As a positive-sense single-strand RNA virus, coronavirus (CoV) possesses some of the largest genomes among RNA viruses, ～30 Kb in size and encodes more than two-dozen proteins that ensure a long-lasting parasitic cellular life lever-aging on both informational inheritability and operational integrity by constantly changing the underlying molecular constituents toward harmony with those of the hosts whose genomes harbor over 20,000 genes and 2–3 Gb in sizes. We, taking the advantage of the unprecedented accumulation of genomic sequences, interrogate mutation spectra of SARS-CoV-2 as a whole or of the major clades in details using comprehensive genomic tools and structure chemistry princi-ples. Two key mechanisms are associated with variable mutation patterns (permutations); one takes the advantage of protein-coding rules to maintain cellular homeostasis including composition dynamics of the host RNA and pro-tein reservoirs and the other concerns strand-biased replica-tion to fine-tuning these mutation spectra that are attributable to the strands and the round of replication. The former is supported by both global sweeping of amino acids for distinct chemical and structural characteristics and local fitness mutation-selection for catalytic specificity and structural subtleties, and the latter is validated whenaltered mutation spectra among phylogenetic hierarchies becomes comprehensible. In this context, SARS-CoV-2 is extraordinarily different from both SARS-CoV and MERS-CoV, whose both G+C and A+G contents have been drifting toward the low ends, a signature of diminishing selective pressure, approaching those of the deteriorated, parasitic, and less pathogenic human CoVs, such as hsa-Cov-229E, hsaCov-OC43, hsaCov-HKU1, and hsaCov-NL63. With such trends and principles, genotypic variations can be analyzed in details to associate with phenotypic vari-ables including both molecular anomalies and clinical symp-toms. These mechanisms provide novel guidance for genome analysis of RNA viruses and shed lights on rational design-ing of targeted drugs, vaccines and diagnostics.