Nearly neutral theory of molecular evolution
suggests that most mutations observed on DNA level have slightly negative effect on fitness– see the Effective neutral mutations. The nearly neutral theory of molecular evolution provides a potential explanation of the causes of the existence of the effect of generation time of organism on the rate of the molecular clock for synonymous but not for nonsynonymous mutations (Ohta 1993; Ohta 1996) (see V.5). This explanation is based on the more or less reasonable assumption that a large portion of nonsynonymous mutations is slightly detrimental for their bearers. The rate of fixation of slightly negative mutations (k) or, to be more exact, the percentage of negative mutations that fall in the category of slightly negative mutations acting as effectively neutral mutations, is inversely proportional to the effective size of the population. Organisms with a long generation time, i.e. in general large organisms, mostly have a substantially smaller effective population size than organisms with a short generation time. Consequently, a greater fraction of nonsynonymous mutations fall in the category of selectively neutral for them and thus they have an overall larger fixation rate. As a consequence, the effect of the generation time on the number of mutations formed per year (negative) and the effect of the generation time on the rate of their fixation (positive) are mutually cancelled out for mutations in the coding region.