L-Shaped Distributions of the Relative Substitution Rates (c/micro) in SARS-COV-2 with or without Molecular Clocks, Challenging Mainstream Evolutionary Theories

A definitive test to quantify fitness changes of mutations is required to end a continuing 50-year "neutralist-selectionist" debate in evolutionary biology. Our previous work introduced a substitution-mutation rate ratio c/micro test (c: substitution rate in Translated Region/TR or UnTranslated Region/UTR; micro mutation rate) to quantify the selection pressure and thus the proportions of strictly neutral, nearly neutral, beneficial, and deleterious mutations in a genome. Intriguingly, both a L-shaped probability distribution of c/micro and molecular clock were observed for SARS-COV-2's genome. We found that the proportion of the different mutation types from the distribution is not consistent with the hypotheses of the three existing evolution theories (Kimura's Neutral Theory/KNT, Ohta's Nearly Neutral Theory/ONNT and the Selectionist Theory/ST), and a balance condition explains the molecular clock, thus we proposed a new theory named as Near-Neutral Balanced Selectionist Theory (NNBST). In this study, the c/micro analysis was extended beyond the genome to 26 TRs, 12 UTRs, and 10 TRSs (Transcriptional Regulatory Sequences) of SARS-COV-2. While L-shaped probability distributions of c/micro were observed for all of 49 segments, molecular clocks were observed for only 24 segments, supporting NNBST and Near-Neutral Unbalanced Selectionist Theory (NNUST) to explain the molecular evolution of 24/25 segments with/without molecular clocks. Thus, the Near-Neutral Selectionist Theory (NNST) integrates traditional neutral and selectionist theories to deepen our understanding of how mutation, selection, and genetic drift influence genomic evolution.