Molecular evolution in large steps - Codon substitutions under positive selection

Abstract

Molecular evolution is believed to proceed in small steps. The step size can be defined by a distance reflecting physico-chemical disparities between amino acid (AA) pairs that can be exchanged by single 1 bp mutations. We show that AA substitution rates are strongly and negatively correlated with this distance but only when positive selection is relatively weak. We use the McDonald and Kreitman (MK) test to separate the influences of positive and negative selection. While negative selection is indeed stronger on AA substitutions generating larger changes in chemical properties of amino acids, positive selection operates by different rules. For 65 of the 75 possible pairs, positive selection is comparable in strength regardless of AA distance. However, the 10 pairs under the strongest positive selection all exhibit large leaps in chemical properties. Five of the 10 pairs are shared between hominoids and Drosophila, thus hinting at a common but modest biochemical basis of adaptation across taxa. The hypothesis that adaptive changes often take large functional steps will need to be extensively tested. If validated, molecular models will need to better integrate positive and negative selection in the search for adaptive signal.An opposite argument for large-step evolution can be stated as follows: Natural selection, either positive or negative, can "discern" large-step changes better than small-step ones. For example, replacing isoleucine (Ile) with the chemically similar Valine (Val) would not alter the protein structure as much as its replacement by Arginine (Arg), which is very different chemically. In this view, an Ile à Arg replacement may be either much worse, or much better, than the Ile à Val replacement. Therefore, while negative selection would accept small-step changes (e.g., Ile à Val), positive selection might in fact favor large-step ones (e.g., Ile à Arg). The conventional wisdom is a postulate, not a fact.Clearly, the arguments must be resolved by empirical means. The companion study (Chen and Wu) has shown that AA substitutions start to deviate from the small-step rule when negative selection becomes weaker and/or positive selection becomes stronger. In the same vein, this study aims to separate the two effects on the rate of AA substitutions.

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

“…4 when Ka/Ks increases: weaker negative selection and/or stronger positive selection. Separating the two effects will be the subject of the accompanying study (Chen, et al 2019). Where Ka/Ks < 0.4, we can nevertheless draw the following conclusion: The evolution of genes under strong negative selection takes small steps and follows a nearly universal rule.…”

“…In comparison with previous studies that link AA properties with molecular evolution at the codon level (Zuckerkandl and Pauling 1965;Epstein 1967;Clarke 1970;Grantham 1974;Miyata, et al 1979;Kimura 1983;Tang, et al 2004), this study shows clearly the need to separate the effects of negative and positive selection. While the working of negative selection is, to some extent, predictable, positive selection may show very different patterns, which will be addressed in the accompanying study (Chen, et al 2019). Indeed, some previous studies have reported unusual AA substitution patterns in extreme environments or under domestication, where positive selection could be prevalent (Lu, et al 2006;Luo, et al 2017;Xu, et al 2017).…”

“…With the AA distance as the step size of molecular evolution, the effects of negative and positive selection are separately analyzed in this and the companion report (Chen, et al 2019). Here, we ask whether negative selection drives small-step evolution and whether there exist common rules at the codon level across a wide range of taxa.…”

“…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).…”

Δ-dN/dS: A New Criteria to Distinguish among Different Selection Modes in Gene Evolution

“…Our analysis in cancer genes has been confirmed by a genome-wide analysis (Fig.2). (Dagan et al 2002;Smith 2003;Hanada et al 2007;Weber et al 2014;Figuet et al 2016;Braun 2018;Chen et al 2019b). The Dr/Dc ratio analysis postulates that, under positive selection more radical amino acid replacements may occur than conservative replacements, and vice versa under negative selection.…”