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PubMed2003

A new MITE family, Pangrangja, in Gramineae species.

The miniature inverted-repeat transposable element (MITE) is a type of class II transposon. We have isolated a new MITE, Pangrangja, from the species Oryza. Although Pangrangja elements are present in a number of Gramineae species, they are more prevalent in A genome Oryza species, Triticum, Aegilops, Hordeum, and Tripsacum. The Pangrangja has a 16 bp terminal inverted repeat (TIR) and conserved trinucleotides 5'-TTG-3' and 5'-AAA-3' at both ends. The TIR starts with 5'-CAGT-3', similar to the MITEs of the Emigrant family. The sequences between TIRs are very AT-rich and vary in length from 161 bp in A genome Oryza species to 513 bp in Hordeum vulgare. While the size and sequence of Pangrangia elements are conserved in the A genome Oryza species, there is some sequence variation in other plants. In an analysis of the mobile history of Oryza sativa, eight RESites (related to empty sites) were found and grouped into three types depending on the presence or absence of the conserved trinucleotides 5'-TTG-3' and 5'-AAA-3'. Since one of the RESites showed a perfect palindromic 22 bp sequence into which 180 bp of the Pangrangja element was inserted, the possible role of secondary structure of the palindromic sequences is discussed. We also suggest that as Pangrangja MITE-AFLP has been successful in many different Gramineae, Pangrangja elements may be useful in the genomic analysis of grasses.

Base Sequence↗
PubMed1994

Molecular variation in a novel polymorphic antigen associated with Plasmodium falciparum merozoites.

A cDNA clone encoding part of a novel polymorphic merozoite antigen from Plasmodium falciparum was isolated by screening a cDNA library with human immune serum from Papua New Guinea. Immunofluorescence microscopy and immunoblotting with affinity-purified antibodies recognized a highly polymorphic antigen, Ag956, present in schizonts and merozoites. Biosynthetic labeling and immunoprecipitation experiments demonstrated that Ag956 is proteolytically cleaved during merozoite maturation. The complete genomic sequence of Ag956 from the D10 clone of P. falciparum isolate FC27 encodes a secreted protein of calculated molecular mass 43,243 that is very hydrophilic and contains a region of unusual heptad repeats of the general structure AXXAXXX. This antigen has been named the secreted polymorphic antigen associated with merozoites (SPAM). The sequence of a second SPAM allele from the 3D7 clone of isolate NF54 reveals that the alanine heptad repeats and the hydrophilic C-terminal half of the protein are conserved. Variation among SPAM alleles is the result of deletions and amino acid substitutions in non-repetitive sequences within and flanking the alanine heptad-repeat domain. Heptad repeats in which the a and d position contain hydrophobic residues generate amphipathic alpha-helices which give rise to helical bundles or coiled-coil structures in proteins. Thus, SPAM is the first example of a P. falciparum antigen in which a repetitive sequence has features characteristic of a well-defined structural element.

Amino Acid Sequence↗
PubMed1987

DNA and protein heterogeneity in serial isolates of human immunodeficiency virus (HIV-1): indication of change in vivo.

Structural heterogeneity in human immunodeficiency virus (HIV-1) isolates from different sources has been reported. In order to investigate if the virus exhibits heterogeneity in vivo, HIV-1 was isolated over a 3 year period (1983-1985) from a blood donor who progressed from the asymptomatic carrier state to frank AIDS. The HIV-1 specific proteins were characterized and compared by metabolic labelling and immunoprecipitation of infected cells and by Western blot analysis of gradient purified isolates. The data indicate polymorphism in the apparent size of gag gene-encoded p55 and env gene-encoded p41 proteins. The possibility of genomic variations was evaluated by studying the restriction enzyme polymorphism of integrated proviral DNA. Genetic diversity between 1983, 1984 and 1985 isolates was demonstrated by a change in the number and/or size of restriction fragments. In addition, genetic variation was also observed in HIV-1 isolated from the blood transfusion recipient of this donor. Subsequent analysis of the quantitative and qualitative titre of HIV-1 specific antibodies in the donor recipient sera demonstrated a concomitant change with the observed structural variation in the virus. These studies may be useful in elucidating virus or host-related critical events which lead to the onset of AIDS following infection with HIV-1.

Antibodies, Monoclonal↗
PubMed2002

Cloning and genetic analysis of subtilases in sapstaining fungi.

In order to assess the genetic variance of a group of homologous subtilases in sapstaining fungi, molecular techniques were employed. First, PCR screening with degenerate primers and dot-blot analyses were used to screen 31 different isolates, representing nine species, of sapstaining fungi for the presence of subtilase-like sequences. Restriction fragment length polymorphism PCR and sequence analysis techniques were then used to determine the inter- and intraspecies variation of these genes. A labelled chemiluminescent probe was then used to screen an Ophiostoma floccosum 387N genomic library for subtilase genes. Over ten positive clones were found and one was subcloned and sequenced. Randomly amplified cDNA ends PCR techniques were then employed to obtain full-length subitilase gene sequence information from isolates of four different species. The obtained sequences were found to be homologous with other fungal subtilases and common structural features of the inferred proteins with proteinase K were apparent. Southern blot analysis was used to verify and determine the copy number of the subtilase genes in these fungi. In the work presented here, it was found that all of the isolates tested seemed to contain some sort of subtilase gene sequence and that there was inter- and intraspecies variation in the number and type of subtilase genes present. The data indicated that three distinct groups of subtilase genes are present in sapstaining fungi. However, individual isolates were found to contain only one or two of these gene types.

Amino Acid Sequence↗
PubMed2026

Swimming Upstream to Understand Congenital Anomalies of the Kidney and Urinary Tract: Zebrafish Models for Developmental Biology, Disease Mechanisms, and Functional Interpretation of Genetic Variation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of pediatric chronic kidney disease (CKD) and comprise a heterogeneous group of developmental disorders with a substantial genetic contribution. Advances in next-generation sequencing have facilitated the identification of numerous candidate genes and rare variants associated with CAKUT. However, establishing causality and defining the biological functions of implicated genes remain major challenges. Functional validation is therefore essential to bridge the gap between gene discovery and mechanistic understanding, enabling the interpretation of genetic variation within the context of kidney development and disease. The zebrafish (Danio rerio) has emerged as a powerful in vivo model for studying renal development and interrogating the function of CAKUT-associated genes. Its utility stems from a high degree of genetic and developmental conservation with humans, conserved nephrogenic pathways, optical transparency during embryogenesis, and the relative ease of genetic manipulation. In this review, we provide an overview of zebrafish kidney development within the broader context of vertebrate nephrogenesis, highlighting the key genetic programs governing intermediate mesoderm specification, nephron segmentation, and pronephric morphogenesis. We then systematically examine CAKUT-associated genes that have been modeled in zebrafish, focusing on studies that have linked genetic perturbations to renal development and structural phenotypes. Finally, we discuss the strengths and limitations of zebrafish models for functional genomics and variant interpretation and consider their emerging role in bridging genetic discovery with mechanistic insights into CAKUT pathogenesis.

Animals↗
PubMed2006

Inversion polymorphisms and non-contiguous terminal deletions: the cause and the (unpredicted) effect of our genome architecture.

Molecular definition at the BAC level of an 8p dicentric chromosome and an 8p deleted chromosome is reported in a patient with two different cell lines. The dicentric, which differed from that generating the recurrent inv dup del(8p) for the location of its break point, originated during the paternal meiosis on the background of the classical 8p23.1 inversion polymorphism. The breakage of this dicentric gave rise to the 8p deleted chromosome which, as a result of the inversion, had two non-contiguous deletions. These findings confirm previous data on 1p distal deletions, showing that at least some of the deletions stem from the breakage of dicentric chromosomes. They suggest that non-contiguous deletions may be frequent among distal deletions. This type of rearrangement can easily be overlooked when two contiguous clones, one absent and the other present by FISH analysis, are taken as boundaries of the deletion break point; in this case only high resolution array-CGH will reveal their real frequency. The definition of such non-contiguous distal deletions is relevant for phenotype/karyotype correlations. There are historical examples of blunders caused by overlooking a second non-contiguous deletion. This paper shows how small scale structural variations, such as common polymorphic inversions, may cause complex rearrangements such as terminal deletions.

Abnormalities, Multiple↗
PubMed2004

On the effect of fluctuating recombination rates on the decorrelation of gene histories in the human genome.

We show how to incorporate fluctuations of the recombination rate along the chromosome into standard gene-genealogical models for the decorrelation of gene histories. This enables us to determine how small-scale fluctuations (Poissonian hot-spot model) and large-scale variations (Kong et al. 2002) of the recombination rate influence this decorrelation. We find that the empirically determined large-scale variations of the recombination rate give rise to a significantly slower decay of correlations compared to the standard, unstructured gene-genealogical model assuming constant recombination rate. A model with long-range recombination-rate variations and with demographic structure (divergent population) is found to be consistent with the empirically observed slow decorrelation of gene histories. Conversely, we show that small-scale recombination-rate fluctuations do not alter the large-scale decorrelation of gene histories.

Chromosomes, Human, Pair 5↗
PubMed1997

Genomic structures of cardiotoxin 4 and cobrotoxin from Naja naja atra (Taiwan cobra).

Two genomic DNAs with the size of 2.3 kb and 2.4 kb, which were isolated from the liver of Naja naja atra (Taiwan cobra), encoded the precursors of cardiotoxin 4 and cobrotoxin, respectively. Both genes shared virtually identical overall organization with three exons separated by two introns, which were inserted in the similar positions of the gene's coding regions. Moreover, their nucleotide sequences shared approximately 84.2% identity. This result reveals the evolutionary relationship between cardiotoxin and cobrotoxin. The exon/intron structures of cardiotoxin 4 and cobrotoxin genes were similar to that reported for erabutoxin c gene, a neurotoxin genomic DNA from a sea snake (Laticauda semifasciata). However, in contrast to the finding that the intron 2 of these genes had a similar size, a notable variation with the size of intron 1 was observed (1233 bp, 1269 bp and 197 bp for cardiotoxin 4, cobrotoxin and erabutoxin c genes, respectively). The different size with intron 1 is due to the middle region at the first intron of cardiotoxin 4 and cobrotoxin genes, which encoded small nucleolar RNA (snoRNA), being absent in that of erabutoxin c gene. These results, together with the finding of the potential mobility of snoRNA genes during evolution, suggest that intron insertions or deletions of snoRNA genes occur with the evolutionary divergence of snake neurotoxins and cardiotoxins.

Amino Acid Sequence↗
PubMed1986

Progress in molecular parasitology.

Substantial progress has been made in the last ten years in understanding the structural and functional organization of parasitic protozoa and helminths and the complex physiological relationships that exist between these organisms and their hosts. By employing the new powerful techniques of biochemistry, molecular biology and immunology the genomic organization in parasites, the molecular basis of parasite's variation in surface antigens and the biosynthesis, processing, transport and membrane anchoring of these and other surface proteins were extensively investigated. Significant advances have also been made in our knowledge of the specific and often peculiar strategies of intermediary metabolism, cell compartmentation, the role of oxygen for parasites and the mechanisms of antiparasitic drug action. Further major fields of interest are currently the complex processes which enables parasites to evade the host's immune defense system and other mechanisms which have resulted in the specific adaptations which enabled parasites to survive within their host environments. Various approaches in molecular and biochemical parasitology and in immunoparasitology have been proven to be of high potential for serodiagnosis, immunoprophylaxis and drug design.

Animals↗
PubMed2005

Genomic structure and promoter activity of the E1AF gene, a member of the ETS oncogene family.

E1AF is a member of the ETS oncogene family and is thought to be a human homologue of mouse PEA3. We have isolated a genomic clone of E1AF and analyzed the promoter activity of its 5'-flanking region. We identified a variation in exon 1, which depends on the cell type. There was no typical TATA box in the 5'-flanking region, but putative binding sites of a number of transcription factors including PEA3 as well as CAAT boxes were seen. A luciferase reporter assay indicated that the 5'-flanking region possesses promoter activity. Northern blot studies demonstrated significant expression of the E1AF gene in restricted tissues such as the pituitary gland, placenta, and fetal kidney. Moreover, the E1AF promoter was activated by E1AF itself and estrogen receptor. These findings suggest that E1AF is a housekeeping gene, whose expression is controlled in specific tissues.

5' Flanking Region↗
PubMed2000

The controlled chaos of shifty pathogens.

Bacterial pathogens use novel mechanisms to vary their surface structures. Three new genome sequences provide a perspective on these mechanisms in Borrelia burgdorferi, Neisseria meningitidis, and Campylobacter jejuni, which cause lyme disease, meningitis and gastroenteritis, respectively.

Amino Acid Sequence↗
PubMed2003

The Lymantria dispar nucleopolyhedrovirus contains the capsid-associated p24 protein gene.

During the course of investigations on a wild-type strain of Lymantria dispar multinucleocapsid nucleopolyhedrovirus (LdMNPV), a region of the viral genome was analyzed and found to contain 697 bp that is lacking in the sequenced strain (5-6) of LdMNPV (Kuzio et al., Virology 253, 17-34, 1999). The sequenced strain of LdMNPV contains a mutation in the 25 K few polyhedra (FP) gene, and exhibits the phenotype of a FP mutant. The additional sequence was located at approximately 81.4 map units within the viral genome, and was found in 10 different wild-type LdMNPV genotypic variants analyzed. Since the additional sequence wasfound in all wild-type virus strains analyzed, this sequence should be included in the representative LdMNPV genome. Sequence analysis of the genomic region containing the additional sequences revealed the presence of a homologue of the Autographa californica MNPV capsid-associated p24 gene (ORF 129). This gene, absent in LdMNPV isolate 5-6, is also present in the Orgyia pseudotsugata MNPV, Bombyx mori NPV, Spodoptera exigua MNPV, S. litura MNPV, Mamestra configurata MNPV, Helicoverpa armigera SNPV, H. zea SNPV, Buzura suppressaria SNPV, Xestia c-nigrum granulovirus, Plutella xylostella GV, and Cydia pomonella GV.

Animals↗
PubMed2003

Recent duplication of the common carp (Cyprinus carpio L.) genome as revealed by analyses of microsatellite loci.

Genome duplications may have played a role in the early stages of vertebrate evolution, near the time of divergence of the lamprey lineage. Additional genome duplication, specifically in ray-finned fish, may have occurred before the divergence of the teleosts. The common carp (Cyprinus carpio) has been considered tetraploid because of its chromosome number (2n = 100) and its high DNA content. We studied variation using 59 microsatellite primer pairs to better understand the ploidy level of the common carp. Based on the number of PCR amplicons per individual, about 60% of these primer pairs are estimated to amplify duplicates. Segregation patterns in families suggested a partially duplicated genome structure and disomic inheritance. This could suggest that the common carp is tetraploid and that polyploidy occurred by hybridization (allotetraploidy). From sequences of microsatellite flanking regions, we estimated the difference per base between pairs of alleles and between pairs of paralogs. The distribution of differences between paralogs had two distinct modes suggesting one whole-genome duplication and a more recent wave of segmental duplications. The genome duplication was estimated to have occurred about 12 MYA, with the segmental duplications occurring between 2.3 and 6.8 MYA. At 12 MYA, this would be one of the most recent genome duplications among vertebrates. Phylogenetic analysis of several cyprinid species suggests an evolutionary model for this tetraploidization, with a role for polyploidization in speciation and diversification.

Animals↗
PubMed1986

Antigenic and molecular evolution of the vaccine strain of type 3 poliovirus during the period of excretion by a primary vaccinee.

A 4 month old child was immunized with a vaccine containing the Sabin live attenuated vaccine strains of all three serotypes of poliovirus. The antigenic and molecular evolution of the Sabin strain of poliovirus type 3 was then followed throughout the entire period of virus excretion. Novel strains appeared at 8, 42 and 52 days post-vaccination and were the products of both intertypic recombination between type 2 and type 3 poliovirus in regions of the genome coding for non-structural proteins and of point mutations in the region coding for the structural proteins. Excretion of virus continued for 73 days. All strains examined reacted with all monoclonal antibodies specific for the main immunodominant antigenic site of type 3 poliovirus, but variation was observed at other, immunorecessive sites. These findings have possible implications for the evolution of the virus in vaccinees or in epidemics and are consistent with the known antigenic stability of the virus.

Antibodies, Monoclonal↗
PubMed2004

The small chromosomes of Trypanosoma brucei involved in antigenic variation are constructed around repetitive palindromes.

Most eukaryotic genomes contain large regions of satellite DNA. These arrays are often associated with essential chromosomal functions, but remain largely absent from genome projects because of difficulties in cloning and sequence assembly. The numerous small chromosomes of the parasite Trypanosoma brucei fall into this category, yet are critical to understanding the genome because of their role in antigenic variation. Their relatively small size, however, makes them particularly amenable to physical mapping. We have produced fine-resolution maps of 17 complete minichromosomes and partial maps of two larger intermediate-sized chromosomes. This revealed a canonical structure shared by both chromosomal classes based around a large central core of 177-bp repeats. Around the core are variable-length genic regions, the lengths of which define chromosomal class. We show the core region to be a repetitive palindrome with a single inversion point common to all the chromosomes of both classes, suggesting a mechanism of genesis for these chromosomes. Moreover, palindromy appears to be a feature of (peri)centromeres in other species that can be easily overlooked. We propose that sequence inversion is one of the higher-order sequence motifs that confer chromosomal stability.

Animals↗
PubMed1994

Sequence variability of hepatitis C virus and its clinical relevance.

Chronic type C hepatitis is a potentially serious disease that can lead to cirrhosis and hepatocellular carcinoma. This complex disease is caused by the hepatitis C virus (HCV), a positive sense, single-stranded RNA virus. HCV has been assigned to a separate genus within the Flaviviridae, and shares a close relationship to the pestiviruses. Nucleotide sequence variation has been observed in genomes amplified from serum of patients with HCV infection, and cloning of RNA amplified from patients infected with HCV has confirmed the heterogeneity of the agent responsible for post-transfusion and sporadic hepatitis C. The variability of HCV is structured in a way that immediately suggests a two tiered classification: this nomenclature comprises 'types' corresponding to the major branches in a phylogenetic tree of sequences from genomic or subgenomic regions of the genome, and 'subtypes', corresponding to the more closely related sequences within some of the major groups. This genotyping designation has provided an epidemiological tool for studying geographical differences in hepatitis C infection. Clearly discernible patterns of genotype distribution have been found in those countries that have been studied so far. In many European countries genotype distributions vary with the age of patients, reflecting rapid changes in genotype distribution with time within a single geographical area. Unfortunately we know very little about modes of transmission within different communities. There is considerable interest in the clinical significance of different HCV genotypes, and the intriguing question of whether these differences may affect the spectrum of the disease associated with hepatitis C. These data also have implications for diagnosis and treatment of acute and chronic hepatitis C. A uniform typing scheme and nomenclature will facilitate our understanding of the disease caused by this virus worldwide.

Genotype↗
PubMed2004

Pronounced genetic population structure in a potentially vagile fish species (Pristipomoides multidens, Teleostei; Perciformes; Lutjanidae) from the East Indies triangle.

The East Indies triangle, bordered by the Phillipines, Malay Peninsula and New Guinea, has a high level of tropical marine species biodiversity. Pristipomoides multidens is a large, long-lived, fecund snapper species that is distributed throughout the East Indies and Indo-Pacific. Samples were analysed from central and eastern Indonesia and northern Australia to test for genetic discontinuities in population structure. Fish (n = 377) were collected from the Indonesian islands of Bali, Sumbawa, Flores, West Timor, Tanimbar and Tual along with 131 fish from two northern Australian locations (Arafura and Timor Seas) from a previous study. Genetic variation in the control region of the mitochondrial genome was assayed using restriction fragment length polymorphism and direct sequencing. Haplotype diversity was high (0.67-0.82), as was intraspecific sequence divergence (range 0-5.8%). F(ST) between pairs of populations ranged from 0 to 0.2753. Genetic subdivision was apparent on a small spatial scale; F(ST) was 0.16 over 191 km (Bali/Sumbawa) and 0.17 over 491 km (Bali/Flores). Constraints to dispersal that contribute to, and maintain, the observed degree of genetic subdivision are experienced presumably by all life history stages of this tropical marine finfish. The constraints may include (1) little or no movement of eggs or larvae, (2) little or no home range or migratory movement of adults and (3) loss of larval cohorts due to transport of larvae away from suitable habitat by prevailing currents.

Analysis of Variance↗
PubMed2000

DNA methylation and chromosome instability in lymphoblastoid cell lines.

In order to gain more insight into the relationships between DNA methylation and genome stability, chromosomal and molecular evolutions of four Epstein-Barr virus-transformed human lymphoblastoid cell lines were followed in culture for more than 2 yr. The four cell lines underwent early, strong overall demethylation of the genome. The classical satellite-rich, heterochromatic,juxtacentromeric regions of chromosomes 1, 9, and 16 and the distal part of the long arm of the Y chromosome displayed specific behavior with time in culture. In two cell lines, they underwent a strong demethylation, involving successively chromosomes Y, 9, 16, and 1, whereas in the two other cell lines, they remained heavily methylated. For classical satellite 2-rich heterochromatic regions of chromosomes 1 and 16, a direct relationship could be established between their demethylation, their undercondensation at metaphase, and their involvement in non-clonal rearrangements. Unstable sites distributed along the whole chromosomes were found only when the heterochromatic regions of chromosomes 1 and 16 were unstable. The classical satellite 3-rich heterochromatic region of chromosomes 9 and Y, despite their strong demethylation, remained condensed and stable. Genome demethylation and chromosome instability could not be related to variations in mRNA amounts of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B and DNA demethylase. These data suggest that the influence of DNA demethylation on chromosome stability is modulated by a sequence-specific chromatin structure.

Ataxia Telangiectasia↗