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In somatic cells, microRNAs (miRNAs) bind to the genomes of RNA viruses and influence their translation and replication. In London and Berlin samples represented in GISAID database, we traced severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) lineages and divided these sequenced in two groups, "Ancestral variants" and "Omicrons," and analyzed them through the prism of the tissue‐specific binding between host miRNAs and viral messenger RNAs. We demonstrate a significant number of miRNA‐binding sites in the NSP4 region of the SARS‐CoV‐2 genome, with evidence of evolutionary pressure within this region exerted by human intestinal miRNAs. Notably, in infected cells, NSP4 promotes the formation of double‐membrane vesicles, which serve as the scaffolds for replication‐transcriptional complexes and protect viral RNA from intracellular destruction. In 3 years of selection, the loss of many miRNA‐binding sites in general and those within the NSP4 in particular has shaped the SARS‐CoV‐2 genomes. With that, the descendants of the BA.2 variants were promoted as dominant strains, which define current momentum of the pandemics. [ABSTRACT FROM AUTHOR]