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PubMed2005

Characterization of hypervariable region in hepatitis C virus envelope protein during acute and chronic infection.

Hepatitis C virus (HCV) causes persistent infection in most patients. To clarify the mechanisms underlying establishment of this persistent infection, nucleotide sequences of the E1/E2 region were characterized in 5 patients with acute and chronic HCV infection. We used direct DNA sequencing methods to identify the major sequence of HCV in each patient. Each HCV genome displayed a high frequency of nucleotide sequence variation in the hypervariable region (HVR) of E2. However, patient-specific conserved nucleotide sequences were identified in the E1/E2 region during the course of infection and conserved the higher-order protein structure. In the acute phase HCV infection, amino acid substitution in HVR-1 as the monthly rate of amino acids substitution per site (%) between each point exceeded 10.2%. In the chronic phase HCV infection, a significantly lower rate of amino acid substitution was observed in patients. The host immune responses to HVR-1 of each HCV isolates from all clinical courses were characterized using synthetic peptides and ELISA. One chronic patient serum (genotype 1b) did not react at all to its own HVR-1 peptides, however another patient (genotype 2b) reacted to all clinical course. These results indicated that HVR-1 might not always exhibit neutralizing epitopes of HCV infection. The sequence variation in HVR-1 may instead indicate the existence of various clones in acute phase infection and the adaption of these clones is thought to have caused persistent and chronic infection in each patient.

Acute Disease↗
PubMed1999

Linkage analysis of molecular markers and quantitative trait loci in populations of inbred backcross lines of Brassica napus L.

Backcross populations are often used to study quantitative trait loci (QTL) after they are initially discovered in balanced populations, such as F(2), BC(1), or recombinant inbreds. While the latter are more powerful for mapping marker loci, the former have the reduced background genetic variation necessary for more precise estimation of QTL effects. Many populations of inbred backcross lines (IBLs) have been developed in plant and animal systems to permit simultaneous study and dissection of quantitative genetic variation introgressed from one source to another. Such populations have a genetic structure that can be used for linkage estimation and discovery of QTL. In this study, four populations of IBLs of oilseed Brassica napus were developed and analyzed to map genomic regions from the donor parent (a winter-type cultivar) that affect agronomic traits in spring-type inbreds and hybrids. Restriction fragment length polymorphisms (RFLPs) identified among the IBLs were used to calculate two-point recombination fractions and LOD scores through grid searches. This information allowed the enrichment of a composite genetic map of B. napus with 72 new RFLP loci. The selfed and hybrid progenies of the IBLs were evaluated during two growing seasons for several agronomic traits. Both pedigree structure and map information were incorporated into the QTL analysis by using a regression approach. The number of QTL detected for each trait and the number of effective factors calculated by using biometrical methods were of similar magnitude. Populations of IBLs were shown to be valuable for both marker mapping and QTL analysis.

Brassica↗
PubMed1997

Human renin binding protein: complete genomic sequence and association of an intronic T/C polymorphism with the prorenin level in males.

The role of renin binding protein (RnBP) in human (patho)physiology, despite its biochemical characterization, is as yet unclear. RnBP has been shown to bind and inactivate renin, a key player of the blood pressure regulating renin-angiotensin system. This renders the RnBP gene a promising candidate gene in human hypertension. Herein, a molecular genetic approach was employed to investigate if RnBP might affect renin, prorenin and/or blood pressure levels. Sequencing of the human Xq28 chromosomal region provided the precise chromosomal location and full genomic sequence of the RnBP gene. All 11 exons, adjacent intronic splice sites and the promoter region were sequenced in 20 patients with essential hypertension of early onset and possible X-linked inheritance and in four normotensive individuals. The only variant found was a single base exchange polymorphism 61 base pairs upstream of the intron 6/exon 7 boundary (T61C). Several cardiovascular parameters, the renin, and prorenin levels and the T61C allele status were determined in 505 Caucasian individuals. Male individuals without medication who were hemizygous for the C allele were characterized by lower prorenin levels (196 +/- 15 versus 256 +/- 12 mU/l, P = 0.05) and a significantly higher renin/prorenin ratio (10.7 +/- 1.5 versus 7.7 +/- 0.3%, P = 0.002), whereas no variations in circulating renin, blood pressure, heart rate and left ventricular mass index were associated with the C allele. No significant association was observed in women. The data do not exclude a role of RnBP in essential hypertension. The complete genomic structure of the RnBP gene, including the identified repetitive sequence elements, provides an essential tool for further studies of the RnBP gene in hypertensive patients with a different genetic background.

Base Sequence↗
PubMed2003

G+C3 structuring along the genome: a common feature in prokaryotes.

The heterogeneity of gene nucleotide content in prokaryotic genomes is commonly interpreted as the result of three main phenomena: (1) genes undergo different selection pressures both during and after translation (affecting codon and amino acid choice); (2) genes undergo different mutational pressure whether they are on the leading or lagging strand; and (3) genes may have different phylogenetic origins as a result of lateral transfers. However, this view neglects the necessity of organizing genetic information on a chromosome that needs to be replicated and folded, which may add constraints to single gene evolution. As a consequence, genes are potentially subjected to different mutation and selection pressures, depending on their position in the genome. In this paper, we analyze the structuring of different codon usage measures along completely sequenced bacterial genomes. We show that most of them are highly structured, suggesting that genes have different base content, depending on their location on the chromosome. A peculiar pattern of genome structure, with a tendency toward an A+T-enrichment near the replication terminus, is found in most bacterial phyla and may reflect common chromosome constraints. Several species may have lost this pattern, probably because of genome rearrangements or integration of foreign DNA. We show that in several species, this enrichment is associated with an increase of evolutionary rate and we discuss the evolutionary implications of these results. We argue that structural constraints acting on the circular chromosome are not negligible and that this natural structuring of bacterial genomes may be a cause of overestimation in lateral gene transfer predictions using codon composition indices.

Base Composition↗
PubMed2005

Disparate evolution of prion protein domains and the distinct origin of Doppel- and prion-related loci revealed by fish-to-mammal comparisons.

Prions result from the misfolding and selective accumulation of the host-encoded prion protein (PrP) in the brain. Despite intensive research on mammalian models, basic questions about the biological role of PrP and the evolutionary origin of prion disease remain unanswered. Following our previous identification of novel fish PrP homologues, here we generated new fish PrP sequences and performed genomic analysis to demonstrate the existence of two homologous PrP loci in bony fish, which display extensive molecular variation and are highly expressed in adult and developing fish brains. The fish PrP genomic regions contain PrP-related loci directly downstream of each PrP locus, suggesting an independent origin of prion-related proteins in fish and mammals. Our structural prediction analysis uncovers a conserved molecular "bauplan" for all vertebrate PrPs. The C- and N-terminal protein domains have evolved independently from one another, the former having retained its basic globular structure despite high sequence divergence and the latter having undergone differential expansion-degeneration cycles in its repetitive domains. Our evolutionary analysis redefines fundamental concepts on the functional significance of PrP domains and opens up new possibilities for the experimental analysis of prion misfolding and neurodegeneration in a non-mammalian model like the zebrafish.

Amino Acid Sequence↗
PubMed2026

No evidence of fine-scale local adaptation of winter moths to variable tree phenology.

Spatial variation in plant phenology can impose strong selective pressures on herbivorous insects whose fitness relies on synchrony with host plants, promoting local adaptation to host timing. Winter moths (Operophtera brumata) have been shown to synchronize egg hatching with host budburst, but whether this reflects local adaptation remains unclear. We used three complementary approaches to assess small-scale local adaptation of winter moths to oak phenology in Wytham Woods, UK, a 385-hectare woodland with repeatable variation in individual oak budburst phenology. We experimentally investigated whether host tree phenology predicts hatch timing using common gardens across multiple temperatures, evaluated fitness benefits of synchrony using translocations, and assessed population structure and gene-environment associations using whole-genome sequencing. We found no support for local adaptation to individual trees. Common garden experiments revealed systematic differences in hatch timing which were unrelated to host budburst, while translocations indicated no fitness consequences of asynchrony. Genetic analyses showed no detectable population structure or association with budburst timing. Local adaptation to host phenology therefore appears not to arise on individual trees but may instead occur at broader spatial scales. Understanding the scale of local adaptation is essential for predicting how insect-plant synchrony will respond to environmental change across heterogeneous landscapes.

Animals↗
PubMed2001

Complete nucleotide sequence of a Staphylococcus aureus exfoliative toxin B plasmid and identification of a novel ADP-ribosyltransferase, EDIN-C.

The complete nucleotide sequence of pETB, a 38.2-kb Staphylococcus aureus plasmid encoding the exfoliative toxin B (ETB), was determined. A total of 50 open reading frames were identified on the plasmid genome and, among these, 32 showed sequence similarity to known proteins. pETB contains three copies of IS257, which divide the pETB genome into three regions: (i) a cadmium resistance operon-containing region, (ii) a lantibiotic production gene-containing region, and (iii) the remaining part where genes for plasmid replication and/or maintenance are dispersed. In the third region, genes of various kinds of functions are present among the replication- and maintenance-related genes. They include two virulence-related genes, the etb gene and a gene encoding a novel ADP-ribosyltransferase closely related to EDIN, which belongs to the C3 family of ADP-ribosyltransferases modifying Rho GTPases. They also include genes for a cell wall-anchoring surface protein and a phage resistance protein. Based on the determined sequence of pETB, the genome structures of etb-bearing plasmids (ETB plasmids) from various clinical isolates were analyzed by the PCR scanning method. The data indicate that, although the ETB plasmids are highly heterogeneous in genome size, the fundamental genome organization is well conserved. The size variation of the plasmid is mainly attributed to defined regions which may be hot spots for gene shuffling.

Amino Acid Sequence↗
PubMed2001

Resistance gene complexes: evolution and utilization.

More than 30 genes have been characterized from different plant species that provide resistance to a variety of different pathogen and pest species. The structures of most are consistent with a role in pathogen recognition and defense response signaling. Resistance genes are very abundant in plant genomes and most belong to tightly linked gene families. Evolution of R genes is driven by selection on allelic variation created by mutation and re-assorted by recombination between alleles and sometimes between different gene family members. Selection favors genes that can recognize pathogen avr gene products that are present in pathogen populations. Selection at linked gene families favors haplotypes with useful combinations of genes but a limited physiological cost to the plant. Future utilization of R genes will include transfer between related genera and identification or construction of genes that condition durable resistance to variable pathogens. Genes with durable resistance may interact with conserved pathogen elicitors or condition resistance responses that are independent of specific Avr gene interactions.

Evolution, Molecular↗
PubMed2004

Lack of interferon sensitivity-determining region in the genome of hepatitis B virus genotype Ba.

BACKGROUND/AIMS: In chronic hepatitis B, both host and viral factors may predict the response to interferon (IFN) treatment. Whether IFN sensitivity-determining regions exist within the hepatitis B virus (HBV) genomic background remains largely unknown. We therefore performed full-length viral genomic comparison between HBVs obtained from IFN responders and non-responders. METHODS: We enrolled 18 HBV genotype Ba patients who had received 24-week IFN 5 MU three times weekly and were followed monthly for 12 months post-treatment. There were 10 responders and eight non-responders. Pretreatment full-length viral nucleotide consensus sequence was obtained. In six non-responders and four responders, post-treatment viral nucleotide sequence was further compared with their corresponding pre-treatment specimens. In addition, the average number of nucleotide substitutions of the HBV quasispecies was compared between three responders and three non-responders. RESULTS: HBV nucleotide consensus sequence was identical between responders and non-responders. We found 0-15 (mean 7.7) nucleotide substitutions in the post-treatment HBV genome in the six non-responders and 0-14 (mean 3.8) nucleotide substitutions in the four responders, respectively. Genetic complexity of HBV quasispecies was comparable between responders and non-responders. CONCLUSIONS: Our results suggest that an IFN sensitivity-determining region might not exist within the genome of HBV genotype Ba. Host factors and virus-host interactions may be more important in determining the response to IFN treatment.

Adult↗
PubMed2005

Changes in alternative splicing of human and mouse genes are accompanied by faster evolution of constitutive exons.

Alternative splicing is known to be an important source of protein sequence variation, but its evolutionary impact has not been explored in detail. Studying alternative splicing requires extensive sampling of the transcriptome, but new data sets based on expressed sequence tags aligned to chromosomes make it possible to study alternative splicing on a genome-wide scale. Although genes showing alternative splicing by exon skipping are conserved as compared to the genome as a whole, we find that genes where structural differences between human and mouse result in genome-specific alternatively spliced exons in one species show almost 60% greater nonsynonymous divergence in constitutive exons than genes where exon skipping is conserved. This effect is also seen for genes showing species-specific patterns of alternative splicing where gene structure is conserved. Our observations are not attributable to an inherent difference in rate of evolution between these two sets of proteins or to differences with respect to predictors of evolutionary rate such as expression level, tissue specificity, or genetic redundancy. Where genome-specific alternatively spliced exons are seen in mammals, the vast majority of skipped exons appear to be recent additions to gene structures. Furthermore, among genes with genome-specific alternatively spliced exons, the degree of nonsynonymous divergence in constitutive sequence is a function of the frequency of incorporation of these alternative exons into transcripts. These results suggest that alterations in alternative splicing pattern can have knock-on effects in terms of accelerated sequence evolution in constant regions of the protein.

Alternative Splicing↗
PubMed2006

Molecular-genetic biodiversity in a natural population of the yeast Saccharomyces cerevisiae from "Evolution Canyon": microsatellite polymorphism, ploidy and controversial sexual status.

The yeast S. cerevisiae is a central model organism in eukaryotic cell studies and a major component in many food and biotechnological industrial processes. However, the wide knowledge regarding genetics and molecular biology of S. cerevisiae is based on an extremely narrow range of strains. Studies of natural populations of S. cerevisiae, not associated with human activities or industrial fermentation environments, are very few. We isolated a panel of S. cerevisiae strains from a natural microsite, "Evolution Canyon" at Mount Carmel, Israel, and studied their genomic biodiversity. Analysis of 19 microsatellite loci revealed high allelic diversity and variation in ploidy level across the panel, from diploids to tetraploids, confirmed by flow cytometry. No significant differences were found in the level of microsatellite variation between strains derived from the major localities or microniches, whereas strains of different ploidy showed low similarity in allele content. Maximum genetic diversity was observed among diploids and minimum among triploids. Phylogenetic analysis revealed clonal, rather than sexual, structure of the triploid and tetraploid subpopulations. Viability tests in tetrad analysis also suggest that clonal reproduction may predominate in the polyploid subpopulations.

Alleles↗
PubMed1984

Variant antigen genes of Trypanosoma brucei: genomic alteration of a spliced leader orphon and retention of expression-linked copies during differentiation.

Variant surface glycoprotein (VSG) gene expression in Trypanosoma brucei involves not only the sequential activation of individual VSG genes during mammalian bloodstream stage antigenic variation but also the regulation of gene expression during cyclic transmission through alternate mammalian and insect hosts. In the bloodstream stage, transcriptional activation of many VSG genes is correlated with the appearance of an additional copy of the gene in a novel genomic location, the expression-linked copy. The parasite loses the ability to synthesize VSG during differentiation from mammalian bloodstream to insect procyclic stage. Five different bloodstream populations were individually converted to procyclic forms. In each case, the procyclic cells retained the expression-linked copy of the bloodstream parent, and it remained in the same immediate genomic context. Transcripts homologous to the VSG structural gene exon were found in bloodstream stage RNA but not in procyclic RNA. Nevertheless, transcripts containing sequences homologous to the VSG mRNA spliced leader were abundant in both procyclic and bloodstream stage cells. When the genomic organization of sequences homologous to the VSG leader was examined, a specific alteration correlated with procylic differentiation was found. These data are discussed in light of biological studies on antigenic variation.

Animals↗
PubMed2005

Genetic lineages in the yellow fever mosquito Aedes (Stegomyia) aegypti (Diptera: Culicidae) from Peru.

The yellow fever mosquito Aedes aegypti was introduced in Peru in 1852 and was considered to be eradicated in 1958. In 2001, Ae. aegypti had been recorded in 15 out of 24 Peruvian Departments. Peru has great ecological differences between the east and west sides of Andes. Because of this, we consider that Ae. aegypti populations of both east and west sides can have a genetically distinct population structure. In this study we examined genetic variability and genealogical relationships among three Ae. aegypti Peruvian populations: Lima, Piura (west Andes), and Iquitos (east Andes) using a fragment of the ND4 gene of the mitochondrial genome. Three haplotypes were detected among 55 samples. Lima and Iquitos showed the same haplotype (Haplotype I), whereas Piura has two haplotypes (Haplotype II and III). Haplotype II is four mutational steps apart from Haplotype I, while Haplotype III is 13 mutational steps apart from Haplotype I in the network. The analysis of molecular variation showed that mostly of the detected genetic variation occurs at interpopulational level. The significant value Phi(st) suggests that Piura population is structured in relation to Lima and Iquitos populations and the gene flow of the ND4 is restricted in Piura when compared to Lima and Iquitos. Genetic relationship between haplotype I and haplotype II suggests introduction of the same mtDNA lineage into those localities. However the existence of a genetically distant haplotype III also suggests introduction of at least two Ae. aegypti lineages in Peru.

Aedes↗
PubMed1992

Human immunodeficiency virus type 1 envelope gene structure and diversity in vivo and after cocultivation in vitro.

Nested-primer polymerase chain reaction (PCR) has been applied to the molecular cloning of 4.6-kb half-genome fragments of human immunodeficiency virus type 1 (HIV-1) taken directly from the peripheral blood mononuclear cells (PBMC) of an individual with neurological symptoms of HIV-1 infection. In a similar manner, gp120-coding portions of the envelope gene were cloned after PBMC from the same blood sample were cocultivated with uninfected PBMC for 28 days. The complete 1.6-kb nucleotide sequence of the gp120 gene was determined from each of 35 clones examined. Two of 13 (15%) PBMC-derived gp120 genes and 3 of 22 (14%) coculture-derived gp120 genes were defective as a result of frameshifts and an in-frame stop codon(s). Mean diversity between individual gp120-coding sequences in PBMC was fivefold greater (3.24%) than after coculture (0.65%). A predominant sequence of "strain" was found after coculture that was distinct from the diverse viral genotypes detected in vivo and therefore was selectively amplified during in vitro propagation. Multiple distinct third variable (V3) regions encoding the principal neutralizing domain of the envelope protein were detected in PBMC-derived genes, suggesting the presence of immunologic diversity of HIV env genes in vivo not reflected in the cocultured virus sample. The large size of the HIV fragments generated in this study will permit analysis of the diversity of immunologic reactivity, gene function, and pathogenicity of HIV genomes present within infected individuals, including the functional significance of the loss of diversity that occurs upon coculture.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Population-associated differences between the phase variable LPS biosynthetic genes of Helicobacter pylori.

BACKGROUND: Population structures are normally determined using genes under minimal functional selection. In this study we have assessed genes that are not always essential, show differences in alleles between strains, and are involved in the directly host-selectable phenotype of LPS biosynthesis. RESULTS: Eight complete LPS biosynthesis genes, seven of which are associated with phase variation in some or all strains of Helicobacter pylori, have been sequenced and their divergence analyzed. The differences observed indicate that recombination within these genes largely reflects exchange between strains within the population lineages previously determined on the basis of MLST using housekeeping genes. This indicates that the differences that are used for MLST are likely to broadly associate with genes under functional selection, and differences in strain behaviour. However, instances of exchange between the subpopulations were identified, including the hpAfrica2 subpopulation. Further, there were other differences in gene complements and the chromosomal location of genes indicative of greater diversity within the population than is revealed by the available genome sequences and comparative genome hybridization studies. CONCLUSION: These results indicate that the described population structure based upon MLST is broadly a good basis for studying the biology of H. pylori, but that individual alleles may not follow these associations. As a consequence, when working in unsequenced strains, it is necessary to carefully check the presence, sequence, and distribution of any individual gene of interest.

Alleles↗
PubMed2001

Antigenic variation of Anaplasma marginale: major surface protein 2 diversity during cyclic transmission between ticks and cattle.

The rickettsial pathogen Anaplasma marginale expresses a variable immunodominant outer membrane protein, major surface protein 2 (MSP2), involved in antigenic variation and long-term persistence of the organism in carrier animals. MSP2 contains a central hypervariable region of about 100 amino acids that encodes immunogenic B-cell epitopes that induce variant-specific antibodies during infection. Previously, we have shown that MSP2 is encoded on a polycistronic mRNA transcript in erythrocyte stages of A. marginale and defined the structure of the genomic expression site for this transcript. In this study, we show that the same expression site is utilized in stages of A. marginale infecting tick salivary glands. We also analyzed the variability of this genomic expression site in Oklahoma strain A. marginale transmitted from in vitro cultures to cattle and between cattle and ticks. The structure of the expression site and flanking regions was conserved except for sequence that encoded the MSP2 hypervariable region. At least three different MSP2 variants were encoded in each A. marginale population. The major sequence variants did not change on passage of A. marginale between culture, acute erythrocyte stage infections, and tick salivary glands but did change during persistent infections of cattle. The variant types found in tick salivary glands most closely resembled those present in bovine blood at the time of acquisition of infection, whether infection was acquired from an acute or from a persistent rickettsemia. These variations in structure of an expression site for a major, immunoprotective outer membrane protein have important implications for vaccine development and for obtaining an improved understanding of the mechanisms of persistence of ehrlichial infections in humans, domestic animals, and reservoir hosts.

Anaplasma↗
PubMed1990

Repeat unit sequence variation in minisatellites: a novel source of DNA polymorphism for studying variation and mutation by single molecule analysis.

Variation in internal minisatellite structure can be analyzed by mapping variant repeat units within amplified alleles. A system capable of distinguishing greater than 10(70) allelic states at the human hypervariable locus D1S8 has been developed. Population surveys of internal allelic structure indicate that D1S8 alleles evolve rapidly along haploid chromosome lineages. Internal mapping of deletion mutant alleles physically selected from genomic DNA provides further evidence that germline and somatic mutations altering the number of allelic repeat units seldom if ever arise by unequal exchange between alleles. The existence of low level germline mosaicism for new mutants further indicates that many germline mutation events are premeiotic. Physical selection of new mutants also allows minisatellite mutation rates to be estimated directly in human DNA.

Alleles↗