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PubMed2006

Temperature adaptation of synonymous codon usage in different functional categories of genes: a comparative study between homologous genes of Methanococcus jannaschii and Methanococcus maripaludis.

Synonymous codon usage of homologous sequences between Methanococcus jannaschii and Methanococcus maripaludis have been analyzed in three broad functional categories of genes namely: (i) information storage and processing; (ii) metabolism; and (iii) cellular processes and signaling. Average values of synonymous nucleotide substitutions per synonymous site are significantly lower for information processing genes compared to either metabolic or cellular processing genes. These results suggests that synonymous codon usage has been subject to greater constraint in the information storage and processing group of genes compared to other functional categories of genes. For metabolic and cellular processing genes, correspondence analysis based on relative synonymous codon usage (RSCU) values separates the genes along the first major axes according to the genome type; while in the information processing group, genes are separated along the second major axes according to the genome type. Further study on synonymous substitution rate for information processing genes shows a stronger selective constraint on synonymous codon usage of six amino acids, G,A,R,P,Y,F. Randomization of the original transcript of M. jannaschii for information processing genes suggests that variation in selective constraint between synonymous codon usage is related to the potential formation of mRNA secondary structures which contribute to the folding stability.

Adaptation, Biological↗
PubMed1994

Topoisomerase I action on the heterochromatic DNA from the brine shrimp Artemia franciscana: studies in vivo and in vitro.

The genomes of higher eukaryotes contain various amounts of tandem repeated DNA sequences (satellite DNA) typically located in the constitutive heterochromatin, the most highly condensed region of interphase chromosomes. We have previously demonstrated that an AluI DNA family of repeats is the major component of constitutive heterochromatin in the brine shrimp Artemia franciscana. The analysis of cloned heterochromatic fragments revealed that this repetitive DNA shows a stable curvature conferring a solenoidal geometry to the double helix. In this paper we provide evidence, using the antitumour drug camptothecin, that, in vivo, topoisomerase I cleaves heterochromatin with a frequency comparable with that observed in the whole genome. The analysis of the break sites shows that the enzyme cleaves heterochromatic DNA at specific sites characterized by a degenerate consensus sequence. Moreover the enzyme-mediated breaks have, in vitro, a degenerate consensus sequence similar to, but not identical with, the in vivo one. Some of these sites are influenced by the DNA flanking the heterochromatic insert, suggesting that structural variations could modify the enzyme specificity.

Animals↗
PubMed2000

Genetic analysis and conservation of 31 surviving individuals of a rare New Zealand tree, Metrosideros bartlettii (Myrtaceae).

Metrosideros bartlettii (Myrtaceae) is a distinctive and extremely rare tree, endemic to New Zealand, first discovered in 1975. Prior to this study, a total of 19 adult individuals of the species had been reported; these are located in three small forest remnants in the far north of the North Island of New Zealand. Here we describe a total of 31 adult M. bartlettii at the three sites, including 12 individuals newly discovered by us. We analyse the genetic diversity of the species, using microsatellites to examine the chloroplast genome and amplified fragment length polymorphisms (AFLPs) to monitor nuclear variation. The results clearly demonstrate that M. bartlettii is a unique species, distinct from its two closest relatives M. robusta and M. excelsa. Analysis of genetic diversity within the 31 remaining individuals of M. bartlettii showed an average heterozygosity (< H >) of 0.18 and a proportion of polymorphic genes (< P >) of 0.44. Population structure, as shown by 286 AFLP loci, varied between the three geographical sites; the site with fewest individuals, containing two trees, showed some separation from the populations at the other two locations. These two latter sites, by contrast, had highly overlapping AFLP population diversity profiles. The implications of these results for conservation of the species are discussed.

Conservation of Natural Resources↗
PubMed2004

Different regulatory mechanisms underlie similar transposable element profiles in pufferfish and fruitflies.

Comparative analysis of recently sequenced eukaryotic genomes has uncovered extensive variation in transposable element (TE) abundance, diversity, and distribution. The TE profile in the sequenced pufferfish genomes is more similar to that of Drosophila melanogaster than to human or mouse, in that pufferfish TEs exhibit low overall abundance, high family diversity, and localization in the heterochromatin. It has been suggested that selection against the deleterious effects of ectopic recombination between TEs has structured the TE profile in Drosophila and pufferfish but not in humans. We test this hypothesis by measuring the sample frequency of 48 euchromatic TE insertions in the genome of the green spotted pufferfish (Tetraodon nigroviridis). We estimate the strength of selection acting on recent insertions by analyzing the site frequency spectrum using a maximum-likelihood approach. We show that in contrast to Drosophila, euchromatic TE insertions in Tetraodon are selectively neutral and that the low copy number and compartmentalized distribution of TEs in the Tetraodon genome must be caused by regulation by means other than purifying selection acting on recent insertions. Inference of regulatory processes governing TE profiles should take into account factors such as effective population size, incidence of inbreeding/outcrossing, and other species-specific traits.

Animals↗
PubMed1996

Charcot-Marie-Tooth disease and related inherited neuropathies.

Charcot-Marie-Tooth disease (CMT) was initially described more than 100 years ago by Charcot, Marie, and Tooth. It was only recently, however, that molecular genetic studies of CMT have uncovered the underlying causes of most forms of the diseases. Most cases of CMT1 are associated with a 1.5-Mb tandem duplication in 17p11.2-p12 that encompasses the PMP22 gene. Although many genes may exist in this large duplicated region, PMP22 appears to be the major dosage-sensitive gene. CMT1A is the first autosomal dominant disease associated with a gene dosage effect due to an inherited DNA rearrangement. There is no mutant gene, but instead the disease phenotype results from having 3 copies of a normal gene. Furthermore, these findings suggest that therapeutic intervention in CMT1A duplication patients may be possible by normalizing the amount of PMP22 mRNA levels. Alternatively, CMT1A can be caused by mutations in the PMP22 gene. Other forms of CMT are associated with mutations in the MPZ (CMT1B) and Cx32 (CMTX) genes. Thus, mutations in different genes can cause similar CMT phenotypes. The related but more severe neuropathy, Dejerine-Sottas syndrome (DSS), can also be caused by mutations in the PMP22 and MPZ genes. All 3 genes thus far identified by CMT researchers appear to play an important role in the myelin formation or maintenance of peripheral nerves. CMT1A, CMT1B, CMTX, hereditary neuropathy with liability to pressure palsies (HNPP), and DSS have been called myelin disorders or "myelino-pathies." Other demyelinating forms, CMT1C and CMT-AR, may be caused by mutations of not yet identified myelin genes expressed in Schwann cells. The clinically distinct disease HNPP is caused by a 1.5-Mb deletion in 17p11.2-p12, which spans the same region duplicated in most CMT1A patients. Underexpression of the PMP22 gene causes HNPP just as overexpression of PMP22 causes CMT1A. Thus, 2 different phenotypes can be caused by dosage variations of the same gene. It is apparent that the CMT1A duplication and HNPP deletion are the reciprocal products of a recombination event during meiosis mediated through the CMT1A-REPs. CMT1A and HNPP could be thought of as a "genomic disease" more than single gene disorders. Other genetic disorders may also prove to arise from recombination events mediated by specific chromosomal structural features of the human genome (102). Further studies on the recombination mechanism of CMT and HNPP might reveal the causes of site specific homologous recombination in the human genome. The discovery of the PMP22 gene in the 1.5-Mb CMT1A duplication/HNPP deletion critical region also suggests that the clinical phenotype of chromosome aneuploid syndromes may result from the effect of a small subset of dosage-sensitive genes mapping within the region of aneuploidy. The understanding of the molecular basis of CMT1 and related disorders has allowed accurate DNA diagnosis and genetic counseling of inherited peripheral neuropathies and will make it possible to develop rational strategies for therapy. As several loci for CMT2 have been identified, the genes responsible for CMT2 will most likely be disclosed using positional cloning and candidate gene approaches in the near future.

Age of Onset↗
PubMed2006

Novel mitochondrial mutation in the ND4 gene associated with Leigh syndrome.

We analyzed the complete mitochondrial genome of a 3-month-old female child with basal ganglionic lesions and other clinical features suggestive of Leigh syndrome, which is caused by variations in mitochondrial and nuclear genes. Our study revealed a novel, homoplasmic T11984C missense mutation in ND4 gene, which replaces a highly conserved amino acid tyrosine with histidine. Computational analysis showed that this mutation alters the secondary structure of ND4 subunit. As the mutation observed in this study was novel and homoplasmic, we speculate that there could be interplay of this mitochondrial mutation along with nuclear gene(s) in the pathogenesis.

Amino Acid Sequence↗
PubMed2002

Application of DNA fingerprinting in medicolegal practice.

Fingerprinting is thought to establish the identify of an individual in forensic cases. The technique is extensively used for forensic purposes. Deoxyribonucleic acid (DNA) is the vehicle of generational transference of heritable unit. While arching markers for genetic disease professor Alec Jeffreys discovered that certain regions of DNA showed variations in the number of tandem repeats known as variable number of tandem repeats (VNTRs). Thus DNA fingerprint was named by observing the number of repeated sequences which differ from individual to individual. The structure of DNA is quite flexible, within the nucleus of each cell resides an identical copy of the individual's genetic material, DNA. The coding regions of the genomic DNA are known as genes. The DNA fingerprinting in forensic science has generated considerable excitement in the criminal justice community. DNA fingerprinting can be applied to identify an individual in criminal and civil cases. Polymerase chain reaction has revolutionised molecular biology it has an ability to amplify (usually fewer than 3000 bp) a particular sequence of DNA into million of copies in a very short period. Consequently only a very tiny amount of an organism's DNA needs to be available originally. This property of polymerase chain reaction has enabled to analyse many forensic samples particularly which are degraded. Microsatellite DNA or commonly as short tandem repeats are scattered throughout the human genome and occur on an average of every 10,000 nucleotides. Microsatellite markers are considered to be the most powerful genetic markers. Collection, preservation and handling are the integral part of DNA fingerprinting analysis. There are various methods to isolate DNA from different biological materials but presently most of the laboratories prefer using FTA paper. The age of humans can be estimated by using DNA based on telomere shortening.

Clinical Medicine↗
PubMed1997

Allelic variation in the mouse Tap-1 and Tap-2 transporter genes.

The TAP1 and TAP2 proteins form a heterodimer that transports short peptides from the cytosol into the endoplasmic reticulum lumen. Extensive allelic polymorphism of the rat TAP transporter has been shown to affect the repertoire of peptides presented by MHC class I molecules. Structural polymorphism in the human TAP genes is much more limited and has not been observed to have functional consequences. We have examined the polymorphism in mouse TAP1 and TAP2 in inbred mice. While the number of polymorphic positions in these molecules is more similar to that in human than to that in the rat, all strains examined have a structurally unique TAP transporter, suggesting the possibility of functional polymorphism. Furthermore, allelic variations in the mouse transporter are predominantly located in or adjacent to membrane-spanning domains, although no significant bias in the ratio of nonsynonymous to synonymous substitutions is observed. We also report that mouse TAP1 begins 172 amino acids upstream of the previously published start site and report the genomic organization of mouse Tap-1 and Tap-2.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Allelic variation of HERV-K(HML-2) endogenous retroviral elements in human populations.

Human endogenous retroviruses (HERVs) are the remnants of ancient germ cell infection by exogenous retroviruses and occupy up to 8% of the human genome. It has been suggested that HERV sequences have contributed to primate evolution by regulating the expression of cellular genes and mediating chromosome rearrangements. After integration approximately 28 million years ago, members of the HERV-K (HML-2) family have continued to amplify and recombine. To investigate the utility of HML-2 polymorphisms as markers for the study of more recent human evolution, we compiled a list of the structure and integration sites of sequences that are unique to humans and screened each insertion for polymorphism within the human genome databases. Of the total of 74 HML-2 sequences, 18 corresponded to complete or near-complete proviruses, 49 were solitary long terminal repeats (LTRs), 6 were incomplete LTRs, and 1 was a SVA retrotransposon. A number of different allelic configurations were identified including the alternation of a provirus and solitary LTR. We developed polymerase chain reaction-based assays for seven HML-2 loci and screened 109 human DNA samples from Africa, Europe, Asia, and Southeast Asia. Our results indicate that the diversity of HML-2 elements is higher in African than non-African populations, with population differentiation values ranging from 0.6 to 9.8%. These findings denote a recent expansion from Africa. We compare the phylogenetic relationships of HML-2 sequences that are unique to humans and consider whether these elements have played a role in the remodeling of the hominid genome.

Alleles↗
PubMed2003

First demonstration of a lack of viral sequence evolution in a nonprogressor, defining replication-incompetent HIV-1 infection.

It is universally acknowledged that genetic diversity is a hallmark of HIV-1 infection, and it is one of the traits that has considerably hampered the development of an effective vaccine. In a study of full-length HIV-1 genomic sequences (>9 kb), we show unique evidence for complete absence of viral evolution in an individual with truly nonprogressive infection. Gross gene defects were not detected, but the state of replication incompetence was attributed to the presence of stop codons in the structural genes gag p17 and p24 and in pol RT, which emerged as a consequence of G-A hypermutation. These inactivating mutations may have occurred early, soon after infection, during the clonal stage of primary viral replication, since these are the sole archival strains present today. This genetic homogeneity, with <1% variation between strains over an 8-year period, suggests that only limited proviral integration events occurred in this patient. Further study on the antigenic properties of this strain may assist in the development of HIV vaccines and therapeutics.

Amino Acid Sequence↗
PubMed2006

Variations in the alpha2A-adrenergic receptor gene and their functional effects.

BACKGROUND AND OBJECTIVES: The alpha2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. METHODS: We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3'-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. RESULTS: We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 +/- 6.1 pg/mL versus 218.4 +/- 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. CONCLUSION: We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers.

Adult↗
PubMed2005

Directed evolution of metabolic pathways.

The modification of cellular metabolism is of biotechnological and commercial significance because naturally occurring metabolic pathways are the source of diverse compounds used in fields ranging from medicine to bioremediation. Directed evolution is the experimental improvement of biocatalysts or cellular properties through iterative genetic diversification and selection procedures. The creation of novel metabolic functions without disrupting the balanced intracellular pool of metabolites is the primary challenge of pathway manipulation. The introduction of coordinated changes across multiple genetic elements, in conjunction with functional selection, presents an integrated approach for the modification of metabolism with benign physiological consequences. Directed evolution formats take advantage of the dynamic structures of genomes and genomic sub-structures and their ability to evolve in multiple directions in response to external stimuli. The elucidation, design and application of genome-restructuring mechanisms are key elements in the directed evolution of cellular metabolic pathways.

Biotechnology↗
PubMed2002

Salivary (SD-type) cystatins: over one billion years in the making--but to what purpose?

Human saliva contains relatively abundant proteins that are related ancestrally in sequence to the cystatin superfamily. Most, although not all, members of this superfamily are potent inhibitors of cysteine peptidases. Four related genes have been identified, CST1, 2, 4 and 5, encoding cystatins SN, SA, S, and D, respectively. CST1, 4, and probably CST5 are now known to be expressed in a limited number of other tissues in the body, primarily in exocrine epithelia, and the term SD-type cystatin is more appropriate than 'salivary cystatin'. These genes are co-ordinately regulated in the submandibular gland during post-natal development. The organization of these tissue-specifically-expressed genes in the genome, and their phylogeny, indicate that they evolved from an ancestral housekeeping gene encoding the ubiquitously expressed cystatin C, and are members of a larger protein family. Their relationship to rat cystatin S, a developmentally regulated rodent submandibular gland protein, remains to be established. In this review, the evolution of the SD-type cystatins in the cystatin superfamily, their genomics, expression, and structure-function relationships are examined and compared with known cystatin functions, with the goal of providing clues to their biological roles.

Adjuvants, Immunologic↗
PubMed1980

Molecular structure of adeno-associated virus variant DNA.

When lysates of human cells, infected jointly with the defective parvovirus, adeno-associated virus (AAV), and a helper adenovirus, are banded to equilibrium in CsCl buoyant density gradients, virus particles of various densities are obtained. Infectious AAV particles mainly band at a density of 1.41 g/cm3 with a minor component at 1.45 g/cm3. Noninfectious AAV particles band at densities between 1.41 and 1.32 g/cm3. We have analyzed, by mapping with site-specific endodeoxyribonucleases, the molecular structure of the variant AAV DNA molecules obtained from these light density particles. The size of variant DNA molecules ranged from 100 to 3% of genome length. In general, the variant DNAs are deleted for internal regions but retain the genome termini. Some of the variant DNAs appear to be cross-linked, spontaneously renaturing molecules having structures analogous to replicating forms of AAV DNA.

Adenoviruses, Human↗
PubMed2026

A genetic signal at 8q12.3 modulates GGT levels via the Runx1-CYP7B1 axis in female ethnic minorities from Guizhou.

Gamma-glutamyl transferase (GGT) regarded as a biomarker of liver dysfunction or excessive alcohol consumption; however, existing genome-wide association studies (GWAS) have been conducted predominantly in European populations and East Asian populations from Japan and the Taiwan region, with limited investigation in ethnic minorities from Guizhou Province. Previous genetic studies have demonstrated that Guizhou ethnic minorities share an East Asian genetic background while exhibiting specific genetic structures, a pattern that is also confirmed by our principal component analysis (PCA) results. We therefore performed a GWAS in this population and identified a genome-wide significant signal at 8q12.3 in female ethnic minorities from Guizhou. Fine-mapping and functional annotation analyses suggest that a regulatory pathway involving Runt-related transcription factor 1 (Runx1)-Cytochrome P450 family 7 subfamily B member 1 (CYP7B1)-cholesterol-reactive oxygen species (ROS)-glutathione (GSH) may contribute to the regulation of GGT levels. Mendelian randomization (MR) analyses further supported a causal relationship between GGT levels and autoimmune hepatitis (AIH). These findings uncover a genetic mechanism underlying GGT variation at 8q12.3 in female ethnic minorities from Guizhou, implicating a pathway linked to cholesterol metabolism and oxidative stress, and providing potential targets and insights for precision prevention and treatment of related diseases.

Female↗
PubMed1990

Heterogeneity of nitrogen mustard-induced DNA damage and repair at the level of the gene in Chinese hamster ovary cells.

We here present a general method to detect alkylation damage in specific genomic regions. Cells are treated with nitrogen mustard or dimethyl sulfate; the DNA is extracted and restricted, and the parental DNA is separated. Strand breaks are created at sites of N-alkylpurines by neutral depurination followed by alkaline hydrolysis. The DNA is then separated on alkaline agarose gels and transferred, and gene fragments are detected after hybridization with specific probes. Using this approach, we have examined damage formation and repair in the active genes dihydrofolate reductase and adenosine phosphoribosyltransferase, in a fragment containing the inactive c-fos gene and in a nontranscribed region downstream from the dihydrofolate reductase gene in Chinese hamster ovary cells. We find variations in the formation of nitrogen mustard adducts in these different regions. Nitrogen mustard adducts are preferentially repaired from the active genes as compared to the inactive gene and the noncoding region. However, we find no preferential damage or repair in these regions of the N7-methylpurines after dimethyl sulfate damage. Thus, there are significant differences in the repair mechanisms for two alkylating agents; this may implicate that there are important differences in the structural alterations in chromatin invoked by these agents. As a comparison to the studies of adduct levels in specific genomic regions, we have examined the overall genome, average adduct formation, and repair by these agents in the hamster cells. We used alkaline sucrose gradient sedimentation, and also a novel approach: quantitation of the DNA smears stained by ethidium bromide in the alkaline gels (used in the gene-selective repair analysis). Both these techniques gave similar data for adduct formation and repair; there was less initial damage formation and repair in the average genome than in specific genomic regions.

Animals↗
PubMed2001

Quantitative mutant analysis of viral quasispecies by chip-based matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry.

RNA viruses exist as quasispecies, heterogeneous and dynamic mixtures of mutants having one or more consensus sequences. An adequate description of the genomic structure of such viral populations must include the consensus sequence(s) plus a quantitative assessment of sequence heterogeneities. For example, in quality control of live attenuated viral vaccines, the presence of even small quantities of mutants or revertants may indicate incomplete or unstable attenuation that may influence vaccine safety. Previously, we demonstrated the monitoring of oral poliovirus vaccine with the use of mutant analysis by PCR and restriction enzyme cleavage (MAPREC). In this report, we investigate genetic variation in live attenuated mumps virus vaccine by using both MAPREC and a platform (DNA MassArray) based on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Mumps vaccines prepared from the Jeryl Lynn strain typically contain at least two distinct viral substrains, JL1 and JL2, which have been characterized by full length sequencing. We report the development of assays for characterizing sequence variants in these substrains and demonstrate their use in quantitative analysis of substrains and sequence variations in mixed virus cultures and mumps vaccines. The results obtained from both the MAPREC and MALDI-TOF methods showed excellent correlation. This suggests the potential utility of MALDI-TOF for routine quality control of live viral vaccines and for assessment of genetic stability and quantitative monitoring of genetic changes in other RNA viruses of clinical interest.

Animals↗
PubMed1979

Genome structure and divergence of nucleotide sequences in echinodermata.

The arrangement of repetitive and single-copy DNA sequences has been studied in DNA of some species of Echinodermata--sea urchin, starfishes and sea-cucumber. Comparison of the reassociation kinetics of short and long DNA fragments indicates that the pattern of DNA sequence organization of all these species is similar to the so-called "Xenopus pattern" characteristic of the genomes of most animals and plants. However, substantional variations have been found in the amount of repetitive nucleotide sequences in DNA of different species and in the length of DNA regions containing adjacent single-copy and repetitive sequences. Measurements of the size of S1-nuclease resistant reassociated repetitive DNA sequences show a variability of ratios between long and short repetitive DNA sequences of different species.--The degree of divergence of short and long repetitive DNA sequences and single-copy DNA was studied by molecular hybridization of the sea urchin Strongylocentrotus intermedius 3H-DNA with the DNA of other species and by determination of the thermostability of the hybridized molecules so obtained. All three fractions of S. intermedius DNA contain sequences homologous to DNA of the other echinoderm species studied. The results obtained suggest that short repetitive DNA sequences are those which have been most highly conserved throughout the evolution of Echinodermata. A new hypothesis is proposed to explain the nature of the evolutionary changes in DNA sequence interspersion patterns.

Animals↗