Non-compensatory mutations in Spike protein positively selected on RNA structures might be signatures to trace cross-species barrier jumps of Betacoronavirus

Similar to other RNA viruses, the evolution and emergence of <i>Betacoronavirus</i> the cross-species transmission is involved. In general, the standard health surveillance system is based on protein-coding information, but since the COVID-19 pandemic it has been extended to wide-genome analysis. The evolutionary jump from natural reservoirs to human hotspot mutations is mainly traced-back to its effect on coding sequence. However, the impact on the structured RNA genome of <i>Betacoronavirus</i> is mainly unexplored. To develop a new landscape of changes in the RNA viral genome were analyzed 1,252,952 viral genomes of circulating SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses distributed worldwide in bats, intermediate animals, and humans. The protein-coding and viral genome architecture were studied for trace back novel insights from cross-species horizontal transmission events. Phylogenetic analyses confirm that bats are natural harbors of <i>Betacoronavirus</i>, with high variation rates in viral proteins, mainly in the S protein S1 subunit. The substitutions (G &gt; T; A577S) in SARS-CoV, (C &gt; T; S746R and C &gt; T; N762A) in MERS-CoV, and (A &gt; G; D614G) in SARS-CoV-2 overlap with mutations that modify secondary RNA structures in the RNA genome complement. These findings provide pivotal factors that might be underlying the eventual jumping the species barrier from bats to the intermediate host which could contribute to their evolutionary diversification. At here also it was found that <i>Betacoronavirus</i> from intermediates and humans are evolutionary related and share a significant proportion of RNA structures than those in bats which could be used as signatures of cross-species barrier jumps.