MicroRNA-driven evolutionary pressure in SARS-CoV-2: the role of hsa-miR-6512 in mutational dynamics.

The SARS-CoV-2 pandemic, first reported as an acute respiratory disease in December 2019 in Wuhan, China, has profoundly impacted global communities, with approximately seven million deaths reported by the World Health Organization to date. Coronaviruses exhibit a high recombination rate due to RNA-dependent RNA polymerase transcription errors, resulting in mutations that are selectively conserved under evolutionary pressures and transmitted to subsequent generations. In this study, we investigated the role of host microRNAs (miRs) in exerting evolutionary pressures on SARS-CoV-2. We identified miRNAs binding to the Wuhan strain genome and compared their binding regions with mutated strains. Our bioinformatics analysis revealed a significant number of conserved mutations within the seed regions of microRNA binding sites in the later variants. For functional validation, we focused on hsa-miR-6512, targeting the Wuhan strain’s surface glycoprotein gene (S). This miRNA’s binding site is lost in later variants, including Alpha, and this mutation was conserved across Beta, Gamma, Mu, and Omicron. Expression of hsa-miR-6512 was assessed, and its interaction with the S gene was compared between Wuhan and Omicron strains. Our findings suggest that miRNA–genome interactions may influence the evolutionary trajectory of SARS-CoV-2 and propose miRNAs as promising targets for therapeutic strategies.