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PubMed1996

Hamming chromatography.

Selection of molecules with desired properties from random pools of biopolymers has become a powerful tool in biotechnology. On designing an evolution experiment, a certain knowledge of the concomitant fitness landscape is clearly helpful to set up the optimal experimental conditions. The correlation function is a useful means of characterizing a given landscape, since it can be efficiently measured if one has a method of separating a pool of random sequences according to their Hamming distance from a moderately small number of test sequences. In this paper we describe a special type of hybridization chromatography, where a mixture of oligomers (partially) complementary to a given test sequence is hybridized to the test sequence, covalently bound to a matrix. DNA oligomers are eluted in an 'effective temperature gradient' using conditions that minimize the differences of effects of GC versus AT pairs on the melting temperatures. This method should be a means to quickly separate error classes and thus be the crucial step in characterizing fitness landscapes of biopolymers through an experimental approach. It would also be a useful tool to design sequence pools with a bias towards desired mutant spectra.

Bacteriophage T7↗
PubMed1982

Evolutionary selection for perfect hairpin structures in viral DNAs.

Several recent discoveries have pointed to nucleic acid secondary structure as an additional dimension in gene expression. Further evidence for the formation of hairpins in RNA is the fact that cruciforms exist in negatively supercoiled DNAs. As potential binding sites for proteins, these structures have been proposed to play a part in the regulation of various crucial reactions, such as replication, transcription, or RNA processing. As any random nucleotide sequence can self-anneal with an approximately 50% chance of forming some Watson-Crick-type base pairs, it is difficult to assess which, if any, of all possible hairpin-like secondary structures may be biologically relevant. We have computed the expected distribution of perfectly base-paired structures as a function of loop size and stem length and compared it with the distribution observed in the complete genome of eight DNA viruses from animals, plants and bacteria. We report here that hairpins having six or more consecutive base pairs in the stem are not distributed randomly long the genome, occur much more often than chance would predict, and are particularly over-represented in regions that appear to have regulatory significance. The average loop size was found to decrease with an increase in stem length. These results support our previous hypothesis that these structures are biologically relevant.

Bacteriophages↗
PubMed2006

Different papillomaviruses have different repertoires of transcription factor binding sites: convergence and divergence in the upstream regulatory region.

BACKGROUND: Papillomaviruses (PVs) infect stratified squamous epithelia in warm-blooded vertebrates and have undergone a complex evolutionary process. The control of the expression of the early ORFs in PVs depends on the binding of cellular and viral transcription factors to the upstream regulatory region (URR) of the virus. It is believed that there is a core of transcription factor binding sites (TFBS) common to all PVs, with additional individual differences, although most of the available information focuses only on a handful of viruses. RESULTS: We have studied the URR of sixty-one PVs, covering twenty different hosts. We have predicted the TFBS present in the URR and analysed these results by principal component analysis and genetic algorithms. The number and nature of TFBS in the URR might be much broader than thus far described, and different PVs have different repertoires of TFBS. CONCLUSION: There are common fingerprints in the URR in PVs that infect primates, although the ancestors of these viruses diverged a long time ago. Additionally, there are obvious differences between the URR of alpha and beta PVs, despite these PVs infect similar histological cell types in the same host, i.e. human. A thorough analysis of the TFBS in the URR might provide crucial information about the differential biology of cancer-associated PVs.

Binding Sites↗
PubMed1999

Biased nucleotide composition of the genome of HERV-K related endogenous retroviruses and its evolutionary implications.

The human genome contains a large number of sequences that belong to the HERV-K family of human endogenous retroviruses. Most of these elements are likely remnants of ancient infections by ancestral exogenous retroviruses. To obtain further insight into the evolutionary history and molecular mechanisms responsible for the diversity of the human HERV-K elements, we analyzed several aspects of their genome structure. The nucleotide composition of the HERV-K genome was found to be highly biased and asymmetric, with an abundance of the A nucleotide in the viral (+) strand. A similar trend has been reported for the genomes of several exogenous retroviruses, with different nucleotides as the preferred building block. Other genome characteristics that were reported previously for actively replicating retroviruses are also apparent for the endogenous HERV-K virus. In particular, we observed suppression of the dinucleotide CpG, which represents potential methylation sites, and a strong preference for synonymous substitutions within the open reading frame of the reverse transcriptase (RT) enzyme. Furthermore, the mutational spectrum of the HERV-K RT enzyme was evaluated by nucleotide sequence comparison of 34 available elements. Interestingly, this analysis revealed a striking similarity with the mutational pattern of the HIV-1 RT enzyme, with a preference for G-to-A and C-to-T transitions. It is proposed that the mutational bias of the HERV-K RT enzyme played a role in the shaping of this retroviral genome, which was actively replicating more than 30 million years ago. This effect can still be observed in the contemporary endogenous HERV-K elements.

Base Composition↗
PubMed1991

Equine arteritis virus is not a togavirus but belongs to the coronaviruslike superfamily.

The nucleotide sequence of the genome of equine arteritis virus (EAV) was determined from a set of overlapping cDNA clones and was found to contain eight open reading frames (ORFs). ORFs 2 through 7 are expressed from six 3'-coterminal subgenomic mRNAs, which are transcribed from the 3'-terminal quarter of the viral genome. A number of these ORFs are predicted to encode structural EAV proteins. The organization and expression of the 3' part of the EAV genome are remarkably similar to those of coronaviruses and toroviruses. The 5'-terminal three-quarters of the genome contain the putative EAV polymerase gene, which also shares a number of features with the corresponding gene of corona- and toroviruses. The gene contains two large ORFs, ORF1a and ORF1b, with an overlap region of 19 nucleotides. The presence of a "shifty" heptanucleotide sequence in this region and a downstream RNA pseudoknot structure indicate that ORF1b is probably expressed by ribosomal frameshifting. The frameshift-directing potential of the ORF1a/ORF1b overlap region was demonstrated by using a reporter gene. Moreover, the predicted ORF1b product was found to contain four domains which have been identified in the same relative positions in coronavirus and torovirus ORF1b products. The sequences of the EAV and coronavirus ORF1a proteins were found to be much more diverged. The EAV ORF1a product contains a putative trypsinlike serine protease motif. Our data indicate that EAV, presently considered a togavirus, is evolutionarily related to viruses from the coronaviruslike superfamily.

Amino Acid Sequence↗
PubMed2004

Virological effects of ISIS 14803, an antisense oligonucleotide inhibitor of hepatitis C virus (HCV) internal ribosome entry site (IRES), on HCV IRES in chronic hepatitis C patients and examination of the potential role of primary and secondary HCV resistance in the outcome of treatment.

Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.

5' Untranslated Regions↗
PubMed1996

Search for ancient patterns in protein sequences.

Proteins of related functions are often similar in sequence, reflecting a common phylogenetic origin. Proteins with no known homology are probably diversified proteins, too distantly related to known sequences in databases to retain significant similarity. All proteins, however, probably share common ancestries if one moves far enough back in evolution; therefore, given the huge accumulation of protein sequences in current databases, it could be expected that some proteins with no obvious sequence resemblance to any other share some residues that could represent footprints of ancient common ancestries. To identify such putative footprints, we have searched for short stretches of amino acids present in a given protein sequence that are also found in a significant number of nonrelated proteins in the database. The significantly high frequency of occurrence of these "patterns" in the database would support a common evolutionary source, and a diversity of non-related proteins that contain the pattern would express their ancient origin. Using this strategy, significant patterns were found in actual exons, but not in randomized amino acid sequences, nor in "translated" sequences of noncoding DNA, suggesting that this strategy actually leads to the identification of patterns with a biological significance. These significant patterns are not randomly positioned along the sequences analyzed, but they tend to accumulate within specific regions, producing a profile of discrete "domains." In some well-known proteins analyzed in this study, some of these domains are coincident with known motifs. Thus, the procedure described in this paper could be useful for identifying ancient patterns and domains in protein sequences, some of which could also have a functional or structural significance.

Amino Acid Sequence↗
PubMed2005

Paleogenomic record of the extinction of human endogenous retrovirus ERV9.

An outstanding question of genome evolution is what stops the invasion of a host genome by transposable elements (TEs). The human genome, harboring the remnants of many extinct TE families, offers an extraordinary opportunity to investigate this problem. ERV9 is an endogenous retrovirus repeatedly mobilized during primate evolution, 15 to 6 million years ago (MYA), which left a trace of over a hundred provirus-like copies and at least 4,000 solitary long terminal repeats (LTRs) in the human genome. Then, its proliferation ceased for unknown reasons, and the family went extinct. We have made a detailed reconstruction of its last active subfamily, ERV9_XII, by examining 115 solitary LTRs from it. These insertions were grouped into 11 sets according to shared nucleotide variants, which could be placed in a sequential order of 10 to 6 MYA. At least 75% of the subfamily was produced 8 to 6 MYA, during a stage of intense proliferation. With new analytical tools, we show that the youngest and most prolific sets may have been produced by effectively instantaneous expansions of corresponding single-sequence variants. The extinction of this family apparently was not a consequence of its slow gradual degeneration, but the outcome of the fixation of specific restrictive alleles in the human-chimpanzee ancestral population. Three species-specific insertions (two in humans and one in chimpanzees) were identified, further supporting that extinction took place when these two species were beginning to diverge. These are the only fixed differences of this kind so far observed between humans and chimpanzees, apart from those belonging to the human endogenous retrovirus K family.

Animals↗
PubMed2005

Characterization of the 1918 influenza virus polymerase genes.

The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors, thereby having a role in host specificity. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.

Adaptation, Physiological↗
PubMed2026

HLA class I escape drives the evolution of SARS-CoV-2 in human populations.

The role of escape from the cytotoxic T cell (CTL) response in Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) evolution remains controversial. Here, we study the origin and spread of SARS-CoV-2 variants whose mutations reduce presentation by the human leukocyte antigen (HLA) class I alleles common in human populations. We find that 35% of mutations that are characteristic of the variants of concern, and 39% of all subsequent viral mutations, facilitate escape of viral epitopes from presentation. Mutations allowing escape from more common HLA alleles reach higher frequencies, particularly in those countries where these HLA alleles are more frequent, indicating that escape is selected by the local genetic composition of the human host population. We also show that viral mutations that accumulated in general-population transmission chains matched population HLA class I allele frequencies as well as, or better than, mutations acquired during persistent infections, suggesting that selection in favor of escape mutations is not limited to immunocompromised individuals. Together, these data reveal CTL escape as a facet of selection, a driver of evolution, and an epidemiological concern for SARS-CoV-2.

Humans↗
PubMed1995

Evolution of subgroup A respiratory syncytial virus: evidence for progressive accumulation of amino acid changes in the attachment protein.

The variability of the attachment (G) proteins of 48 subgroup A isolates of respiratory syncytial virus (RSV) isolated over 38 years has been examined. Nucleotide sequences of two variable regions of the G protein genes were determined following amplification by PCR. The isolates showed temporal rather than geographical clustering, and there was evidence for progressive accumulation of amino acid changes at an average rate of approximately 0.25% per year estimated over the entire protein. The cocirculation of lineages of RSV at present appears to be the result of a process of evolution and survival of particular genotypes and the extinction of others. Analysis of reactivity of the isolates with monoclonal antibodies showed that their antigenic profiles closely paralleled their relatedness by nucleotide sequence, suggesting that antigenic drift due to immune selection may be occurring.

Amino Acid Sequence↗
PubMed2006

Combinatorial engineering of a gene therapy vector: directed evolution of adeno-associated virus.

BACKGROUND: Viruses are being exploited as vectors to deliver therapeutic genetic information into target cells. The success of this approach will depend on the ability to overcome current limitations, especially in terms of safety and efficiency, through molecular engineering of the viral particles. METHODS: Here we show that in vitro directed evolution can be successfully performed to randomize the viral capsid by error prone PCR and to obtain mutants with improved phenotype. RESULTS: To demonstrate the potential of this technology we selected several adeno-associated virus (AAV) capsid variants that are less efficiently neutralized by human antibodies. These mutations can be used to generate novel vectors for the treatment of patients with pre-existing immunity to AAV. CONCLUSIONS: Our results demonstrate that combinatorial engineering overcomes the limitations of rational design approaches posed by incomplete understanding of the infectious process and at the same time offers a powerful tool to dissect basic viral biology by reverse genetics.

Amino Acid Sequence↗
PubMed1991

Neutralization-resistant antigenic variants of caprine arthritis-encephalitis lentivirus associated with progressive arthritis.

Fifteen newborn Saanen goats were orally infected with a biologically cloned isolate of caprine arthritis-encephalitis virus (CAEV-63). At 33.5 months after infection, 8 of 12 seropositive goats had CAEV-63-specific neutralizing antibody. Five neutralization-positive goats developed clinically apparent arthritis of carpal joints, three of which had periarticular swelling indicating severe synovitis. Arthritis was not evident in age-matched controls or infected goats without neutralizing antibody. Multiple viral isolates were obtained from synovial fluid or synovial fluid cells of arthritic joints between 36.4 and 44.9 months after infection, and successive isolates from individual joints were defined as antigenic variants expressing type-specific neutralization epitopes. Thus, the evolution of neutralizing antibody does not arrest viral replication or development of progressive inflammatory lesions. Rather, some antigenic variants produced in the presence of neutralizing antibody are clonally expanded within carpal joints, and severe joint inflammation is specifically associated with these variants.

Animals↗
PubMed1986

Relationship between antibody titres against human cytomegalovirus detected by enzyme immunoassay and titres to individual viral polypeptides studied by immunoblotting.

Several sera with different IgG and IgM titres measured by enzyme immunoassay were studied in serial dilutions for their reactivity with human Cytomegalovirus structural polypeptides separated in SDS-PAGE and electrotransferred to nitrocellulose. The different immunogenicity of the viral proteins is documented and a hypothetical evolution of the humoral immune response to individual polypeptides is presented.

Antibodies, Viral↗
PubMedDate not supplied

Growth and progression of head and neck cancer: a report of the Upper Aerodigestive Cancer Task Force Workshop.

Factors governing the initiation, growth, and progression of squamous cell carcinoma were the focus of a recent Upper Aerodigestive Cancer Task Force workshop sponsored by the National Cancer Institute. The goal of the daylong workshop was to identify critical research concepts in head and neck cancer biology. Discussed were the multistep processes potentially involved in tumor evolution, including the role of carcinogens, viral promotors, host and tumor karyotypes, microenvironment growth factors and growth factor receptors, as well as host/tumor components inherent to the metastatic process. Concepts developed from research in other neoplastic processes but potentially relevant to head and neck cancer were emphasized. The process of identifying critical research directions is the first step by the National Cancer Institute in program development designed to advance the treatment of head and neck cancer.

Carcinogens↗
PubMed2002

Divergent evolution of hemagglutinin and neuraminidase genes in recent influenza A:H3N2 viruses isolated in Canada.

Limited information is available concerning the molecular drift of the influenza neuraminidase (NA) genes. We report on the genetic variability of the NA gene from 31 influenza A:H3N2 viruses isolated in the Province of Québec (Canada) during the last three flu seasons (1997-2000). Amino acid substitutions within the NA protein were observed at rates of 1.01% and 0.45% between strains of the 1997-1998 and 1998-1999 seasons and between those of the 1998-1999 and 1999-2000 seasons, respectively. In most strains (28/31), amino acid changes occurred within at least one of four codons (197, 339, 370, and 401) previously implicated as antigenic sites. The 8 functional and 10 framework residues that compose the catalytic site of the NA enzyme were completely conserved over the study period. All isolates contained the seven conserved asparagine-linked glycosylation sites found in the NA of the progenitor A/Hong Kong/8/68 strain. In addition, most strains (30/31) had an eighth potential glycosylation site at position 329, whereas a ninth one was found at position 93 in 16 strains. The NA of all strains in this study was related to that of the vaccine strain A/Beijing/353/89, whereas the HA genes of these strains were related to the A/Beijing/32/92 vaccine strain. Thus, it appears that recent influenza strains continue to evolve from a reassortant produced during the cocirculation of the two above variants. Interestingly, some strains whose HA genes were closely related showed significant differences in their NA genes and conversely. This study confirms the importance of analyzing both the NA and the HA genes to assess the evolution of recent influenza epidemic strains.

Canada↗
PubMed2003

Genetic characterisation of a Hantavirus isolated from a laboratory-acquired infection.

Seoul (SEO) viruses belong to the Hantavirus genus (family Bunyaviridae), cause the moderate form of haemorrhagic fever with renal syndrome, and have been associated with laboratory-acquired infections in many countries. To investigate the pedigree of an isolate, designated IR461, which was obtained from a laboratory-acquired infection in a UK research institute, we determined the nucleotide sequences of the small (S) and medium (M) genome segments. In addition, we determined the sequences of the S segments of two Chinese isolates (R22 and L99) and an American isolate (Tchoupitoulas [TCH]). The S segments range within 1769-1785 nucleotides in length and showed identities of >88% in nucleotide sequence and 97% in amino acid sequence to those of published S segment sequences. The M RNA segment of IR461 is 3651 nucleotides long and shows >84% identity at the nucleotide level and >98% at the amino acid level to the M segments of other SEO viruses. These data confirm that SEO viruses show the least diversity within the Hantavirus genus. Phylogenetic analyses of the sequences showed geographic clustering of the Chinese SEO viruses, and that IR461 was more closely related to SEO viruses isolated in the New World than to those from the Far East.

China↗