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PubMed1994

Analysis of hepatitis C virus genotypes by a line probe assay and correlation with antibody profiles.

The 5' untranslated regions derived from 54 patients with a chronic hepatitis C virus infection were analyzed to determine the (sub)type of hepatitis C virus. Labelled polymerase chain reaction products from 5' untranslated region were used as probes for reverse hybridization in a line probe assay (Inno-LiPA) and results were validated by comparison with direct sequencing data. Five different genotypes could be distinguished based on 5' untranslated region sequence diversity. Results of typing by line probe assay and direct sequencing were similar. Antibody responses against core, NS-3, NS-4 and NS-5 epitopes were detected by RIBA-4 and Inno-LIA HCVAb II confirmatory assays. There was no consistent correlation between genotype and anti-HCV responses, although types 2, 3 and 4 hepatitis C virus isolates show poor reactivity with NS-4 ep!%"pes.

Base Sequence↗
PubMed1992

Do the ends justify the mean? Proline mutations at the ends of the keratin coiled-coil rod segment are more disruptive than internal mutations.

Intermediate filament (IF) assembly is remarkable, in that it appears to be self-driven by the primary sequence of IF proteins, a family (40-220 kd) with diverse sequences, but similar secondary structures. Each IF polypeptide has a central 310 amino acid residue alpha-helical rod domain, involved in coiled-coil dinner formation. Two short (approximately 10 amino acid residue) stretches at the ends of this rod are more highly conserved than the rest, although the molecular basis for this is unknown. In addition, the rod is segmented by three short nonhelical linkers of conserved location, but not sequence. To examine the degree to which different conserved helical and nonhelical rod sequences contribute to dimer, tetramer, and higher ordered interactions, we introduced proline mutations in residues throughout the rod of a type I keratin, and we removed existing proline residues from the linker regions. To further probe the role of the rod ends, we introduced more subtle mutations near the COOH-terminus. We examined the consequences of these mutations on (a) IF network formation in vivo, and (b) 10-nm filament assembly in vitro. Surprisingly, all proline mutations located deep in the coiled-coil rod segment showed rather modest effects on filament network formation and 10-nm filament assembly. In addition, removing the existing proline residues was without apparent effect in vivo, and in vitro, these mutants assembled into 10-nm filaments with a tendency to aggregate, but with otherwise normal appearance. The most striking effects on filament network formation and IF assembly were observed with mutations at the very ends of the rod. These data indicate that sequences throughout the rod are not equal with respect to their role in filament network formation and in 10-nm filament assembly. Specifically, while the internal rod segments seem able to tolerate considerable changes in alpha-helical conformation, the conserved ends seem to be essential for creating a very specific structure, in which even small perturbations can lead to loss of IF stability and disruption of normal cellular interactions. These findings have important implications for the disease Epidermolysis Bullosa Simplex, arising from point mutations in keratins K5 or K14.

Amino Acid Sequence↗
PubMed1995

Genes and languages in Europe: an analysis of mitochondrial lineages.

When mitochondrial DNA sequence variation is analyzed from a sample of 637 individuals in 14 European populations, most populations show little differentiation with respect to each other. However, the Saami distinguish themselves by a comparatively large amount of sequence difference when compared with the other populations, by a different distribution of sequence diversity within the population, and by the occurrence of particular sequence motifs. Thus, the Saami seem to have a long history distinct from other European populations. Linguistic affiliations are not reflected in the patterns of relationships of mitochondrial lineages in European populations, whereas prior studies of nuclear gene frequencies have shown a correlation between genetic and linguistic evolution. It is argued that this apparent contradiction is attributable to the fact that genetic lineages and gene frequencies reflect different time perspectives on population history, the latter being more in concordance with linguistic evolution.

Base Sequence↗
PubMed2003

PANTHER: a library of protein families and subfamilies indexed by function.

In the genomic era, one of the fundamental goals is to characterize the function of proteins on a large scale. We describe a method, PANTHER, for relating protein sequence relationships to function relationships in a robust and accurate way. PANTHER is composed of two main components: the PANTHER library (PANTHER/LIB) and the PANTHER index (PANTHER/X). PANTHER/LIB is a collection of "books," each representing a protein family as a multiple sequence alignment, a Hidden Markov Model (HMM), and a family tree. Functional divergence within the family is represented by dividing the tree into subtrees based on shared function, and by subtree HMMs. PANTHER/X is an abbreviated ontology for summarizing and navigating molecular functions and biological processes associated with the families and subfamilies. We apply PANTHER to three areas of active research. First, we report the size and sequence diversity of the families and subfamilies, characterizing the relationship between sequence divergence and functional divergence across a wide range of protein families. Second, we use the PANTHER/X ontology to give a high-level representation of gene function across the human and mouse genomes. Third, we use the family HMMs to rank missense single nucleotide polymorphisms (SNPs), on a database-wide scale, according to their likelihood of affecting protein function.

Algorithms↗
PubMed1991

The expression of the Ig H chain repertoire in developing bone marrow B lineage cells.

Analyses of rearranged Ig H chain V region genes of bone marrow pre-B cells demonstrate extensive sequence diversity, particularly within the third hypervariable region (HCDR3). This diversity is constrained, however, through preferential utilization of certain D gene segments and possibly VH gene segments and a preponderance of productive rearrangements, primarily those expressing D gene segments in a preferred reading frame. The predominance of productively rearranged V genes with D regions translated in a preferred frame, is, at least in part, the consequence of selective clonal expansion encompassing at least five to six divisions subsequent to VH-D-JH rearrangement. Selection for clonal expansion appears to be dependent on recognition of the nascent H chain product of certain productively rearranged genes.

Antibody Diversity↗
PubMed1995

Rapid identification of mycobacteria from AIDS patients by capillary electrophoretic profiling of amplified SOD gene.

Aim-Rapid differentiation of mycobacterial species at the genomic level.Methods-The manganese superoxide dismutase (SOD) gene (464 bp) and 16SrRNA (353 bp) from 104 isolates (18 species) of mycobacteria were amplified using polymerase chain reaction (PCR). Products were sequenced and a phenogram of SOD sequences derived. PCR products of SOD gene were digested with HaeIII, and restriction fragment profiles visualised using capillary electrophoresis.Results-Novel SOD sequences were found for M szulgai, M marinum, M phlei, M smegmatis, M chelonei, M paratuberculosis, M malmoense, M intracellulare serotype 7, M intracellulare serotype 18, and M celatum types 1, 2, and 3. Phylogenetic analysis indicated that 18 of 19 species studied had 8-29% interspecies and <6% intraspecies sequence diversity in the SOD gene. No consistent differences were detected between AIDS and non-AIDS isolates. M paratuberculosis showed a unique SOD sequence with a 1.1% (SD 0.5%) diversity from M avium. Capillary electrophoresis profiles were able to differentiate 16 of 18 species within 24 hours.Conclusions-A phenogram of SOD sequences clearly delineated all mycobacterial species and showed two distinct clusters, fast growing species, and the M avium complex (MAC). Within the MAC, M avium (five types), M intracellulare (five types), M scrofulaceum (two types), and M paratuberculosis (one type) could be demonstrated. Phylogenetic diversity of M celatum from MAC, previously suggested by 16SrRNA data, was confirmed. This simple and rapid method for DNA extraction, in conjunction with capillary electrophoresis of SOD restriction fragments, allows rapid identification of mycobacterial isolates.

Journal Article↗
PubMed1997

Isolation and characterisation of a diverse family of Arabidopsis two and three-fingered C2H2 zinc finger protein genes and cDNAs.

In animal systems the C2H2 zinc finger protein (ZFP) gene family is the largest group of regulatory proteins and its members have a wide and important role in growth and development. It is likely that this family of ZFP transcription factors will also be important in plants. We have used a PCR approach employing highly degenerate oligonucleotide primers to isolate several Arabidopsis genomic and cDNA clones encoding potential ZFPs. In addition we have used the sequence information from these clones to identify two ESTs as members of this family. Five two-fingered and one three-fingered ZFPs have been identified. Outside of the zinc finger regions, there is considerable sequence diversity, including the sequence and length of the interfinger region; the expression pattern of each gene is different. This is the first report of the isolation of a three-fingered plant C2H2 ZFP gene and we discuss its possible evolutionary origin from two-fingered ZFP genes.

Amino Acid Sequence↗
PubMed2002

Numerous, robust genetic markers for Plasmodium chabaudi by the method of amplified fragment length polymorphism.

We have used the method of amplified fragment length polymorphism (AFLP) to identify genetic polymorphisms between two cloned isolates of the rodent malaria parasite Plasmodium chabaudi chabaudi. The method employs polymerase chain reaction (PCR)-amplification of genomic DNA fragments cut with specific combinations of restriction endonucleases; we used EcoRI and Tru1I (isoschizomer of MseI). We have identified 819 parasite clone-specific AFLPs between P. c. chabaudi clones AS and AJ. Of these, 403 fragments were specific to AS and 416 to AJ. In preparing blood stage parasites for DNA, nucleated host cells were removed by successive filtration of infected blood through powdered cellulose and Plasmodipur filters. This reduced nucleated host cell contamination to around 1-10 per million parasite nuclei and reduced host DNA to below the limit of detection by the AFLP method. Analysis of our results showed that the total number of PCR-amplified fragments of parasite DNA was consistent with the predicted number of EcoRI sites in the parasite genome. 19.4% of all amplified fragments were P. c. chabaudi clone-specific. From this figure we estimated that the diversity between clones AS and AJ, measured as the probability of a sequence difference, was between about 8 x 10(-3) and 4.6 x 10(-4) per base pair. This is consistent with the sequence diversity found between alleles of candidate drug resistance genes from P. c. chabaudi clones AS and AJ identified and sequenced in this laboratory.

Animals↗
PubMed1994

Functional consequences of amino-terminal diversity of the catalytic subunit of the Na,K-ATPase.

One region of marked sequence diversity among the highly homologous alpha isoforms of the Na,K-ATPase is the lysine-rich NH2 terminus. Expression of a mutant cDNA encoding an alpha 1 protein, minus the 32 NH2-terminal residues, results in a modified enzyme (alpha 1M32), which behaves similarly to alpha 1 in overall Na/K exchange activity (Vmax) and apparent affinities for intracellular Na+ and extracellular K+. However, with membranes isolated from HeLa cells expressing the rat alpha 1M32 mutant, as well as membranes from cells expressing the rat alpha 1 and the ouabain-resistant mutated forms of rat alpha 2 (alpha 2*) and alpha 3 (alpha 3*) developed by Jewell and Lingrel (Jewell, E. A., and Lingrel, J. B. (1991) J. Biol. Chem. 266, 16925-16930), distinct Na,K-ATPase kinetics are observed. Thus, at 1 microM ATP, the effects of K+ on the Na-ATPase activity of alpha 2* and alpha 1M32 are similar; both are activated, whereas alpha 1 and alpha 3 are inhibited by the addition of K+ at low (0.1 mM) concentration. These effects are attributed to different rates of a step involved in K+ deocclusion (E2(K)<-->E1K<-->E1 + K+) and are consistent with our earlier evidence (Wierzbicki, W., and Blostein, R. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 70-74) for a role of the NH2 terminus in the K+ deocclusion pathway of the Na,K-ATPase reaction. These differences are not directly related to differences in apparent affinities for ATP, since alpha 3* has alpha 1-like high affinity K+ inhibition but resembles alpha 2* and alpha 1M32 with respect to a lower K'ATP. Na-ATPase activities of alpha 2*, alpha 3*, and alpha 1M32, but not alpha 1, are activated by Li+ but not Rb+, consistent with a relatively faster rate of Li+ deocclusion (Post, R. L., Hegyvary, C., and Kume, S. (1972) J. Biol. Chem. 247, 6530-6540), as well as higher affinity of alpha 3 for extracellular K+ (Li+) activation of dephosphorylation (E2P + K+<-->E2(K) + Pi). Inhibition of Na-ATPase by higher concentrations (> or = 1 mM) K+ is observed with all isoforms and is attributed to K+ acting at inhibitory cytoplasmic sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed2007

Multilocus analysis of nucleotide variation of Oryza sativa and its wild relatives: severe bottleneck during domestication of rice.

Varying degrees of reduction of genetic diversity in crops relative to their wild progenitors occurred during the process of domestication. Such information, however, has not been available for the Asian cultivated rice (Oryza sativa) despite its importance as a staple food and a model organism. To reveal levels and patterns of nucleotide diversity and to elucidate the genetic relationship and demographic history of O. sativa and its close relatives (Oryza rufipogon and Oryza nivara), we investigated nucleotide diversity data from 10 unlinked nuclear loci in species-wide samples of these species. The results indicated that O. rufipogon and O. nivara possessed comparable levels of nucleotide variation ((sil) = 0.0077 approximately 0.0095) compared with the relatives of other crops. In contrast, nucleotide diversity of O. sativa was as low as (sil) = 0.0024 and even lower ((sil) = 0.0021 for indica and 0.0011 for japonica), if we consider the 2 subspecies separately. Overall, only 20-10% of the diversity in the wild species was retained in 2 subspecies of the cultivated rice (indica and japonica), respectively. Because statistic tests did not reject the assumption of neutrality for all 10 loci, we further used coalescent to simulate bottlenecks under various lengths and population sizes to better understand the domestication process. Consistent with the dramatic reduction in nucleotide diversity, we detected a severe domestication bottleneck and demonstrated that the sequence diversity currently found in the rice genome could be explained by a founding population of 1,500 individuals if the initial domestication event occurred over a 3,000-year period. Phylogenetic analyses revealed close genetic relationships and ambiguous species boundary of O. rufipogon and O. nivara, providing additional evidence to treat them as 2 ecotypes of a single species. Lowest linkage disequilibrium (LD) was found in the perennial O. rufipogon where the r(2) value dropped to a negligible level within 400 bp, and the highest in the japonica rice where LD extended to the entirely sequenced region ( approximately 900 bp), implying that LD mapping by genome scans may not be feasible in wild rice due to the high density of markers needed.

Base Sequence↗
PubMed1992

Evolution of the mammalian G protein alpha subunit multigene family.

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. The multigene family of G protein alpha subunits, which interact with receptors and effectors, exhibit a high level of sequence diversity. In mammals, 15 G alpha subunit genes can be grouped by sequence and functional similarities into four classes. We have determined the murine chromosomal locations of all 15 G alpha subunit genes using an interspecific backcross derived from crosses of C57BL/6J and Mus spretus mice. These data, in combination with mapping studies in humans, have provided insight into the events responsible for generating the genetic diversity found in the mammalian alpha subunit genes and a framework for elucidating the role of the G alpha subunits in disease.

Animals↗
PubMed2007

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Aged↗
PubMed2005

MADS box genes in oil palm (Elaeis guineensis): patterns in the evolution of the SQUAMOSA, DEFICIENS, GLOBOSA, AGAMOUS, and SEPALLATA subfamilies.

MADS box genes code for a large family of transcription factors which regulate development in higher plants, notably flower formation. We describe here a study of members of the MADS box gene family in oil palm (Elaeis guineensis Jacq.), a representative of the family Arecaceae and order Arecales, a key group of monocotyledons which has been unreported in previous phylogenetic reconstructions of the different recognized clades of MADS box genes. In this study, 13 oil palm MADS box genes were identified and characterized. They were found to belong to five different subfamilies, namely, the previously defined SQUAMOSA, AGAMOUS, AGAMOUS-like2, DEFICIENS, and GLOBOSA groups. Genes belonging to each of these groups play a critical role in the determination of flower structure as defined by the ABCDE model. The in planta expression profiles of the oil palm MADS box genes were studied by RT-PCR and phylogenetic sequence diversity within individual subfamilies was investigated by comparing their deduced protein sequences with those of other angiosperms. Most of the oil palm sequences studied were observed to group with distinct supported clades within their subfamily. Some unexpected groupings were observed between monocot sequences (including oil palm ones) of non-Poaceae origin, probably illustrating the importance of obtaining adequate taxon representation in monocot molecular phylogenies.

Arecaceae↗
PubMedDate not supplied

Structure and variation within variant surface glycoproteins of Trypanosoma brucei.

Variant surface glycoproteins of the African trypanosomes are members of a multigene family which show extraordinary amino sequence diversity. The extent of this diversity and the significance of homologies both in the amino acid sequence and in the post-translational modifications are discussed in the light of what is predicted for the structure of these molecules and what is now known from X-ray crystallographic analysis.

Amino Acid Sequence↗
PubMed2003

Phylogeny of Astragalus in China: molecular evidence from the DNA sequences of 5S rRNA spacer, ITS, and 18S rRNA.

Radix Astragali (root of Astragalus; Huangqi) is a traditional Chinese medicine commonly used as an immunostimulant, hepatoprotective, diuretic, antidiabetic, analgesic, expectorant, and sedative drug. Although the species of Radix Astragali have been defined as Astragalus membranaceus and A. membranaceus var. mongholicus in Pharmacopoeia of China, their taxonomy remains controversial. The phylogenetic relationships among 10 Astragalus taxa, which are commonly found in China including A. membranaceus, A. membranaceus var. mongholicus, Astragalus propinquus, Astragalus lepsensis, Astragalus aksuensis, Astragalus hoantchy, Astragalus hoantchy subsp. dshimensis,Astragalus lehmannianus, Astragalus sieversianus, and Astragalus austrosibiricus, were determined using the DNA sequences of the 5S ribosomal RNA (5S rRNA) spacer, internal transcribed spacer region (ITS), and 18S rRNA coding region. The 5S rRNA spacer, ITS, and 18S rRNA, amplified by polymerase chain reaction from the isolated genomic DNAs, were sequenced. By using neighbor-joining and maximum parsimony analyses, phylogenetic trees were mapped by their sequence diversity. A. membranaceus and A. membranaceus var. mongholicus shared the greatest sequence homology. In addition, A. propinquus shared a closer relationship with A. membranaceus and A. membranaceus var. mongholicus, while other Astragalus species were less closely related. This is the first paper to show the phylogenetic relationship of Astragalus species related to Radix Astragali in China by the molecular genetic approach.

Astragalus Plant↗
PubMed2000

Organization and expression of calicivirus genes.

The application of molecular techniques to the characterization of caliciviruses has resulted in an extensive database of sequence information. This information has led to the identification of 4 distinct genera. The human enteric caliciviruses have been assigned to 2 of these genera. This division is reflected not only in sequence diversity but in a fundamental difference in genome organization. Complete genome sequences are now available for 5 enteric caliciviruses and demonstrate that human and animal enteric caliciviruses are phylogenetically closely related. Currently, there is no cell culture system for the human viruses; therefore, studies have relied on heterologous expression and in vitro systems. These studies have shown that in both human and animal viruses the viral nonstructural proteins are produced from a polyprotein precursor that is cleaved by a single viral protease. The purpose of this article is to provide an overview of the current knowledge of genome structure and gene expression in the enteric caliciviruses.

Animals↗
PubMed2005

Estimating a nucleotide substitution rate for maize from polymorphism at a major domestication locus.

To estimate a rate for single nucleotide substitutions for maize (Zea mays ssp. mays), we have taken advantage of data from genetic and archaeological studies of the domestication of maize from its wild ancestor, teosinte (Z. mays ssp. parviglumis). Genetic studies have shown that the teosinte branched1 (tb1) gene was a major target of human selection during maize domestication, and sequence diversity in the intergenic region 5' to the tb1-coding sequence is extraordinarily low. We show that polymorphism in this region is consistent with new mutation following fixation for a small number of tb1 haplotypes during domestication. Archeological studies suggest that maize was domesticated approximately 6,250-10,000 years ago and subsequently the size of the maize population is thought to have expanded rapidly. Using the observed number of mutations within the region of selection at tb1, the approximate age of maize domestication, and approximations for the maize genealogy, we have derived estimates for the nucleotide substitution rate for the tb1 intergenic region. Using two approaches, one of which is a coalescent approach, we obtain rate estimates of approximately 2.9 x 10(-8) and 3.3 x 10(-8) substitutions per site per year. We also show that the pattern of polymorphism in the tb1 intergenic region appears to have been strongly affected by the mutagenic effect of DNA methylation. Excluding target sites of symmetric DNA methylation (CG and CNG sites) from analysis, the mutation rate estimates are reduced by approximately 50%-60%, while the rates for CG and CNG sites are nearly an order of magnitude higher. We use rate estimates from the tb1 region to estimate the timing of expansion of transposable elements in the maize genome and suggest that this expansion occurred primarily within the last million years.

Base Sequence↗
PubMed2006

Construction of an artificial ribozyme which ligates an RNA fragment activated by nicotinamide mononucleotide.

A new strategy termed "Design & Selection" has been developed for construction of artificial ribozymes. In this strategy, two distinct approaches (de novo rational design and in vitro selection) were successfully combined. De novo rational design was employed for construction of a structural scaffold of a new ribozyme whereas in vitro selection was adopted for isolation of a catalytic unit, sequence and structure of which were unpredictable. Using this strategy, a ligase ribozyme (DSL ribozyme) has been isolated. To validate versatility of Design & Selection strategy, we attempted to isolate a new catalytic unit utilizing a nicotinamide mononucleotide as a leaving group in RNA-RNA ligation reaction. Into the de novo designed scaffold RNA, 45 random nucleotides were inserted. The resulting RNA library consisting of the scaffold and randomized regions was subjected to in vitro selection. Using the library with 10(14) sequence diversity, a new class of ribozyme bearing a novel catalytic unit sequence was successfully isolated.

Catalytic Domain↗