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PubMed1996

Genetic conservation of Highlands J viruses.

We studied molecular evolution of the mosquito-borne alphavirus Highlands J (HJ) virus by sequencing PCR products generated from 19 strains isolated between 1952 and 1994. Sequences of 1200 nucleotides including portions of the E1 gene and the 3' untranslated region revealed a relatively slow evolutionary rate estimated at 0.9-1.6 x 10(-4) substitutions per nucleotide per year. Phylogenetic trees indicated that all HJ viruses descended from a common ancestor and suggested the presence of one dominant lineage in North America. However, two or more minor lineages probably circulated simultaneously for periods of years to a few decades. Strains isolated from a horse suffering encephalitis, and implicated in a recent turkey outbreak, were not phylogenetically distinct from strains isolated in other locations during the same time periods. Our findings are remarkably similar to those we obtained previously for another North American alphavirus, eastern equine encephalomyelitis virus, with which Highlands J shares primary mosquito and avian hosts, geographical distribution, and ecology. These results support the hypotheses that the duration of the transmission season affects arboviral evolutionary rates and vertebrate host mobility influences genetic diversity.

Alphavirus↗

PubMed2002

Comparative rates of nucleotide sequence variation in the hypervariable region of E1/E2 and the NS5b region of hepatitis C virus in patients with a spectrum of liver disease resulting from a common source of infection.

The association of the severity of liver disease and the molecular evolution of hepatitis C virus (HCV) during chronic infection remains unclear and controversial. To address this we have studied the interpatient variability in the nucleotide sequence of two regions of the HCV genome, E1/E2, which contain the hypervariable region 1 and the nonstructural NS5b region, in a cohort of Irish female patients who were all recipients of a single source of HCV genotype 1b-contaminated anti-D immunoglobulin in 1977 and 1978 and who over the subsequent 20 years developed a spectrum of liver disease. In addition, quasispecies analysis was used to evaluate intrapatient variability in the E1/E2 region in four patients with mild and four with severe disease. Phylogenetic and evolutionary rate analyses of the nucleotide sequences demonstrated that there was no significant difference between those who developed mild disease and those who had progressed to severe disease or cirrhosis. These findings suggest that other factors, either additional viral or host, may be important in the pathogenesis and clinical outcome of chronic hepatitis C virus infection.

Amino Acid Sequence↗

PubMed1991

Attempted nonenzymatic template-directed oligomerizations on a polyadenylic acid template: implications for the nature of the first genetic material.

Previous attempts to produce nonenzymatic template-directed oligomerizations of activated pyrimidines on polypurine templates have been unsuccessful. The only efficient reactions are those where the template is composed primarily of pyrimidines, especially cytosine. Because molecular evolution requires that a synthesized daughter polynucleotide be capable of acting as a template for the synthesis of the original polynucleotide, the one-way replication achieved thus far is inadequate to initiate an evolving system. Several uracil analogs were used in this investigation in order to search for possible replacements for uracil. The monomers used in this investigation were the imidazolides of UMP, xanthosine 5'-monophosphate, the bis-monophosphates of the acyclic nucleosides of uracil, and 2,4-quinazolinedione. The concentrations of various salts, buffers, pH, and temperature were among the different variables investigated in attempts to find conditions that would permit template-directed oligomerizations. Although the different monomers in this study demonstrated varying abilities to form very short oligomers, we were unable to detect any enhancement of this oligomerization that could be attributed to the poly(A) template. Although special conditions might be found that would allow purine-rich templates to work, these reactions cannot be considered robust. The results of our experiments suggest that pyrimidines were not part of the original replicating system on the primitive Earth. It has already been shown that ribose is an unlikely component of the first replicating systems, and we now suggest that phosphate was absent as well. This is due to the low solubility of phosphate in the present ocean (3 x 10(-6) M), as well as the difficulty of prebiotic activation of phosphates.

Evolution, Molecular↗

PubMed1985

Alanine synthesis from glyceraldehyde and ammonium ion in aqueous solution.

Alanine is formed under anaerobic conditions from glyceraldehyde and ammonium ion in aqueous solutions of sodium phosphate (pH 7.0) or imidazole-imidazolium chloride (pH 7.0) at ambient temperature. In 500 mM imidazole (pH 7.0), alanine synthesis from 10 mM glyceraldehyde and 15 mM ammonium ion is roughly 6 times more rapid in the presence of 10 mM 3-mercaptopropionate (0.62% yield at 60 days) than in its absence (0.10% yield at 60 days). Likewise, the formation of alanine in 500 mM sodium phosphate (pH 7.0) from 5 mM glyceraldehyde and 10 mM ammonium ion is more rapid in the presence of 10 mM N-acetylcysteine than in its absence. In this reaction with N-acetylcysteine, the ratio of the yield of alanine to the yield of lactate is fairly constant. The yield of alanine is about 4.5% that of lactate. Alanine synthesis in the presence of thiol probably proceeds via alanyl thioester, which is produced by rearrangement of the imine of the hemithioacetal of pyruvaldehyde, a product of glyceraldehyde dehydration. The significance of this reaction for molecular evolution is discussed.

Acetylcysteine↗

PubMed1996

Strong evolutionary conservation of broadly expressed protein isoforms in the troponin I gene family and other vertebrate gene families.

It is well established that different protein classes undergo molecular evolution at different rates, presumably reflecting differing functional constraints. However, it is also the case that different isoforms of the "same" protein, encoded by a multigene family, may evolve at different rates. Here I report a relationship within gene families between isoform evolutionary rate and gene expression profile: Broadly expressed isoforms show stronger sequence conservation than do narrowly expressed isoforms. This observation emerged initially from cDNA cloning and sequencing studies, described here, of a vertebrate gene family encoding three differentially expressed isoforms of the muscle protein troponin I. However, the expression breadth/sequence conservation relationship applies to vertebrate gene families in general. In a broad and arbitrary survey sampling of sequence data on well-characterized vertebrate gene families, I found that in 14/15 families the most strongly conserved isoform was the most broadly expressed isoform, or one of several similarly broadly expressed isoforms. Broadly expressed isoforms are presumably subjected to greater negative selection pressure because they must function in a more diverse biochemical environment than do narrowly expressed isoforms. The expression breadth/evolutionary rate relationship has several interesting implications regarding the overall process of gene family evolution by duplication/divergence from ancestral genes.

Amino Acid Sequence↗

PubMed1997

Comparison of protein structures using 3D profile alignment.

A novel method for protein structure comparison using 3D profile alignment is presented. The 3D profile is a position-dependent scoring matrix derived from three-dimensional structures and is basically used to estimate sequence-structure compatibility for prediction of protein structure. Our idea is to compare two 3D profiles using a dynamic programming algorithm to obtain optimal alignment and a similarity score between them. When the 3D profile of hemoglobin was compared with each of the profiles in the library, which contained 325 profiles of representative structures, all the profiles of other globins were detected with relatively high scores, and proteins in the same structural class followed the globins. Exhaustive comparison of 3D profiles in the library was also performed to depict protein relatedness in the structure space. Using multidimensional scaling, a planar projection of points in the protein structure space revealed an overall grouping in terms of structural classes, i.e., all-alpha, all-beta, alpha/beta, and alpha+beta. These results differ in implication from those obtained by the conventional structure-structure comparison method. Differences are discussed with respect to the structural divergence of proteins in the course of molecular evolution.

Algorithms↗

PubMed1997

Comparisons of the nucleotide substitution process among repetitive segments of the alpha- and beta-spectrin genes.

The actin-cross-linking protein spectrin is a prominent component of the membrane cytoskeleton. Spectrin is a tetramer of two antiparallel alphabeta-dimers which share a unique and ancient gene structure. The alpha-spectrin and beta-spectrin genes are composed primarily of tandemly repeated 106-amino-acid segments, each of which forms a triple alpha-helical coiled coil. Both the genes and the repeats themselves are homologous. The two genes are thought to be the result of a gene duplication event, and each gene is the product of duplications of the 106-amino-acid repeats. In this work we compare the process of molecular evolution across the repeated segments of the alpha- and beta-spectrin genes. We find that the alpha-spectrin segments have, for the most part, evolved in a homogeneous fashion, while considerable heterogeneity is found among beta-spectrin segments. Several segments with unique known functions are found to have evolved differently than the others. On the basis of heterogeneity of the evolutionary process, we suggest that at least one repeat has a unique function that has yet to be documented. We also present new statistical methods for comparing the evolutionary process between different regions of DNA sequences.

Animals↗

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↗

PubMed1998

Synonymous and nonsynonymous rate variation in nuclear genes of mammals.

A maximum likelihood approach was used to estimate the synonymous and nonsynonymous substitution rates in 48 nuclear genes from primates, artiodactyls, and rodents. A codon-substitution model was assumed, which accounts for the genetic code structure, transition/transversion bias, and base frequency biases at codon positions. Likelihood ratio tests were applied to test the constancy of nonsynonymous to synonymous rate ratios among branches (evolutionary lineages). It is found that at 22 of the 48 nuclear loci examined, the nonsynonymous/synonymous rate ratio varies significantly across branches of the tree. The result provides strong evidence against a strictly neutral model of molecular evolution. Our likelihood estimates of synonymous and nonsynonymous rates differ considerably from previous results obtained from approximate pairwise sequence comparisons. The differences between the methods are explored by detailed analyses of data from several genes. Transition/transversion rate bias and codon frequency biases are found to have significant effects on the estimation of synonymous and nonsynonymous rates, and approximate methods do not adequately account for those factors. The likelihood approach is preferable, even for pairwise sequence comparison, because more realistic models about the mutation and substitution processes can be incorporated in the analysis.

Animals↗

PubMed1998

Sequence diversity in the 16S-23S intergenic spacer region (ISR) of the rRNA operons in representatives of the Escherichia coli ECOR collection.

The ribosomal RNA multigene family in Escherichia coli comprises seven rrn operons of similar, but not identical, sequence. Four operons (rrnC, B, G, and E) contain genes in the 16S-23S intergenic spacer region (ISR) for tRNA(Glu-2) and three (rrnA, D, and H) contain genes for tRNA(Ile-1) and tRNA(Ala-1B). To increase our understanding of their molecular evolution, we have determined the ISR sequence of the seven operons in a set of 12 strains from the ECOR collection. Each operon was specifically amplified using polymerase chain reaction primers designed from genes or open reading frames located upstream of the 16S rRNA genes in E. coli K12. With a single exception (ECOR 40), ISRs containing one or two tRNA genes were found at the same respective loci as those of strain K12. Intercistronic heterogeneity already found in K12 was representative of most variation among the strains studied and the location of polymorphic sites was the same. Dispersed nucleotide substitutions were very few but 21 variable sites were found grouped in a stem-loop, although the secondary structure was conserved. Some regions were found in which a stretch of nucleotides was substituted in block by one alternative, apparently unrelated, sequence (as illustrated by the known putative insertion of rsl in K12). Except for substitutions of different sizes and insertions/deletions found in the ISR, the pattern of nucleotide variation is very similar to that found for the 16S rRNA gene in E. coli. Strains K12 and ECOR 40 showed the highest intercistronic heterogeneity. Most strains showed a strong tendency to homogenization. Concerted evolution could explain the notorious conservation of this region that is supposed to have low functional restrictions.

Base Sequence↗

PubMed2004

Retroelements and formation of chimeric retrogenes.

It is very likely that formation of new genes is the main pathway of molecular evolution in living organisms. Many such genes are products of preexisting reshuffling of genetic material. In these processes a very important role is played by mutations associated with the activity of transposable elements, mostly retroelements (REs) for higher eukaryotes. The life cycle of REs involves a stage of so-called reverse transcription of their RNA intermediates, i.e. synthesis of complementary DNA on an RNA template. Transcriptionally active sequences of RE origin are referred to as retrogenes. REs create chimeric genes by a variety of mechanisms: new RE insertions, recombinations between RE sequences, formation of functional gene active pseudogenes and template switches during reverse transcription of messenger RNA. The abovementioned events are also able to give rise to new RE families. These mechanisms are reviewed here along with the description of major RE groups.

Animals↗

PubMed2004

Genomic organization of the complex alpha-gliadin gene loci in wheat.

To better understand the molecular evolution of the large alpha-gliadin gene family, a half-million bacterial artificial chromosome (BAC) library clones from tetraploid durum wheat, Triticum turgidum ssp. durum (2n = 4x = 28, genome AB), were screened for large genomic segments carrying the alpha-gliadin genes of the Gli-2 loci on the group 6 homoeologous chromosomes. The resulting 220 positive BAC clones--each containing between one and four copies of alpha-gliadin sequences--were fingerprinted for contig assembly to produce contiguous chromosomal regions covering the Gli-2 loci. While contigs consisting of as many as 21 BAC clones and containing up to 17 alpha-gliadin genes were formed, many BAC clones remained as singletons. The accuracy of the order of BAC clones in the contigs was verified by Southern hybridization analysis of the BAC fingerprints using an alpha-gliadin probe. These results indicate that alpha-gliadin genes are not evenly dispersed in the Gli-2 locus regions. Hybridization of these BACs with probes for long terminal repeat retrotransposons was used to determine the abundance and distribution of repetitive DNA in this region. Sequencing of BAC ends indicated that 70% of the sequences were significantly similar to different classes of retrotransposons, suggesting that these elements are abundant in this region. Several mechanisms underlying the dynamic evolution of the Gli-2 loci are discussed.

Base Sequence↗

PubMed2003

Genetic and ecological correlates of intraspecific variation in pitviper venom composition detected using matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS) and isoelectric focusing.

The ability to detect biochemical diversity in animal venoms has wide-ranging implications for a diverse array of scientific disciplines. Matrix-assisted laser desorption time-of-flight mass spectrometry (and, for comparative purposes, isoelectric focusing) were used to characterize venoms from a geographically diverse sample of Trimeresurus stejnegeri ( n < 229) from Taiwan. Previously unrealized levels of heterogeneity were detected in venom phospholipase A(2) isoforms (PLA(2)) and in whole venom profiles. Geographic variation in venom was primarily between Taiwan and two Pacific islets. Despite the common assumption that venom variation is a product of neutral molecular evolution, statistical testing failed to link venom variation with phylogenetic descent convincingly. Instead, pronounced differences in venom composition may be the product of natural selection for regional diets or of independent founder effects. More data are required on the functional differences between the isoforms to distinguish between these alternatives.

Animals↗

PubMed2003

Selection for highly biased amino acid frequency in the TolA cell envelope protein of Proteobacteria.

The bacterial cell envelope protein TolA functions to maintain the integrity of the cell membrane. This protein contains high levels of alanine and lysine that are used in the formation of alpha helices, which are required for normal protein function. The neutral model of molecular evolution predicts that amino acid composition and nucleotide composition are driven by the underlying GC content, as a result of mutation bias. However, this study shows that selection has acted to maintain high levels of alanine and lysine in the TolA protein of Proteobacteria, which in turn has biased nucleotide composition in the corresponding tolA gene.

Amino Acids↗

PubMed2005

Inter- and intralocus recombination drive MHC class IIB gene diversification in a teleost, the three-spined stickleback Gasterosteus aculeatus.

The mutational mechanism underlying the striking diversity in MHC (major histocompatibility complex) genes in vertebrates is still controversial. In order to evaluate the role of inter- and intragenic recombination in MHC gene diversification, we examined patterns of nucleotide polymorphism across an exon/intron boundary in a sample of 31 MHC class IIB sequences of three-spined stickleback (Gasterosteus aculeatus). MHC class IIB genes of G. aculeatus were previously shown to be under diversifying (positive) selection in mate choice and pathogen selection experiments. Based on recoding of alignment gaps, complete intron 2 sequences were grouped into three clusters using maximum-parsimony analysis. Two of these groups had >90% bootstrap support and were tentatively assigned single locus status. Intron nucleotide diversity within and among loci was low (p-distance within and among groups = 0.016 and 0.019, respectively) and fourfold lower than the rate of silent mutations in exon 2, suggesting that noncoding regions are homogenized by frequent interlocus recombination. A substitution analysis using GENECONV: revealed as many intergenic conversion events as intragenic ones. Recombination between loci may explain the occurrence of sequence variants that are particularly divergent, as is the case in three-spined stickleback, with nucleotide diversity attaining dN = 0.39 (peptide-binding residues only). For both MHC class II loci we also estimated the amount of intragenic recombination as population rate (4N(e)r) under the coalescent and found it to be approximately three times higher compared to point mutations (Watterson estimate per gene, 4N(e)mu). Nonindependence of molecular evolution across loci and frequent recombination suggest that MHC class II genes of bony fish may follow different evolutionary dynamics than those of mammals. Our finding of widespread recombination suggests that phylogenies of MHC genes should not be based on coding segments but rather on noncoding introns.

Animals↗

PubMed2004

Linkage of the beta-like omega-globin gene to alpha-like globin genes in an Australian marsupial supports the chromosome duplication model for separation of globin gene clusters.

The structure, function, and evolutionary history of globin genes have been the subject of extensive investigation over a period of more than 40 years, yet new globin genes with highly specialized functions are still being discovered and much remains uncertain about their evolutionary history. Here we investigate the molecular evolution of the beta-globin gene family in a marsupial species, the tammar wallaby, Macropus eugenii. We report the complete DNA sequences of two beta-like globin genes and show by phylogenetic analyses that one of these genes is orthologous to embryonically expressed epsilon-globin genes of marsupials and eutherians and the other is orthologous to adult expressed beta-globin genes of marsupials and eutherians. We show that the tammar wallaby contains a third functional beta-like globin gene, omega-globin, which forms part of the alpha-globin gene cluster. The position of omega-globin on the 3' side of the alpha-globin cluster and its ancient phylogenetic history fit the criteria, originally proposed by Jeffreys et al. (1980), of a "fossil" beta-globin gene and suggest that an ancient chromosome or genome duplication preceded the evolution of unlinked clusters of alpha- and beta-globin genes in mammals and avians. In eutherian mammals, such as humans and mice, omega-globin has been silenced or translocated away from the alpha-globin locus, while in marsupials omega-globin is coordinately expressed with the adult alpha-globin gene just prior to birth to produce a functional hemoglobin (alpha2 omega2).

Amino Acid Sequence↗

PubMed2004

Recombination in primeval genomes: a step forward but still a long leap from maintaining a sizable genome.

A stubborn question in early molecular evolution is how to sustain the "minimum" informational length required for the basic features of life with a putative low-copying fidelity RNA polymerase ribozyme. Proposals to circumvent the information crisis have primarily focused on networks of cooperative molecules or compartmentalization of non-cooperative unlinked templates, but success has been very limited so far. Lehman (2003) has recently suggested that recombination--a frequently ignored player in early evolution--could have been crucial to building up primeval genomes of sizable length. Here we investigate this claim by assuming (without loss of generality) that genes were already enclosed in a compartment (vesicle, protocell). The numerical results show a quite intricate interplay among mutation, recombination, and gene redundancy. Provided that the minimum number of gene copies per protocell was enough for recombination to recreate wildtype templates--but not too high to impose an unbearable burden of mutants--informational content could have increased by at least 25% by keeping the same mutational load as that for a population without recombination. However, the upper bound of informational length would still be far from the "minimal life" provisions.

Chromosome Positioning↗

PubMed2006

Positive and negative selection in the beta-esterase gene cluster of the Drosophila melanogaster subgroup.

We examine the pattern of molecular evolution of the beta-esterase gene cluster, including the Est-6 and psiEst-6 genes, in eight species of the Drosophila melanogaster subgroup. Using maximum likelihood estimates of nonsynonymous/synonymous rate ratios, we show that the majority of Est-6 sites evolves under strong (48% of sites) or moderate (50% of sites) negative selection and a minority of sites (1.5%) is under significant positive selection. Est-6 sites likely to be under positive selection are associated with increased intraspecific variability. One positively selected site is responsible for the EST-6 F/S allozyme polymorphism; the same site is responsible for the EST-6 functional divergence between species of the melanogaster subgroup. For psiEst-6 83.7% sites evolve under negative selection, 16% sites evolve neutrally, and 0.3% sites are under positive selection. The positively selected sites of psiEst-6 are located at the beginning and at the end of the gene, where there is reduced divergence between D. melanogaster and D. simulans; these regions of psiEst-6 could be involved in regulation or some other function. Branch-site-specific analysis shows that the evolution of the melanogaster subgroup underwent episodic positive selection. Collating the present data with previous results for the beta-esterase genes, we propose that positive and negative selection are involved in a complex relationship that may be typical of the divergence of duplicate genes as one or both duplicates evolve a new function.

Animals↗