The patterns of synonymous codon usage in 91 Drosophila melanogaster genes have been examined. Codon usage varies strikingly among genes. This variation is associated with differences in G+C content at silent sites, but (unlike the situation in mammalian genes) these differences are not correlated with variation in intron base composition and so are not easily explicable in terms of mutational biases. Instead, those genes with high G+C content at silent sites, resulting from a strong "preference" for a particular subset of the codons that are mostly C-ending, appear to be the more highly expressed genes. This suggests that G+C content is reduced in sequences where selective constraints are weaker, as indeed seen in a pseudogene. These and other data discussed are consistent with the effects of translational selection among synonymous codons, as seen in unicellular organisms. The existence of selective constraints on silent substitutions, which may vary in strength among genes, has implications for the use of silent molecular clocks.

Silent sites in Drosophila genes are not neutral: evidence of selection among synonymous codons.

tRNA gene number and codon usage in the C. elegans genome are co-adapted for optimal translation of highly expressed genes.

A Glossary of Genetics and Cytogenetics

We first review what is known about patterns of codon usage bias in Drosophila and make the following points: (i) Drosophila genes are as biased or more biased than those in microorganisms. (ii) The level of bias of genes and even the particular pattern of codon bias can remain phylogenetically invariant for very long periods of evolution. (iii) However, some genes, even very tightly linked genes, can change very greatly in codon bias across species. (iv) Generally G and especially C are favored at synonymous sites in biased genes. (v) With the exception of aspartic acid, all amino acids contribute significantly and about equally to the codon usage bias of a gene. (vi) While most individual amino acids that can use G or C at synonymous sites display a preference for C, there are exceptions: valine and leucine, which prefer G. (vii) Finally, smaller genes tend to be more biased than longer genes. We then examine possible causes of these patterns and discount mutation bias on three bases: there is little evidence of regional mutation bias in Drosophila, mutation bias is likely toward A+T (the opposite of codon usage bias), and not all amino acids display the preference for the same nucleotide in the wobble position. Two lines of evidence support a selection hypothesis based on tRNA pools: highly biased genes tend to be highly and/or rapidly expressed, and the preferred codons in highly biased genes optimally bind the most abundant isoaccepting tRNAs. Finally, we examine the effect of bias on DNA evolution and confirm that genes with high codon usage bias have lower rates of synonymous substitution between species than do genes with low codon usage bias. Surprisingly, we find that genes with higher codon usage bias display higher levels of intraspecific synonymous polymorphism. This may be due to opposing effects of recombination.

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Evolution of codon usage bias in Drosophila

Codon usage bias of 1,117 Drosophila melanogaster genes, as well as fewer D pseudoobscura and D virilis genes, was examined from the perspective of relative abundance of isoaccepting tRNAs and their changes during development We found that each amino acid contributes about equally and highly significantly to overall codon usage bias, with the exception of Asp which had very low contribution to overall bias Asp was also the only amino acid that did not show a clear preference for one of its synonymous codons Synonymous codon usage in Drosophila was consistent with ``optimal'' codons deduced from the isoaccepting tRNA availability Interestingly, amino acids whose major isoaccepting tRNAs change during development did not show as strong bias as those with developmentally unchanged tRNA pools Asp is the only amino acid for which the major isoaccepting tRNAs change between larval and adult stages We conclude that synonymous codon usage in Drosophila is well explained by tRNA availability and is probably influenced by developmental changes in relative abundance

Bradley N. White

Papers

Activity of a transfer RNA modifying enzyme during the development of Drosophila and its relationship to the su(s) locus.

Analysis of tRNAs during the development of Drosophila.

Properties of tRNAPhe from Drosophila

Studies on lysine, glutamine and glutamic acid tRNAs from Drosophila.

Small analytical BD-cellulose columns for rapid chromatography of aminoacyl-tRNAs