Natural selection on synonymous sites is correlated with gene length and recombination in Drosophila

Evolutionary analysis of codon bias in Drosophila indicates that synonymous mutations are not neutral, but rather are subject to weak selection at the translation level. Here we show that the effectiveness of natural selectio n on synonymous sites is strongly correlated with the rate of recombination , in accord with the nearly neutral hypothesis. This correlation, however, is apparent only in genes encoding shore proteins. Long coding regions have both a lower codon bias and higher synonymous substitution rates, suggesti ng that they are affected less efficiently by selection. Therefore, both th e length of the coding region and the recombination rate modulate codon bia s. In addition, the data indicate that selection coefficients for synonymou s mutations must vary by a minimum of one or two orders of magnitude. Two h ypotheses are proposed to explain the relationship among the coding region length, the codon bias, and the synonymous divergence and polymorphism leve ls across the range of recombination rates in Drosophila. The first hypothe sis is that selection coefficients on synonymous mutations are inversely re lated to the total length of the coding region. The second hypothesis propo ses that interference among synonymous mutations reduces the efficacy of se lection on these mutations. Mle investigated this second hypothesis by carr ying our forward simulations of weakly selected mutations in model populati ons. These simulations show that even with realistic recombination rates, t his interference, which we call the "small-scale" Hill-Robertson effect, ca n have a moderately strong influence on codon bias.