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Detecting positive and purifying selection at synonymous sites in yeast and worm.

ABSTRACT: We present a new computational method to identify positive and purifying selection at synonymous sites in yeast and worm. We define synonymous substitutions that change codons from preferred to unpreferred or vice versa as nonconservative synonymous substitutions and all other substitutions as conservative. Using a maximum-likelihood framework, we then test whether conservative and nonconservative synonymous substitutions occur at equal rates. Our approach replaces the standard rate of synonymous substitutions per synonymous site, dS, with two new rates, the conservative synonymous substitution rate (dS(C)) and the nonconservative synonymous substitution rate (dS(N)). Based on the ratio dS(N)/dS(C), we find that 0.05% of all yeast genes and none of worm genes show evidence of positive selection at synonymous sites (dS(N)/dS(C) > 1). On the other hand, 9.44% of all yeast genes and 5.12% of all worm genes show evidence of significant purifying selection on synonymous sites (dS(N)/dS(C) < 1). We also find that dS(N) correlates strongly with gene expression level, whereas the correlation between expression level and dS(C) is very weak. Thus, dS(N) captures most of the signal of selection for translational accuracy and speed, whereas dS(C) is not strongly influenced by this selection pressure. We suggest that the ratio dN/dS(C) may be more appropriate than the ratio dN/dS to identify positive or purifying selection on amino acids.

SUBMITTER: Zhou T

PROVIDER: S-EPMC2915641 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Detecting positive and purifying selection at synonymous sites in yeast and worm.

Zhou Tong T Gu Wanjun W Wilke Claus O CO

Molecular biology and evolution 20100315 8

We present a new computational method to identify positive and purifying selection at synonymous sites in yeast and worm. We define synonymous substitutions that change codons from preferred to unpreferred or vice versa as nonconservative synonymous substitutions and all other substitutions as conservative. Using a maximum-likelihood framework, we then test whether conservative and nonconservative synonymous substitutions occur at equal rates. Our approach replaces the standard rate of synonymou ...[more]

PMID: 20231333

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Project description:Evolution of protein sequences is largely governed by purifying selection, with a small fraction of proteins evolving under positive selection. The evolution at synonymous positions in protein-coding genes is not nearly as well understood, with the extent and types of selection remaining, largely, unclear. A statistical test to identify purifying and positive selection at synonymous sites in protein-coding genes was developed. The method compares the rate of evolution at synonymous sites (Ks) to that in intron sequences of the same gene after sampling the aligned intron sequences to mimic the statistical properties of coding sequences. We detected purifying selection at synonymous sites in approximately 28% of the 1,562 analyzed orthologous genes from mouse and rat, and positive selection in approximately 12% of the genes. Thus, the fraction of genes with readily detectable positive selection at synonymous sites is much greater than the fraction of genes with comparable positive selection at nonsynonymous sites, i.e., at the level of the protein sequence. Unlike other genes, the genes with positive selection at synonymous sites showed no correlation between Ks and the rate of evolution in nonsynonymous sites (Ka), indicating that evolution of synonymous sites under positive selection is decoupled from protein evolution. The genes with purifying selection at synonymous sites showed significant anticorrelation between Ks and expression level and breadth, indicating that highly expressed genes evolve slowly. The genes with positive selection at synonymous sites showed the opposite trend, i.e., highly expressed genes had, on average, higher Ks. For the genes with positive selection at synonymous sites, a significantly lower mRNA stability is predicted compared to the genes with negative selection. Thus, mRNA destabilization could be an important factor driving positive selection in nonsynonymous sites, probably, through regulation of expression at the level of mRNA degradation and, possibly, also translation rate. So, unexpectedly, we found that positive selection at synonymous sites of mammalian genes is substantially more common than positive selection at the level of protein sequences. Positive selection at synonymous sites might act through mRNA destabilization affecting mRNA levels and translation.

Dataset Information

Detecting positive and purifying selection at synonymous sites in yeast and worm.

Publications

Detecting positive and purifying selection at synonymous sites in yeast and worm.

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