The (+)RNA genome of the pandemic SARS-CoV-2 virus is about 30,000
nucleotides long [1]. Since December 2019, when the original strain
(WuhanHu-1) has emerged, the SARS-CoV-2 acquired more than 10,000
recorded nucleotide mutations [2], with an estimated mutation rate
between 0.0004 and 0.002 mutations per nucleotide per year [3]. The
current release of the GISAID database contains more than 14 million
SARS-CoV-2 sequences [4] and allows the tracking of the evolution of
the virus with unprecedented precision. As widely discussed, SARS-CoV-2
is being shaped by the pressure exerted by neutralizing antibodies and
applied upon the receptor-binding domain of the Spike (S) protein
[5]. It should be, however, noted that antibodies are far from being
the only adversarial factor encountered by the virus upon infection. In
particular, the binding of host miRNA to other (+)RNA viruses provides a
substantial evolutionary pressure [6] as these molecules suppress
both the translation and the replication of virus along with altering
some aspects of their pathogenesis [7–9].
(+)RNA virus with multiple human miRNAs [10–13]. A majority of
studies have not, however, taken into account the ability of the
SARS-CoV-2 virus to evolve, and, accordingly, to selectively alter its
miRNA binding regions, especially these enriched in binding seeds. Only
a few published works utilized the sequences from various Variants of
Concern (VOCs) [14].
Human genomes encode many miRNAs, a majority of which display
differential expression in human tissues. It is obvious that only miRNA
species expressed in replication-permissive host cells will be relevant
to SARS-CoV-2 evolution. In humans, the SARS-CoV-2 virus predominantly
replicates in the type 2 alveocytes of the lung. In addition,
significant clinical data indicate the presence of the virus in the
intestinal epithelium, which expresses both ACE2 and TMPRSS2 [15].
Moreover, intestinal viral persistence is commonly detected. It is now
recognized that long-term residence of SARS-CoV-2 in the human gut
supports low-intensity inflammation, which contributes to the
complications of COVID-19, collectively known as post-COVID or long
COVID [16].
For three years of the pandemic, the SARS-CoV-2 virus has significantly
mutated. Due to the degeneracy of the genetic code, many mutations have
not led to a change in the sequence of viral proteins and, therefore,
are classified as silent [17]. Nevertheless, silent nucleotide
changes have managed to get fixed in the virus genome. In evolution, the
fixation of the mutation may take place either by chance, or under the
influence of the selective forces acting upon RNA itself rather than on
the encoded proteins. The binding of the cellular miRNAs to the viral
genome may be capable of exerting such pressure. The hypothesis that the
evolutionary pressure exerted by binding of miRNA species expressed in
human lung and intestinal tissue has shaped up the genome of the current
variants of SARS-CoV-2 virus dominating the globe was tested.