Hearing silence: non-neutral evolution at synonymous sites in mammals

Chamary, JV; Parmley, Joanna L.; Hurst, Laurence D.

doi:10.1038/nrg1770

Cited by 744 publications

(676 citation statements)

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“…We also did not consider additional measures, such as codon bias, which have been used to assess the efficacy of selection in Drosophila because, despite some evidence for selection on silent sites in primates (Comeron 2006), their applicability to primates is unclear (Duret 2002). A concern with the use of d N /d S might be that synonymous sites are not strictly neutral in primates (Chamary et al 2006;Comeron 2006). However, even if this were true, selective pressures on synonymous sites are highly unlikely to be as strong as on nonsynonymous sites (Hellmann et al 2003b;Lu and Wu 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Li 1997). Synonymous sites are thought to be neutral or nearly neutral in many species, including primates (Lu and Wu 2005); indeed, while there is some evidence that they evolve under selection (Chamary et al 2006;Comeron 2006), they tend to be much less constrained than do nonsynonymous sites (Hellmann et al 2003b). Thus, a high ratio of d N /d S (close to or greater than one) indicates relatively little constraint on replacement sites, while a lower ratio points to greater constraint.…”

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confidence: 99%

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No effect of recombination on the efficacy of natural selection in primates

Bullaughey¹,

Przeworski²,

Coop³

2008

Genome Res.

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Population genetic theory suggests that natural selection should be less effective in regions of low recombination, potentially leading to differences in rates of adaptation among recombination environments. To date, this prediction has mainly been tested in Drosophila, with somewhat conflicting results. We investigated the association between human recombination rates and adaptation in primates, by considering rates of protein evolution (measured by d N /d S ) between human, chimpanzee, and rhesus macaque. We found no correlation between either broad-or fine-scale rates of recombination and rates of protein evolution, once GC content is taken into account. Moreover, genes in regions of very low recombination, which are expected to show the most pronounced reduction in the efficacy of selection, do not evolve at a different rate than other genes. Thus, there is no evidence for differences in the efficacy of selection across recombinational environments. An interesting implication is that indirect selection for recombination modifiers has probably been a weak force in primate evolution.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

No effect of recombination on the efficacy of natural selection in primates

Bullaughey¹,

Przeworski²,

Coop³

2008

Genome Res.

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Section: Acc E P Ted P R E P R I Ntmentioning

confidence: 99%

“…Each family can consist of up to five members, for example there is one tRNA trp but five tRNA leu and these members can differ in their anticodon sequence as well as in tRNA backbone residue sequence (Goodenbour & Pan 2006).These multivalent tRNAs allow for binding to synonymous codons through movement (or 'wobble') in the 5' anti-codon. Therefore, even though there are 61 codons that encode the amino acids, fewer than 61 tRNAs are required (Cannarozzi et al 2010) Synonymous codon substitutions had originally been regarded as "silent" in nature as they did not affect the amino acid sequence of the protein, and were therefore regarded as unimportant (Chamary et al 2006). However, in the last three decades, it has become recognized that synonymous codon substitutions can have a significant effect on expression of heterologous proteins in recombinant expression systems, leading to the concept of codon optimization that may…”

Section: Introductionmentioning

confidence: 99%

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Webster

Teh

K.‐C.

2016

Biotech & Bioengineering

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Degeneracy in the genetic code allows multiple codon sequences to encode the same protein. Codon usage bias in genes is the term given to the preferred use of particular synonymous codons. Synonymous codon substitutions had been regarded as "silent" as the primary structure of the protein was not affected; however, it is now accepted that synonymous substitutions can have a significant effect on heterologous protein expression. Codon optimization, the process of altering codons within the gene sequence to improve recombinant protein expression, has become widely practised.Multiple inter-linked factors affecting protein expression need to be taken into consideration when optimizing a gene sequence. Over the years, various computer programmes have been developed to aid in the gene sequence optimization process. However, as the rulebook for altering codon usage to affect protein expression is still not completely understood, it is difficult to predict which strategy, if any, will design the 'optimal' gene sequence.In this review, codon usage bias and factors affecting codon selection will be discussed and the evidence for codon optimization impact will be reviewed for recombinant protein expression using plants as a case study. These developments will be relevant to all recombinant expression systems, however, molecular pharming in plants is an area which has consistently encountered difficulties with low levels of recombinant protein expression, and should benefit from an evidence based rational approach to synthetic gene design. This article is protected by copyright. All rights reserved

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“…The latter has most often been assumed to reflect neutral change and has been used to normalize the mutation rates in a given gene, with the K a /K s ratio serving as an inverse measure of protein sequence conservation (Hurst 2002). More recently, the neutrality of K s has been challenged, with accumulating evidence for selection acting at synonymous sites (for reviews, see Chamary et al 2006;Xing and Lee 2006). Some of this evidence has been based on comparisons between mutation rates in predicted exonic splicing enhancers (ESEs) versus control sequences, concluding that the former tend to be conserved.…”

mentioning

confidence: 99%

Positive selection acting on splicing motifs reflects compensatory evolution

Ke¹,

Zhang²,

Chasin³

2008

Genome Res.

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We have used comparative genomics to characterize the evolutionary behavior of predicted splicing regulatory motifs. Using base substitution rates in intronic regions as a calibrator for neutral change, we found a strong avoidance of synonymous substitutions that disrupt predicted exonic splicing enhancers or create predicted exonic splicing silencers. These results attest to the functionality of the hexameric motif set used and suggest that they are subject to purifying selection. We also found that synonymous substitutions in constitutive exons tend to create exonic splicing enhancers and to disrupt exonic splicing silencers, implying positive selection for these splicing promoting events. We present evidence that this positive selection is the result of splicing-positive events compensating for splicing-negative events as well as for mutations that weaken splice-site sequences. Such compensatory events include nonsynonymous mutations, synonymous mutations, and mutations at splice sites. Compensation was also seen from the fact that orthologous exons tend to maintain the same number of predicted splicing motifs. Our data fit a splicing compensation model of exon evolution, in which selection for splicing-positive mutations takes place to counter the effect of an ongoing splicing-negative mutational process, with the exon as a whole being conserved as a unit of splicing. In the course of this analysis, we observed that synonymous positions in general are conserved relative to intronic sequences, suggesting that messenger RNA molecules are rich in sequence information for functions beyond protein coding and splicing.[Supplemental material is available online at www.genome.org.]In addition to sequences that specify their cognate polypeptides, the open reading frames of eukaryotic messenger RNAs (mRNAs) are likely to contain additional information governing the functioning of these molecules; these functions include exon splicing and mRNA transport, localization, stability, and translation. If so, the evolution of mRNA sequence would be constrained by purifying selection against the loss of this information. This selection should be evident by examining the rate and quality of base substitutions that do not alter protein coding (synonymous substitutions) but may alter one of the abovementioned functions.Mutation rates in open reading frames have been extensively characterized by two parameters: K a , the rate of mutations that result in amino acid substitutions; and K s , the rate at synonymous sites. The latter has most often been assumed to reflect neutral change and has been used to normalize the mutation rates in a given gene, with the K a /K s ratio serving as an inverse measure of protein sequence conservation (Hurst 2002). More recently, the neutrality of K s has been challenged, with accumulating evidence for selection acting at synonymous sites (for reviews, see Chamary et al. 2006;Xing and Lee 2006). Some of this evidence has been based on comparisons between mutation rates in predicted exonic splicing e...

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Hearing silence: non-neutral evolution at synonymous sites in mammals

Cited by 744 publications

References 128 publications

No effect of recombination on the efficacy of natural selection in primates

No effect of recombination on the efficacy of natural selection in primates

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

Positive selection acting on splicing motifs reflects compensatory evolution

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