV2 in Wuhan, a strain was evolved with
more infective power (8). Genomic analysis shows that this strain bears
a nonsynonymous mutation (D614G) at the S1/S2 boundary that can generate
extra TMPRSS2 serine protease cleavage site (9). However, it is
predicted that people with an SNP (Del C) at the intergenic region
between TMPRSS2 and MX1 gene apparently are infected more as this
deletion is prevalent in Europe and United states and also in Indian
subcontinent than other parts of the world (MAF, Minor Allele Frequency
of Caucasian (CEU) 0.49; Indian 0.35; African, 0.005 and Chinese, 0.006;
www.ensembl.org). This SNP is in cis-
eQTL for both TMPRSS2 and MX1 gene and increase their expression in
human lungs and other tissues [
Fig.2 ]. Further analysis
suggests that this SNP region is H3K27AC layered (ucsc.genome.edu) with
regulatory region. Hi-C interactions confirms this region contains a TAD
(Topologically Associated Domain) and promote interaction of this SNP
region with MX1 and TMPRSS2 promoter [
Suppl. materials 3A ].
The flanking region of this SNP contain two regulatory motifs – a CTCF
binding region and promoter flanking region. Immediate flanking
nucleotides consist of a protein binding motif (GWAAATGA)
[
Fig.3B, Suppl. Materials 3B ]. Most conspicuous feature is
that 300bp flanking sequences of this SNP are identified at several
genomic locations implying that these sequences may act as a global
regulatory element [
Fig.3A, Suppl. Materials 2 ]. It appears
that Del C SNP is a strong regulatory element and modulate the
expression of TMPRSS2 and MX1 gene and these proteins may have a major
role in controlling the infectivity of SARS-COV2 in Caucasians and
Indians. With extensive experiments, recently Zhang et al (2020) showed
that 614G mutated protein increase the number of binding sites by
shedding
the S1 protein and increase infectivity(10).