Features of recent codon evolution: a comparative polymorphism-fixation study

Abstract

Features of amino-acid and codon changes can provide us important insights on protein evolution. So far, investigators have often examined mutation patterns at either interspecies fixed substitution or intraspecies nucleotide polymorphism level, but not both. Here, we performed a unique analysis of a combined set of intra-species polymorphisms and inter-species substitutions in human codons. Strong difference in mutational pattern was found at codon positions 1, 2, and 3 between the polymorphism and fixation data. Fixation had strong bias towards increasing the rarest codons but decreasing the most frequently used codons, suggesting that codon equilibrium has not been reached yet. We detected strong CpG effect on CG-containing codons and subsequent suppression by fixation. Finally, we detected the signature of purifying selection against Amid R:U dinucleotides at synonymous dicodon boundaries. Overall, fixation process could effectively and quickly correct the volatile changes introduced by polymorphisms so that codon changes could be gradual and directional and that codon composition could be kept relatively stable during evolution.

Figure 1

Normalized frequencies of nucleotide changes at the polymorphic and fixed sites in amino-acid coding regions. Figures 1(a)–1(c) show the frequencies of polymorphism (Poly) and fixation mutations at the first (a), second (b), and third (c) positions of a codon. (d) Frequency of all the mutation data. Dotted lines indicate the polymorphism and solid lines indicate the fixation.

Figure 2

Normalized difference of codon changes (gain and loss) at the polymorphic and fixed sites in amino-acid coding regions. The normalized difference of a codon was defined as the difference of the number of mutations removing the codon from that creating the codon and divided by the total number of mutations in the codon. Codons are ordered (left: ancient; right: recent) in their temporal order in the genetic code according to Trifonov [2]. The codons associated with codon capture are in lower case.

Figure 3

Normalized difference of codon changes (gain and loss) at polymorphic and fixes sites. Codons are ordered in the ascending order of frequencies in human codon usage based on the Codon Usage Database. The solid vertical line separates rare and nonrare codons. The 10 rarest codons are shown in the left side of the dotted line.

Figure 4

Nonsynonymous to synonymous substitutions (N/S) ratio calculated by the polymorphic and fixed nucleotide changes. Two codons (ATG and TGG) are not included because of their lack of synonymous substitutions. Symbol “#” indicates NCG codons. Codons are placed by the descending order of the polymorphism's N/S ratios.