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PubMed2006

Differential evidence of natural selection on two leading sporozoite stage malaria vaccine candidate antigens.

Experimental malaria vaccines based on two sporozoite stage candidate antigens of Plasmodium falciparum, the circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP), have undergone clinical trials of efficacy. The relevance of naturally existing polymorphism in these molecules remains unknown. Sequence polymorphism in the genes encoding these antigens was studied in a Gambian population (sample of 48 trap and 44 csp gene sequences) to test for signatures of selection that would result from naturally acquired immunity. Allele frequency distributions were analyzed and compared with data from another population (in Thailand). Patterns of non-synonymous and synonymous polymorphism in P. falciparum and in Plasmodium vivax were compared with divergence from related species. Results indicate that polymorphism in TRAP is under strong selection for amino acid sequence diversity and that allele frequencies are under balancing selection within the Gambian P. falciparum population. There was no such evidence for CSP, calling into question the idea that most polymorphisms in this gene are under immune selection. There was a weak trend for regions known to encode T cell epitopes to have slightly higher indices suggesting balancing selection. Overall, the results predict more allele-specific immunity to TRAP than to CSP and should be considered in design and efficacy testing of vaccine candidates based on these antigens.

Amino Acid Sequence↗
PubMed2005

Diversification before the most recent glaciation in Balanus glandula.

A deep genetic cline between southern populations of the barnacle Balanus glandula (from about Monterey Bay southward) and northern populations (from northern California through Alaska) has recently been described. If this pattern is due to historical isolation and genetic drift, we expect it to have formed recently and represent a transient, nonequilibrium state. However, this cline appears to have formed well before the last glacial maximum. Our assays of sequence diversity at a region of mitochondrial cytochrome oxidase I, combined with coalescent estimators of the time of separation for these two regions, suggest that a late Pleistocene event more than 100 thousand years ago may be responsible for the initial separation. This suggests that either strong oceanographic mechanisms or natural selection have maintained the cline, because there has clearly been adequate time for this cline or polymorphism to resolve itself by genetic drift and migration. However, reliance on only a single mitochondrial marker for which the substitution rate has been estimated still limits the resolution of our analysis.

Animals↗
PubMed1994

Extreme population structuring in the threatened ghost bat, Macroderma gigas: evidence from mitochondrial DNA.

The ghost bat, Macroderma gigas, has undergone a major range contraction and is currently restricted around a few, highly disjunct maternity sites. The amount and distribution of mitochondrial DNA (mtDNA) variation within extant populations has been used to assess levels of current and historical maternal gene flow between these populations. An approximately 330 base pair fragment spanning a hypervariable area of the mtDNA control region was amplified and sequenced by using 22 individuals from four current ghost bat populations. The mean sequence diversity of 4.5% between populations was six times higher than that within populations (0.68%), and alleles within populations were monophyletic. Restriction enzyme analysis of amplified products from an additional 100 individuals revealed fixed allelic differences in the distribution of control region genotypes between the four populations. It is suggested that this extreme genetic subdivision is a consequence of long-term female philopatry. For the purposes of management each population should be treated as an independent entity. The depth of the genetic structuring suggests that the isolation of extant populations preceded the historical range contraction.

Alleles↗
PubMed2006

The genetic structure of Australasian green turtles (Chelonia mydas): exploring the geographical scale of genetic exchange.

Ecological and genetic studies of marine turtles generally support the hypothesis of natal homing, but leave open the question of the geographical scale of genetic exchange and the capacity of turtles to shift breeding sites. Here we combine analyses of mitochondrial DNA (mtDNA) variation and recapture data to assess the geographical scale of individual breeding populations and the distribution of such populations through Australasia. We conducted multiscale assessments of mtDNA variation among 714 samples from 27 green turtle rookeries and of adult female dispersal among nesting sites in eastern Australia. Many of these rookeries are on shelves that were flooded by rising sea levels less than 10 000 years (c. 450 generations) ago. Analyses of sequence variation among the mtDNA control region revealed 25 haplotypes, and their frequency distributions indicated 17 genetically distinct breeding stocks (Management Units) consisting either of individual rookeries or groups of rookeries in general that are separated by more than 500 km. The population structure inferred from mtDNA was consistent with the scale of movements observed in long-term mark-recapture studies of east Australian rookeries. Phylogenetic analysis of the haplotypes revealed five clades with significant partitioning of sequence diversity (Phi = 68.4) between Pacific Ocean and Southeast Asian/Indian Ocean rookeries. Isolation by distance was indicated for rookeries separated by up to 2000 km but explained only 12% of the genetic structure. The emerging general picture is one of dynamic population structure influenced by the capacity of females to relocate among proximal breeding sites, although this may be conditional on large population sizes as existed historically across this region.

Animal Migration↗
PubMed2004

Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon- alpha.

Treatment of hepatitis C virus (HCV) infection with interferon (IFN)- alpha and ribavirin combination therapy results in superior clinical antiviral responses than does monotherapy with IFN. To explore the virological basis of the effects of combination therapy, we analyzed the effects of IFN- alpha and ribavirin, singly and in combination, on intracellular HCV replication by use of an HCV replicon system. A new replicon that expressed a selectable chimeric reporter protein comprising firefly luciferase and neomycin phosphotransferase was constructed. The replicon was highly sensitive to IFN-alpha (50% inhibitory concentration [IC(50)], 0.5 U/mL). Therapy with ribavirin showed weak suppression of HCV replication at a lower concentration (IC(50), 126 mu mol/L). The nucleotide sequence diversity of the replicon was increased significantly by therapy with ribavirin, suggesting that error-prone HCV replication was induced by the drug. Importantly, use of a clinically achievable concentration of ribavirin (approximately 10 mu mol/L) in combination with IFN showed strong synergistic inhibitory effects on HCV replication. Our results suggest that the direct effects of ribavirin on the genetic stability of the HCV subgenome and its synergistic action combined, with IFN-alpha, may explain the improved clinical responses to combination therapy.

Amino Acid Sequence↗
PubMed2004

Analysis of the S-locus structure in Prunus armeniaca L. Identification of S-haplotype specific S-RNase and F-box genes.

The gametophytic self-incompatibility (GSI) system in Rosaceae has been proposed to be controlled by two genes located in the S -locusan S-RNase and a recently described pollen expressed S -haplotype specific F-box gene (SFB). However, in apricot (Prunus armeniaca L.) these genes had not been identified yet. We have sequenced 21 kb in total of the S -locus region in 3 different apricot S -haplotypes. These fragments contain genes homologous to the S-RNase and F-box genes found in other Prunus species, preserving their basic gene structure features and defined amino acid domains. The physical distance between the F-box and the S-RNase genes was determined exactly in the S2-haplotype (2.9 kb) and inferred approximately in the S 1-haplotype (< 49 kb) confirming that these genes are linked. Sequence analysis of the 5' flanking regions indicates the presence of a conserved region upstream of the putative TATA box in the S-RNase gene. The three identified S-RNase alleles (S1, S2 and S4) had a high allelic sequence diversity (75.3 amino acid identity), and the apricot F-box allelic variants (SFB1, SFB2 and SFB4) were also highly haplotype-specific (79.4 amino acid identity). Organ specific-expression was also studied, revealing that S1- and S2-RNases are expressed in style tissues, but not in pollen or leaves. In contrast, SFB1 and SFB2 are only expressed in pollen, but not in styles or leaves. Taken together, these results support these genes as candidates for the pistil and pollen S-determinants of GSI in apricot.

5' Flanking Region↗
PubMed2002

Heterogeneity of linkage disequilibrium in human genes has implications for association studies of common diseases.

Linkage disequilibrium (LD) is the central concept of genetic association studies. Although LD has been shown not to be uniformly distributed across the genome, limited information is available about the characteristics of LD within candidate genes at large. We screened coding and regulatory regions of 50 candidate genes for cardiovascular diseases and identified 228 polymorphisms. The overall sequence diversity was 3.81 +/- 0.31 x 10(-4). Intragenic LD was generally very strong, with 40% of the 464 pairs of polymorphisms exhibiting a complete LD. However, if we consider /D'/ = 0.7 as an arbitrary limit for useful LD in association studies, 26% of the pairs fell below this threshold, half of which being in negative LD, a situation where LD is even more difficult to detect. Non-synonymous coding polymorphisms, which are more likely to have a functional role, were more represented among low-frequency alleles and were more often in complete negative LD with other polymorphisms. This implies that in many situations the power to detect the effect of a non-synonymous polymorphism by measuring a nearby marker might be low. Although intragenic LD was partly a function of physical distance, gene-specific patterns of LD were observed, making it difficult to provide general guidelines for selecting the most useful polymorphisms in association studies. For all these reasons, association studies should concentrate on the overall sequence variation of functionally important regions of candidate genes and not only on a few polymorphisms. The variability of important intergenic regions identified by different approaches including comparative genomics will also have to be assessed.

Cardiovascular Diseases↗
PubMed2001

Splice isoforms of ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in human brain.

In human brain we were able to demonstrate sequence diversity of the ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). Six different isoforms of PFK-2/FBPase-2, two of which are identical with the ubiquitous PFK-2/FBPase-2 and the inducible PFK-2, respectively, could be identified. The heterogeneity of human brain PFK-2/FBPase-2 isoforms is generated by alternative splicing. Three hitherto unrecognized exons were detected. The multiple PFK-2/FBPase-2 transcripts encode proteins which differ with respect to their length and to the amino acid composition of the carboxyl-termini. The isoform pattern of ubiquitous PFK-2/FBPase-2 is more complex in human brain than in skeletal muscle and liver.

Alternative Splicing↗
PubMed2006

Histone H3 variants in male gametic cells of lily and H3 methylation in mature pollen.

Histones are vital structural proteins of chromatin that influence its dynamics and function. The tissue-specific expression of histone variants has been shown to regulate the expression of specific genes and genomic stability in animal systems. Here we report on the characterization of five histone H3 variants expressed in Lilium generative cell. The gcH3 and leH3 variants show unique sequence diversity by lacking a conserved lysine residue at position 9 (H3K9). The gH3 shares conserved structural features with centromeric H3 of Arabidopsis. The gH3 variant gene is strongly expressed in generative cells and gH3 histone is incorporated in to generative cell chromatin. The lysine residue of H3 at position 4 (H3K4) is highly methylated in the nuclei of generative cells of mature pollen, while methylation of H3K4 is low in vegetative cell nuclei. Taken together, these results suggest that male gametic cells of Lilium have unique chromatin state and histone H3 variants and their methylation might be involved in gene regulation of male gametic cells.

Amino Acid Sequence↗
PubMed1990

A defect in mismatch repair in Saccharomyces cerevisiae stimulates ectopic recombination between homeologous genes by an excision repair dependent process.

Null mutations in three recombination and DNA repair genes were studied to determine their effects on mitotic recombination between the duplicate AdoMet (S-adenosylmethionine) synthetase genes (SAM1 and SAM2) in Saccharomyces cerevisiae. SAM1 and SAM2, located on chromosomes XII and IV, respectively, encode functionally equivalent although differentially regulated AdoMet synthetases. These similar but not identical (homeologous) genes are 83% homologous at the nucleotide level and this identity is limited solely to the coding regions of the genes. Single frameshift mutations were introduced into the 5' end of SAM1 and the 3' end of SAM2 by restriction site ablation. The sequences surrounding these mutations differ significantly in their degree of homology to the corresponding area of the other gene. Mitotic ectopic recombination between the mutant sam genes occurs at a rate of 8.4 x 10(-9) in a wild-type genetic background. Gene conversion of the marker within the region of greater sequence homology occurs 20-fold more frequently than conversion of the marker within the region of relative sequence diversity. The relative orientation of the two genes prevents the recovery of translocations. Mitotic recombination between the sam genes is completely dependent on the DNA repair and recombination gene RAD52. A mutation in PMS1, a mismatch repair gene, causes a 4.5-fold increase in the rate of ectopic recombination. RAD1, an excision repair gene, is required to observe this increased rate of ectopic conversion. In addition, RAD1 is involved in modulating the pattern of coconversion during recombination between the homeologous sam genes. These results suggest that interactions between mismatch repair, excision repair and recombinational repair functions are involved in determining the ectopic gene conversion frequency between the sam genes.

Base Sequence↗
PubMed1999

Reduced sequence variability on the Neo-Y chromosome of Drosophila americana americana.

Sex chromosomes are generally morphologically and functionally distinct, but the evolutionary forces that cause this differentiation are poorly understood. Drosophila americana americana was used in this study to examine one aspect of sex chromosome evolution, the degeneration of nonrecombining Y chromosomes. The primary X chromosome of D. a. americana is fused with a chromosomal element that was ancestrally an autosome, causing this homologous chromosomal pair to segregate with the sex chromosomes. Sequence variation at the Alcohol Dehydrogenase (Adh) gene was used to determine the pattern of nucleotide variation on the neo-sex chromosomes in natural populations. Sequences of Adh were obtained for neo-X and neo-Y chromosomes of D. a. americana, and for Adh of D. a. texana, in which it is autosomal. No significant sequence differentiation is present between the neo-X and neo-Y chromosomes of D. a. americana or the autosomes of D. a. texana. There is a significantly lower level of sequence diversity on the neo-Y chromosome relative to the neo-X in D. a. americana. This reduction in variability on the neo-Y does not appear to have resulted from a selective sweep. Coalescent simulations of the evolutionary transition of an autosome into a Y chromosome indicate there may be a low level of recombination between the neo-X and neo-Y alleles of Adh and that the effective population size of this chromosome may have been reduced below the expected value of 25% of the autosomal effective size, possibly because of the effects of background selection or sexual selection.

Alcohol Dehydrogenase↗
PubMed1996

Human immunodeficiency virus type 1 molecular evolution and the measure of selection.

Human immunodeficiency virus (HIV) envelope genes are highly variable between and often within individuals. Part of this variability is thought to be the result of immune-mediated positive selection for sequence diversity. To measure positive selection it has become customary in HIV research to calculate the ratio of the proportions of synonymous (ds) and nonsynonymous (dn) substitutions per potential synonymous or nonsynonymous site, respectively. However, another measure that can be used is the difference between ds and dn, delta d. We show, by example, that using the ratio, ds/dn, or the difference, delta d, may lead us to different conclusions regarding the existence of positive selection pressure. We conclude by noting that until we understand the processes that mediate nucleotide variation in a host selective environment, inferences based on summary statistics characterizing types of nucleotide substitutions should be made with caution.

Base Sequence↗
PubMed1996

Independent evolution of the env and pol genes of HIV-1 during zidovudine therapy.

OBJECTIVE: To determine the effect that selection for antiviral resistance in the HIV-1 pol gene has on the level of variation and pattern of evolution in the V3 region of env. DESIGN: Proviral genomes obtained from two patients before, during and after the termination of zidovudine (ZDV) therapy (approximately 2 years) were amplified and sequenced in pol and env, and the evolution of the V3 hypervariable region compared with that of the reverse transcriptase domain of pol. METHODS: Gene fragments were polymerase chain reaction-amplified from patients' peripheral blood mononuclear cells. Nucleotide sequencing was carried out using T7 DNA polymerase and dye-labelled terminators on an automated DNA sequencer. Sequences were analysed using maximum likelihood phylogenetic techniques. RESULTS: Both patients showed multiple resistance-associated mutations after 1 year of ZDV therapy. Sequence diversity in V3 showed no reduction during the period of treatment. Substantial change continued to occur in this region and multiple lineages were present in both patients, in contrast to the single lineage observed in the pol gene of one (patient 74), a difference confirmed by likelihood ratio tests. CONCLUSIONS: There is no evidence from this study that selection due to antivirals has any significant impact on the evolution of the env gene. The independence in the evolution of these genes implies that recombination was occurring between the two genes during the study period. Such independent evolution should be allowed for in developing strategies for HIV therapy involving multiple target genes.

Amino Acid Sequence↗
PubMed2005

Genetic heterogeneity of the hypervariable region I of Hepatitis C virus and lymphoproliferative disorders.

B-cell lymphoproliferative disorders (BCLD) have been associated with chronic hepatitis C virus (HCV) infection. The HCV glycoprotein E2 (gpE2) hypervariable region I (HVR-I) may be a potential antigenic candidate to promote B-cell proliferation. The purpose of this study was to analyze the influence of HVR-I sequence variability in the development of BCLD. HVR-I sequences were studied in 29 chronically HCV-infected patients with (n=15) or without (n=14) BCLD. After PCR amplification of the gpE2 region, analysis of the 81 bp HVR-I encoding fragment was performed on 7-18 clones per patient. HVR-I sequence complexity was slightly lower in patients with BCLD (mean 0.347) than without (0.468) (P=0.2), though, sequence diversities were similar (0.0370 vs 0.0954, P=0.239). Phylogenetic analysis did not reveal any BCLD-associated clustering. In our population, neither the recently described insertion between positions 1 and 2 of HVR-I nor residues at positions 4 and 13 were particularly linked to BCLD. As previously described, we confirm the high degree of conservation of HVR-I residues T-2, G-6 and G-23 in our patients. Contrary to recent findings, our analysis based on multiple clones per patient analysis did not reveal any particular motif associated with BCLD.

Adult↗
PubMed2001

Immunologic and virologic analyses of an acutely HIV type 1-infected patient with extremely rapid disease progression.

The immunologic and virologic factors that impact on the rate of disease progression after acute infection with human immunodeficiency virus (HIV) type 1 are poorly understood. A patient with an extraordinarily rapid disease course leading to AIDS-associated death within 6 months of infection was studied intensively for the presence of anti-HIV immune reactivities as well as changes in the genetic and biologic properties of virus isolates. Although altered humoral responses were evident, the most distinctive immunologic feature was a nearly complete absence of detectable HIV-specific CTL responses. In addition to a rapid decline in CD3+CD4+ cells, elevated percentages of CD8+CD45RA+ and CD8+CD57+ cells and diminished CD8+CD45R0+ and CD8+CD28+ cells were evident. Primary viral isolates recovered throughout the course of infection exhibited limited sequence diversity. Cloned viral envelopes were found to have unusually broad patterns of coreceptor usage for cell-cell fusion, although infectivity studies yielded no evidence of infection via these alternative receptors. The infectivity studies demonstrated that these isolates and their envelopes maintained an R5 phenotype throughout the course of disease. The absence of demonstrable anti-HIV CTL reactivities, coupled with a protracted course of seroconversion, highlights the importance of robust HIV-specific immune responses in the control of disease progression.

Acute Disease↗
PubMed2003

HutC/FarR-like bacterial transcription factors of the GntR family contain a small molecule-binding domain of the chorismate lyase fold.

Numerous bacterial transcription factors contain a DNA-binding helix-turn-helix domain and a signaling domain, linked together in a single polypeptide. Typically, this signaling domain is a small-molecule-binding domain that undergoes a conformational change upon recognizing a specific ligand. The HutC/FarR-like transcription factors of the GntR family are one of the largest groups of transcription factors in the proteomes of most free-living bacteria. Using sensitive sequence profile analysis we show that the HutC/FarR-like transcription factors contain a conserved ligand-binding domain, which possesses the same fold as chorismate lyase (Escherichia coli UbiC gene product). This relationship suggests that the C-terminal domain of the HutC/FarR-like transcription factors binds small molecules in a cleft similar to the substrate-binding site of the chorismate lyases. The sequence diversity within the predicted binding cleft of the HutC/FarR ligand-binding domains is consistent with the ability of these transcription factors to respond to diverse small molecules, such as histidine (HutC), fatty acids (FarR), sugars (TreR) and alkylphosphonate (PhnF). UbiC-like chorismate lyases function in the ubiquinone biosynthesis pathway, and have characteristic charged, catalytic residues. Genome comparisons reveal that chorismate lyase orthologs are found in several bacteria, chloroplasts of eukaryotic algae and euryarchaea. In contrast, the GntR transcription regulators lack the conserved catalytic residues of the chorismate lyases, and have so far been detected only in bacteria. An ancestral, generic small-molecule-binding domain appears to have given rise to the enzymatic and non-catalytic ligand-binding versions of the same fold under the influence of different selective pressures.

Archaea↗
PubMed2003

Microarray analysis of evolution of RNA viruses: evidence of circulation of virulent highly divergent vaccine-derived polioviruses.

Two approaches based on hybridization of viral probes with oligonucleotide microarrays were developed for rapid analysis of genetic variations during microevolution of RNA viruses. Microarray analysis of viral recombination and microarray for resequencing and heterogeneity analysis were able to generate instant genetic maps of vaccine-derived polioviruses (VDPVs) and reveal the degree of their evolutionary divergence. Unlike conventional methods based on cDNA sequencing and restriction fragment length polymorphism, the microarray approaches are better suited for analysis of heterogeneous populations and mixtures of different strains. The microarray hybridization profile is very sensitive to the cumulative presence of small quantities of different mutations, including those that cannot be revealed by sequencing, making this approach useful for characterization of profiles of nucleotide sequence diversity in viral populations. By using these methods, we identified a type-3 VDPV isolated from a healthy person and missed by conventional methods of screening. The mutational profile of the polio strain was consistent with >1 yr of circulation in human population and was highly virulent in transgenic mice, confirming the ability of VDPV to persist in communities despite high levels of immunity. The proposed methods for fine genotyping of heterogeneous viral populations can also have utility for a variety of other applications in studies of genetic changes in viruses, bacteria, and genes of higher organisms.

Animals↗
PubMed2002

Genetic evolution of structural region of hepatitis C virus in primary infection.

AIM: To investigate the dynamics of hepatitis C virus (HCV) variability through putative envelope genes during primary infection and the mechanism of viral genetic evolution in infected hosts. METHODS: Serial serum samples prospectively collected for 12 to 34 months from a cohort of acutely HCV-infected individuals were obtained, and a 1-kb fragment spanning E1 and the 5' half of E2, including Thirty-three cloned cDNAs representing each specimen were assessed by a method that combined a single-stranded conformational polymorphism (SSCP) and heteroduplex analysis (HDA) method to determine the number of clonotypes hypervariable region, was amplified by reverse transcriptase PCR and cloned. Nonsynonymous mutations per nonsynonymous site (dn), synonymous mutations per synonymous site (ds), dn/ds ratio and genetic distances within each sample were evaluated for intrahost evolutionary analysis. RESULTS: Quasispecies complexity and sequence diversity were lower in early samples and a further increase after seroconversion, although ds value in the envelope genes was higher than dn value during primary infection. The trend, pronounced in most of samples, toward lower ds values in the E1 than in the 5' portion of E2. Quasispecies complexity was higher and E2 dn/ds ratio was a trend toward higher value in later samples during persistent viremia. We also found individual features of HCV genetic evolution in different subjects who were infected with different HCV genotypes. CONCLUSION: Mutations of actively replicating virus arise stochastically with certain functional constaints. A complexity quasispecies exerted by a combination of either neutral evolution or selective forces shows clear differences in individuals, and associated with HCV persistence.

Adult↗