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PubMed1993

The Haemophilus influenzae dnaG sequence and conserved bacterial primase motifs.

The dnaG gene encodes primase which synthesizes the primer RNA essential for Escherichia coli chromosomal DNA replication. The nucleotide sequence was determined for the Haemophilus influenzae dnaG gene and used in the molecular evolutionary analysis of primases from six bacterial species. The predicted amino acid (aa) sequence of H. influenzae DnaG contains 593 residues and shares 56% identity with E. coli DnaG. The N-terminal 60% of six aligned bacterial primases contains all 71 absolutely conserved aa residues and several conserved motifs. All six bacterial primases which were sequenced contained a conserved CPFHXEKTPSF(T/S/A)VXXXKQX(F/Y)HCFGC zinc finger (zf) in the N terminus. A basic region in the N-terminal half of the primases contains a conserved motif, G(R/K)X(V/I/L)X(F/Y) (G/S/A)(G/S/A)RX(V/I/L)XXXXP, termed 'RNAP-basic', which is shared only with RNA polymerase (RNAP) large subunits. This conserved sequence represents the first motif common and specific to primases and RNAP subunits. The consensus sequence, PKYLNSPET, lies adjacent to this basic region in bacterial primases and may represent a signature sequence for bacterial DnaG. The C-terminal regions of these primases do not appear to share primary sequence similarities. These findings support our hypothesis that the primase active site of DnaG is located in the N-terminal 60% of the enzyme.

Amino Acid Sequence↗

PubMed1992

Sequence and secondary structure comparisons of ITS rDNA in mosquitoes (Diptera: Culicidae).

Sequences of the internal transcribed spacers (ITS1 and ITS2) of the mosquito Aedes aegypti, and the ITS2 of six related species, A. simpsoni, A. albopictus, A. vexans, A. triseriatus, Haemagogus mesodentatus, and Psorophora ferox are reported. Intraspecific variation in A. aegypti ITS1 is 1.07% among four clones from three individuals, and in the ITS2 is 1.17% among 15 clones from four individuals. In A. simpsoni, intraspecific ITS2 variation is 0.46% among 10 clones from a single individual. Alignment of the ITS2 sequence of the seven species reveals several homologous domains. Secondary structure predictions for the ITS2 region indicate that these domains base pair to form a core region central to several stem features. The sequence outside the ITS2 homologous domains tends to be GC-rich and characteristically slippage generated; these areas preserve or add to the stem length of the predicted secondary structures. These ITS2 intraspacer variable regions resemble previously described expansion segments of the 28S gene region. Evolutionary analysis of the ITS2 of these species, using both sequence and secondary structure information, leads to the prediction of divergence in the mosquito tribe Aedini that is not clearly reflected in current taxonomic designations.

Aedes↗

PubMed2004

Negative selection on neutralization epitopes of poliovirus surface proteins: implications for prediction of candidate epitopes for immunization.

For development of effective vaccines against viruses, it is of importance to choose appropriate epitopes as the target for immunization. These epitopes should eventually be determined experimentally, but it would be helpful if we could predict candidate epitopes computationally because it accelerates the entire process. To predict candidate epitopes for immunization, it is of great interest to characterize the target epitopes of poliovirus vaccine, which has empirically proven to be the most effective among all vaccines available. Here I show that almost all amino acid sites of poliovirus surface proteins VP1, VP2, and VP3 including neutralization epitopes are negatively selected and no site is under positive selection. These results, together with those obtained in previous studies, indicate that vaccines directed against epitopes, which consist of negatively selected sites protect vaccinees more effectively than those directed against epitopes which contain positively selected sites. These observations suggest that candidate epitopes for immunization are predicted by the molecular evolutionary analysis of viral protein (and its coding nucleotide) sequences, as the epitopes which consist exclusively of negatively selected amino acid sites.

Amino Acids↗

PubMed2026

Comparison of phylogenetic metrics of transmission between symptomatic and asymptomatic tuberculosis in individuals who were incarcerated in Brazil in 2008-24: a retrospective genomic epidemiology study.

BACKGROUND: Tuberculosis control efforts have traditionally targeted symptomatic individuals; however, the role of asymptomatic cases in sustaining transmission is increasingly recognised. We aimed to quantify the contribution of asymptomatic tuberculosis to recent transmission using genomic and epidemiological data from a high-transmission setting. METHODS: We conducted a retrospective genomic epidemiology study of Mycobacterium tuberculosis isolates collected in Mato Grosso do Sul, Brazil, between Aug 25, 2008, and March 19, 2024. Available isolates underwent whole-genome sequencing. Demographic, clinical, incarceration history, and laboratory metadata were obtained from surveillance records. From Jan 1, 2017, to March 19, 2024, active case finding was conducted in the state's three largest prisons (all male-only facilities), during which sputum samples were collected from individuals irrespective of symptoms and tested using GeneXpert and culture. Comparisons of transmission between individuals with and without symptoms were restricted to individuals who were incarcerated and were identified through active case finding and for whom high-quality, M tuberculosis lineage 4 genomes were available. Metrics of recent transmission included phylogenetic clustering, time-scaled haplotype density (THD), local branching index (LBI), and transmission probabilities inferred using Bayesian Reconstruction and Evolutionary Analysis of Transmission Histories. FINDINGS: 4448 tuberculosis cases were notified in Mato Grosso do Sul in 2008-24. After excluding cases for which M tuberculosis isolates were not available or had low sequencing quality, who had contaminated cultures or mixed infection, or who were infected with non-lineage 4 M tuberculosis, we included 2362 lineage 4 M tuberculosis isolates with high-quality genome sequences. 1849 (78·3%) of 2362 isolates were part of a genomic cluster. Among 2362 individuals with tuberculosis, 1137 (48·1%) were incarcerated at diagnosis. Of these individuals, 505 were identified through active case finding in three male-only prisons. The median age was 30 years (IQR 25-37); 304 (60·2%) had mixed ethnicity, 90 (17·8%) were White, 56 (11·1%) were Black, 13 (2·6%) were Indigenous, and six (1·2%) were Asian. 277 (54·9%) had symptomatic disease and 228 (45·1%) had asymptomatic tuberculosis. There were no significant differences between symptomatic and asymptomatic individuals in phylogenetic clustering (213 [76·9%] of 277 vs 195 [85·5%] of 228; p=0·37), THD (median 0·39 [IQR 0·06-0·62] vs 0·50 [0·09-0·65]; p=0·12), or LBI (0·00863 [0·00810-0·00988] vs 0·00871 [0·00829-0·01020]; p=0·088). Bayesian transmission trees showed no significant difference in the number of secondary infections inferred from symptomatic compared with asymptomatic individuals (p=0·56). These findings were consistent across genomic clusters and robust to model assumptions. INTERPRETATION: We identified no differences in transmission between individuals who were symptomatic and those who were asymptomatic using multiple genomic measures. In this high-transmission setting, where systematic screening is implemented, our findings indicate that asymptomatic tuberculosis substantially contributes to tuberculosis transmission at the population level. These results suggest that symptom-based case detection alone is likely to be insufficient to interrupt transmission and highlight the importance of expanded screening strategies in high-risk populations. FUNDING: US National Institutes of Health and the Brazilian National Research Council (CNPq).

Humans↗

PubMed2004

Primitive complement system--recognition and activation.

The complement system, composed of more than 30 serum and cell surface components, is collaborating in recognition and elimination of pathogens as a part of both the innate and acquired immune systems. The two collagenous lectins, mannose-binding lectin (MBL) and ficolins, are one of the pattern recognition molecules acting in innate immunity and upon recognition of the pathogens, they trigger the activation of the lectin complement pathway through attached serine proteases (MASPs). A similar lectin-base complement system, consisting of the lectin-protease complex and C3, is present in ascidians, our closest invertebrate relatives and functions in an opsonic manner. On the other hand, ongoing genome projects in both vertebrates and invertebrates revealed that most domains used by mammalian complement components are found in both protostomes and deuterostomes. However, the unique combinations of them as found in mammalian complement components are present only in deuterostomes, indicating the deuterostome origin of the complement system. Unexpectedly, the complement system of an invertebrate deuterostome, ascidian, shows a similar level of complexity as that of mammals, suggesting that expansion of complement genes by gene duplications occurred independently both in the ascidian and vertebrate lineages. Although most characteristic domain structures of the mammalian complement components are found in ascidians, detailed evolutionary analysis casts doubt on their mutual reactivity in several points. Thus, another integrative step seems to have been required to establish the modern complement system of higher vertebrates.

Animals↗

PubMed2026

Genomic and functional characterization of sugar transporters reveals potential roles in sugar accumulation in a modern sugarcane cultivar.

Sugarcane (Saccharum spp.) is a globally important sugar crop whose productivity depends on efficient sugar transport from source to sink organs. However, systematic identification and functional characterization of sugar transporters (STs) in sugarcane cultivars remain limited. Here, we identified 190 non-redundant ST genes in sugarcane cultivar Guitang 42 (GT42) and phylogenetically classified them into nine groups within the Monosaccharide Transporter (MST), Sucrose Transporter (SUT), and Sugars Will Eventually be Exported Transporters (SWEET) families. Comparative evolutionary analysis revealed significant lineage-specific expansions in the PMT, STP subfamilies, and SWEET families compared to diploid and wild relatives, likely driven by polyploidization and intensive selection for sugar yield. Transcriptomic profiling across tissues and internode elongation stages demonstrated marked tissue-specific and developmental expression patterns. Yeast complementation assays confirmed the transport activity of candidate MSTs, SUTs and SWEETs, with confocal microscopy verifying their distinct subcellular localization at the plasma membrane, tonoplast, or endoplasmic reticulum. Furthermore, transient overexpression of several candidate transporters (ScSWEET4-T2, ScSWEET15, and ScTST4-T1) in Nicotiana benthamiana modulated soluble sugar accumulation, and their expression in sugarcane protoplasts activated key sugar-responsive marker genes (ScGPT2 and ScWIP4). Together, our study establishes a systematic genomic framework and identifies candidate functional transporters that govern sugar partitioning and storage, providing valuable genetic targets for molecular breeding and quality enhancement in sugarcane.

Functional characterization↗

PubMed2004

Structure of the neural (N-) cadherin prodomain reveals a cadherin extracellular domain-like fold without adhesive characteristics.

Classical cadherins mediate cell-cell adhesion through calcium-dependent homophilic interactions and are activated through cleavage of a prosequence in the late Golgi. We present here the first three-dimensional structure of a classical cadherin prosequence, solved by NMR. The prototypic prosequence of N-cadherin consists of an Ig-like domain and an unstructured C-terminal region. The folded part of the prosequence-termed prodomain-has a striking structural resemblance to cadherin "adhesive" domains that could not have been predicted from the amino acid sequence due to low sequence similarities. Our detailed structural and evolutionary analysis revealed that prodomains are distant relatives of cadherin "adhesive" domains but lack all the features known to be important for cadherin-cadherin interactions. The presence of an additional "nonadhesive" domain seems to make it impossible to engage homophilic interactions between cadherins that are necessary to activate adhesion, thus explaining the inactive state of prodomain-bearing cadherins.

Amino Acid Sequence↗

PubMed2004

Morphological and functional asymmetry in alpha-proteobacteria.

The release of an increasing number of complete bacterial genomic sequences allows the evolutionary analysis of processes such as regulatory networks. CtrA is a response regulator of the OmpR subfamily, belonging to a complex regulatory network in the dimorphic bacterium Caulobacter crescentus. It coordinates the cell cycle with an asymmetric division, which is part of the adaptation of Caulobacter to poor-nutrient environments. CtrA is only found in alpha-proteobacteria, a group of bacteria encompassing genera with very distinct lifestyles, including host-associated bacteria. Analyses of CtrA regulatory networks and morphological examinations of some alpha-proteobacteria are presented. Our observations suggest that the core of the CtrA regulation network is conserved and that alpha-proteobacteria divide asymmetrically. We propose that the two daughter cells might be differentiated bacteria, each one displaying specific functions.

Bacterial Proteins↗

PubMed2004

Multilocus sequence typing--what is resolved?

Nucleotide sequence-based methods for bacterial typing (multilocus sequence typing; MLST) allow rapid and global comparisons between results from different laboratories. Combining this advantage with the reduced cost of high throughput sequencing, increasing automation and the amenability of sequence data for evolutionary analysis, it seems inevitable that sequence-based typing will eventually predominate over gel-based methods such as pulsed-field gel electrophoresis (PFGE) for most bacterial species. The increasing availability of multiple genome sequences for single pathogenic species, and the recent development of many new MLST schemes, means that a re-examination of the utility of multilocus sequencing, and in particular the choice of gene loci, is now appropriate.

Bacteria↗

PubMed2002

Evolutionary behavioral genetics in Drosophila.

Behavioral genes have a special evolutionary interest because they are potentially involved in speciation and in many forms of adaptation. Dozens of loci affecting different aspects of behavior have been already identified and cloned in Drosophila. Some of these genes determine variation in such ethologically complex phenotypes as the male "love song" that is produced during courtship and the locomotor "sleep-wake" activity cycles that are controlled by the circadian clock. Although the evolutionary analysis of most behavioral genes in Drosophila is relatively new, it has already given important insights into the forces shaping the molecular variation at these loci and their functional consequences.

Amino Acid Sequence↗

PubMed2003

Rapid sequence divergence in mammalian beta-defensins by adaptive evolution.

beta-Defensin genes encode broad spectrum antimicrobial cationic peptides. We have analysed the largest murine and human clusters of these genes, which localise to mouse and human chromosome 8. Using hidden Markov models, we identified novel mouse and human beta-defensin genes. We subsequently found full-length expressed transcripts for these novel genes. Expression in the mouse was high in brain and reproductive tissues. Fourteen murine beta-defensins could be grouped into two clear sub-groups by virtue of their position and high signal sequence (exon 1 encoded) identity. In contrast, there was a very low level of sequence conservation in the exon 2 region encoding the mature antimicrobial peptide. Evolutionary analysis revealed strong evidence that following gene duplication, exon 1 and surrounding non-coding DNA show little divergence within subfamilies. The focus for rapid sequence divergence is localised in the DNA encoding the mature peptide and this is driven by accelerated positive selection. In the human we also conclude that the locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes prior to human-baboon divergence. This mechanism of adaptive evolution is consistent with the role of this gene family as defence against bacterial pathogens. In order to look at function of these rapidly evolving genes, we characterised one of the novel mouse beta-defensin genes. This gene deviates from the canonical six cysteine motif present in the mature functional peptide of all other beta defensins. This defensin related gene (Defr1) is most highly expressed in testis and heart and the genomic organisation is highly similar to Defb3-6. A synthetic Defr1 peptide was shown to exist as a dimer and yet displayed both antimicrobial and chemotactic activity. The antimicrobial activity of Defr1 against S. aureus, E. coli and B. cepacia was found to be reduced in raised concentration of NaCl, but its action against P. aeruginosa was independent of NaCl concentration. These data have major implications on the structure and functions of these important host defence molecules.

Adaptation, Physiological↗

PubMed1997

High prevalence of GB virus C/hepatitis G virus infection among the Jewish population in Uzbekistan.

Although a new virus, GB virus C/hepatitis G virus (GBV-C/HGV), has been isolated from patients with hepatitis by two different research groups, its prevalence in the world and pathogenesis are still unknown. In this study, 92 samples from the Jewish population of Uzbekistan were investigated for the prevalence of GBV-C/HGV. GBV-C/HGV RNA was detected by reverse transcription polymerase chain reaction (RT-PCR) using specific primers derived from the 5'-untranslated region (5'-UTR). Sequences were analyzed by a molecular evolutionary method. Of 92 samples, GBV-C/HGV RNA was detected in ten (10.9%), HCV RNA was present in two (2.2%), and HBsAg in eight (8.7%). HTLV-I and HIV infection was not detected. Single GBV-C/HGV infection was detected in eight (80%), and co-infection with HBV or HCV was detected in only two of the GBV-C/HGV infections. Alanine aminotransferase (ALT) levels were elevated in three (3.3%), but none with single GBV-C/HGV infection had an elevated ALT level. Nine people (90%) with GBV-C/HGV infection were distributed under the mean age of the population (P < 0.05). Molecular evolutionary analysis showed all GBV-C/HGV strains in this study were related to the HGV derived from the US. These results indicate that (1) GBV-C/HGV infection is highly prevalent among the Jewish population in Uzbekistan; (2) single GBV-C/HGV infections without persistent hepatitis are common; and (3) GBV-C/HGV infection is present among the younger generation.

Adolescent↗

PubMed2003

The SmtB/ArsR family of metalloregulatory transcriptional repressors: Structural insights into prokaryotic metal resistance.

The SmtB/ArsR family of prokaryotic metalloregulatory transcriptional repressors represses the expression of operons linked to stress-inducing concentrations of di- and multivalent heavy metal ions. Derepression results from direct binding of metal ions by these homodimeric "metal sensor" proteins. An evolutionary analysis, coupled with comparative structural and spectroscopic studies of six SmtB/ArsR family members, suggests a unifying "theme and variations" model, in which individual members have evolved distinct metal selectivity profiles by alteration of one or both of two structurally distinct metal coordination sites. These two metal sites are designated alpha3N (or alpha3) and alpha5 (or alpha5C), named for the location of the metal binding ligands within the known or predicted secondary structure of individual family members. The alpha3N/alpha3 sensors, represented by Staphylococcus aureus pI258 CadC, Listeria monocytogenes CadC and Escherichia coli ArsR, form cysteine thiolate-rich coordination complexes (S(3) or S(4)) with thiophilic heavy metal pollutants including Cd(II), Pb(II), Bi(III) and As(III) via inter-subunit coordination by ligands derived from the alpha3 helix and the N-terminal "arm" (CadCs) or from the alpha3 helix only (ArsRs). The alpha5/alpha5C sensors Synechococcus SmtB, Synechocystis ZiaR, S. aureus CzrA, and Mycobacterium tuberculosis NmtR form metal complexes with biologically required metal ions Zn(II), Co(II) and Ni(II) characterized by four or more coordination bonds to a mixture of histidine and carboxylate ligands derived from the C-terminal alpha5 helices on opposite subunits. Direct binding of metal ions to either the alpha3N or alpha5 sites leads to strong, negative allosteric regulation of repressor operator/promoter binding affinity, consistent with a simple model for derepression. We hypothesize that distinct allosteric pathways for metal sensing have co-evolved with metal specificities of distinct alpha3N and alpha5 coordination complexes.

Amino Acid Sequence↗

PubMed2001

Gene conversions in genes encoding outer-membrane proteins in H. pylori and C. pneumoniae.

Helicobacter pylori and Chlamydia pneumoniae are both pathogenic to humans. Their genomes have recently been completed, allowing detailed study of their evolution and organization. Here we describe an evolutionary analysis of the H. pylori and C. pneumoniae genes that encode their outer-membrane proteins. By comparing complete genome sequences of two H. pylori strains and two C. pneumoniae strains, we identify multiple independent conversions among these genes. Such recombination events might provide a selective advantage for these bacterial pathogens.

Bacterial Outer Membrane Proteins↗

PubMed2001

Evidence for purifying selection acting on silent sites in BRCA1.

In mammals, it is usually assumed that selection cannot be strong enough to act on nucleotide mutations that do not cause a change at the protein level (i.e. 'silent' or 'synonymous' mutations). Here we report the results of a molecular evolutionary analysis of BRCA1. We find a repeatable pronounced peak in the ratio of nonsynonymous to synonymous substitutions between codons 200-300. Unusually, this peak is caused by a plummet in the silent-site rate of evolution. The most parsimonious interpretation of these data is that purifying selection is acting on silent sites.

Animals↗

PubMedDate not supplied

The modelling of metabolic systems. Structure, control and optimality.

This article gives an overview of recent developments in the modelling of the structure, control and optimality of metabolic networks. In particular, methods of algebraically analysing the topology of such networks are presented. By these methods, conservation relations and elementary modes of functioning (biochemical routes) can be detected. The principles of metabolic control analysis are outlined. Various recent extensions of this theory are presented, such as an analysis in terms of time dependent variables and modular analysis. Evolutionary optimisation principles are applied to explain the catalytic efficiency of single enzymes as well as the structural design of metabolic pathways. Special results concern the optimal distribution of ATP consuming and ATP producing reactions in glycolysis.

Catalysis↗

PubMed2003

Pseudogenization of the tumor-growth promoter angiogenin in a leaf-eating monkey.

Physiological functions of human genes may be studied by gene-knockout experiments in model organisms such as the mouse. This strategy relies on the existence of one-to-one gene orthology between the human and mouse. When lineage-specific gene duplication occurs and paralogous genes share a certain degree of functional redundancy, knockout mice may not provide accurate functional information on human genes. Angiogenin is a small protein that stimulates blood-vessel growth and promotes tumor development. Humans and related primates only have one angiogenin gene, while mice have three paralogous genes. This makes it difficult to generate angiogenin-knockout mice and even more difficult to interpret the genotype-phenotype relation from such animals should they be generated. We here show that in the douc langur (Pygathrix nemaeus), an Asian leaf-eating colobine monkey, the single-copy angiogenin gene has a one-nucleotide deletion in the sixth codon of the mature peptide, generating a premature stop codon. This nucleotide deletion is found in five unrelated individuals sequenced, and therefore is likely to have been fixed in the species. Five colobine species that are closely related to the douc langur have intact angiogenin genes, suggesting that the pseudogenization event was recent and unique to the douc langur lineage. This natural knockout experiment suggests that primate angiogenin is dispensable even in the wild. Further physiological studies of douc langurs may offer additional information on the role of this cancer-related gene in normal physiology of primates, including humans. Our findings also provide a strong case for the importance of evolutionary analysis in biomedical studies of gene functions.

Amino Acid Sequence↗

PubMed2002

The evolution of developmental regulatory pathways.

Evolutionary analysis of the content of developmental regulatory pathways has been advanced by the publication of pairs of complete genome sequences from representative taxonomic groups. Annotation of the fission yeast, rice, and mouse genomes confirms that most regulatory families are shared among eukaryotes but also shows that certain gene families have restricted distributions. Theoretical advances in the past few years include development of the theory of scale-free networks, which provides a new framework in which to consider the connectivity and evolution of regulatory systems, and introduction of algorithms that use comparative data to enhance detection of transcriptional regulatory motifs.

Animals↗