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PubMed2005

Genomic divergence of Escherichia coli strains: evidence for horizontal transfer and variation in mutation rates.

This report describes the sequencing in the Escherichia coli B genome of 36 randomly chosen regions that are present in most or all of the fully sequenced E. coli genomes. The phylogenetic relationships among E. coli strains were examined, and evidence for the horizontal gene transfer and variation in mutation rates was determined. The overall phylogenetic tree indicated that E. coli B and K-12 are the most closely related strains, with E. coli O157:H7 being more distantly related, Shigella flexneri 2a even more, and E. coli CFT073 the most distant strain. Within the B, K-12, and O157:H7 clusters, several regions supported alternative topologies. While horizontal transfer may explain these phylogenetic incongruities, faster evolution at synonymous sites along the O157:H7 lineage was also identified. Further interpretation of these results is confounded by an association among genes showing more rapid evolution and results supporting horizontal transfer. Using genes supporting the B and K-12 clusters, an estimate of the genomic mutation rate from a long-term experiment with E. coli B, and an estimate of 200 generations per year, it was estimated that B and K-12 diverged several hundred thousand years ago, while O157:H7 split off from their common ancestor about 1.5-2 million years ago.

Codon↗
PubMed1997

Molecular analysis of the intergenic region of the duplicated Amy genes of Drosophila melanogaster and Drosophila teissieri.

The intergenic regions between the duplicated amylase coding regions (Amy) of D. melanogaster and D. teissieri were sequenced. Their lengths in D. melanogaster and D. teissieri were 4,536 bp and 4,621 bp, respectively. Since homology between the upstream regions of the two duplicated genes was found up to 450 bp from the initiation codon of the Amy genes, the ancestral Amy coding region duplicated together with at least 450 bp of the 5'-flanking region as one unit. Comparison of the regions between the two species revealed that the level of divergence was very heterogeneous. Although the mean level of the nucleotide difference in this region was 0.107, no nucleotide substitution was found in four subregions whose sizes were more than 100 bp. Since the probability of these four subregions being completely conserved between D. melanogaster and D. teissieri was very low, these subregions were considered to have relatively important roles in evolution. Large insertions and deletions were not observed in this region but small ones were observed all over the region except for an about 1-kb subregion. This 1-kb region corresponded to an open reading frame encoding a protein which had some sequence identity with the proteins of the serine protease inhibitor superfamily (serpin). Since we could find a transcript of this gene and the synonymous substitution rate was higher than the replacement substitution rate, we suggest that this gene encodes an active serpin in Drosophila.

Amino Acid Sequence↗
PubMed1998

DNA strand biases and the mutational resilience of genes.

This paper quantifies the resilience of a gene to each class of base substitution. The resilience of a gene is defined as the set of probabilities of synonymous base substitution (one for each type of base substitution on each DNA strand), and is derived from the fraction of all possible substitutions which result in no change of encoded amino acids. We discuss the resilience of the common mutational target genes, lacI and hypoxanthine-guanine phosphoribosyltransferase (hprt), and the p53 tumour suppressor gene. There are inherent strand biases to mutation in terms of the resilience differences between the non-template and template DNA strands. The ability to quantify resilience differences between the two DNA strands contributes to our understanding of strand bias to mutation.

Bacterial Proteins↗
PubMed2004

Detecting selection in noncoding regions of nucleotide sequences.

We present a maximum-likelihood method for examining the selection pressure and detecting positive selection in noncoding regions using multiple aligned DNA sequences. The rate of substitution in noncoding regions relative to the rate of synonymous substitution in coding regions is modeled by a parameter zeta. When a site in a noncoding region is evolving neutrally zeta = 1, while zeta > 1 indicates the action of positive selection, and zeta < 1 suggests negative selection. Using a combined model for the evolution of noncoding and coding regions, we develop two likelihood-ratio tests for the detection of selection in noncoding regions. Data analysis of both simulated and real viral data is presented. Using the new method we show that positive selection in viruses is acting primarily in protein-coding regions and is rare or absent in noncoding regions.

Base Sequence↗
PubMed1995

A new HLA-C allele, Cw*1403, associated with HLA-B44 in Japanese.

An allele encoding an HLA-C antigen, tentatively called CX44, associated with HLA-B44 was identified as a new member of the Cw14 group, Cw*1403. The nucleotide sequence of Cw*1403 was closest to that of Cw*1401: five bases were different between the two alleles, in which three bases in Cw*1403 (two in exon 3 and one in exon 4) were the same as those of most HLA-C alleles. Two substitutions from guanine to adenine were found in the new allele, both of which are in exon 2, one at position 134 (61 of exon 2) and the other at position 201 (128 of exon 2). The former nucleotide substitution leads to the substitution of amino acid residue 21 from Arg to His, and the other substitution was synonymous. The former substitution was shared with Cw2, 3, 5, 13, and 15 alleles, and the latter was shared with Cw2, 4, 5, 8, 12, 13, 15 and 16 alleles. The other seven unrelated Japanese samples with CX44 were analyzed by a PCR-SSO method. It was confirmed that all the seven samples have the same substitutions as the sequenced allele, and the allele demonstrates a strong association with A33, B44, DR13, and DQ1, which are known to form a common haplotype in Japanese and Koreans.

Alleles↗
PubMed2003

Single nucleotide variation analysis in 65 candidate genes for CNS disorders in a representative sample of the European population.

The detailed investigation of variation in functionally important regions of the human genome is expected to promote understanding of genetically complex diseases. We resequenced 65 candidate genes for CNS disorders in an average of 85 European individuals. The minor allele frequency (MAF), an indicator of weak purifying selection, was lowest in radical amino acid alterations, whereas similar MAF was observed for synonymous variants and conservative amino acid alterations. In noncoding sequences, variants located in CpG islands tended to have a lower MAF than those outside CpG islands. The transition/transversion ratio was increased among both synonymous and conservative variants compared with noncoding variants. Conversely, the transition/transversion ratio was lowest among radical amino acid alterations. Furthermore, among nonsynonymous variants, transversions displayed lower MAF than did transitions. This suggests that transversions are associated with functionally important amino acid alterations. By comparing our data with public SNP databases, we found that variants with lower allele frequency are underrepresented in these databases. Therefore, radical variants obtain distinctively lower database coverage. However, those variants appear to be under weak purifying selection and thus could play a role in the etiology of genetically complex diseases.

Alleles↗
PubMed2005

A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages.

The P2X(7) receptor is a ligand-gated cation channel that is highly expressed on mononuclear leukocytes and that mediates ATP-induced apoptosis and killing of intracellular pathogens. There is a wide variation in P2X(7) receptor function between subjects, explained in part by four loss-of-function polymorphisms (R307Q, E496A, I568N, and a 5'-intronic splice site polymorphism), as well as rare mutations. In this study, we report the allele frequencies of 11 non-synonymous P2X(7) polymorphisms and describe a fifth loss-of-function polymorphism in the gene (1096C --> G), which changes Thr(357) to Ser (T357S) with an allele frequency of 0.08 in the Caucasian population. P2X(7) function was measured by ATP-induced ethidium(+) influx into peripheral blood lymphocytes and monocytes and, when compared with wild-type subjects, was reduced to 10-65% in heterozygotes, 1-18% in homozygotes, and 0-10% in compound heterozygotes carrying T357S and a second loss-of-function polymorphism. Overexpression of the T357S mutant P2X(7) in either HEK-293 cells or Xenopus oocytes gave P2X(7) function of approximately 50% that of wild-type constructs. Differentiation of monocytes to macrophages, which also up-regulates P2X(7), restored P2X(7) function to near normal in cells heterozygous for T357S and to a value 50-65% of wild-type in cells homozygous for T357S or compound heterozygous for T357S/E496A. However, macrophages from subjects that are compound heterozygous for either T357S/R307Q or T357S/stop codon had near-to-absent P2X(7) function. These functional deficits induced by T357S were paralleled by impaired ATP-induced apoptosis and mycobacteria killing in macrophages from these subjects. Lymphocytes, monocytes, and macrophages from subjects homozygous for T357S or compound heterozygous for T357S and a second loss-of-function allele have reduced or absent P2X(7) receptor function.

Adenosine Triphosphate↗
PubMed1994

Construction and characterization of recombinant Vibrio cholerae strains producing inactive cholera toxin analogs.

The catalytic A subunit of cholera toxin (CT-A) is capable of ADP-ribosylating the guanine nucleotide-binding protein, which regulates cell adenylyl cyclase, leading to the life-threatening diarrhea of cholera. Amino acids involved in the enzymatic activity of CT-A have previously been identified. By means of site-directed mutagenesis, an analog of the CT-A subunit gene was created with codon substitutions for both Arg-7 and Glu-112, each of which has been shown to produce subunits lacking ADP-ribosyltransferase activity. The mutated gene fragment was exchanged for the wild-type copy in the previously cloned ctxAB operon from El Tor biotype, Ogawa serotype Vibrio cholerae strain 3083, which produces CT-2. Further, the zonula occludens toxin gene, zot, was inactivated by an insertional mutation to create the new plasmid construct pCT-2*. Additionally, a DNA fragment encoding the B subunit of CT-1 (CT produced by classical biotype, Inaba serotype V. cholerae strain 569B) was exchanged for the homologous part in pCT-2*, resulting in the creation of pCT-1*. These plasmid constructs were introduced into the CT-negative V. cholerae mutant strain JBK70 (E1 Tor biotype, Inaba serotype); CT-A-B+ derivatives CVD101 and CVD103 of classical biotype Ogawa and Inaba serotype strains 395 and 569B, respectively; El Tor biotype Inaba and Ogawa serotype strains C6706 and C7258, respectively, recently isolated in Peru; and O139 (synonym Bengal) strain SG25-1 from the current epidemic in India. Recombinant toxins (CT-1* and CT-2*), partially purified from culture supernatants of transformed JBK70, were shown to be inactive on mouse Y1 adrenal tumor cells and in an in vitro ADP-ribosyltransferase assay. CT-1* and CT-2* reacted with polyclonal and monoclonal antibodies against both A and B subunits of CT. The toxin analogs reacted with antibodies against CT-A and CT-B on cellulose acetate strips and in a GM1 enzyme-linked immunosorbent assay; they reacted appropriately with B-subunit epitype-specific monoclonal antibodies in checkerboard immunoblots, and they formed precipitin bands with GM1-ganglioside in Ouchterlony tests. However, the reactions of the modified proteins with anti-A-subunit monoclonal antibodies were weaker than the reactions with wild-type holotoxins. V, cholerae strains carrying ctxA*, with either ctxB-1 or ctxB-2, and inactivated zot genes were created by homologous recombination. The recombinant strains and the purified toxin analogs were inactive in the infant rabbit animal model.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Length polymorphism in the threonine-glycine-encoding repeat region of the period gene in Drosophila.

Single-fly polymerase chain reaction amplification and direct DNA sequencing revealed high levels of length polymorphism in the threonine-glycine encoding repeat region of the period (per) gene in natural populations of Drosophila melanogaster. DNA comparison of two alleles of identical lengths gave a high number of synonymous substitutions suggesting an ancient time of separation. However detailed examination of the sequences of different Thr-Gly length variants indicated that this divergence could be understood in terms of four deletion/insertion events. In Drosophila pseudoobscura a length polymorphism is observed in a five-amino acid degenerate repeat, which corresponds to melanogaster's Thr-Gly domain. In spite of the differences between D. melanogaster and D. pseudoobscura in the amino acid sequence of the repeats, the predicted secondary structures suggest evolutionary and mechanistic constraints on the per protein of these two species.

Amino Acid Sequence↗
PubMed2002

A comparative genomic method for computational identification of prokaryotic translation initiation sites.

The ever growing number of completely sequenced prokaryotic genomes facilitates cross-species comparisons by genomic annotation algorithms. This paper introduces a new probabilistic framework for comparative genomic analysis and demonstrates its utility in the context of improving the accuracy of prokaryotic gene start site detection. Our frame work employs a product hidden Markov model (PROD-HMM) with state architecture to model the species-specific trinucleotide frequency patterns in sequences immediately upstream and downstream of a translation start site and to detect the contrasting non-synonymous (amino acid changing) and synonymous (silent) substitution rates that differentiate prokaryotic coding from intergenic regions. Depending on the intricacy of the features modeled by the hidden state architecture, intergenic, regulatory, promoter and coding regions can be delimited by this method. The new system is evaluated using a preliminary set of orthologous Pyrococcus gene pairs, for which it demonstrates an improved accuracy of detection. Its robustness is confirmed by analysis with cross-validation of an experimentally verified set of Escherichia coli K-12 and Salmonella thyphimurium LT2 orthologs. The novel architecture has a number of attractive features that distinguish it from previous comparative models such as pair-HMMs.

Algorithms↗
PubMed2005

[Mutation detection of mismatch repair genes in hereditary nonpolyposis colorectal cancer by denaturing high-performance liquid chromatography].

OBJECTIVES: To establish DHPLC method in detecting mutations of mismatch repair genes, hMLH1 and hMSH2, and to identify germline mutations of hMLH1 and hMSH2 in HNPCC kindreds fulfilling Chinese HNPCC criteria. METHODS: Fourteen peripheral blood DNA samples from 14 unrelated HNPCC probands fulfilling Chinese HNPCC criteria were obtained respectively. PCR amplified 35 exons of two main mismatch repair genes, hMLH1 and hMSH2. DHPLC followed by DNA sequencing was used to detect and confirm mutations. RESULTS: a total of 41 colorectal cancers and 19 extracolonic tumors were developed in 14 HNPCC kindreds, and gastric cancer was the most common extracolonic tumor type. Twelve single nucleotide changes were identified by DHPLC in 14 probands. Among them, three were missense mutations, one was a nonsense mutation. Other single nucleotide changes included five single nucleotide polymorphisms, two intron single nucleotide changes, one synonymous mutation. hMLH1 EXON19 CODON749 TAC-->TAG (Tyr-->X), hMSH2 EXON12 CODON629 CAA-->CGA (Gln-->Arg) and hMSH2 EXON15 CODON839 CAT-->CGT (His-->Arg) were new discovered mutations. CONCLUSIONS: (1) DHPLC was considered to be highly effective, convenient technique with consistent results for the mutation detection of hMLH1 and hMSH2 genes. (2) Valid mutations of hMLH1 and hMSH2 genes were identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria and missense mutation was the most common mutational types in this cohort of families.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Evolution of the interleukin-1 gene family in mammals.

The phylogeny of interleukin-1 family genes shows that human interleukin-1 alpha (IL-1 alpha) is more closely related to IL-1 alpha of the bovine than to IL-1 alpha of the mouse, whereas human interleukin-1 beta (IL-1 beta) is more closely related to IL-1 beta of the mouse than to IL-1 beta of the bovine. The IL-1 receptor antagonist (IL-1ra) shows homology to the C-terminal region of both IL-1 alpha and IL-1 beta. In the C-terminal region, the IL-1 alpha genes of human and mouse have diverged more from each other at nonsynonymous sites than have either IL-1 beta or IL-1ra; because the same pattern is not seen at synonymous sites, it must be due not to a difference in mutation rate but rather to a greater degree of functional constraint on this region in the IL-1 beta and IL-1ra proteins than in the IL-1 alpha protein. But synonymous sites in IL-1 beta of mouse have evolved more rapidly than in IL-1 beta of human, indicating a higher rate of mutation in the former gene. In the N-terminal region of the protein, nonsynonymous sites have evolved at similar rates in IL-1 alpha and IL-1 beta. The first exon of the IL-1ra gene, which encodes the leader peptide, shows evidence of homology with the first exon of IL-1 beta, which is not translated. Thus, it seems likely that IL-1ra evolved by duplication of an IL-1 beta gene and loss of expression of exons 2-4.

Amino Acid Sequence↗
PubMed2004

Evidence for abundant slightly deleterious polymorphisms in bacterial populations.

The nearly neutral theory of molecular evolution predicts that slightly deleterious mutations subject to purifying selection are widespread in natural populations, particularly those of large effective population size. To test this hypothesis, the standardized difference between pairwise nucleotide difference and number of segregation sites (corrected for number of sequences) was estimated for 149 population data sets from 84 species of bacteria. This quantity (Tajima's D-statistic) was estimated separately for synonymous (D(syn)) and nonsynonymous (D(non)) polymorphisms. D(syn) was positive in 70% of data sets, and the overall median D(syn) (0.873) was positive. By contrast D(non) was negative in 68% of data sets, and the overall median D(non) (-0.656) was negative. The preponderance of negative values of D(non) is evidence that there are widespread rare nonsynonymous polymorphisms in the process of being eliminated by purifying selection, as predicted to occur in populations with large effective size by the nearly neutral theory. The major exceptions to this trend were seen among surface proteins, particularly those of bacteria parasitic on vertebrates, which included a number of cases of polymorphisms apparently maintained by balancing selection.

Bacteria↗
PubMed1997

Size and sequence polymorphism in the isocitrate dehydrogenase kinase/phosphatase gene (aceK) and flanking regions in Salmonella enterica and Escherichia coli.

The sequence of aceK, which codes for the regulatory catalytic enzyme isocitrate dehydrogenase kinase/phosphatase (IDH K/P), and sequences of the 5' flanking region and part or all of the 3' flanking region were determined for 32 strains of Salmonella enterica and Escherichia coli. In E. coli, the aceK gene was 1734 bp long in 13 strains, but in three strains it was 12 bp shorter and the stop codon was TAA rather than TGA. Strains with the shorter aceK lacked an open reading frame (f728) downstream between aceK and iclR that was present, in variable length, in the other strains. Among the 72 ECOR strains, the truncated aceK gene was present in all isolates of the B2 group and half of those of the D group. Other variant conditions included the presence of IS1 elements in two strains and large deletions in two strains. The aceK-aceA intergenic region varied in length from 48 to 280 bp in E. coli, depending largely on the number of repetitive extragenic palindromic (REP) sequences present. Among the ECOR strains, the number of REP elements showed a high degree of phylogenetic association, and sequencing of the region in the ECOR strains permitted partial reconstruction of its evolutionary history. In S. entica, the normal length of aceK was 1752 bp, but three other length variants, ranging from 1746 to 1785 bp, were represented in five of the 16 strains examined. The flanking intergenic regions showed relatively minor variation in length and sequence. The occurrence of several nonrandom patterns of distribution of polymorphic synonymous nucleotide sites indicated that intragenic recombination of horizontally exchanged DNA has contributed to the generation of allelic diversity at the aceK locus in both species.

Bacterial Proteins↗
PubMed2005

Nucleotide substitution and recombination at orthologous loci in Staphylococcus aureus.

The pattern of nucleotide substitution was examined at 2,129 orthologous loci among five genomes of Staphylococcus aureus, which included two sister pairs of closely related genomes (MW2/MSSA476 and Mu50/N315) and the more distantly related MRSA252. A total of 108 loci were unusual in lacking any synonymous differences among the five genomes; most of these were short genes encoding proteins highly conserved at the amino acid sequence level (including many ribosomal proteins) or unknown predicted genes. In contrast, 45 genes were identified that showed anomalously high divergence at synonymous sites. The latter genes were evidently introduced by homologous recombination from distantly related genomes, and in many cases, the pattern of nucleotide substitution made it possible to reconstruct the most probable recombination event involved. These recombination events introduced genes encoding proteins that differed in amino acid sequence and thus potentially in function. Several of the proteins are known or likely to be involved in pathogenesis (e.g., staphylocoagulase, exotoxin, Ser-Asp fibrinogen-binding bone sialoprotein-binding protein, fibrinogen and keratin-10 binding surface-anchored protein, fibrinogen-binding protein ClfA, and enterotoxin P). Therefore, the results support the hypothesis that exchange of homologous genes among S. aureus genomes can play a role in the evolution of pathogenesis in this species.

Codon↗
PubMed2004

Genome-wide patterns of nucleotide substitution reveal stringent functional constraints on the protein sequences of thermophiles.

To test the hypothesis that the proteins of thermophilic prokaryotes are subject to unusually stringent functional constraints, we estimated the numbers of synonymous and nonsynonymous nucleotide substitutions per site between 17,957 pairs of orthologous genes from 22 pairs of closely related species of Archaea and Bacteria. The average ratio of nonsynonymous to synonymous substitutions was significantly lower in thermophiles than in nonthermophiles, and this effect was observed in both Archaea and Bacteria. There was no evidence that this difference could be explained by factors such as nucleotide content bias. Rather, the results support the hypothesis that proteins of thermophiles are subject to unusually strong purifying selection, leading to a reduced overall level of amino acid evolution per mutational event. The results show that genome-wide patterns of sequence evolution can be influenced by natural selection exerted by a species' environment and shed light on a previous observation that relatively few of the mutations arising in a thermophilic archaeon were nucleotide substitutions in contrast to indels.

Adaptation, Biological↗
PubMed2003

Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus.

We report an association between a non-familial form of photosensitive Lupus-specific skin disease, subacute cutaneous lupus erythematosus (SCLE), and a new single nucleotide polymorphism (SNP) in the C1QA gene. We also describe an association between this SNP and lower levels of serum C1q. This SNP consists of adenine replacing the third guanine in the codon for aminoacid residue Gly70 (position excludes the 22 amino acid leading peptide) that is located in the second exon of the C1QA gene. We have designated this SNP C1qA-Gly70GGA (the GenBank sequence at this location is C1qA-Gly70GGG). A survey of 19 SCLE patients showed that 11 (58%) were homozygous for C1qA-Gly70GGA SNP, seven (37%) were heterozygous, and only one patient (5%) was homozygous for the GenBank sequence. In contrast, only 13 of 62 (21%) normal controls were homozygous for the C1qA-Gly70GGA SNP, 41 (66%) controls were heterozygous and eight (13%) controls were homozygous for the GenBank sequence. Thus, the C1qA-Gly70GGA SNP is strongly associated with SCLE (P-value = 0.005 by chi-square analysis with Yates correction). This SNP would traditionally be classified as clinically silent as it does not encode a different amino acid. However, our studies have suggested that this SNP appears to be associated with a functional abnormality of C1q expression since its presence correlates inversely with serum levels of C1q antigenic protein in both SCLE patients and normal controls. The mechanism by which this phenotypic change is associated with the translationally silent (synonymous) ClqA-Gly70GGA genetic variation is currently unknown.

Base Sequence↗
PubMed2002

Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease.

Stroke is a major cause of morbidity and mortality in sickle cell (SS) disease. Genetic risk factors have been postulated to contribute to this clinical outcome. The human genome project has substantially increased the catalog of variations in genes, many of which could modify the risk for manifestations of disease outcome in a monogenic disease, namely SS. VCAM1 is a cell adhesion molecule postulated to play a critical role in the pathogenesis of SS disease. We identified a total of 33 single nucleotide polymorphisms (SNPs) by sequencing the entire coding region, 2134 bp upstream of the 5' end of the published cDNA, 217 bp downstream of the 3' end of the cDNA, and selected intronic regions of the VCAM1 locus. Allelic frequencies for selected SNPs were determined in a healthy population. We subsequently analyzed 4 nonsynonymous coding, 2 synonymous coding, and 4 common promoter SNPs in a genetic association study of clinically apparent stroke in SS disease conducted in a cohort derived from a single institution in Jamaica (51 symptomatic cases and 51 matched controls). Of the 10 candidate SNPs analyzed in this pilot study, the variant allele of the nonsynonymous SNP, VCAM1 G1238C, may be associated with protection from stroke (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.83, P =.04). Further study is required to confirm the importance of this variant in VCAM1 as a clinically useful modifier of outcome in SS disease.

Alleles↗