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PubMed2001

Intricacies in ATP-dependent clamp loading: variations across replication systems.

DNA replication requires the coordinated effort of many proteins to create a highly processive biomachine able to replicate entire genomes in a single process. The clamp proteins confer on replisomes this property of processivity but in turn require clamp loaders for their functional assembly onto DNA. A more detailed view of the mechanisms for holoenzyme assembly in replication systems has been obtained from the advent of novel solution experiments and the appearance of low- and high-resolution structures for the clamp loaders.

Adenosine Triphosphate↗
PubMed2006

Possible ancestral structure in human populations.

Determining the evolutionary relationships between fossil hominid groups such as Neanderthals and modern humans has been a question of enduring interest in human evolutionary genetics. Here we present a new method for addressing whether archaic human groups contributed to the modern gene pool (called ancient admixture), using the patterns of variation in contemporary human populations. Our method improves on previous work by explicitly accounting for recent population history before performing the analyses. Using sequence data from the Environmental Genome Project, we find strong evidence for ancient admixture in both a European and a West African population (p approximately 10(-7)), with contributions to the modern gene pool of at least 5%. While Neanderthals form an obvious archaic source population candidate in Europe, there is not yet a clear source population candidate in West Africa.

Animals↗
PubMed1994

[T-lymphocyte receptor genes: genome organization and genetic mechanisms of repertoire diversity].

The T-cell receptor (TCR) is fundamental to the immune process in both health and disease. Reviewed here is the genetic organisation of the gene complexes which encode the TCR polypeptide chains alpha, beta, gamma, and delta. The TCR is by necessity a diverse structure and we consider the genetic mechanisms responsible for this. These include multiple variable gene segment isotypes, somatic recombination of gene segments, imprecisions in the recombination process and allelic variations in gene segments structure and regulation.

Analysis of Variance↗
PubMed1992

Genetic variation in vivo and proposed functional domains of the 5' noncoding region of poliovirus RNA.

Poliovirus has a single-stranded RNA genome of about 7,440 nucleotides (nt) with an unusually long 750-nt noncoding region in the 5' end (5'NCR). Several regulatory functions have been assigned to the 5'NCR. We sequenced the 5'NCRs of 33 wild-type 3 poliovirus strains to study the range and distribution of naturally occurring sequence variations. In this regard, the 5'NCR can be divided into a conserved part (nt 1 to 650) and a hypervariable part (nt 651 to 750). In the conserved part, altogether 234 unevenly distributed nucleotide positions (36%) showed variation. When these positions were plotted against the predicted secondary-structure models, it was found that the existence of most of the proposed stem-loop structures was supported by extensive structure-conserving substitutions in the stems. Regions with conserved sequences, as well as mutational hot spots, were observed. The hypervariable part of the 5'NCR varied up to 56% between the strains studied. The A + U percentage was significantly higher than in the conserved part. The number of AUG codons varied between 5 and 15 in the conserved part of the 5'NCR, while none was found in the hypervariable part. These results provide information that can be used in site-directed mutagenesis and other approaches targeted to reveal the functional domains of the 5'NCR.

Base Sequence↗
PubMed2005

Measures of human population structure show heterogeneity among genomic regions.

Estimates of genetic population structure (F(ST)) were constructed from all autosomes in two large SNP data sets. The Perlegen data set contains genotypes on approximately 1 million SNPs segregating in all three samples of Americans of African, Asian, and European descent; and the Phase I HapMap data set contains genotypes on approximately 0.6 million SNPs segregating in all four samples from specific Caucasian, Chinese, Japanese, and Yoruba populations. Substantial heterogeneity of F(ST) values was found between segments within chromosomes, although there was similarity between the two data sets. There was also substantial heterogeneity among population-specific F(ST) values, with the relative sizes of these values often changing along each chromosome. Population-structure estimates are often used as indicators of natural selection, but the analyses presented here show that individual-marker estimates are too variable to be useful. There is inherent variation in these statistics because of variation in genealogy even among neutral loci, and values at pairs of loci are correlated to an extent that reflects the linkage disequilibrium between them. Furthermore, it may be that the best indications of selection will come from population-specific F(ST) values rather than the usually reported population-average values.

Chromosomes, Human↗
PubMed1992

The hog cholera virus.

Hog cholera virus (HCV) is a spherical enveloped particle of about 40-60 nm dia. The viral genome is a single strand RNA of about 12,000 bases with positive polarity. One single large open reading frame codes for presumably four structural, i.e. three glycoproteins and a core protein, and about three to five nonstructural proteins. The functional role is not yet fully clear for all viral proteins. HCV belongs to the pestivirus group and it is closely related to bovine viral diarrhoea and border disease viruses. The relationship extends to morphology, antigenicity, host spectrum and molecular properties. Pestiviruses hold generic status in the family Flaviviridae.

Animals↗
PubMed1994

Hepatitis C virus (HCV) genotype distribution in German isolates: studies on the sequence variability in the E2 and NS5 region.

We report on molecular characterization of hepatitis C virus (HCV) isolates in intravenous drug abusers, as compared to non-drug using patients with posttransfusion hepatitis or sporadic hepatitis of unknown origin. Virus typing was performed by RFLP analysis of PCR products in the 5' NCR. Subtyping was done by hybridization with subtype specific probes or by sequencing in the NS4 and NS5 region, respectively. HCV subtype 1b was found most commonly among all the isolates. However, the subtype 3a had a high prevalence (about 46%) in the group of drug addicts. In these subtype 3a isolates the N-terminal part of the E2 protein was highly variable. This confirms the presence of a hypervariable region (HVR1) in this envelope protein found in all hepatitis C viruses. Each subtype 3a isolate examined had a characteristic unique hypervariable region in the E2 protein. It is noteworthy that there are four amino acids in this region which were highly conserved between all HCV sequences published. It can be assumed that such conserved amino acids are significant for structure and function of this viral protein. In our HCV subtype 3a isolates the NS5 sequences were highly conserved.

Amino Acid Sequence↗
PubMed2006

Vertical distribution and diversity of bacteria and archaea in sulfide and methane-rich cold seep sediments located at the base of the Florida Escarpment.

The bacterial and archaeal communities of the sediments at the base of the Florida Escarpment (Gulf of Mexico, USA) were investigated using molecular phylogenetic analysis. The total microbial community DNA of each of three vertical zones (top, middle and bottom) of a sediment core was extracted and the 16S rRNA genes were amplified by PCR, cloned and sequenced. Shannon-Weaver Diversity measures of bacteria were high in all three zones. For the archaea, diversity was generally low, but increased with depth. The archaeal clonal libraries were dominated by representatives of four groups of organisms involved in the anaerobic oxidation of methane (ANME groups). Phylogenetic analysis of bacteria suggests the dominance of epsilon-proteobacteria in the top zone, the epsilon-, delta- and gamma-proteobacteria in the middle zone and the delta-proteobacteria in the bottom zone of the core. Members of the Cytophaga-Flexibacter-Bacteroidetes group, the Chloroflexi/green non-sulfur bacteria, the Gram+ (Firmicutes), the Planctomyces, candidate division WS3 and Fusobacterium were also detected. Our data suggest that the community structure and diversity of microorganisms can shift greatly within small vertical distances, possibly in response to changes in the physical and chemical conditions.

Archaea↗
PubMed1993

Nucleotide sequence analysis of HTLV-I isolated from cerebrospinal fluid of a patient with TSP/HAM: comparison to other HTLV-I isolates.

Human T-cell leukemia virus type I (HTLV-I) has been associated with adult T-cell leukemia/lymphoma and the chronic neurologic disorder tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). To study the genetic structure of the virus associated with TSP/HAM, we have obtained and sequenced a partial genomic clone from an HTLV-I-positive cell line established from cerebrospinal fluid (CSF) of a Jamaican patient with TSP/HAM. This clone consisted of a 4.3-kb viral sequence containing the 5' long terminal repeat (LTR), gag, and N-terminal portion of the pol gene, with an overall 1.3% sequence variation resulting from mostly nucleotide substitutions, as compared to the prototype HTLV-I ATK-1. The gag and pol regions showed only 1.4% and 1.2% nucleotide variations, respectively. However, the U3 region of the LTR showed the highest sequence variation (3.6%), where several changes appear to be common among certain TSP/HAM isolates. Several of these changes reside within the 21-bp boundaries and the Tax-responsive element. It would be important to determine if the observed changes are sufficient to cause neurologic disorders similar to the murine leukemia virus system or simply reflect the divergent pool of HTLV-I from different geographic locations. At this time, we cannot rule out the possibility that the observed changes have either direct or indirect significance for the HTLV-I pathogenesis in TSP/HAM.

Base Sequence↗
PubMed1993

Genome macrorestriction analysis of diversity and variability of Pseudomonas aeruginosa strains infecting cystic fibrosis patients.

Genome macrorestriction fingerprinting with XbaI and DraI was used to analyze the relatedness of 166 Pseudomonas aeruginosa isolates collected from 31 cystic fibrosis patients over a 1- to 20-month period and to correlate their genotype with patterns of resistance to 14 antimicrobial agents. Quantitative comparison of intra- and interpatient similarities of P. aeruginosa macrorestriction patterns disclosed two discrete ranges that clearly discriminated subclonal variation (> 80% relatedness) and clonal diversity (10 to 70% relatedness). Cloning-derived mutants exhibited up to 20% divergence of genomic macrorestriction patterns during the course of chronic colonization of individual patients. Change of susceptibility to multiple antimicrobial agents developed in 50% of sequential pairs of isolates from individual patients. Only 19% of these susceptibility changes were attributable to strain substitution, while the majority (56%) of resistance changes were associated with minor genomic variations of a persistent strain. Sixty-six percent of patients harbored one strain, and 33% carried two strains. Three common strains colonized 5 (28%) of 18 patients attending a cystic fibrosis clinic, and another two strains colonized two patient pairs (31%) of 13 patients staying at a rehabilitation center, suggesting potential cross-infection in these settings. By indexing regional polymorphisms throughout the chromosome structure, macrorestriction analysis can monitor subclonal evolution of P. aeruginosa and identify isogenic resistance mutants. Quantitative macrorestriction fingerprinting enables discrimination between clonal variants and clones of distinct origins and should therefore provide a reliable tool for investigating the mode of acquisition of P. aeruginosa in cystic fibrosis patients.

Cross Infection↗
PubMed2006

Tertiary structural and functional analyses of a viroid RNA motif by isostericity matrix and mutagenesis reveal its essential role in replication.

RNA-templated RNA replication is essential for viral or viroid infection, as well as for regulation of cellular gene expression. Specific RNA motifs likely regulate various aspects of this replication. Viroids of the Pospiviroidae family, as represented by the Potato spindle tuber viroid (PSTVd), replicate in the nucleus by utilizing DNA-dependent RNA polymerase II. We investigated the role of the loop E (sarcin/ricin) motif of the PSTVd genomic RNA in replication. A tertiary-structural model of this motif, inferred by comparative sequence analysis and comparison with nuclear magnetic resonance and X-ray crystal structures of loop E motifs in other RNAs, is presented in which core non-Watson-Crick base pairs are precisely specified. Isostericity matrix analysis of these base pairs showed that the model accounts for the reported natural sequence variations and viable experimental mutations in loop E motifs of PSTVd and other viroids. Furthermore, isostericity matrix analysis allowed us to design disruptive, as well as compensatory, mutations of PSTVd loop E. Functional analyses of such mutants by in vitro and in vivo experiments demonstrated that loop E structural integrity is crucial for replication, specifically during transcription. Our results suggest that the PSTVd loop E motif exists and functions in vivo and provide loss-of-function genetic evidence for the essential role of a viroid RNA three-dimensional motif in rolling-circle replication. The use of isostericity matrix analysis of non-Watson-Crick base pairing to rationalize mutagenesis of tertiary motifs and systematic in vitro and in vivo functional assays of mutants offers a novel, comprehensive approach to elucidate the tertiary-structure-function relationships for RNA motifs of general biological significance.

Base Pairing↗
PubMed1984

The genetics of the gonococcus.

Despite the inherent limitations imposed by working with an organism that still has a very limited genetic map and relatively few systems for manipulation of the genome, much has been learned in the past decade. Recent applications of the technology of monoclonal antibodies and recombinant DNA, coupled with careful studies of the immunobiology of pili and various outer membrane structures have provided exciting insights into the molecular pathogenesis of gonococcal infections. One of the principal lessons is the sophistication of the gonococcal strategies for evading the host defenses, including high-frequency variations of pili and P.II and an extracellular protease for specific cleavage of IgA1. It is unclear how much antigenic variation will limit vaccine development. Regardless, the pursuit of a vaccine has led to important new fundamental knowledge of the genetics and structure-function relationships of several cell surface components, and the future promises to be both rational and interesting.

Anti-Bacterial Agents↗
PubMed2005

Genomic analysis of G protein gamma subunits in human and mouse - the relationship between conserved gene structure and G protein betagamma dimer formation.

Analysis of the genomic sequences, cDNAs and expressed sequence tags (ESTs) in human and mouse for the 12 genes of the gamma subunits of the heterotrimeric G proteins has allowed us to identify the common versus unique elements of the organization and expression of the members of this important gene family. All of the G protein gamma subunit genes are organized around two coding exons, each containing about 100 nucleotides coding for 30-40 amino acids. These two exons each correspond to a functional domain of the protein, which interestingly appears to impose constraints on both the structure of the protein and the structure of the gene. There is large variation in the intron size between these two coding exons, the number and size of 5' and 3' UTRs, and the overall size of the genes. There is general but not absolute conservation in the size and structure of these genes between humans and mice. Alternative splicing and potential differential promoter usage were detected for several Ggamma subunits, indicating possible differential regulation in expression. Only for Ggamma10, however, did we find an alternative coding transcript. This alternative transcript appears to code for a hybrid protein containing a DnaJ domain in place of its Ggamma exon 1 domain, joined to the Ggamma10 second exon domain. The predicted mRNA is expressed in humans, and the protein coded by it is readily translated in vitro. This protein does not form a functional G protein betagamma dimer, but it could generate a chaperone-like protein related to its DNA-J domain. These studies suggest that alternative splicing is not a prominent mechanism for generating G protein subunit diversity from within the human or mouse genomes. Instead, each of the known 12 gamma subunit genes generate transcripts with one prevalent protein.

Alternative Splicing↗
PubMed2004

Partitioning nuclear and chloroplast variation at multiple spatial scales in the neotropical epiphytic orchid, Laelia rubescens.

Insights into processes that lead to the distribution of genetic variation within plant species require recognition of the importance of both pollen and seed movement. Here we investigate the contributions of pollen and seed movement to overall gene flow in the Central American epiphytic orchid, Laelia rubescens. Genetic diversity and structure were examined at multiple spatial scales in the tropical dry forest of Costa Rica using nuclear (allozymes) and chloroplast restriction fragment length polymorphism (RFLP) markers, which were found to be diverse (allozymes, P = 73.3%; HE = 0.174; cpDNA, HE = 0.741). Nuclear genetic structure (FSTn) was low at every spatial scale (0.005-0.091). Chloroplast markers displayed more structure (0.073-0.254) but relatively similar patterns. Neither genome displayed significant isolation-by-distance. Pollen and seed dispersal rates did not differ significantly from one another (mp/ms = 1.40) at the broadest geographical scale, among sites throughout Costa Rica. However, relative contributions of pollen and seeds to gene flow were scale-dependent, with different mechanisms determining the dominant mode of gene flow at different spatial scales. Much seed dispersal is highly localized within the maternal population, while some seeds enter the air column and are dispersed over considerable distances. At the intermediate scale (10s to 100s of metres) pollinators are responsible for substantial pollen flow. This species appears capable of distributing its genes across the anthropogenically altered landscape that now characterizes its Costa Rican dry forest habitat.

Costa Rica↗
PubMed2003

The evolution of CONSTANS-like gene families in barley, rice, and Arabidopsis.

The CO (CONSTANS) gene of Arabidopsis has an important role in the regulation of flowering by photoperiod. CO is part of a gene family with 17 members that are subdivided into three classes, termed Group I to III here. All members of the family have a CCT (CO, CO-like, TOC1) domain near the carboxy terminus. Group I genes, which include CO, have two zinc finger B-boxes near the amino terminus. Group II genes have one B-box, and Group III genes have one B-box and a second diverged zinc finger. Analysis of rice (Oryza sativa) genomic sequence identified 16 genes (OsA-OsP) that were also divided into these three groups, showing that their evolution predates monocot/dicot divergence. Eight Group I genes (HvCO1-HvCO8) were isolated from barley (Hordeum vulgare), of which two (HvCO1 and HvCO2) were highly CO like. HvCO3 and its rice counterpart (OsB) had one B-box that was distantly related to Group II genes and was probably derived by internal deletion of a two B-box Group I gene. Sequence homology and comparative mapping showed that HvCO1 was the counterpart of OsA (Hd1), a major determinant of photoperiod sensitivity in rice. Major genes determining photoperiod response have been mapped in barley and wheat (Triticum aestivum), but none corresponded to CO-like genes. Thus, selection for variation in photoperiod response has affected different genes in rice and temperate cereals. The peptides of HvCO1, HvCO2 (barley), and Hd1 (rice) show significant structural differences from CO, particularly amino acid changes that are predicted to abolish B-box2 function, suggesting an evolutionary trend toward a one-B-box structure in the most CO-like cereal genes.

Amino Acid Motifs↗
PubMed2001

Adaptive hitchhiking effects on genome variability.

The continuing deluge of nucleotide polymorphism data is providing insights into the role of adaptation in shaping genome-wide patterns of variability and molecular evolution. Population genetic models in which linkage and selection interact (i.e. hitchhiking) predict that selection can leave 'footprints' in closely linked genomic regions. New analytical approaches show promise for distinguishing the signature of adaptation from that of several non-adaptive alternatives. Accounting for the effects of population structure and history poses a challenge for future investigations.

Adaptation, Biological↗
PubMed1995

A FORTRAN program to simulate the evolution of genetic variability in a small population.

This paper presents a FORTRAN-77 program that performs Monte Carlo simulation of the evolution of genetic structure in a small population under selection. The aim is to study the possibility of foreseeing a response plateau in a theoretical population, depending on population size and management, and to apply this to small populations actually selected, to predict a possible exhaustion of genetic variability. A set of subroutines describing the different steps in a selection cycle (birth, expression of phenotypic value, genetic evaluation, selection, reproduction, death) is available and the user can choose the sequence of subroutines, the characteristics of individuals submitted to each step, and also build more personal subroutines if necessary. The program is based on the generation of exact genotypes and their transmission from parents to offspring, through simulation of meiosis and pairing of gametes. Parameters concerning the genome, the initial structure of the population and its management are required. The genetic mean and variance of the population for each new cycle of selection are given as outputs. Examples of applications are given and discussed.

Algorithms↗
PubMed2002

[Genetic divergence of Far Eastern dace species belonging to the genus Tribolodon (Pisces, Cyprinidae) and closely related taxa].

Based on a biochemical-genetic approach, heterozygosity and divergence of structural genes of 30 enzyme loci were analyzed in six dace species. In addition, intra- and interspecific divergence of gene expression was analyzed based on a sample of 12 to 15 loci. Mean heterozygosities per individual varied as follows: Tribolodon species, Hobs = 0.007 +/- 0.007 and Hexp = 0.007 +/- 0.007; T. ezoe, Hobs = 0.045 +/- 0.016 and Hexp = 0.067 +/- 0.029. Several variants of genetic distances were estimated. Standard Nei's distances (DN) varied from 0.145 to 0.284 in four dace species studied. As related to Tribolodon dace species, the following genetic distances were obtained for two members of other genera: Pseudaspius leptocephalus, DN = 0.269; Leuciscus waleckii, DN = 0.769. Based on the distance matrices, different clustering algorithms were realized. The main feature shared by different dendrograms was a separate position of the cluster joining Far-Eastern dace species, to which P. leptocephalus and L. waleckii are successively added. Among the species studied, the proportion of loci similar by expression (E) varied from 87 to 100%. The greatest difference was found between anadromous and nonanadromous ecotypes of T. hakonensis, E = 67%. The following conclusions can be made: (1) Four studied species of the genus Tribolodon are rather well genetically differentiated. Diagnostic loci are available. (2) A nominal dace species, T. species, should be considered the fourth isolated species of this genus, which is confirmed by its recent zoological acceptance of this species. (3) The origin and divergence of dace species belonging to the genus Tribolodon are relatively late (1 to 3 Myr ago) historical events. (4) Taxonomically, the genus Tribolodon belong to the tribe Pseudaspinini together with P. leptocephalus, which is confirmed by genetic data. (5) Data on heterozygosity and the divergence of structural and regulatory elements of genome, along with the proposed scheme of speciation types, suggest the following speciation modes for the species studied: for four species, adaptive divergence and for two species, genetic transformation.

Animals↗