A simple model based on mutation and selection explains trends in codon and amino-acid usage and GC composition within and across genomes

Abstract

Background:Correlations between genome composition (in terms of GC content) and usage of particular codons and amino acids have been widely reported, but poorly explained. We show here that a simple model of processes acting at the nucleotide level explains codon usage across a large sample of species (311 bacteria, 28 archaea and 257 eukaryotes). The model quantitatively predicts responses (slope and intercept of the regression line on genome GC content) of individual codons and amino acids to genome composition.Results:Codons respond to genome composition on the basis of their GC content relative to their synonyms (explaining 71-87% of the variance in response among the different codons, depending on measure). Amino-acid responses are determined by the mean GC content of their codons (explaining 71-79% of the variance). Similar trends hold for genes within a genome. Position-dependent selection for error minimization explains why individual bases respond differently to directional mutation pressure.Conclusions:Our model suggests that GC content drives codon usage (rather than the converse). It unifies a large body of empirical evidence concerning relationships between GC content and amino-acid or codon usage in disparate systems. The relationship between GC content and codon and amino-acid usage is ahistorical; it is replicated independently in the three domains of living organisms, reinforcing the idea that genes and genomes at mutation/selection equilibrium reproduce a unique relationship between nucleic acid and protein composition. Thus, the model may be useful in predicting amino-acid or nucleotide sequences in poorly characterized taxa.

Codon usage between genomes is constrained by genome-wide mutational processes

“…Because context-dependent nucleotide biases also influence codon bias (30,31), one would therefore expect growth temperature to correlate with a mutational effect on codon bias. Furthermore, recent work has shown that patterns of codon bias across many different organisms, both thermophilic and mesophilic, can be explained by a single mutational model dependent on positionspecific nucleotide parameters (23). Finally, elevated temperatures result in markedly elevated rates of DNA damage (44), but GC content does not correlate with optimal growth temperature (30), suggesting a role for biases that are not captured by simple GC content.…”

“…In most of these cases, evidence exists that selection at different steps during protein expression shapes codon bias. In addition, global forces differentiate the codon bias of genes between different organisms: species-specific codon bias is strongly correlated with overall genome percentage GC content (22,23), genes from organisms with similar phylogeny or with similar tRNA content have similar codon bias (22), and an organism's optimal growth temperature influences the codon bias of its genes (24). Most of these global forces are thought to be mutational, acting on all DNA sequences, although it has also been argued that growth temperature exerts a selective force on mRNA structure (25) and codon bias (24).…”

Microbes en masse: The sequencing machine

“…She woke at 2 a.m. to find him trembling with excitement after solving a thorny computational problem. The program he had devised crunched through protein-coding sequences from 600 species spanning all domains of life to show that very simple rules involving mutation and selection could explain a major puzzle about DNA: why different organisms prefer different coding sequences for the same amino acid 4 .…”

Response to Comment on "Transitions to Asexuality Result in Excess Amino Acid Substitutions"

“…Unequal frequencies of the four bases may be due to mutation bias, maintained by natural selection, or result from a balance between these two forces (1,2). If mostly maintained by selection, base-composition bias will change when the efficiency of selection is compromised, with the direction and magnitude of change depending on the relative power and direction of pressure from both mutation and selection.…”