SEARCH · Search PubMed

Results for “synonymous codon”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources

PubMed1999

Synonymous rates at the RpII215 gene of Drosophila: variation among species and across the coding region.

The region encompassing the RpII215 gene that encodes the largest component of the RNA polymerase II complex (1889 amino acids) has been sequenced in Drosophila subobscura, D. madeirensis, D. guanche, and D. pseudoobscura. Nonsynonymous divergence estimates (Ka) indicate that this gene has a very low rate of amino acid replacements. Given its low Ka and constitutive expression, synonymous substitution rates are, however, unexpectedly high. Sequence comparisons have allowed the molecular clock hypothesis to be tested. D. guanche is an insular species and it is therefore expected to have a reduced effective size relative to D. subobscura. The significantly higher rate of synonymous substitutions detected in the D. guanche lineage could be explained if synonymous mutations behave as nearly neutral. Significant departure from the molecular clock hypothesis for synonymous and nonsynonymous substitutions was detected when comparing the D. subobscura, D. pseudoobscura, and D. melanogaster lineages. Codon bias and synonymous divergence between D. subobscura and D. melanogaster were negatively correlated across the RpII215 coding region, which indicates that selection coefficients for synonymous mutations vary across the gene. The C-terminal domain (CTD) of the RpII215 protein is structurally and functionally differentiated from the rest of the protein. Synonymous substitution rates were significantly different in both regions, which strongly indicates that synonymous mutations in the CTD and in the non-CTD regions are under detectably different selection coefficients.

Animals↗

PubMed1998

The correlation between synonymous and nonsynonymous substitutions in Drosophila: mutation, selection or relaxed constraints?

Codon usage bias, the preferential use of particular codons within each codon family, is characteristic of synonymous base composition in many species, including Drosophila, yeast, and many bacteria. Preferential usage of particular codons in these species is maintained by natural selection acting largely at the level of translation. In Drosophila, as in bacteria, the rate of synonymous substitution per site is negatively correlated with the degree of codon usage bias, indicating stronger selection on codon usage in genes with high codon bias than in genes with low codon bias. Surprisingly, in these organisms, as well as in mammals, the rate of synonymous substitution is also positively correlated with the rate of nonsynonymous substitution. To investigate this correlation, we carried out a phylogenetic analysis of substitutions in 22 genes between two species of Drosophila, Drosophila pseudoobscura and D. subobscura, in codons that differ by one replacement and one synonymous change. We provide evidence for a relative excess of double substitutions in the same species lineage that cannot be explained by the simultaneous mutation of two adjacent bases. The synonymous changes in these codons also cannot be explained by a shift to a more preferred codon following a replacement substitution. We, therefore, interpret the excess of double codon substitutions within a lineage as being the result of relaxed constraints on both kinds of substitutions in particular codons.

Animals↗

PubMed1993

Chloroplast DNA codon use: evidence for selection at the psb A locus based on tRNA availability.

Codon use in the three sequenced chloroplast genomes (Marchantia, Oryza, and Nicotiana) is examined. The chloroplast has a bias in that codons NNA and NNT are favored over synonymous NNC and NNG codons. This appears to be a consequence of an overall high A + T content of the genome. This pattern of codon use is not followed by the psb A gene of all three genomes and other psb A sequences examined. In this gene, the codon use favors NNC over NNT for twofold degenerate amino acids. In each case the only tRNA coded by the genome is complementary to the NNC codon. This codon use is similar to the codon use by chloroplast genes examined from Chlamydomonas reinhardtii. Since psb A is the major translation product of the chloroplast, this suggests that selection is acting on the codon use of this gene to adapt codons to tRNA availability, as previously suggested for unicellular organisms.

Animals↗

PubMed1989

Inferring the number of evolutionary events from DNA coding sequence differences.

The estimation of the amount of evolutionary divergence that has taken place between two DNA coding sequences depends strongly on the degree of constraint on amino acid replacements. If amino acid replacements are relatively unconstrained, the individual nucleotide is the appropriate unit of analysis and the method of Tajima and Nei can be used. If amino acid replacements are constrained, however, this method is shown to be inapplicable. For sequences with strong amino acid constraints, a method is outlined analogous to the Tajima and Nei method using codons as the unit of analysis. Only synonymous substitutions are used. Codon usage data can be employed to estimate the necessary parameters of the calculation, or a priori models of substitution may be employed. Sequences with significant but intermediate constraints on amino acid replacements are, in principle, unanalyzable.

Animals↗

PubMed2002

Evolution of Ig DNA sequence to target specific base positions within codons for somatic hypermutation.

Ig variable (V) region genes are subjected to a somatic hypermutation process as B lymphocytes participate in immune reactions to protein Ags. Although little is known regarding the mechanism of mutagenesis, a consistent hierarchy of trinucleotide target preferences is evident. Analysis of trinucleotide regional distributions predicted and we now empirically confirm the surprising finding that the framework 2 region of kappa V region genes is highly mutable despite its importance to the structural integrity and function of the Ab molecule. Interestingly, much of this mutability appears to be focused on the third codon position where synonymous substitutions are most likely to occur. We also observed a trend for high predicted mutability for codon positions 1 and 2 in complementarity-determining regions. Consequently, amino acid replacements should occur at a higher rate in complementarity-determining regions than in framework regions due to the distribution and subsequent targeting of microsequences by the mutation mechanism. Our results reveal a subtle tier of V region gene evolution in which DNA sequence has been molded to direct mutations to specific base positions within codons in a manner that minimizes damage and maximizes the benefits of the somatic hypermutation process.

Animals↗

PubMed2006

Identification of four novel HLA-A alleles from an East African population by high-resolution sequence-based typing.

We report here four novel human leukocyte antigen (HLA)-A alleles identified among an East African population during sequence-based HLA-A typing. The novel alleles were confirmed by sequencing two separate polymerase chain reaction products and by molecular cloning and sequencing multiple clones. The new allele A*9202 is identical to A*0202 at exon 2 and exon 3 except for a single nucleotide difference at codon 43 (CGG-->CAG), resulting in a coding change from Arginine to Glutamine. The second new allele has a synonymous change at codon 139 (GCA-->GCG), that differentiates it from A*680101. The new allele has been named by the World Health Organization nomenclature committee as A*680105. The novel allele A*2630 is identical to A*2603 at exon 2 and exon 3 except for a nonsynonymous change at codon 90 (GAC-->GCC), changed from Aspartic acid to Alanine. The fourth new allele is identical to A*290201 except for a single nucleotide difference at codon 138 (ATG-->GTG), resulting in a coding change from Methionine to Valine. The new allele has been named by the World Health Organization nomenclature committee as A*2915. Identification of these novel HLA-A alleles reflects the genetic diversity of this East African population.

Africa, Eastern↗

PubMed2005

The role of selection in the evolution of human mitochondrial genomes.

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

Amino Acid Substitution↗

PubMed1995

Evolution of Mhc class II polymorphism: the rise and fall of class II gene function in primates.

The substitution rate at the codons implicated at ARS of Mhc class II genes has previously been shown to be heavily biased towards nonsynonymous substitutions, indicative of positive selection for polymorphism. Based on our analysis of the number of synonymous changes at codons outside putative ARS in primates, the average age of the polymorphism at class II loci was found to increase in the following order: DPB1, DRB3, DRB5, DRB1, DRB4, DQB1, DQA1. For DRB loci, nonsynonymous changes were found to exceed synonymous changes at HLA-DRB1, DRB3 and DRB5, while no evidence of deviations from equal rates of synonymous and nonsynonymous substitutions were found for DRB6. The pattern of substitutions at the DRB loci of most Catarrhini species indicates constant positive selection at ARS codons over the evolutionary period examined. An exception to the relatively stable selection pattern between species exhibited by most loci is the appearance of polymorphism under positive selection at DRB4 only in the regular chimpanzee. The ds/dn ratios for DQA1 and DQB1 alleles are lower than for the most polymorphic DRB genes. Since the dn/ds ratio of ARS codons may be positively correlated to the ds for non-ARS codons, at least for DQB1, caution must be exercised in interpreting the low ratio for the DQ genes as an indication of weaker selection. The DQA1 allelic lineages show different dn/ds ratios, consistent with the hypothesis that the lineages are constrained from evolving in relation to the diversity of the interacting DQB1 alleles. In contrast to all other class II loci, DPB1 appears to have been subjected to strong positive selection only in the human lineage, and may represent the most conspicuous example of an Mhc locus acquiring an altered function in antigen presentation.

Animals↗

PubMed2004

Experimental reduction of codon bias in the Drosophila alcohol dehydrogenase gene results in decreased ethanol tolerance of adult flies.

The ethanol tolerance of adult transgenic flies of Drosophila containing between zero and ten unpreferred synonymous mutations that reduced codon bias in the alcohol dehydrogenase (Adh) gene was assayed. As the amino acid sequences of the ADH protein were identical in the four genotypes assayed, differences in ethanol tolerance were due to differences in the abundance of ADH protein, presumably driven by the effects of codon bias on translational efficiency. The ethanol tolerance of genotypes decreased with the number of unpreferred synonymous mutations, and a positive correlation between ADH protein abundance and ethanol tolerance was observed. This work confirms that the fitness effects of unpreferred synonymous mutations that reduce codon bias in a highly expressed gene are experimentally measurable in Drosophila melanogaster.

Alcohol Dehydrogenase↗

PubMed1999

Rapid detection by reverse hybridization of mutations in the UL97 gene of human cytomegalovirus conferring resistance to ganciclovir.

UNLABELLED: BACKGROUND OF STUDY: Diseases due to human cytomegalovirus (HCMV) infection constitute a major threat in marrow and solid organ transplant recipients. Ganciclovir (GCV) is widely used in prophylaxis and pre-emptive therapy of active HCMV infection. Resistance to ganciclovir (GCV) may arise at variable frequency under GCV therapy and is conferred by mutations (i) in the UL97 gene (codons 460, 520, and 591-607) encoding a phosphotransferase which is essential for monophosphorylation of GCV and, to a lesser extent, (ii) in the UL54 gene coding for the DNA polymerase of HCMV. OBJECTIVE: The purpose was to develop a rapid assay to screen for emerging GCV resistance mutations in the UL97 gene of HCMV whereby avoiding virus isolation and nucleotide sequencing procedures. STUDY DESIGN: A nested PCR (nPCR) amplifying UL97 codons 450-672 was developed. Nested amplicons were subsequently sequenced directly. Oligonucleotides for use in a reverse hybridization assay were designed to detect relevant non-synonymous mutations at codons UL97 460, 520, 603 and 607. Strain AD169 served as a wild-type control. RESULTS: UL97-specific nPCR amplicons were obtained from 18 EDTA blood samples of ten transplant recipients receiving GCV for more than 30 days. In three consecutive samples from a single patient a GCV resistance mutation at codon 603 (C-->W) was detected. In addition, two out of four cell culture-adapted HCMV isolates known to exhibit GCV resistance in vitro revealed mutations at codons 460 (M-->V) and 607 (C-->Y), respectively. By reverse hybridization a discrimination of single nucleotide changes at codons 460, 520, 603 and 607 was possible whereby matching exactly the results of the nucleotide sequence analysis for all 23 amplicons examined. CONCLUSIONS: Reverse hybridization appeared to be a rapid and convenient alternative to nucleotide sequencing when screening the UL97 gene of HCMV for selected markers of GCV resistance.

Antiviral Agents↗

PubMed1999

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 selection 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 short proteins. Long coding regions have both a lower codon bias and higher synonymous substitution rates, suggesting that they are affected less efficiently by selection. Therefore, both the length of the coding region and the recombination rate modulate codon bias. In addition, the data indicate that selection coefficients for synonymous mutations must vary by a minimum of one or two orders of magnitude. Two hypotheses are proposed to explain the relationship among the coding region length, the codon bias, and the synonymous divergence and polymorphism levels across the range of recombination rates in Drosophila. The first hypothesis is that selection coefficients on synonymous mutations are inversely related to the total length of the coding region. The second hypothesis proposes that interference among synonymous mutations reduces the efficacy of selection on these mutations. We investigated this second hypothesis by carrying out forward simulations of weakly selected mutations in model populations. These simulations show that even with realistic recombination rates, this interference, which we call the "small-scale" Hill-Robertson effect, can have a moderately strong influence on codon bias.

Animals↗

PubMed2006

Degeneracy in the genetic code and its symmetries by base substitutions.

Degeneracy in the genetic code is known to minimise the deleterious effects of the most frequent base substitutions: transitions at the third base of codons are generally synonymous substitutions. Transversions that alter degeneracy were reported by Rumer. Here the other transversions are shown to leave invariant degeneracy when applied to the first base of codons. As a summary, degeneracy is considered with respect to all three types of base substitutions, the transitions and the two types of transversions. The symmetries of degeneracy by base substitutions are independent of the representation of the genetic code and discussed with respect to the quasi-universality of the genetic code.

Amino Acids↗

PubMed1992

Compliance of genetic code with base-composition deflecting pressure.

Gene DNAs of different organisms show a wide variation in their G+C content as much as 20% to 80%. This variation has been regarded as the result of the compliance of the genetic code with the base-composition-deflecting mutational pressure. To make possible a quantitative discussion of this genetic code's elasticity, we made a statistical study of the G+C frequency at the 1st, 2nd, and 3rd positions of codons: 4.5 x 10(6) codons in 11,981 protein coding regions in the DNA data base were analyzed. The data were examined quantitatively by using a species-independent universal equation which describes the base frequencies at the three codon sites in terms of the constraint parameters characteristic of the sites and an intersite interaction. By a best fitting procedure between theoretical curves and data points, the constraint parameters and the characteristic G+C contents to which the 1st and the 2nd site base compositions are bound were determined. The base substituting mutation of the coding sequence under the base-composition-deflecting pressure is divided into following three stages of the different compliance from the elastic one to the rigid: 1) the 3rd position of codons change by synonymous substitution; 2) the 1st and then 2nd positions change accompanying amino acid replacement; and 3) in the organisms exposed under an extremely high base composition deflecting pressure, the codon table is forced to be altered. The compliance parameters were derived quantitatively for the first two stages. In conclusion, a simultaneous analysis of data from organisms as divers as virus and man discovered that there is a set of constraints common to species, which governs the frequency of codon bases, and it can be described by a universal equation.

Animals↗

PubMed1995

Codon bias in actin multigene families and effects on the reconstruction of phylogenetic relationships.

Codon usage patterns and phylogenetic relationships in the actin multigene family have been analyzed for three dipteran species--Drosophila melanogaster, Bactrocera dorsalis, and Ceratitis capitata. In certain phylogenetic tree reconstructions, using synonymous distances, some gene relationships are altered due to a homogenization phenomenon. We present evidence to show that this homogenization phenomenon is due to codon usage bias. A survey of the pattern of synonymous codon preferences for 11 actin genes from these three species reveals that five out of the six Drosophila actin genes show high degrees of codon bias as indicated by scaled chi 2 values. In contrast to this, four out of the five actin genes from the other species have low codon bias values. A Monte Carlo contingency test indicates that for those Drosophila actin genes which exhibit codon bias, the patterns of codon usage are different compared to actin genes from the other species. In addition, the genes exhibiting codon bias also appear to have reduced rates of synonymous substitution. The homogenization phenomenon seen in terms of synonymous substitutions is not observed for nonsynonymous changes. Because of this homogenization phenomenon, "trees" constructed based on synonymous substitutions will be affected. These effects can be overt in the case of multigene families, but similar distortions may underlie reconstructions based on single-copy genes which exhibit codon usage bias.

Actins↗

PubMed2004

Adjusting for selection on synonymous sites in estimates of evolutionary distance.

Evolution at silent sites is often used to estimate the pace of selectively neutral processes or to infer differences in divergence times of genes. However, silent sites are subject to selection in favor of preferred codons, and the strength of such selection varies dramatically across genes. Here, we use the relationship between codon bias and synonymous divergence observed in four species of the genus Saccharomyces to provide a simple correction for selection on silent sites.

DNA↗

PubMed2006

Evolution of amino-acid sequences and codon usage on the Drosophila miranda neo-sex chromosomes.

We have studied patterns of DNA sequence variation and evolution for 22 genes located on the neo-X and neo-Y chromosomes of Drosophila miranda. As found previously, nucleotide site diversity is greatly reduced on the neo-Y chromosome, with a severely distorted frequency spectrum. There is also an accelerated rate of amino-acid sequence evolution on the neo-Y chromosome. Comparisons of nonsynonymous and silent variation and divergence suggest that amino-acid sequences on the neo-X chromosome are subject to purifying selection, whereas this is much weaker on the neo-Y. The same applies to synonymous variants affecting codon usage. There is also an indication of a recent relaxation of selection on synonymous mutations for genes on other chromosomes. Genes that are weakly expressed on the neo-Y chromosome appear to have a faster rate of accumulation of both nonsynonymous and unpreferred synonymous mutations than genes with high levels of expression, although the rate of accumulation when both types of mutation are pooled is higher for the neo-Y chromosome than for the neo-X chromosome even for highly expressed genes.

Amino Acid Sequence↗

PubMed2001

Inferring parameters of mutation, selection and demography from patterns of synonymous site evolution in Drosophila.

Selection acting on codon usage can cause patterns of synonymous evolution to deviate considerably from those expected under neutrality. To investigate the quantitative relationship between parameters of mutation, selection, and demography, and patterns of synonymous site divergence, we have developed a novel combination of population genetic models and likelihood methods of phylogenetic sequence analysis. Comparing 50 orthologous gene pairs from Drosophila melanogaster and D. virilis and 27 from D. melanogaster and D. simulans, we show considerable variation between amino acids and genes in the strength of selection acting on codon usage and find evidence for both long-term and short-term changes in the strength of selection between species. Remarkably, D. melanogaster shows no evidence of current selection on codon usage, while its sister species D. simulans experiences only half the selection pressure for codon usage of their common ancestor. We also find evidence for considerable base asymmetries in the rate of mutation, such that the average synonymous mutation rate is 20-30% higher than in noncoding regions. A Bayesian approach is adopted to investigate how accounting for selection on codon usage influences estimates of the parameters of mutation.

Animals↗

PubMed1998

The genetic code is one in a million.

Statistical and biochemical studies of the genetic code have found evidence of nonrandom patterns in the distribution of codon assignments. It has, for example, been shown that the code minimizes the effects of point mutation or mistranslation: erroneous codons are either synonymous or code for an amino acid with chemical properties very similar to those of the one that would have been present had the error not occurred. This work has suggested that the second base of codons is less efficient in this respect, by about three orders of magnitude, than the first and third bases. These results are based on the assumption that all forms of error at all bases are equally likely. We extend this work to investigate (1) the effect of weighting transition errors differently from transversion errors and (2) the effect of weighting each base differently, depending on reported mistranslation biases. We find that if the bias affects all codon positions equally, as might be expected were the code adapted to a mutational environment with transition/transversion bias, then any reasonable transition/transversion bias increases the relative efficiency of the second base by an order of magnitude. In addition, if we employ weightings to allow for biases in translation, then only 1 in every million random alternative codes generated is more efficient than the natural code. We thus conclude not only that the natural genetic code is extremely efficient at minimizing the effects of errors, but also that its structure reflects biases in these errors, as might be expected were the code the product of selection.

Amino Acids↗