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PubMed1988

Molecular-genetic evidence for the relationship of Mycobacterium leprae to slow-growing pathogenic mycobacteria.

A total of 1170 nucleotides of the 16S rRNA from Mycobacterium leprae were compared to the homologous regions of M. tuberculosis, M. bovis Vallée, M. avium, M. scrofulaceum, M. phlei, M. fortuitum and one representative each of the genera Corynebacterium, Nocardia, and Rhodococcus. Homology values were calculated and a phylogenetic tree was constructed from the evolutionary distance values. Despite differences in DNA G + C content and genome size, M. leprae is a true member of the slow-growing pathogenic mycobacteria, branching off intermediate to the other members of this subgroup. Slow- and fast-growing mycobacteria are phylogenetically well separated but constitute an individual branch of the actinomycetes proper. Significant structural variation of certain regions of the 16S rRNA may allow construction of M. leprae-specific probes used for rapid identification.

Animals↗

PubMed1981

Defective packing of an unusual DNA in a virulent Erwinia phage, Erh 1.

A newly isolated bacteriophage, Erh 1, for Erwinia herbicola, has been characterized. This virulent phage has been found to have an elongated rod-like head and a short complex tail structure. One major protein and 5 minor proteins have been identified as phage components. The head structure was found to be transparent, flexible and could be twisted or flattened by various treatments. The DNA, isolated from highly purified phage particles, was linear, double-stranded, had a G-C content of 46-47% and displayed two unique features. (1) The isolated phage DNA molecules were highly heterogeneous in contour lengths; the most prevalent molecules had a length of 6-12 mu, but molecules have been measured with lengths ranging from 2.3 mu to 37 mu. (2) One or two long single-stranded regions, "gaps," ranging in length from 0.3 to 3.1 mu with an average length of 1.4 +/- 0.7 mu, were found in about 25% of the phage DNA molecules. Upon density gradient centrifugation of p32 labeled phage, it was found that most of the DNA was contained in apparently noninfectious, defective particles, with densities ranging from 1.34 to 1.41 while most of the infectious particles were found in fractions of density of 1.44 +/- 0.02. When used to multiply infect cells, the lower density particles were able to complement each other and form infectious centers. Further, it was found that infectious particles themselves were heterogeneous and had sedimentation constants varying from 600 S to 1400 S. From the distribution of DNA sizes in these particles, the variations in sedimentation behavior, and the flexibility of the head structure of most particles, it appears that the head structure is formed first and then the DNA is packed inefficiently into this head structure. Apparently, most phage particles are only partly filled and do not contain a complete genome while a few others may contain a large amount of redundant viral DNA.

Bacteriophages↗

PubMed2003

Genomic structure of human OKL38 gene and its differential expression in kidney carcinogenesis.

We previously demonstrated the growth inhibitory property of OKL38 and its possible roles in mammary carcinogenesis. To further understand the regulation and roles of OKL38 in tumorigenesis we proceeded to clone and characterize the human OKL38 gene and three of its variants with transcripts of 1.9, 2.2, and 2.4 kb. The human OKL38 gene spans approximately 18 kb and contains 8 exons and 7 introns with exon size ranging from 92 to 1270 bp. RT-PCR and sequence analysis suggest that different transcripts were arrived through differential promoter usage and alternate splicing. Multiple Tissue Expression array (MTE) and Multiple Tissue Northern blot (MTN) indicated that OKL38 was ubiquitously expressed in all tissues with high expression in liver, kidney, and testis. The cancer profiling array (CPA) of paired normal/tumor cDNA showed that OKL38 mRNA was down-regulated in 70% (14 of 20) of kidney tumors. Western analysis revealed that the OKL38 protein was undetectable in 78% (7 of 9 pairs) of kidney tumor tissues. Immunohistological analysis showed that 64% (14 of 22) of kidney tumors were either lost or underexpressed OKL38 protein compared with the adjacent normal tissue. A transfection study using OKL38-eGFP recombinant construct showed that overexpression of the 52 kDa OKL38 protein in A498 cells resulted in growth inhibition and cell death. This study demonstrates the complex genomic structure of the OKL38 gene and its growth inhibitory and cytotoxic properties. Our data suggest the potential use of OKL38 in diagnosis, prognosis, and/or treatment of kidney cancer.

Apoptosis Regulatory Proteins↗

PubMed2000

Antigenic variation of Anaplasma marginale by expression of MSP2 mosaics.

Anaplasma marginale is a tick-borne pathogen, one of several closely related ehrlichial organisms that cause disease in animals and humans. These Ehrlichia species have complex life cycles that require, in addition to replication and development within the tick vector, evasion of the immune system in order to persist in the mammalian reservoir host. This complexity requires efficient use of the small ehrlichial genome. A. marginale and related ehrlichiae express immunoprotective, variable outer membrane proteins that have similar structures and are encoded by polymorphic multigene families. We show here that the major outer membrane protein of A. marginale, MSP2, is encoded on a polycistronic mRNA. The genomic expression site for this mRNA is polymorphic and encodes numerous amino acid sequence variants in bloodstream populations of A. marginale. A potential mechanism for persistence is segmental gene conversion of the expression site to link hypervariable msp2 sequences to the promoter and polycistron.

Amino Acid Sequence↗

PubMed2026

The SMN locus in the T2T era: Structure, gene conversion, and clinical implications.

Long-read sequencing, paralog-aware variant calling, and telomere-to-telomere (T2T) human genome assemblies now enable the resolution of copy-, haplotype-, and nucleotide-level complexities in segmentally duplicated loci, which were previously inaccessible with short-read sequencing. In this review, we highlight how current technologies and analysis methods reveal extensive diversity in copy number (CN), structure, and gene conversion within the spinal muscular atrophy-associated survival motor neuron (SMN) locus. We summarize how understanding population-level structural variation could be translated into clinical practice, where a nucleotide-level view of the SMN locus may refine prognostic accuracy beyond SMN2 CN and explain variable treatment responses. Finally, we discuss how the approaches and methodologies required to study the SMN locus may be applied elsewhere, providing a scaffold to characterize other complex human genetic regions.

Humans↗

PubMed1987

Molecular aspects of the epidemiology of virus disease.

With regard to molecular epidemiology, influenza A viruses belong to the best-studied virus systems. At least two large reservoirs of influenza A viruses have been built up in nature, one in humans and another one in water fowls. The latter one is very heterogenous, consisting of viruses belonging to 13 hemagglutinin (HA) and 9 neuraminidase (NA) subtypes in almost all possible combinations. The segmented structure of the influenza virus genome allows the creation of new influenza strains by reassortment. By replacement of the HA gene of human strains new pandemic viruses can be generated (antigenic shift). The particular structure of the HA enables the human influenza A-viruses to create variants which can escape the immune response of the host (antigenic drift). The nucleoprotein is responsible for keeping those two large reservoirs apart. Mixing of genes of viruses from these two reservoirs seems to happen predominantly by double infection of pigs, which apparently are tolerant for infection by either human or avian influenza viruses. The molecular mechanisms described for influenza viruses can be explained by the particular structure of their genome and their components and cannot be generalized. Each virus has developed its own strategy to multiply and to spread.

Animals↗

PubMed2004

Design and analysis of admixture mapping studies.

Admixture between populations originating on different continents can be exploited to detect disease susceptibility loci at which risk alleles are distributed differentially between these populations. We first examine the statistical power and mapping resolution of this approach in the limiting situation in which gamete admixture and locus ancestry are measured without uncertainty. We show that, for a rare disease, the most efficient design is to study affected individuals only. In a typical African American population (two-way admixture proportions 0.8/0.2, ancestry crossover rate 2 per 100 cM), a study of 800 affected individuals has 90% power to detect at P values <10(-5) a locus that generates a risk ratio of 2 between populations, with an expected mapping resolution (size of 95% confidence region for the position of the locus) of 4 cM. In practice, to infer locus ancestry from marker data requires Bayesian computationally intensive methods, as implemented in the program ADMIXMAP. Affected-only study designs require strong prior information on the frequencies of each allele given locus ancestry. We show how data from unadmixed and admixed populations can be combined to estimate these ancestry-specific allele frequencies within the admixed population under study, allowing for variation between allele frequencies in unadmixed and admixed populations. Using simulated data based on the genetic structure of the African American population, we show that 60% of information can be extracted in a test for linkage using markers with an ancestry information content of 36% at 3-cM spacing. As in classic linkage studies, the most efficient strategy is to use markers at a moderate density for an initial genome search and then to saturate regions of putative linkage with additional markers, to extract nearly all information about locus ancestry.

Black People↗

PubMed2001

Diversity, origin, and distribution of retrotransposons (gypsy and copia) in conifers.

We examined the diversity, evolution, and genomic organization of retroelements in a wide range of gymnosperms. In total, 165 fragments of the reverse transcriptase (RT) gene domain were sequenced from PCR products using newly designed primers for gypsy-like retrotransposons and well-known primers for copia-like retrotransposons; representatives of long interspersed nuclear element (LINE) retroposons were also found. Gypsy and copia-like retroelements are a major component of the gymnosperm genome, and in situ hybridization showed that individual element families were widespread across the chromosomes, consistent with dispersion and amplification via an RNA intermediate. Most of the retroelement families were widely distributed among the gymnosperms, including species with wide taxonomic separation from the Northern and Southern Hemispheres. When the gymnosperm sequences were analyzed together with retroelements from other species, the monophyletic origin of plant copia, gypsy, and LINE groups was well supported, with an additional clade including badnaviral and other, probably virus-related, plant sequences as well as animal and fungal gypsy elements. Plant retroelements showed high diversity within the phylogenetic trees of both copia and gypsy RT domains, with, for example, retroelement sequences from Arabidopsis thaliana being present in many supported groupings. No primary branches divided major taxonomic clades such as angiosperms, monocotyledons, gymnosperms, or conifers or (based on smaller samples) ferns, Gnetales, or Sphenopsida (Equisetum), suggesting that much of the existing diversity was present early in plant evolution, or perhaps that horizontal transfer of sequences has occurred. Within the phylogenetic trees for both gypsy and copia, two clearly monophyletic gymnosperm/conifer clades were revealed, providing evidence against recent horizontal transfer. The results put the evolution of the large and relatively conserved genome structure of gymnosperms into the context of the diversity of other groups of plants.

Animals↗

PubMed2006

Heterogeneity in tandem octanucleotides within Haemophilus influenzae lipopolysaccharide biosynthetic gene losA affects serum resistance.

Haemophilus influenzae is subject to phase variation mediated by changes in the length of simple sequence repeat regions within several genes, most of which encode either surface proteins or enzymes involved in the synthesis of lipopolysaccharides (LPS). The translational repeat regions that have been described thus far all consist of tandemly repeated tetranucleotides. We describe an octanucleotide repeat region within a putative LPS biosynthetic gene, losA. Approximately 20 percent of nontypeable H. influenzae strains contain copies of losA and losB in a genetic locus flanked by infA and ksgA. Of 30 strains containing losA at this site, 24 contained 2 tandem copies of the octanucleotide CGAGCATA, allowing full-length translation of losA (on), and 6 strains contained 3, 4, 6, or 10 tandem copies (losA off). For a serum-sensitive strain, R3063, with losA off (10 repeat units), selection for serum-resistant variants yielded a heterogeneous population in which colonies with increased serum resistance had losA on (2, 8, or 11 repeat units), and colonies with unchanged sensitivity to serum had 10 repeats. Inactivation of losA in strains R3063 and R2846 (strain 12) by insertion of the cat gene decreased the serum resistance of these strains compared to losA-on variants and altered the electrophoretic mobility of LPS. We conclude that expression of losA, a gene that contributes to LPS structure and affects serum resistance, is determined by octanucleotide repeat variation.

Blood Bactericidal Activity↗

PubMed1997

Nucleotide compositional constraints on genomes generate alanine-, glycine-, and proline-rich structures in transcription factors.

Correlation between amino acid composition and nucleotide composition is examined. Class III POU transcription factors having higher third GC contents showed higher contents of alanine, glycine, and proline residues encoded by GC-rich nucleotides, and vice versa. This correlation was observed even among various types of transcription factors from vertebrates and invertebrates regardless of functional and structural constraints inherent to each protein. Furthermore, reptile class III POU sequences revealed no evolutionary directionality increasing the GC contents from cold- to warm-blooded vertebrates.

Alanine↗

PubMed1992

Highly repeated DNA sequences in birds: the structure and evolution of an abundant, tandemly repeated 190-bp DNA fragment in parrots.

Up to 6.8% of the parrot (Psittaciformes) genome consists of a tandemly repeated, 190-bp sequence (P1) located in the centromere of many if not all chromosomes. Monomer repeats from 10 different psittacine species representing four subfamilies were isolated and cloned. The intraspecific sequence variation ranged from 1.5 to 7%. The interspecific sequence variation ranged from less than 3% between two species of cockatoos to approximately 45% between cockatoos and other parrots. The monomer sequences of all 10 parrot species contained several conserved (> 90%) sequence elements at identical locations within the repeat. A comparison with tandemly repeated DNA sequences in other avian species showed that several of these conserved elements were also present at similar locations within the 184-bp repeat of the Chilean flamingo (Phoenicopterus chilensis), suggesting a great antiquity of the repeat. One of the elements was also found in the tandemly repeated sequences of the crane (Gruidae) and falcon (Falconidae) families. The data were used for the construction of a partial most parsimonious relationship that supports a regional subdivision of the Psittaciformes.

Animals↗

PubMed1998

[The structure, function and mutation of Rb gene promoter in normal individuals and retinoblastoma patients].

OBJECTIVE: To investigate the DNA sequence of the 5' untranslated region of the Rb gene in normal individuals and retinoblastoma patients and identify the elements involved in transcription regulation of Rb gene. METHODS: SSCP analysis and direct genomic DNA sequencing were used to identify variations or alterations in DNA of normal adult WBC and tumor DNA of retinoblastoma patients. The different DNA fragments located in the 5' untranslated region of Rb gene were amplified and inserted into an expression plasmid with a CAT reporter gene. The capacity of transcription regulation of isolated DNA fragments was determined by CAT assay. RESULTS: A 240 bp DNA fragment located between -327(-)-87 bp upstream of the first starting codon was shown to be the sequence with essential promoter function. The Sp1/RBF-1, ATF and E2F binding sites were present in this region and positive and negative elements were found further upstream and downstream. Four of 5 naturally occurring mutations were identified in either Sp1/RBF-1 or ATF binding sites from 302 patients with retinoblastoma. All these mutants had reduced CAT activity. However, 100 cases of normal adults did not show any variant DNA sequence in the same region. CONCLUSION: The promoter DNA sequence of Rb gene is quite stable. Its variation usually leads to reduction in promoter activity which may be associated with genetic susceptibility to retinoblastoma.

Adult↗

PubMed1993

Failure to detect hepatitis C virus (HCV) genome by polymerase chain reaction in human anti-HCV-positive intravenous immunoglobulins.

The prevalence of HCV antibodies was determined by a second-generation ELISA and a four-antigen recombinant immunoblot assay in nine intravenous immunoglobulin (IVIG) preparations commercially available in Italy. In addition, the clinical safety of six of them was ascertained by polymerase chain reaction (PCR) of HCV RNA and a prospective study in 14 patients with immunodeficiency disorders. Results indicated that all IVIG preparations were anti-HCV-positive. However, there were substantial variations in their anti-HCV antibody titres. The preparations retained IgG subclass reactivities to HCV-associated structural (C22-3) and non-structural (C33c, C100-3) proteins. Our sensitive and specific PCR assay was unable to detect HCV RNA in the six preparations tested. Clinical surveillance of IVIG-treated patients prospectively evaluated over a mean period of 8.3 months failed to detect clinical and/or biochemical evidence of hepatitis.

Base Sequence↗

PubMed2000

Matrilineal genetic structure and female-mediated gene flow in red grouse (Lagopus lagopus scoticus): an analysis using mitochondrial DNA.

DNA sequence variation at the hypervariable 5' end of the mitochondrial control region was examined in 247 individuals to detect genetic divergence among 14 populations of red grouse (Lagopus lagopus scoticus) in northeastern Scotland. Ten haplotypes were resolved, several of which were shared among populations. Analysis of molecular variance, Nei's gamma ST, and a cladistic estimate of the amount of gene flow indicated a lack of overall population differentiation. Patterns of overall panmixia are in stark contrast to previous reports of localized subdivision among the same set of populations detected using hypervariable microsatellite markers. Because grouse cocks are territorial and show extreme natal philopatry and females are the dispersing sex, such discordance could be explained by sex-biased dispersal, with extensive female-mediated gene flow preventing mitochondrial DNA divergence. However, it is difficult to reconcile how effective dispersal of females would not homogenize both mitochondrial and nuclear structure simultaneously. We use a model that examines the spatial and temporal dynamics of diparentally and uniparentally inherited genes to show that, under realistic ecological scenarios and with specific differences in the dispersal of males and females, the local effective size of the nuclear genome can be less than that of the mitochondrial and the patterns of structuring we observe are meaningful.

Animals↗

PubMed2025

Phylogenetics and genomic variation of Hepatocystis isolated from shotgun sequencing of wild primate hosts.

Hepatocystis are apicomplexan parasites nested within the Plasmodium genus that infect primates and other vertebrates, yet few isolates have been genetically characterized. Using taxonomic classification and mapping characteristics, we searched for Hepatocystis infections within publicly available, blood-derived whole genome sequence (WGS) data from 326 wild non-human primates (NHPs) in 17 genera. We identified 37 Hepatocystis infections in Papio cynocephalus (yellow baboons) and four species of Chlorocebus monkeys (grivets, green monkeys, vervet monkeys, and malbroucks) sampled from locations in west, east, and south Africa. Hepatocystis cytb sequences from Papio and Chlorocebus hosts each clustered within host species among previously reported isolates from other NHP taxa. Utilizing the low-coverage sequence data (0.11-0.76X per sample) recovered across the nuclear Hepatocystis genome, we identified 349,893 polymorphic sites. Principle components analysis based on genotype likelihoods across all samples showed evidence for population structure by primate host species. Across the genome, windows of high SNP density revealed candidate hypervariable loci including Hepatocystis-specific gene families possibly involved in immune evasion and genes that may be involved in adaptation to their insect vector and hepatocyte invasion. Overall, this work demonstrates how WGS data from wild NHPs can be leveraged to study the evolution of apicomplexan parasites and potentially test for association between host genetic variation and parasite infection.

Animals↗

PubMed2002

Methylation-sensitive RFLPs: characterisation of two oil palm markers showing somaclonal variation-associated polymorphism.

The occurrence of "mantled" somaclonal variants (approx. 5%), which display alterations in floral organ structure, among populations of somatic embryo-derived oil palms ( Elaeis guineensis Jacq.) currently hampers any scaling-up of clonal plant micropropagation. As a first step towards the identification of abnormality-discriminating markers, we have screened a set of 27 oil palm cDNA probes for methylation-sensitive restriction fragment length polymorphisms (RFLPs) using callus genomic DNA digested with the isoschizomeric enzymes MspI and HpaII. Only two probes (CPHO62 and -63) were found to differentiate reproducibly in two different genotypic backgrounds between nodular compact calli (NCC) and fast-growing calli (FGC), which generate 5% and 100% "mantled" plantlets, respectively. Comparative analyses were then conducted on DNA from inflorescences and leaves of normal and abnormal adult regenerants. With both probes, the observed methylation patterns were strongly clone-dependent and monomorphic with respect to the phenotype of the regenerants, except for the type-specific banding pattern obtained with the CPHO62 probe on material from the LMC3 clonal offspring. The results presented here mirror the higher difference in genomic DNA methylation observed between normal and abnormal embryogenic calli when compared to more differentiated plant material. Moreover, they reinforce the paramount interest of NCC and FGC callus lines as a material of choice in the search for early epigenetic markers of the "mantled" somaclonal variation. The potential use of methylation-sensitive RFLPs for the early detection of somaclonal variation at early stages of the micropropagation process is discussed.

Journal Article↗

PubMed2006

Design of microarray experiments for genetical genomics studies.

Microarray experiments have been used recently in genetical genomics studies, as an additional tool to understand the genetic mechanisms governing variation in complex traits, such as for estimating heritabilities of mRNA transcript abundances, for mapping expression quantitative trait loci, and for inferring regulatory networks controlling gene expression. Several articles on the design of microarray experiments discuss situations in which treatment effects are assumed fixed and without any structure. In the case of two-color microarray platforms, several authors have studied reference and circular designs. Here, we discuss the optimal design of microarray experiments whose goals refer to specific genetic questions. Some examples are used to illustrate the choice of a design for comparing fixed, structured treatments, such as genotypic groups. Experiments targeting single genes or chromosomic regions (such as with transgene research) or multiple epistatic loci (such as within a selective phenotyping context) are discussed. In addition, microarray experiments in which treatments refer to families or to subjects (within family structures or complex pedigrees) are presented. In these cases treatments are more appropriately considered to be random effects, with specific covariance structures, in which the genetic goals relate to the estimation of genetic variances and the heritability of transcriptional abundances.

Animals↗

PubMed1995

Characterisation of Haemophilus influenzae proteins by two-dimensional gel electrophoresis.

The proteins of nontypable and type b Haemophilus influenzae isolates were characterised using two-dimensional polyacrylamide gel electrophoresis (2-D PAGE). Coomassie Brilliant. Blue R-250 was used for protein detection. Two hundred and twenty eight proteins were resolved from whole cell lysates prepared from a standard nontypable H. influenzae strain (designated HI-64443) when isoelectric focusing was used for the first-dimensional separation of 2-D PAGE. When nonequilibrium pH gel electrophoresis (NEPHGE) was used to separate basic proteins in the first dimension, 50 proteins were detected for HI-64443; 20 of the basic proteins detected were considered to be unique for this separation protocol. The apparent molecular weights and isoelectric points were determined for 82 of the proteins resolved for HI-64443. The variation of the proteins from the standard bacterial strain (HI-64443) was determined for nontypable H. influenzae isolates. On the basis of their electrophoretic mobilities, 17.5% of the proteins of HI-64443 were shared by four other nontypable H. influenzae strains analysed. These data identified both conserved and variable proteins among the nontypable H. influenzae isolates analysed. The results obtained indicated that 2-D PAGE was able to discriminate nontypable H. influenzae into population clones identified by other procedures. The 2-D protein profiles obtained for type b H. influenzae strains were similar to those obtained for nontypable H. influenzae strains. The extent of the protein variation observed between type b and nontypable H. influenzae strain was similar to that observed among nontypable strains alone. These data are discussed in relation to the application of 2-D PAGE as a tool for studies on bacterial epidemiology and for the analysis of the genome structure and gene expression of Haemophilus influenzae.

Bacterial Proteins↗