Molecular evolution in small steps under prevailing negative selection – A nearly-universal rule of codon substitution

Abstract

The widely accepted view that evolution proceeds in small steps is based on two premises: i) negative selection acts strongly against large differences (Kimura 1983); and ii) positive selection favors small-step changes (Fisher 1930). The two premises are not biologically connected and should be evaluated separately.We now extend the approach of Tang et al. (2004) to codon evolution for the entire genome. Codon substitution rate is a function of the physico-chemical distance between amino acids (AAs), equated with the step size of evolution. This step size depends on a large number of physico-chemical properties as 46 of the 48 properties examined affect the rate. Between 9 pairs of closely-related species of plants, invertebrates and vertebrates, the evolutionary rate is indeed strongly and negatively correlated with the AA distance (Δ U , scaled to [0, 1]). While the analyses corroborate the published results that relied on partial genomes, there is an important difference: Δ U is strongly correlated with the evolutionary rate (R 2 > 0.8) only when the genes are under predominant negative selection. Nevertheless, since most genes in most taxa are strongly constrained by negative selection, Δ U would appear to be a nearly-universal measure of codon evolution. In conclusion, the driving force of the small-step evolution at the codon level is negative selection. The unanswered question of whether positive selection may, or may not, follow the small-step rule will be addressed in a companion study (Chen, et al. 2019).

Moderating the neutralist–selectionist debate: exactly which propositions are we debating, and which arguments are valid?

“…Among the factors traditionally thought to determine functional constraint are functional density (i.e. the proportion of critical sites) (Dickerson, 1971;Zuckerkandl, 1976) and the physicochemical differences between amino acid sequences and their 'single-mutation derivatives' (Epstein, 1967;Grantham, 1974;Kimura, 1983;Graur, 1985;Tang et al, 2004;Chen et al, 2019). In practice, the functional constraint of a protein can be measured based on the second criterion (e.g.…”