Quasi-neutral molecular evolution — When positive and negative selection cancel out

Abstract In the absence of both positive and negative selection, DNA sequences evolve at the neutral rate, R = 1. Due to the prevalence of negative selection, R∼1 is rarely achieved in organismal evolution. However, when R ∼ 1 is observed, it does not necessarily indicate neutral evolution because positive and negative selection could be equally strong but in opposite directions - hereby referred to as quasi-neutrality. We now show that somatic-cell evolution could be the paradigm of quasi-neutral evolution for these reasons: 1) Quasi-neutrality is much more likely in small populations (size N < 50) than in large ones; 2) Stem cell population sizes in single niches of normal tissues, from which tumors likely emerges, have small N’s (usually < 50); 3) the genome-wide evolutionary rate across tissue types is close to R = 1; 4) Relative to the average of R ∼ 1, many genes evolve at a much higher or lower rate, thus hinting both positive and negative selection; 5) When N < 50, selection efficacy decreases rapidly as N decreases even when the selection intensity stays constant; 6) Notably, N is smaller in the small intestine (SmI) than in the colon (CO); hence, the ∼ 70 fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous mutations and fewer deleterious ones in the CO. Under quasineutrality, positive and negative selection can be measured in the same system as the two forces are simultaneously present or absent.