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PubMed1994

Selection intensity for codon bias.

The patterns of nonrandom usage of synonymous codons (codon bias) in enteric bacteria were analyzed. Poisson random field (PRF) theory was used to derive the expected distribution of frequencies of nucleotides differing from the ancestral state at aligned sites in a set of DNA sequences. This distribution was applied to synonymous nucleotide polymorphisms and amino acid polymorphisms in the gnd and putP genes of Escherichia coli. For the gnd gene, the average intensity of selection against disfavored synonymous codons was estimated as approximately 7.3 x 10(-9); this value is significantly smaller than the estimated selection intensity against selectively disfavored amino acids in observed polymorphisms (2.0 x 10(-8)), but it is approximately of the same order of magnitude. The selection coefficients for optimal synonymous codons estimated from PRF theory were consistent with independent estimates based on codon usage for threonine and glycine. Across 118 genes in E. coli and Salmonella typhimurium, the distribution of estimated selection coefficients, expressed as multiples of the effective population size, has a mean and standard deviation of 0.5 +/- 0.4. No significant differences were found in the degree of codon bias between conserved positions and replacement positions, suggesting that translational misincorporation is not an important selective constraint among synonymous polymorphic codons in enteric bacteria. However, across the first 100 codons of the genes, conserved amino acids with identical codons have significantly greater codon bias than that of either synonymous or nonidentical codons, suggesting that there are unique selective constraints, perhaps including mRNA secondary structures, in this part of the coding region.

Codon↗
PubMed1997

Nucleotide polymorphism in colicin E2 gene clusters: evidence for nonneutral evolution.

To explore the molecular mechanisms behind the diversification of colicin gene clusters, we examined DNA sequence polymorphism for the colicin gene clusters of 14 colicin E2 (ColE2) plasmids obtained from natural isolates of Escherichia coli. Two types of ColE2 plasmids are revealed, with type II gene clusters generated by recombination between type I ColE2 and ColE7 gene clusters. The levels and patterns of DNA polymorphism are different between the two types. Type I polymorphism is distributed evenly along the gene cluster, while type II accumulates polymorphism at an elevated rate in the 5' end of the colicin gene. These differences may be explained by recombinational origins of type II gene clusters. The pattern of divergence between the ColE2 gene cluster and its close relative ColE9 is not correlated with the pattern of polymorphism within ColE2, suggesting that this gene cluster is not evolving in a neutral fashion. A statistical test confirms significant departures from the predictions of neutrality. These data lend further support to the hypothesis that colicin gene clusters may evolve under the influence of nonneutral forces.

Base Sequence↗
PubMed1995

Enhancer-trap targeting at the Broad-Complex locus of Drosophila melanogaster.

Here, we describe the exact replacement of a defective unmarked P element by an enhancer-trap transposon marked by the miniwhite gene and carrying lacZ as a reporter gene. The original defective P element was located in an intron of the Broad-Complex (BRC), a key gene involved in metamorphosis. Replacement events resulted from conversions induced by the P-element transposase from a donor enhancer-trap element located on another chromosome. Six independent conversion events were selected. In all converted chromosomes, the enhancer-trap transposon was in the same orientation as the original P element. From the pattern of X-gal staining observed, lacZ expression likely reflects the regulatory influence of BRC enhancers on the convertant transposon. Reversion to wild type was achieved by excision of the enhancer-trap transposon. The six convertants were analyzed in detail at the nucleotide level. The occurrence of a polymorphism at position 33 of the P-element sequences led us to propose a conversion mechanism involving homologous P sequences for repair. This is in contrast to previously analyzed P-element transposase-induced conversion events and proposed models relying on sequence identity between genomic Drosophila sequences. The lack of any homology requirement other than between P element sequences means that our findings can be easily generalized. Targeting a marked P-element derivative at a precise site without loss or addition of genetic information makes it possible to exploit the hundreds of defective P elements scattered throughout the Drosophila genome by replacing them with engineered P elements, already available.

Animals↗
PubMed2005

C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis.

RATIONALE: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. OBJECTIVES: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. METHODS: In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. MEASUREMENTS AND MAIN RESULTS: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage >or= II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96-13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5-17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5-18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8-16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5-23.1; corrected p = 0.0009). CONCLUSIONS: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.

Case-Control Studies↗
PubMed2006

Unique evolutionary mechanism in R-genes under the presence/absence polymorphism in Arabidopsis thaliana.

While the presence/absence polymorphism is commonly observed in disease resistance (R-) genes in Arabidopsis, only a few R-genes under the presence/absence polymorphism (R-P/A) have been investigated. To understand the mechanism of the molecular evolution of R-P/A, we investigated genetic variation of nine R-P/A in A. thaliana from worldwide populations. The number of possessed R-genes varied widely among accessions (two to nine, on average 4.3 +/- 1.6/accession). No pair of accessions shared the same haplotype, and no clear geographic differentiation was observed with respect to the pattern of presence/absence of the R-genes investigated. Presence allele frequencies also varied among loci (25-70%), and no linkage disequilibrium was detected among them. Although the LRR region in regular R-genes is known to be highly polymorphic and has a high Ka/Ks ratio in A. thaliana, nucleotide sequences of this region in the R-P/A showed a relatively low level of genetic variation (pi = 0.0002-0.016) and low Ka/Ks (0.03-0.70, <1). In contrast, the nucleotide diversities around the deletion junction of R-P/A were constantly high between presence and absence accessions for the R-genes (D(xy) = 0.031-0.103). Our results suggest that R-P/A loci evolved differently from other R-gene loci and that balancing selection plays an important role in molecular evolution of R-P/A.

Alleles↗
PubMed2000

Intergenic spacer (IGS) polymorphism: a new genetic marker for differentiation of Toxoplasma gondii strains and Neospora caninum.

The region between the 28S and 18S rRNA genes, including the intergenic spacer (IGS) region and the 5S rRNA gene, from 32 strains of Toxoplasma gondii and the NC1 strain of Neospora caninum was amplified and used for DNA sequencing and/or restriction fragment length polymorphism (RFLP) analysis. The 5S rDNA sequences from 20 strains of T. gondii were identical. The IGS region between the 5S and 18S rRNA genes (nontranscribed spacer 2 or NTS 2) showed 10 nucleotide variations. Six of the 10 variant positions correlated with the murine virulence of the strains. Intraspecific polymorphisms distinguished the virulent strains of zymodemes 5, 6, and 8 from other virulent strains (in zymodeme 1). RFLP methods (IGS-RFLP) were developed and used to characterize the virulent and avirulent patterns among 29 T. gondii strains. Sequence diversity of 19.8% was found between T. gondii and N. caninum when comparing a region of 919 bp at the 3' end of NTS 2. The sequence variation in ribosomal IGS could therefore be a useful marker for Toxoplasma strain identification and for distinguishing N. caninum from T. gondii.

Animals↗
PubMed2003

Isolation and characterization of serine protease gene(s) from Perkinsus marinus.

This study reports the first serine protease gene(s) isolated from Perkinsus marinus. Using universal primers, a 518 bp subtilisin-like serine protease gene fragment was amplified from P. marinus genomic DNA and used as a probe to screen a lambda-phage P. marinus genomic library; 2 different lambda-phage clones hybridized to the digoxigenin(DIG)-labeled subtilisin-like gene fragment. Following subcloning and sequencing of the larger DNA fragment, a 1254 bp open reading frame was identified and later confirmed, by 5' and 3' random amplification of cDNA ends (RACE) and northern blot analysis, to contain the entire coding-region sequence. Sequence analysis of the 3' RACE results from 2 isolate cultures, VA-2 (P-1) and LA 10-1, revealed multiple polymorphic sites within and among isolates. We identified 2 different types of cDNA clones with 95.53% nucleotide sequence similarity, suggesting the possibility of 2 closely related genes within the P. marinus genome. Southern blot analysis of genomic DNA from 12 genetically distinct P. marinus isolate cultures revealed 2 different banding patterns among isolates.

Amino Acid Sequence↗
PubMed2001

Geographical variation of the liver fluke, Clonorchis sinensis, from Korea and China based on the karyotypes, zymodeme and DNA sequences.

Genetic characterization was carried out in order to reveal the geographical variations of the oriental liver fluke, Clonorchis sinensis (Trematoda: Opisthorchiidae), collected in Korea and China. The chromosome number was 2n=56 in both Korean (Kimhae) and Chinese (Liaoning) flukes, and chromosomes were divided into two groups based on their sizes; consisting of 8 pairs of large and 20 pairs of small chromosomes. However, the karyotypes showed some differences between Korean and Chinese flukes. Isozyme analysis showed that two loci from each enzyme of aconitase and esterase (alpha-Na and beta-Na); only one locus each from six enzymes, glucose-6-phosphate dehydrogenase (G6PD), alpha-glycerophosphate dehydrogenase (GPD), 3-hydroxybutyrate dehydrogenase (HBDH), malate dehydrogenase (MDH), phosphoglucose isomerase (PGl) and phosphoglucomutase (PGM). Most of loci in two populations of C. sinensis showed homozygous monomorphic banding patterns and one of them, GPD was specific as genetic markers between two different populations. Two populations were very closely clustered within the range of genetic identity value of 0.998-1.0. We also compared patterns of intraspecific polymorphism of two markers with contrasted modes of evolution, nuclear ribosomal DNA (rDNA) and mitochondrial DNA (mtDNA) of the liver fluke from Kimhae, Guangxi and Liaoning. They showed a high homology. In conclusion, three populations of C. sinensis from Korea and China showed high homogeneity in the nucleotide sequences of the 18S rDNA, ITS2 and mtCOI gene.

Animals↗
PubMed2001

Genomic approaches to typing, taxonomy and evolution of bacterial isolates.

The current literature on bacterial taxonomy, typing and evolution will be critically examined from the perspective of whole-genome structure, function and organization. The following three categories of DNA band pattern studies will be reviewed: (i) random whole-genome analysis; (ii) specific gene variation and (iii) mobile genetic elements. (i) The use of RAPD, PFGE and AFLP to analyse the whole genome will provide a skeleton of polymorphic sites with exact genomic positions as whole-genome sequence data become available. (ii) Different genes provide different levels of evolutionary information for determining isolate relatedness depending on whether they are highly variable (prone to recombination events and horizontal transfer), housekeeping genes with only a small number of single nucleotide differences between isolates or part of the rrn multigene family that is prone to intragenomic recombination and concerted evolution. Comparative analyses of these different gene classes can provide enhanced information about isolate relatedness. (iii) Mobile genetic elements such as insertion sequences, transposons, plasmids and bacteriophages integrate into the bacterial genome at specific (e.g. tRNA genes) or non-specific sites to alter band patterns produced by PFGE, RAPD or AFLP. From the literature it is not clear what level of genetic element duplication constitutes non-relatedness of isolates. A model is presented that incorporates all of the above genomic characteristics for the determination of isolate relatedness in taxonomic, typing and evolutionary studies.

Bacteria↗
PubMed2002

Quasispecies in the 5' untranslated genomic region of bovine viral diarrhoea virus from a single individual.

The variability of the 5' untranslated genomic region (5'UTR) of bovine viral diarrhoea virus (BVDV) RNA obtained from a single individual was analysed. Lung, kidney and spleen tissues from a naturally infected foetus were used as the source of viral RNA. A fragment of 288 bases of the internal ribosome entry site from the BVDV 5'UTR was amplified by RT-PCR using a proofreading DNA polymerase. PCR products were cloned into pGem and, subsequently, transformed into Escherichia coli. The single-strand conformational polymorphisms of 158 lung-derived clones were analysed; a total of 11 banding patterns was observed. DNAs corresponding to all patterns were sequenced. Of the randomly selected clones, 11 and 10 clones derived from the kidney and spleen, respectively, were also sequenced. All sequences presented differences ranging from 1 to 6 nt substitutions. Analysis of the secondary structure of the variant sequences and comparisons to variant nucleotide sites from the 5'UTR of several BVDV isolates showed that the observed changes were almost free of randomness. Clustering and phylogenetic analyses suggested the existence of low-kinetic variants. BVDV quasispecies may be involved in establishing persistent infections by means of eluding maternal antibodies. The methods described here may be adapted easily both to analyse large numbers of samples from other genomic regions and for the study of BVDV quasispecies evolution in other systems.

5' Untranslated Regions↗
PubMed1995

Genetic variability in mitochondrial DNA of the screwworm, Cochliomyia hominivorax (Diptera: Calliphoridae), from Brazil.

Restriction fragment length polymorphism (RFLP) analysis of mitochondrial DNA (mtDNA) was used to examine genetic variation and population structure of screwworm flies in four populations from São Paulo State, Brazil. The total DNA of 405 individuals was digested with 15 restriction endonucleases and probed with five cloned HindIII fragments representing the entire mitochondrial genome of Cochliomyia hominivorax. The survey revealed that four enzymes (HaeIII, HindIII, MspI, and PvuII) were suitable to detect mtDNA variation among all populations. Based on the fragment patterns obtained for these four enzymes, a total of 15 haplotypes in combination was detected. Heteroplasmic individuals for the PvuII pattern were obtained in one of the populations. The estimated average for nucleotide sequence divergence (delta) was 0.92%. The cladogram of the geographical distribution among the observed haplotypes suggests that the sampled screwworms probably belong to a single evolutionary lineage with populations interconnected by reduced gene flow.

Animals↗
PubMed2006

Screening for inter-individual splicing differences in human GSTM4 and the discovery of a single nucleotide substitution related to the tandem skipping of two exons.

The glutathione S-transferase Mu class (GSTM) genes encode phase II metabolism enzymes that are involved in the detoxification of various carcinogens and drugs. Some genetic polymorphisms in GSTM genes are related to disease phenotypes and drug-metabolism differences in the population. Polymorphisms that alter gene-splicing patterns are functionally very important because they often lead to the insertion or deletion of many amino acids. To identify inter-individual differences in the splicing pattern of the GSTM4 gene, we used reverse transcriptase polymerase chain reaction (RT-PCR) to screen cDNA from 96 human liver samples. We discovered a novel splice variant of GSTM4 that resulted from tandem skipping of exons 4 and 5. This exon-skipping event is associated with a mutation at the splice acceptor site in intron 4.

DNA, Complementary↗
PubMed1993

Screening for point mutations in exon 10 of the low density lipoprotein receptor gene by analysis of single-strand conformation polymorphisms: detection of a nonsense mutation-FH469-->Stop.

DNA from 40 unrelated familial hypercholesterolemia (FH) heterozygotes were subjected to analyses of single-strand conformation polymorphisms (SSCPs) of exon 10 of the low density lipoprotein receptor (LDLR) gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. Three of the patterns represented the three genotypes of a recently described sense mutation in codon 450. A method based upon the polymerase chain reaction (PCR) was developed to analyze this mutation. The frequencies of the wild-type (G at nucleotide 1413) and mutant (A at nucleotide 1413) alleles were 0.56 and 0.44, respectively. The fourth pattern was found in only one FH heterozygote and was caused by heterozygosity at nucleotide 1469 (G/A). Nucleotide 1469 is the second base of codon 469Trp(TGG). The G-->A mutation changes this codon into the amber stop codon, and is referred to as FH469-->Stop. The mutant receptor consists of the amino terminal 468 amino acids. Because the truncated receptor has lost the membrane-spanning domain, it will not be anchored in the cell membrane. FH469-->Stop destroys an AvaII restriction site, and this characteristic was used to develop a PCR method to establish its frequency in Norwegian FH subjects. Two out of 204 (1%) unrelated FH heterozygotes possessed the mutation.

Adult↗
PubMed1998

Departure from neutrality at the mitochondrial NADH dehydrogenase subunit 2 gene in humans, but not in chimpanzees.

To test whether patterns of mitochondrial DNA (mtDNA) variation are consistent with a neutral model of molecular evolution, nucleotide sequences were determined for the 1041 bp of the NADH dehydrogenase subunit 2 (ND2) gene in 20 geographically diverse humans and 20 common chimpanzees. Contingency tests of neutrality were performed using four mutational categories for the ND2 molecule: synonymous and nonsynonymous mutations in the transmembrane regions, and synonymous and nonsynonymous mutations in the surface regions. The following three topological mutational categories were also used: intraspecific tips, intraspecific interiors, and interspecific fixed differences. The analyses reveal a significantly greater number of nonsynonymous polymorphisms within human transmembrane regions than expected based on interspecific comparisons, and they are inconsistent with a neutral equilibrium model. This pattern of excess nonsynonymous polymorphism is not seen within chimpanzees. Statistical tests of neutrality, such as TAJIMA's D test, and the D and F tests proposed by FU and LI, indicate an excess of low frequency polymorphisms in the human data, but not in the chimpanzee data. This is consistent with recent directional selection, a population bottleneck or background selection of slightly deleterious mutations in human mtDNA samples. The analyses further support the idea that mitochondrial genome evolution is governed by selective forces that have the potential to affect its use as a "neutral" marker in evolutionary and population genetic studies.

Animals↗
PubMed2006

Characterization of infectious bursal disease viruses from Argentina.

Infectious bursal disease (IBD) viruses detected in commercial flocks of different regions of Argentina were analyzed by reverse transcription-polymerase chain reaction-restriction fragment length polymorphism (RFLP) of a VP2 gene fragment, followed by sequence analysis. Two out of eight IBD viruses presented an SspI restriction site, typical of the very virulent phenotype. Three IBD viruses presented a SacI restriction site, typical of classic virulent strains, and one isolate presented restriction sites for both enzymes. The Argentine IBD viruses showed three different molecular patterns by RFLP with the restriction endonuclease BstNI and five different patterns with MboI. By comparison of nucleotide and deduced amino acid sequences of the hypervariable region of the VP2 protein, four Argentine viruses were found to be closely related to Brazilian subclinical strains and two isolates were found to be related to vaccine IBDV strains in use in Argentina. Strain LD9569 was genetically characterized as a very virulent strain and was found to be closely related to international and regional vvIBDV strains. This is the first report on variability of IBDV strains circulating in Argentina.

Amino Acid Sequence↗
PubMed2000

Acyclovir resistance in herpes simplex virus isolates from keratitis cases: an analysis from a developing country.

Seven herpes simplex type-1 (HSV-1) isolates from herpes simplex keratitis (HSK) cases clinically resistant to acyclovir (ACV) were analyzed for the mechanism of ACV resistance in them. The purpose of the study was to focus the attention of ophthalmologists on the frequency of occurrence of ACV resistance in HSK and to characterize such a phenomenon. We employed in-vitro plaque reduction assay, thymidine kinase assay, polymerase chain reaction, single-strand confirmation polymorphism analysis and sequencing to detect any mutation(s) in thymidine kinase gene in this analytical study. Four of the seven HSV-1 isolates proved ACV resistant by plaque reduction assay and three of them showed reduced thymidine kinase activity. Altered mobility pattern indicative of mutation within 335 base pair PCR product bracketing the suggested homopolymer mutational hotspot (7 Guanosine) was detected in 2 of these 3 isolates. DNA sequencing showed a deletion at nucleotide position 336 from the tk gene transcription start in both the isolates. This mutation has generated the first TGA stop codon 27 nucleotides downstream in the tk open reading frame. Our study also suggests the need of clinical/molecular surveillance of ACV resistance in HSV types in a given geographic location for better management of HSV infections.

Acyclovir↗
PubMed1995

Nucleotide polymorphism in the 5' promoter region of esterase 6 in Drosophila melanogaster and its relationship to enzyme activity variation.

A 974-bp region immediately 5' of the esterase 6 gene was sequenced in 17 field derived third chromosome isoallelic lines. Twenty-three polymorphisms were identified, only two in the first 400 bp 5' but 16 in a 325-bp region from -494 to -819 bp. This distribution differs from previously published patterns in Drosophila simulans and D. mauritiana, where the first 800 bp are highly conserved. Fourteen common polymorphisms in the 325-bp region above are all in strong linkage disequilibrium with each other. Moreover, most of the haplotypes defined by the total of 23 polymorphisms fall into two groups that differ as a block at all 14 of these latter sites. Sequence differences between the two groups include some restriction sites that were scored in an earlier study of RFLPs and EST6 enzyme phenotypes among 42 isoallelic lines from the same population. By collating the two studies, we show that one haplotype group yields approximately 15% lower EST6 enzyme activity in adult males than the other. The promoter haplotypes show only weak disequilibrium with the esterase 6 fast/slow allozyme polymorphism, so it seems unlikely that previously reported latitudinal clines in the allozyme frequencies are due to their hitchhiking along with selection on the promoter difference.

Animals↗
PubMed1989

[DNA fingerprints and hypervariable regions: genetic marker with many application potentials in medicine and biology].

DNA polymorphisms are based on variations in the nucleotide sequences of the DNA within a given population and are transmitted from parents to offspring by Mendelian inheritance. Most of these mutations are phenotypically silent. Two different types of DNA polymorphisms are restriction fragment length polymorphisms and highly variable regions (HVRs), the latter with many different alleles at a given locus. Molecular probes for HVRs (or DNA minisatellites) can detect a great number of cross-hybridising fragments dispersed throughout the genome. The polymorphic patterns of these fragments are completely individual-specific, hence termed DNA "fingerprints". DNA "fingerprinting" has been shown to be a powerful tool for establishing family relationships, for example in paternity disputes, and for the positive identification of individuals in forensic medicine. The technique may be used to document marrow engraftment in patients who have undergone allogeneic bone marrow transplantation. DNA "fingerprinting" is a new method of assessing clonality in human tumours by identifying clonal somatic mutations in the tumour DNA. Cloning of individual DNA "fingerprint" fragments yields locus-specific HVR probes which, due to their high rate of heterozygosity, are ideal for linkage analysis and prenatal diagnosis in single gene disorders. This is exemplified by adult polycystic kidney disease, which has been found by a 3'alpha-globin-HVR probe to be closely linked to the alpha-globin-gene cluster on chromosome 16p. Locus-specific HVR probes have been used for the molecular diagnosis of clonal chromosomal deletions or loss of heterozygosity at particular loci in a large variety of tumours. These findings are the basis for the identification of anti-oncogenes or putative tumour-suppressor genes in the human genome.

Animals↗