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PubMed1998

Evolutionary rates for tuf genes in endosymbionts of aphids.

The gene encoding elongation factor Tu (tuf) in aphid endosymbionts (genus Buchnera) evolves at rates of 1.3 x 10(-10) to 2.5 x 10(-10) nonsynonymous substitutions and 3.9 x 10(-9) to 8.0 x 10(-9) synonymous substitutions per position per year. These rates, which are at present among the most reliable substitution rates for protein-coding genes of bacteria, have been obtained by calibrating the nodes in the phylogenetic tree produced from the Buchnera EF-Tu sequences using divergence times for the corresponding ancestral aphid hosts. We also present data suggesting that the rates of nonsynonymous substitutions are significantly higher in the endosymbiont lineages than in the closely related free-living bacteria Escherichia coli and Salmonella typhimurium. Synonymous substitution rates for Buchnera approximate estimated mutation rates for E. coli and S. typhimurium, as expected if synonymous changes act as neutral mutations in Buchnera. We relate the observed differences in substitution frequencies to the absence of selective codon preferences in Buchnera and to the influence of Muller's ratchet on small asexual populations.

Amino Acid Sequence↗
PubMed1997

A theoretical method for evaluating the relative importance of positive selection and neutral drift from observed base changes.

To evaluate the relative importance of positive selection and neutral drift from the nucleotide base changes observed in the homologous alignment of genes, a theoretical equation of base changes is formulated by including both the influence of selection and the base substitutions due to mutations. Under the assumption that the average rate of base substitutions estimated from synonymous changes is the "true" mutation rate applicable at all positions, this method is applied to the vertebrate globin gene family, and evaluates the departures of base change rates from the "true" mutation rate at the first and second codon positions as a consequence of preferential selection for the conservation of important function. In addition to the strong effect of selection on the amino acid residues in the internal region mostly common to myoglobin and hemoglobin chains, the distinctive directions of selective parameter values are seen at sites on the globin surface, distinguishing the subunit contact residues of hemoglobins from the polar residues on the surface of myoglobins. Moreover, this effect of selection distinguishing between the myoglobin and hemoglobin chain genes becomes weaker in cold-blooded vertebrates, especially in fish, strongly suggesting the possibility that the clear distinction between these globins is a result of selection out of the changes regarded as neutral ones in an ancestor of vertebrates. Thus, the present method may also serve to investigate the homology of many other proteins from the aspect of molecular evolution, mainly focusing on the evolution of their biological functions.

Animals↗
PubMed2004

Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene.

BACKGROUND AND OBJECTIVES: Hemophilia B is an X-linked recessive, bleeding disorder caused by mutations in the factor IX gene. A wide range of mutations, showing large molecular heterogeneity, has been described in hemophilia B patients. Our study was aimed at characterizing mutations in the factor IX gene in a cohort of North Indian hemophilia B patients. DESIGN AND METHODS: Polymerase chain reaction (PCR) amplification and direct sequencing of all regions of likely functional significance- the coding regions, promoter, the 5' UTR, the splice junctions and parts of the 3' UTR of the factor IX gene was done in 18 families carrying a severe form of hemophilia B. RESULTS: We identified 10 point mutations (including 2 novel ones); one novel deletion and one donor splice site mutation. Recurrence of a nonsense and a missense mutation was observed. The mutation in 3 families could not be characterized. None of the 14 polymorphic positions reported in the Haemophilia B Mutation database in the regions sequenced were polymorphic; herein we report four novel synonymous single base mismatches. One mutation reported to be causative in the database was found to be more likely a non-causal polymorphism. INTERPRETATION AND CONCLUSIONS: Our data confirm the remarkable heterogeneity of the mutational spectrum in hemophilia B among affected families. This is the first mutation report on the disease in the Indo-Aryan population from the Indian subcontinent. Identification of a causative mutation leads to more precise carrier detection than does conventional polymorphism-based linkage analysis. This can effectively be used to establish genotype/ phenotype relationships.

Amino Acid Substitution↗
PubMed2006

Large-scale analyses of synonymous substitution rates can be sensitive to assumptions about the process of mutation.

A popular approach to examine the roles of mutation and selection in the evolution of genomes has been to consider the relationship between codon bias and synonymous rates of molecular evolution. A significant relationship between these two quantities is taken to indicate the action of weak selection on substitutions among synonymous codons. The neutral theory predicts that the rate of evolution is inversely related to the level of functional constraint. Therefore, selection against the use of non-preferred codons among those coding for the same amino acid should result in lower rates of synonymous substitution as compared with sites not subject to such selection pressures. However, reliably measuring the extent of such a relationship is problematic, as estimates of synonymous rates are sensitive to our assumptions about the process of molecular evolution. Previous studies showed the importance of accounting for unequal codon frequencies, in particular when synonymous codon usage is highly biased. Yet, unequal codon frequencies can be modeled in different ways, making different assumptions about the mutation process. Here we conduct a simulation study to evaluate two different ways of modeling uneven codon frequencies and show that both model parameterizations can have a dramatic impact on rate estimates and affect biological conclusions about genome evolution. We reanalyze three large data sets to demonstrate the relevance of our results to empirical data analysis.

Amino Acid Substitution↗
PubMed2006

Genetic variations in rice in vitro cultures at the EPSPs-RPS20 region.

In vitro cultures of plant cells have often been utilized to generate genetic variations, which are designated somaclonal variations. Little is known about the major genetic alterations in the cultured cells and the nature of these genetic changes. Here, we examined different lines of rice Oc cells that have been cultured for more than 20 years on agar media or in liquid media. We surveyed 35 clones obtained from PCR amplification of the 3-kb EPSPs-RPS20 region. The sequence divergence among the Oc cells was even greater than that between Japonica and Indica rice cultivars. The divergent sequences appeared to be maintained as multiple copies in a single cell. Surprisingly, the nucleotide substitutions in the Oc cells were characterized by an extremely high frequency of transition mutations of A/T-to-G/C, a feature which is similar to that of the mutations caused by chemical mutagens such as 5-bromouracil and 2-aminopurine. Although no replacements in the exons of this region were observed among the AA-genome Oryza species, our results revealed that the nucleotide substitutions of the cultured cell lines occurred more frequently at replacement sites in the exons than at synonymous sites. These distinct mutation biases found in rice in vitro cultures might contribute importantly to somaclonal variations.

Base Sequence↗
PubMed1995

Intrastrand parity rules of DNA base composition and usage biases of synonymous codons.

When there are no biases in mutation and selection between the two strands of DNA, the 12 possible substitution rates of the four nucleotides reduces to six (type 1 parity rule or PR1), and the intrastrand average base composition is expected to be A = T and G = C at equilibrium without regard to the G + C content of DNA (type 2 parity rule or PR2). Significant deviations from the parity rules in the third codon letters of the four-codon amino acids result mostly from selective biases rather than mutational biases between the two strands of DNA during evolution. The parity rules lay the foundation for evaluating the biases in synonymous codon usage in terms of (1) directional mutation pressure for variation of the DNA G + C content due to mutational biases between alpha-bases (A or T) and gamma-bases (G or C), (2) strand-bias mutation, for example, by DNA repair during transcription, and (3) functional selection in evolution, for example, due to tRNA abundance. The present analysis shows that, although the PR2 violation is common in the third codon letters of four-codon amino acids, the contribution of PR2 violation to the DNA G + C content of the third codon position is small and, in majority of cases, mildly counteracts the effect of the directional mutation pressure on the G + C content.

Animals↗
PubMed2003

Candidate gene analysis of the human metabotropic glutamate receptor type 4 (GRM4) in patients with juvenile myoclonic epilepsy.

Hereditary factors play a major role in the genetically complex etiology of juvenile myoclonic epilepsy (JME). Linkage studies in families of JME probands suggest a susceptibility locus (EJM1) for idiopathic generalized epilepsy (IGE) in the chromosomal region 6p21.3 near the HLA region. The gene encoding the metabotropic glutamate receptor type 4 (GRM4) has been localized within the EJM1-region and represents a high-ranking candidate gene. Therefore, we have sequenced the coding regions and regulatory GRM4 sequences in 20 IGE probands who were derived from families of JME probands providing positive linkage evidence to the HLA-DQ locus. Our mutation analysis detected three synonymous exonic single nucleotide polymorphisms (SNP; exon-7: c.1455T > C, exon-8: c.2002A > G, exon-10: c.2733C > T), one SNP in the 3'-untranslated region (c.2890A > G), and two intronic SNPs (intron-3: IVS3 + 2732A > G, intron-7: IVS7 + 39C > T). None of the identified SNPs was likely to affect receptor function or gene expression. The population-based association study did not show significant differences in the allele and genotype frequencies of the common c.1455T > C SNP between 144 German JME probands and 144 healthy population controls (P > 0.84). Likewise, the family-based transmission disequilibrium test did not indicate a preferential transmission of exon-7 SNP alleles in 31 informative parent-child transmissions (P = 0.86). Our results provide no evidence that genetic variation of the GRM4 gene confers susceptibility to JME-related IGE syndromes.

Adolescent↗
PubMed2002

[Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism caused by inactivating mutations of calcium-sensing receptor].

Calcium-sensing receptor (CaSR) plays an essential role in regulating secretion of parathyroid hormone. After the identification of CaSR, some cases of familial hypocalciuric hypercalcemia (FHH) were shown to have heterozygous inactivating mutations of CaSR. However, linkage study showed that there are additional two genetic loci for FHH in addition to the chromosomal location of CaSR gene. Furthermore, one family with heterozygous inactivating mutation of CaSR was shown to exhibit hypercalcemia with hypercalciuria. Therefore, heterozygous inactivating mutation of CaSR is not synonymous with FHH. In addition, patients with neonatal severe hyperparathyroidism were shown to have homozygous or compound heterozygous inactivating mutations of CaSR.

Calcium↗
PubMed2005

Weak selection revealed by the whole-genome comparison of the X chromosome and autosomes of human and chimpanzee.

The effect of weak selection driving genome evolution has attracted much attention in the last decade, but the task of measuring the strength of such selection is particularly difficult. A useful approach is to contrast the evolution of X-linked and autosomal genes in two closely related species in a whole-genome analysis. If the fitness effect of mutations is recessive, X-linked genes should evolve more rapidly than autosomal genes when the mutations are advantageous, and they should evolve more slowly than autosomal genes when the mutations are deleterious. We found synonymous substitutions on the X chromosome of human and chimpanzee to be less frequent than those on the autosomes. When calibrated against substitutions in the intergenic regions and pseudogenes to filter out the differences in the mutation rate and ancestral population size between X chromosomes and autosomes, X-linked synonymous substitutions are still 10% less frequent. At least 90% of the synonymous substitutions in human and chimpanzee are estimated to be deleterious, but the fitness effect is weaker than the effect of genetic drift. However, X-linked nonsynonymous substitutions are approximately 30% more frequent than autosomal ones, suggesting the fixation of advantageous mutations that are recessive.

Animals↗
PubMed2003

Abundance of plastid DNA insertions in nuclear genomes of rice and Arabidopsis.

Pairwise comparison of whole plastid and draft nuclear genomic sequences of Arabidopsis thaliana and Oryza sativa L. ssp. indica shows that rice nuclear genomic sequences contain homologs of plastid DNA covering about 94 kb (83%) of plastid genome and including one or more full-length intact (without mutations resulting in premature stop codons) homologues of 26 known protein-coding (KPC) plastid genes. By contrast, only about 20 kb (16%) of chloroplast DNA, including a single intact plastid-derived KPC gene, is presented in the nucleus of A. thaliana. Sixteen rice plastid genes have at least one nuclear copy without any mutation or with only synonymous substitutions. Nuclear copies for other ten plastid genes contain both synonymous and non-synonymous substitutions. Multiple ESTs for 25 out of 26 KPC genes were also found, as well as putative promoters for some of them. The study of substitutions pattern shows that some of nuclear homologues of plastid genes may be functional and/or are under the pressure of the positive natural selection. The similar comparative analysis performed on rice chromosome 1 revealed 27 contigs containing plastid-derived sequences, totalling about 84 kb and covering two thirds of chloroplast DNA, with the intact nuclear copies of 26 different KPC genes. One of these contigs, AP003280, includes almost 57 kb (45%) of chloroplast genome with the intact copies of 22 KPC genes. At the same time, we observed that relative locations of homologues in plastid DNA and the nuclear genome are significantly different.

Arabidopsis↗
PubMed1994

Haplotypic divergence coupled with lack of diversity at the Arabidopsis thaliana alcohol dehydrogenase locus: roles for both balancing and directional selection?

We designate a region of the alcohol dehydrogenase locus (Adh) of the weedy crucifer, Arabidopsis thaliana, as "hypervariable" on the basis of a comparison of sequences from ecotypes Columbia and Landsberg. We found eight synonymous and two replacement mutations in the first 262 nucleotides of exon 4, and an additional two mutations in the contiguous region of intron 3. The rest of the sequence (2611 bp) has just three mutations, all of them confined to noncoding regions. Our survey of the hypervariable region among 37 ecotypes of A. thaliana revealed two predominant haplotypes, corresponding to the Columbia and Landsberg sequences. We identified five additional haplotypes and 4 additional segregating sites. The lack of haplotype diversity is presumably in part a function of low rates of recombination between haplotypes conferred by A. thaliana's tendency to self-fertilize. However, an analysis in 32 ecotypes of 12 genome-wide polymorphic markers distinguishing Columbia and Landsberg ecotypes indicated levels of outcrossing sufficient at least to erode linkage disequilibrium between dispersed markers. We discuss possible evolutionary explanations for the coupled observation of marked divergence within the hypervariable region and a lack of haplotype diversity among ecotypes. The sequence of the region for closely related species argues against the possibility that one allele is the product of introgression. We note (1) that several loss of function mutations (both naturally and chemically induced) map to the hypervariable region, and (2) the presence of two amino acid replacement polymorphisms, one of which causes the mobility difference between the two major classes of A. thaliana Adh electrophoretic alleles. We argue that protein polymorphism in such a functionally significant part of the molecule may be subject to balancing selection. The observed pattern of extensive divergence between the alleles is consistent with this explanation because balancing selection on a particular site maintains linked neutral polymorphisms at intermediate frequencies.

Alcohol Dehydrogenase↗
PubMed2002

Effect of chromosome location on bacterial mutation rates.

In previous comparisons of enterobacterial sequences, synonymous substitution rates were higher in genes closer to the replication terminus, suggesting that mutation rates increase with distance from the replication origin. In order to directly test for the effects of chromosomal location on the rates of point mutations, we assayed the reversion rates of two lacZ alleles inserted at four positions in the Salmonella enterica chromosome. Mutation rates at an intermediate locus were significantly higher than those at loci nearer to and farther from the replication origin. The higher reversion rates at this locus were neither the result of an overall increase in mutation rates produced by the insertion at this location nor a function of the mutations' immediate neighbors, but rather a regional effect. At all loci, regardless of chromosome location, T.A --> G.C transversions were more frequent than A.T --> G.C transitions during the exponential phase.

Analysis of Variance↗
PubMed1998

HIV protease genotype and viral sensitivity to HIV protease inhibitors following saquinavir therapy.

OBJECTIVE: To examine the relationship between HIV protease genotype and altered protease inhibitor sensitivity of isolates from patients after therapy with saquinavir (SQV) in its hard gelatin formulation. DESIGN: Forty-one post-therapy isolates and corresponding baseline samples were obtained from 37 patients in four different clinical trials after therapy with SQV for 16-147 weeks. Post-therapy isolates were selected on the basis of preliminary sequence or drug sensitivity data. RESULTS: Fifteen out of 17 isolates without detectable Val-48 or Met-90 mutations retained sensitivity to SQV. (The remaining isolates showed only a marginal increase in median inhibitory concentration.) In addition, three out of 15 isolates with Met-90 retained sensitivity to all other protease inhibitors tested (indinavir, ritonavir, amprenavir, nelfinavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas only four out of 22 showed broad cross-resistance to all protease inhibitors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between those at residues 82 and 74. CONCLUSIONS: Recruitment of Val-48/Met-90 mutations was not found to be synonymous with cross-resistance. Indeed, the majority of isolates with these mutations retained sensitivity to at least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruitment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marker of cross-resistance in SQV-treated patients.

Amino Acid Substitution↗
PubMed2006

Rapid generation of new powdery mildew resistance genes after wheat domestication.

Plant defence against pathogens is controlled by disease resistance (R) gene products that directly or indirectly detect specific pathogen effectors. Plant-pathogen interactions have been proposed to follow a co-evolutionary arms-race model where R genes are recent and evolve rapidly in response to structural changes in matching pathogen effectors. However, the longevity and extensive polymorphism of R genes studied were more consistent with balancing selection maintaining ancient and diverse R genes or alleles. In bread wheat (Triticum aestivum), the Pm3 locus confers race-specific resistance to wheat powdery mildew (Blumeria graminis f.sp. triticii). Here we describe recently generated Pm3 resistance alleles that all derive from one susceptible allele, Pm3CS, which is widespread among hexaploid bread-wheat lines. One group of four Pm3 resistance alleles shows few, clearly delimited, polymorphic sequence blocks of ancient origin, embedded in sequences identical to Pm3CS and possibly derived from gene conversion. A second group of three alleles differs from Pm3CS by only two to five mutations, all non-synonymous, and all in the leucine-rich repeat-encoding region. Transient transformation experiments confirmed that Pm3 resistance specificities are based on one or few amino acid changes. The Pm3CS allele was found in wild tetraploid wheat, the ancestor of hexaploid bread wheat, specifically from southern Turkey, a region proposed to be the site of wheat domestication. Based on these data, we propose that the Pm3 resistance alleles were generated in agricultural ecosystems after domestication of wheat 10,000 years ago. The evolution of Pm3 alleles in wheat is best described by the model of evolved recycling, where novel genetic variation is integrated in plant populations together with recycling of old variation.

Alleles↗
PubMed2005

Novel Plasmodium vivax dhfr alleles from the Indonesian Archipelago and Papua New Guinea: association with pyrimethamine resistance determined by a Saccharomyces cerevisiae expression system.

In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.

Alleles↗
PubMed2001

Vertical transmission of biosynthetic plasmids in aphid endosymbionts (Buchnera).

This study tested for horizontal transfer of plasmids among Buchnera aphidicola strains associated with ecologically and phylogenetically related aphid hosts (Uroleucon species). Phylogenetic congruence of Buchnera plasmid (trpEG and leuABC) and chromosomal (dnaN and trpB) genes supports strictly vertical long-term transmission of plasmids, which persist due to their contributions to host nutrition rather than capacity for infectious transfer. Synonymous divergences indicate elevated mutation on plasmids relative to chromosomal genes.

Animals↗
PubMed1995

p53, Rb and bcl-2 expression during the cell cycle: a study in phytohaemagglutinin stimulated lymphocytes and microwave irradiated lymphoid tissue sections.

AIMS: To determine the expression of p53, Rb, and bcl-2 during the cell cycle in stimulated peripheral blood lymphocytes (PBLs) and microwave heated reactive lymphoid tissue sections. METHODS: The expression of p53, Rb and bcl-2 proteins in paraffin wax embedded tonsil tissue sections was detected by immunohistochemistry using an (APAAP) technique following microwave irradiation. Flow cytometric analysis as performed on phytohaemagglutinin (PHA) stimulated PBLs, with simultaneous S fraction determination. RESULTS: Expression of p53 protein was detected in reactive tonsil germinal centre cells, in some suprabasal cells in the surface and cryptic epithelium, and in some endothelial cells. Analysis of p53 in PHA stimulated PBLs revealed expression of p53 by non-tumoral activated lymphocytes. Rb protein expression was increased in PHA stimulated PBLs and was usually detected in most germinal centre B cells, in isolated paracortical cells, in a fraction of endothelial cells, and in most epithelial suprabasal cells. Expression of bcl-2 in stimulated lymphocytes was inversely correlated with proliferation. This confirms findings in reactive tonsil tissue samples, where proliferating cells located in the germinal centres and paracortical area are mostly bcl-2 negative. CONCLUSIONS: Expression of these three oncogenic and tumour suppressor proteins varies during the cell cycle in non-tumoral cells. Consequently, tumoral growth fraction must be taken into account when analysing dysregulation of these three genes in lymphomas and other tumours. The p53 protein may be detected in benign conditions, as its expression is not synonymous with malignancy or mutation of the p53 gene.

Cell Cycle↗
PubMedDate not supplied

[Detection of p53 protein in advanced head and neck cancer].

P53 protein expression, synonymous to p53 gene mutation, is a common event in head and neck squamous cell carcinoma (HNSCC). However, the correlation between p53 expression and clinico-pathologic parameters remains unclear. Primary tumors for analysis were obtained from 99 patients with HNSCC. The expression of p53 was analyzed with monoclonal D07 antibody (Dako Corp., Glostrup, Denmark). Seventy five percent of 79 valid cases expressed the protein. A correlation was found between alcohol intake and p53 expression. None of the other clinico-pathologic factors were associated to p53 expression. Our results suggest that p53 may be involved in the development of HNSCC. However its clinical significance is still not completely understood.

Aged↗