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PubMed2001

Evolution of hepatitis C virus genome in chronically infected patients receiving ribavirin monotherapy.

Recent results of clinical trials suggest that combination of interferon and ribavirin exhibits an enhanced antiviral effect in the treatment of chronic hepatitis C. To investigate the effect of ribavirin on hepatitis C virus (HCV) infection, we analysed the evolution of the genetic heterogeneity of HCV in relation to the anti-HCV humoral response in patients treated by ribavirin alone. The study population included 35 patients with liver biopsy proven chronic hepatitis C infected with HCV genotype 1. Among them, 26 were treated with ribavirin for at least 12 months and nine untreated patients served as a control group. Serum samples were analysed before and at 6 and 12 months of therapy. Three regions of the HCV genome, i.e. HVR1, a domain of NS5A including part of the interferon sensitivity determining region (ISDR), and a segment of NS5B, were amplified by RT-PCR using specific primers. The PCR products were then studied using single-strand conformation polymorphism (SSCP) analysis followed by either direct sequencing, or cloning and sequencing. In parallel, the humoral anti-E1 response was studied using an ELISA (Innotest HCV E1Ab, Innogenetics). The results of HCV genome analysis showed no significant effect on the amino acid sequence evolution of the HVR1, NS5A and NS5B regions of HCV. Analysis of a phylogenetic tree from the major quasispecies variants showed the absence of correlation with ribavirin response, and the absence of selection of viral strains during ribavirin treatment. A trend towards a decrease in the anti-E1 Ab response was also observed. Altogether these results suggest that ribavirin may not exhibit a direct antiviral effect, but may trigger a favourable response to interferon by modulating the immune response against HCV.

Amino Acid Sequence↗

PubMed1998

Phylogenetic utility of the external transcribed spacer (ETS) of 18S-26S rDNA: congruence of ETS and ITS trees of Calycadenia (Compositae).

The 3' region of the external transcribed spacer (ETS) of 18S-26S nuclear ribosomal DNA was sequenced in 19 representatives of Calycadenia/Osmadenia and two outgroup species (Compositae) to assess its utility for phylogeny reconstruction compared to rDNA internal transcribed spacer (ITS) data. Universal primers based on plant, fungal, and animal sequences were designed to amplify the intergenic spacer (IGS) and an angiosperm primer was constructed to sequence the 3' end of the ETS in members of tribe Heliantheae. Based on these sequences, an internal ETS primer useful across Heliantheae sensu lato was designed to amplify and sequence directly the 3' ETS region in the study taxa, which were the subjects of an earlier phylogenetic investigation based on ITS sequences. Size variation in the amplified ETS region varied across taxa of Heliantheae sensu lato from approximately 350 to 700 bp, in part attributable to an approximately 200-bp tandem duplication in a common ancestor of Calycadenia/Osmadenia. Phylogenetic analysis of the 200-bp subrepeats and examination of apomorphic changes in the duplicated region demonstrate that the subrepeats in Calycadenia/Osmadenia have evolved divergently. Phylogenetic analyses of the entire amplified ETS region yielded a highly resolved strict consensus tree that is nearly identical in topology to the ITS tree, with strong bootstrap and decay support on most branches. Parsimony analyses of combined ETS and ITS data yielded a strict consensus tree that is better resolved and generally better supported than trees based on either data set analyzed separately. We calculated an approximately 1.3- to 2.4-fold higher rate of sequence evolution by nucleotide substitution in the ETS region studied than in ITS-1 + ITS-2. A similar disparity in the proportion of variable (1.3 ETS:1 ITS) and potentially informative (1.5 ETS:1 ITS) sites was observed for the ingroup. Levels of homoplasy are similar in the ETS and ITS data. We conclude that the ETS holds great promise for augmenting ITS data for phylogenetic studies of young lineages.

Base Sequence↗

PubMed1998

Granule-bound starch synthase: structure, function, and phylogenetic utility.

Interest in the use of low-copy nuclear genes for phylogenetic analyses of plants has grown rapidly, because highly repetitive genes such as those commonly used are limited in number. Furthermore, because low-copy genes are subject to different evolutionary processes than are plastid genes or highly repetitive nuclear markers, they provide a valuable source of independent phylogenetic evidence. The gene for granule-bound starch synthase (GBSSI or waxy) exists in a single copy in nearly all plants examined so far. Our study of GBSSI had three parts: (1) Amino acid sequences were compared across a broad taxonomic range, including grasses, four dicotyledons, and the microbial homologs of GBSSI. Inferred structural information was used to aid in the alignment of these very divergent sequences. The informed alignments highlight amino acids that are conserved across all sequences, and demonstrate that structural motifs can be highly conserved in spite of marked divergence in amino acid sequence. (2) Maximum-likelihood (ML) analyses were used to examine exon sequence evolution throughout grasses. Differences in probabilities among substitution types and marked among-site rate variation contributed to the observed pattern of variation. Of the parameters examined in our set of likelihood models, the inclusion of among-site rate variation following a gamma distribution caused the greatest improvement in likelihood score. (3) We performed cladistic parsimony analyses of GBSSI sequences throughout grasses, within tribes, and within genera to examine the phylogenetic utility of the gene. Introns provide useful information among very closely related species, but quickly become difficult to align among more divergent taxa. Exons are variable enough to provide extensive resolution within the family, but with low bootstrap support. The combined results of amino acid sequence comparisons, maximum-likelihood analyses, and phylogenetic studies underscore factors that might affect phylogenetic reconstruction. In this case, accommodation of the variable rate of evolution among sites might be the first step in maximizing the phylogenetic utility of GBSSI.

Amino Acid Sequence↗

PubMed2001

Initiation of therapy during primary HIV type 1 infection results in a continuous decay of proviral DNA and a highly restricted viral evolution.

A latent pool of HIV-1 is established early in memory CD4+ T lymphocytes and persists during antiretroviral therapy. Also, viral replication may continue in subjects despite undetectable viremia. However, it remains unclear whether this residual replication results in any significant sequence evolution. We were therefore interested in studying the viral evolution and HIV-1 DNA dynamics in subjects with primary infection receiving or not receiving early potent antiretroviral therapy. In 16 subjects, HIV-1 DNA load was monitored from 1 to 23 days, up to 1253 days, after onset of symptoms. Extensive sequential cloning and sequence analysis of the V3 region was performed in four subjects. In the treated subjects a continuous decline in the proviral load was found, corresponding to a half-life of about 6 months. As expected in newly infected individuals the founder virus populations showed high intrasubject sequence similarity. Also, a limited increase in the viral divergence was detected during the first 6 months in three treated subjects. Thereafter, no significant sequence changes were found despite analysis of a large number of clones. Our data thus suggest that early and successful therapy in compliant subjects with primary HIV-1 infection results in a highly restricted viral evolution and a decline in the proviral load close to the decay rate of human memory T lymphocytes.

DNA, Viral↗

PubMed2003

A new split of the Hox gene complex in Drosophila: relocation and evolution of the gene labial.

Hox genes encode transcription factors involved in the specification of segment identity in the early metazoan embryo. These genes are usually clustered and arranged in the same order as they are expressed along the anteroposterior body axis. This conserved genomic organization has suggested the existence of functional constraints acting on the genome organization. Partial disassembly of the Hox gene complex (HOM-C) in Caenorhabditis elegans and in two different Drosophila lineages, however, calls into question whether this cluster organization is absolutely required for proper function. Here we report a new split of the HOM-C discovered in the species of the Drosophila repleta group, which relocated the most anterior gene of the complex, lab, to a distant chromosomal site near the two most posterior Hox genes, abd-A and Abd-B. To investigate the evolutionary consequences of natural rearrangements of the Hox gene complex, the gene lab has been cloned and sequenced in D. buzzatii, a member of the D. repleta group with the split, and in D. virilis, a member of a different species group without the split. The results show that the structure of lab in D. buzzatii is intact and place the breakpoint at least 8 kb from its transcription start site. The nucleotide sequence evolution of lab in the genus Drosophila has been investigated by means of maximum likelihood methods. No significant variation has been observed among lineages in the rate of nucleotide substitution or in the nonsynonymous/synonymous substitution ratio. Seemingly, the relocation of lab has not induced a change in evolution rate or degree of functional constraint. Nevertheless, further work is needed to ascertain whether the lab-pb split has had any effects on gene expression.

Amino Acid Sequence↗

PubMed1997

Alternative splicing of the unique "PLUS" domain of chicken PG-M/versican is developmentally regulated.

We investigated the occurrence of alternatively spliced forms (V0, V1, V2, and V3) of PG-M/versican, a large chondroitin sulfate proteoglycan in developing chicken retinas, using the reverse transcription-polymerase chain reaction. We characterized the PLUS domain, which is apparently unique to the chicken molecule and is regulated by alternative splicing. PG-M in chicken retinas consisted of four forms with (V0, V1, V2, and V3) and two forms without (V1 and V3) the PLUS domain (PG-M+ and PG-M-, respectively). The four forms of PG-M+ were found in all samples examined, but the occurrence of the two PG-M- forms was regulated developmentally. Genomic analysis has revealed that the PLUS and CS-alpha domains are encoded by a single exon, and this exon has an internal alternative 5'-splice donor site, allowing alternative spliced forms that do not include the 3'-end of the exon. Sequences corresponding to the chicken PLUS domain (plus) were not found in mouse and human and may have disappeared during evolution. Sequence similarity suggests that the PLUS domain corresponds to the keratan sulfate attachment domain of aggrecan and that it has a distinct function in the chicken eye.

Aggrecans↗

PubMed1999

Sequence variation and evolution of the mitochondrial DNA control region in the musk shrew, Suncus murinus.

The complete mitochondrial DNA (mtDNA) control region was cloned and sequenced in the musk shrew, Suncus murinus, Insectivora. The general aspect was similar to that found in other mammals. We have found in two locations of this region the presence of arrays of tandem repeats like those in other shrew species. One array was located in the left domain containing the termination-associated sequences (TAS) and the length of a copy was 77 bp. The other repeats were situated upstream from the recognition site for the end of H-strand replication in the right domain and were 20 bp long. The left halves of the control region containing the former repeats were sequenced and compared in several laboratory lines and wild animals from different localities, variations in copy number of repeated sequences were found both among individuals and within an individual. A comparative study of repeated sequences provides useful indication for the origin and evolution of tandem repeated sequences. Strand slippage and mispairing during replication of mtDNA with concerted manner is currently regarded as a dominant theory to account molecular mechanism for tandemly repeated sequences, and the pattern of sequence and length variation in our study supports this theory. Our results, however, suggest that the evolution of the repeated sequences containing the TAS in the musk shrew might go through the process of two steps; at the first step one complete repeated and several incomplete repeated sequences had reproduced in common ancestor of the shrew, and the second stage step-up of complete repeated sequences occurred with concerted evolution after differentiation into continental and insular groups.

Animals↗

PubMed1991

Nucleotide sequence, polymorphism, and evolution of ovine MHC class II DQA genes.

The nucleotide sequence of all exons and introns, excluding exon 1, of the ovine major histocompatibility complex (MhcOvar) genes analogous to the HLA-DQA1 and -DQA2 genes has been determined and the gene structure found to be similar to that reported for other species. The predicted amino acid sequences of the Ovar-DQA genes have been compared with the equivalent DQA genes in man, mouse, rat, rabbit, and cattle and used to determine the evolutionary relationships of the sheep class II genes to these other species. Northern blot analysis of sheep mRNA using exon specific probes for each of the two Ovar-DQA genes show that both genes are transcribed, whereas in humans there is no evidence that HLA-DQA2 is transcriptionally active. Restriction fragment length polymorphisms (RFLPs) have been used to define a polymorphic series of alleles in both Ovar-DQA genes and have indicated that the number of DQA genes is not constant in sheep as it is in humans, but varies with the haplotype.

Amino Acid Sequence↗

PubMed1989

String analysis and energy minimization in the partition of DNA sequences.

Two approaches to the understanding of biological sequences are confronted. While the recognition of particular signals in sequences relies on complex physical interactions, the problem is often analysed in terms of the presence or absence of literal motifs (strings) in the sequence. We present here a test-case for evaluating the potential of this approach. We classify DNA sequences as positive or negative depending on whether they contain a single melted domain in the middle of the sequence, which is a global physical property. Two sets of positive "biological" sequences were generated by a computer simulation of evolutionary divergence along the branches of a phylogenetic tree, under the constraint that each intermediate sequence be positive. These two sets and a set of random positive sequences were subjected to pattern analysis. The observed local patterns were used to construct expert systems to discriminate positive from negative sequences. The experts achieved 79% to 90% success on random positive sequences and up to 99% on the biological sets, while making less than 2% errors on negative sequences. Thus, the global constraints imposed on sequences by a physical process may generate local patterns that are sufficient to predict, with a reasonable probability, the behaviour of the sequences. However, rather large sets of biological sequences are required to generate patterns free of illegitimate constraints. Furthermore, depending upon the initial sequence, the sets of sequences generated on a phylogenetic tree may be amenable or refractory to string analysis, while obeying identical physical constraints. Our study clarifies the relationship between experts' errors on positive and negative sequences, and the contributions of legitimate and illegitimate patterns to these errors. The test-case appears suitable both for further investigations of problems in the theory of sequence evolution and for further testing of pattern analysis techniques.

Base Sequence↗

PubMed1997

Role of immunity in maternal-infant HIV-1 transmission.

Factors influencing human immunodeficiency virus type 1 (HIV-1) mother-to-child transmission include both immunological and virological parameters: higher viral loads have been associated with clinical stage of HIV-1-infected individuals as well as higher risk of mother-to-child transmission. Furthermore, we have shown that transmitting mothers more frequently harbour HIV-1 isolates with rapid/high syncytium-inducing (SI) biological phenotype than non-transmitting mothers do. Genetically homogeneous virus populations have been found in HIV-1-infected children at birth, in contrast to the heterogeneous virus populations often found in their infected mothers. This observation suggests that a few virus variants are transmitted or initially are replicating in the child. By comparing the HIV-1 gp120 V3 region of sequentially obtained samples from infected children with samples obtained from their mothers at delivery we found, however, that multiple variants of HIV-1 with different outgrowth kinetics can be transmitted. In addition, we have obtained results indicating an impaired ability of the immune response to adapt to the sequence evolution of HIV-1 in transmitting mothers, as assessed by measuring serum reactivities to peptides representing selected yet closely related V3 sequences. By analysing the presence of antibodies in maternal serum at delivery, which neutralize autologous isolates as well as other primary virus isolates, we have indications that a protective immunity in HIV-1 mother-to-child transmission might exist. Immunotherapy has been assessed in infected adult individuals by passive immunization with a variety of HIV-1-specific antibody products. Data from these studies indicated a differential response to therapy according to the stage of the disease. Active vaccine strategies, including envelope glycoproteins, pursued so far in seronegative adult subjects have shown limitations because broadly neutralizing antibodies, such as can be found in infected individuals, have not been evoked. Further investigations are therefore needed to give support for the potential use of either passive and/or active immunization for the prevention of HIV-1 mother-to-child transmission.

Female↗

PubMed1995

A maximum-likelihood approach to analyzing nonoverlapping and overlapping reading frames.

A model is presented for sequence evolution on the basis of which one can analyze combinations of noncoding, singly coding, and multiply coding regions of aligned homologous DNA sequences. It is a generalization of Kimura's (J. Mol. Evol. 16:111-120, 1980) and Li et al.'s (J. Mol. Evol. 36:96-99, 1985) transition-transversion models with selection on replacement substitutions. Based on a hierarchy of hypotheses, one will be able to estimate selection factors and transition and transversion distances for different combinations of regions ranging from many regions, each with their private set of parameters, to one set of parameters for all regions. The method is demonstrated on two aligned HIV1 retroviruses.

Amino Acid Sequence↗

PubMed2002

Integrated gene and species phylogenies from unaligned whole genome protein sequences.

MOTIVATION: Most molecular phylogenies are based on sequence alignments. Consequently, they fail to account for modes of sequence evolution that involve frequent insertions or deletions. Here we present a method for generating accurate gene and species phylogenies from whole genome sequence that makes use of short character string matches not placed within explicit alignments. In this work, the singular value decomposition of a sparse tetrapeptide frequency matrix is used to represent the proteins of organisms uniquely and precisely as vectors in a high-dimensional space. Vectors of this kind can be used to calculate pairwise distance values based on the angle separating the vectors, and the resulting distance values can be used to generate phylogenetic trees. Protein trees so derived can be examined directly for homologous sequences. Alternatively, vectors defining each of the proteins within an organism can be summed to provide a vector representation of the organism, which is then used to generate species trees. RESULTS: Using a large mitochondrial genome dataset, we have produced species trees that are largely in agreement with previously published trees based on the analysis of identical datasets using different methods. These trees also agree well with currently accepted phylogenetic theory. In principle, our method could be used to compare much larger bacterial or nuclear genomes in full molecular detail, ultimately allowing accurate gene and species relationships to be derived from a comprehensive comparison of complete genomes. In contrast to phylogenetic methods based on alignments, sequences that evolve by relative insertion or deletion would tend to remain recognizably similar.

Algorithms↗

PubMed2002

Detecting genomic features under weak selective pressure: the example of codon usage in animals and plants.

Large scale experiments of gene inactivation in yeast have shown that 50% of genes have no detectable impact on the phenotype, and similar observations have been made in other model organisms. This apparent paradox is probably due to the fact that many genes only have a marginal contribution to the fitness of organisms. Because of the size of populations and the number of generations that can be studied in laboratories, experimental approaches only permit to detect functional elements that have a strong phenotypic impact. Comparative sequence analysis can help to solve this problem: the analysis of sequences evolution permits to detect the action of selection, and hence to reveal functional features of genomes. This approach will be illustrated by the study of synonymous codon usage in animals and plants.

Animals↗

PubMed2002

GenomeHistory: a software tool and its application to fully sequenced genomes.

We present a publicly available software tool (http://www.unm.edu/~compbio/software/GenomeHistory) that identifies all pairs of duplicate genes in a genome and then determines the degree of synonymous and non-synonymous divergence between each duplicate pair. Using this tool, we analyze the relations between (i) gene function and the propensity of a gene to duplicate and (ii) the number of genes in a gene family and the family's rate of sequence evolution. We do so for the complete genomes of four eukaryotes (fission and budding yeast, fruit fly and nematode) and one prokaryote (Escherichia coli). For some classes of genes we observe a strong relationship between gene function and a gene's propensity to undergo duplication. Most notably, ribosomal genes and transcription factors appear less likely to undergo gene duplication than other genes. In both fission and budding yeast, we see a strong positive correlation between the selective constraint on a gene and the size of the gene family of which this gene is a member. In contrast, a weakly negative such correlation is seen in multicellular eukaryotes.

Animals↗

PubMed1996

Phylogenetic analysis using parsimony and likelihood methods.

The assumptions underlying the maximum-parsimony (MP) method of phylogenetic tree reconstruction were intuitively examined by studying the way the method works. Computer simulations were performed to corroborate the intuitive examination. Parsimony appears to involve very stringent assumptions concerning the process of sequence evolution, such as constancy of substitution rates between nucleotides, constancy of rates across nucleotide sites, and equal branch lengths in the tree. For practical data analysis, the requirement of equal branch lengths means similar substitution rates among lineages (the existence of an approximate molecular clock), relatively long interior branches, and also few species in the data. However, a small amount of evolution is neither a necessary nor a sufficient requirement of the method. The difficulties involved in the application of current statistical estimation theory to tree reconstruction were discussed, and it was suggested that the approach proposed by Felsenstein (1981, J. Mol. Evol. 17: 368-376) for topology estimation, as well as its many variations and extensions, differs fundamentally from the maximum likelihood estimation of a conventional statistical parameter. Evidence was presented showing that the Felsenstein approach does not share the asymptotic efficiency of the maximum likelihood estimator of a statistical parameter. Computer simulations were performed to study the probability that MP recovers the true tree under a hierarchy of models of nucleotide substitution; its performance relative to the likelihood method was especially noted. The results appeared to support the intuitive examination of the assumptions underlying MP. When a simple model of nucleotide substitution was assumed to generate data, the probability that MP recovers the true topology could be as high as, or even higher than, that for the likelihood method. When the assumed model became more complex and realistic, e.g., when substitution rates were allowed to differ between nucleotides or across sites, the probability that MP recovers the true topology, and especially its performance relative to that of the likelihood method, generally deteriorates. As the complexity of the process of nucleotide substitution in real sequences is well recognized, the likelihood method appears preferable to parsimony. However, the development of a statistical methodology for the efficient estimation of the tree topology remains a difficult open problem.

Animals↗

PubMed1995

The phylogenetic position of the pterobranch hemichordates based on 18S rDNA sequence data.

Pterobranchs are a class of deuterostome metazoans that are sessile marine suspension feeders. Although this group has been poorly studied, understanding their phylogenetic affinities is central to understanding early metazoan evolution. Sequence data from the 5' end of the 18S rDNA gene was collected from a pterobranch, Rhabdopleura normani, and combined with other available 18S sequences. Using standard phylogenetic methods, the evolutionary relationships of deuterostome metazoans were reconstructed. The pterobranchs are most closely related to the enteropneust hemichordates. This was confirmed by bootstrap analyses and a topology-dependent cladistic permutation tail probability (T-PTP) test. My analysis agrees with Turbeville et al.'s (1994) and Wada and Satoh's (1994) finding that hemichordates are more closely related to echinoderms than to chordates, and it is proposed that Metschnikoff's (1881) name Ambulacraria be adopted for the clade defined by the last common ancestor of the hemichordates and echinoderms. These findings suggest that ciliated gill slits and the dorsal hollow nerve chord are pleisomorphic features of the Deuterostomia.

Animals↗

PubMed2003

Molecular evolution of sensory domains in cyanobacterial chemoreceptors.

Components of the chemotaxis system encoded in multiple homologous operons were identified in five cyanobacterial genomes. Analysis of phylogenetic profiles, genomic context, domain architectures and sequence identity reveal that sensory modules of chemoreceptors that detect environmental cues are the subject of frequent domain birth and death events and have accelerated rates of sequence evolution. This fact could explain a remarkable diversity of the sensing repertoire of chemotaxis receptors in microorganisms.

Bacterial Proteins↗

PubMed1996

Stock structure and homing fidelity in Gulf of Mexico sturgeon (Acipenser oxyrinchus desotoi) based on restriction fragment length polymorphism and sequence analyses of mitochondrial DNA.

Efforts have been proposed worldwide to restore sturgeon populations through the use of hatcheries to supplement natural reproduction and to reintroduce sturgeon where they have become extinct. We examined the population structure and inferred the extent of homing in the anadromous Gulf of Mexico (Gulf) sturgeon (Acipenser oxyrinchus desotoi). Restriction fragment length polymorphism and control region sequence analyses of mitochondrial DNA (mtDNA) were used to identify haplotypes of Gulf sturgeon specimens obtained from eight drainages spanning the subspecies' entire distribution from Louisiana to Florida. Significant differences in haplotype frequencies indicated substantial geographic structuring of populations. A minimum of four regional or river-specific populations were identified (from west to east): (1) Pearl River, LA and Pascagoula River, MS, (2) Escambia and Yellow rivers, FI, (3) Choctawbatchee River, FL and (4) Apalachicola Ochlockonee, and Suwannee rivers, FL. Estimates of maternally mediated gene flow between any pair of the four regional or river-specific stocks ranged between 0.15 to 1.2. Tandem repeats in the mtDNA control region of Gulf sturgeon were not perfectly conserved. This result, together with an absence of heteroplasmy and length variation in Gulf sturgeon mtDNA, indicates that the molecular mechanisms of mtDNA control region sequence evolution differ among acipenserids.

Animals↗