Offprint Order Form — Genetics

To study the roles of translational accuracy, translational efficiency, and the Hill-Robertson effect in codon usage bias, we studied the intragenic spatial distribution of synonymous codon usage bias in four prokaryotic (Escherichia coli, Bacillus subtilis, Sulfolobus tokodaii, and Thermotoga maritima) and two eukaryotic (Saccharomyces cerevisiae and Drosophila melanogaster) genomes. We generated supersequences at each codon position across genes in a genome and computed the overall bias at each codon position. By quantitatively evaluating the trend of spatial patterns using isotonic regression, we show that in yeast and prokaryotic genomes, codon usage bias increases along translational direction, which is consistent with purifying selection against nonsense errors. Fruit fly genes show a nearly symmetric M-shaped spatial pattern of codon usage bias, with less bias in the middle and both ends. The low codon usage bias in the middle region is best explained by interference (the Hill-Robertson effect) between selections at different codon positions. In both yeast and fruit fly, spatial patterns of codon usage bias are characteristically different from patterns of GC-content variations. Effect of expression level on the strength of codon usage bias is more conspicuous than its effect on the shape of the spatial distribution. CODON usage bias refers to the nonrandom usage codons. Neither selection against missense errors nor selection for translational efficiency is expected to be of synonymous codons. Frequently used codons are often termed optimal or major codons, whereas less position dependent within genes, whereas selection against nonsense errors is expected to leave an increfrequently used ones are termed nonoptimal or minor codons. Nonoptimal codons usually correspond to less mental pattern of codon bias along translational direction within genes (Eyre-Walker 1996b). abundant tRNAs than optimal codons do (Ikemura 1981, 1982, 1985; Bulmer 1987; Akashi 2001) and the transRecombination is another important but often controversial factor that affects codon usage bias. Selection lational machinery is more likely to stall there (Kurland 1992). These processing errors, termed premature terat one locus can interfere with selection at another locus, known as the Hill-Robertson effect (Hill and Robmination or nonsense errors, can occur at comparable levels to misincorporation or missense errors, during the ertson 1966). Negative selection against nonoptimal elongation stage of translation (Kurland 1992). Therecodons and positive selection for optimal codons are fore, purifying selection is expected to increase in intenboth likely to be weak (Hartl et al. 1994; Akashi 1995; sity as peptide elongation proceeds (Eyre-Walker Akashi and Schaeffer 1997; Kliman 1999; Maside 1996b; Akashi 2001) and should lead to gradual inet al. 2004). Nevertheless, selection at one codon posicrease in codon usage bias along a gene (Eyre-Walker tion within a gene can interfere with selection at other 1996b). In addition, optimal codons may be selected codon positions in the gene if they are tightly linked for translational efficiency and so are more frequently (Li 1987; McVean and Charlesworth 2000; Comeron used in highly expressed genes (Sharp and Li 1986; and Kreitman 2002). As a result, recombination is exShields and Sharp 1987; Sharp et al. 1993; Hartl pected to increase the selection efficacy on codon usage et al. 1994; Moriyama and Powell 1997; Akashi 2001; bias. Several studies have observed a positive correlation Carlini and Stephan 2003). Therefore, codon usage between recombination rate and codon usage bias (Klibias may be accounted for by negative selection against man and Hey 1993, 2003; Comeron et al. 1999; Betannonoptimal codons and positive selection for optimal court and Presgraves 2002; Comeron and Kreitman 2002; Hey and Kliman 2002). However, there have also been observations suggesting that the Hill-Robertson 1Present address: Department of Biostatistics and Computational Bioleffect has a minor influence on codon usage bias and ogy, University of Rochester, Rochester, NY 14642. is overwhelmed by the mutation pressure associated with 2Corresponding author: Department of Ecology and Evolution, Univerrecombination (Marais et al. 2001, 2003). The controsity of Chicago, 1101 East 57th St., Chicago, IL 60637. E-mail: [email protected] versy around the Hill-Robertson effect on codon bias is Genetics 168: – (November 2004)