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PubMed2004

A harmonic structure of the genetic code.

In this paper is presented a new, very harmonic structure of the genetic code (GC) within a system of "4 x 5" (and/or of "5 x 4") of amino acids (AAs) in two variants. In first variant, the five rows within the system start with one polar charged amino acid (AA) each, making first column, consisting from five polar charged AAs (D, R, K, H, E). Five polar non-charged AAs (N, P, Y, W, Q) follow, then five non-polar AAs as last column (A, L, F, V, I) and, finally, five polar or non-polar AAs, in a combination, as first to last column (A as non-polar; S, T as polar, and G, P as ambivalent AAs). A second variant is subsequent to this one-"4 x 5" system with five nitrogen AAs (K, R, P, H, W), five oxygen (D, E, Y, S, T), five solely carbon (A, L, F, V, I) and five "combined" AAs (G with hydrogen as side chain; C and M with carbon and sulfur; N and Q with carbon, oxygen and nitrogen). A strict balance of atom and nucleon number as well as molecule mass follows the classification in both system variants.

Amino Acids↗
PubMed1994

Analysis of interstrain variation in a putative immediate-early region of human herpesvirus 6 DNA and definition of variant-specific sequences.

Sequences of a 2.6- to 2.9-kb open reading frame in a putative immediate-early region of the human herpesvirus 6 (HHV6) genome were determined and compared in three reference and six local isolates of HHV6. The sequences segregated into two variant groups (A and B) having only 75% nucleotide homology and 62% peptide homology, in part because of deletions in the variant A strains. Among the variant B isolates, further sequence grouping was evident; two clinical isolates segregated with reference strain Z29 into a cluster that had 96.6% nucleotide homology and 92.6% peptide homology when compared to a second variant B cluster of four isolates. Within each cluster of variant B isolates, nucleotide homology was 99.4% or more. Two pairs of isolates had identical sequences. The marked divergence of variants A and B permitted the design of variant-specific oligonucleotide primers that could detect in a single polymerase chain reaction the presence of either or both variant A and B HHV6 DNA. Variation in this gene region of HHV6 is more extensive than in the envelope glycoprotein (gB and gH) coding regions and could be related to known biological differences between variant groups.

Amino Acid Sequence↗
PubMed2005

Genomic organization and evolution of the 5S ribosomal DNA in the ancient fish sturgeon.

Ribosomal DNA in sturgeon is informative when analyzed at the molecular level because it bears unique characteristics that are, to a certain extent, ancestral within vertebrates. In this paper, we examine the structure and the molecular evolution of the 5S ribosomal DNA (rDNA) region in 13 sturgeon species, comparing both the 5S ribosomal RNA (rRNA) genes and the non-transcribed spacer (NTS) sequences between the coding regions. We have found that different NTS and 5S gene variants are intermixed in the 5S rDNA arrays of the different sturgeon species and that all variants are ancestral, having been maintained over many millions of years. Using predictive models, we have found similar levels of sequence diversity in the coding regions, as well as in the non-coding region, but fixed interspecific differences are underrepresented for 5S genes. However, contrary to the expectations, we have not found fixed differences between NTS sequences when comparing many pairs of species. Specifically, when they belong to the same phylogeographic clade of the four into which the sturgeon is divided, but fixation of mutations and divergence is found between species belonging to different phylogeographic clades. Our results suggest that the evolution of the two parts of the 5S rDNA region cannot be explained exclusively as the outcome of a balance between mutational, homogenizing (i.e., gene conversion as a predominant force in sturgeon), and selective forces. Rather, they suggest that other factors (i.e., hybridization) might be superimposed over those forces and thus could to some extent be masking their effects.

Animals↗
PubMed1990

Missense mutations at lysine 350 in beta 2-tubulin confer altered sensitivity to microtubule inhibitors in Chlamydomonas.

Two beta-tubulin mutants of Chlamydomonas reinhardtii, colR4 and colR15, were previously isolated in our laboratory. Each mutant expressed an acidic beta-tubulin variant as a result of an alteration in the coding sequence of one of the two beta-tubulin genes in C. reinhardtii, which in the wild type encode identical proteins. In this report, we describe the identity of the specific beta-tubulin altered in the colR mutants and the precise nature of the genetic lesions. Hybrid selection of mutant poly(A)+ RNA with cDNA probes specific for the two beta-tubulins in C. reinhardtii indicated that both mutations resided in the beta 2-tubulin gene. cDNA libraries were constructed with mutant poly(A)+ RNA, and beta 2-tubulin cDNA clones were isolated. Results of in vitro transcription of cloned beta 2-tubulin cDNAs confirmed the identity of the altered genes. Sequencing of the entire coding regions of the beta 2-tubulin cDNA clones revealed that the mutants carried different single-base substitutions in the same codon for the amino acid at position 350 in the beta 2-tubulin sequence, effecting a change from a lysine to a glutamic acid in the colR4 variant and to a methionine in the colR15 variant. These changes in amino acids are consistent with the difference in the charge of the two variant polypeptides observed in isoelectric focusing. Because both the colR4 and colR15 mutations confer an altered sensitivity to a number of different microtubule inhibitors and herbicides, lysine 350 appears to be of functional importance in the structure of the tubulin molecule.

Amino Acid Sequence↗
PubMed1991

DNA sequence abnormalities of human glucose-6-phosphate dehydrogenase variants.

Over 400 supposedly biochemically and genetically distinct variants of glucose-6-phosphate dehydrogenase (G6PD) have been described in the past. In order to investigate these variants at the DNA sequence level we have now determined the relevant sequences of introns of G6PD and describe a method which allows us to rapidly determine the sequence of the entire coding region of G6PD. This technique was applied to six variants that cause G6PD deficiency to be functionally so severe as to result in nonspherocytic hemolytic anemia. Although the patients were all unrelated, G6PD Marion, Gastonia, and Minnesota each had identical mutations, a G----T at nucleotide (nt) 637 in exon 6 leading to a Val----Leu substitution at amino acid 213. The mutations of Nashville and Anaheim were identical to each other, viz. G----A at nt 1178 in exon 10 producing a Arg----His substitution at amino acid 393. G6PD Loma Linda had a C----A substitution at nt 1089 in exon 10, producing a Asn----Lys change at amino acid 363. The results confirm our earlier results suggesting that the NADP-binding site is in a small region of exon 10 and suggest the possibility that this area is also concerned with the binding of glucose-6-P.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed1998

Characterization of a splice variant of metastasis-associated h-mts1 (S100A4) gene expressed in human infiltrating carcinomas of the breast.

The h-mts1 (S100A4) is a member of the S100 gene family, coding for a calcium-binding protein. It is a metastasis-associated gene whose expression shows strong correlation with the proliferative potential and invasive and metastatic ability of cancers. In a proportion of human intraductal carcinomas of the breast, a shorter variant h-mts1 transcript (h-mts1v) of approximately 450 nucleotides is expressed. We have characterized the transcript using reverse transcriptase-polymerase chain reaction employing exon-specific oligonucleotides. We show here that the noncoding exon 1a/1b is lost in the variant cDNA. Exons 2 and 3, which code for the protein, seem to be present in the variant isoform. The RT-PCR products obtained using exons 2- and 3-specific oligonucleotides showed a high degree of sequence homology with exons 2 and 3 of the h-mts1 gene. The expression of the variant transcript could be influencing disease progression, albeit not as effectively as the normal unspliced h-mts1 transcript.

Base Sequence↗
PubMed1998

Porcine alpha-1,3-galactosyltransferase: full length cDNA cloning, genomic organization, and analysis of splicing variants.

Full length cDNA and genomic DNA of porcine alpha-1,3-galactosyltransferase were isolated, and their structures were analysed. The coding region was encoded by six exons as in the mouse, and the length of each exon was conserved between the two species. The porcine exons were designated Exon 4-9, since in the mouse coding exons started from Exon 4. Introns tended to be longer in the porcine gene; the distance from Exon 4 to the 3'-end of Exon 9 was 24 kb, while this region was 18 kb in the mouse gene. The cDNA structure was extended from the previous data to the 3'-end and to the 5' side of the cDNA. In addition to a cDNA clone with all coding exons, clones lacking parts of these exons were isolated and their structures were determined. One variant lacked Exon 5; the second, Exons 5 and 6; and the third, Exons 5, 6 and 7. The last variant was not found in the mouse, and cDNA transfection of this variant yielded scarcely any enzymatic activity using asialo alpha1-acid glycoprotein as a substrate, and decreased activity using N-acetyllactosamine as a substrate.

Amino Acid Sequence↗
PubMed2000

Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.

Genetic variation in the human population may lead to functional variants of genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having frequencies > or = .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.

Algorithms↗
PubMed1998

A rare CYP19 (aromatase) variant may increase the risk of breast cancer.

The aromatase P450 (coded by the CYP19 gene) is responsible for the rate limiting step in the metabolism of C19 steroids to estrogens and is expressed in most breast carcinomas. A polymorphic tetranucleotide repeat (TTTA)n in intron 5, about 80 nucleotides downstream of exon 4 has previously been described. The allele frequencies of the polymorphic repeat were studied in series of 182 sporadic and 185 familial breast cancer patients as well as in 252 healthy control individuals. Five different alleles containing 7, 8, 9, 11 and 12-TTTA-repeats were detected. A relatively rare allele (A1) containing the longest repeat (TTTA)12 was found significantly more frequently in breast cancer patients than in control individuals. This indicates that individuals carrying the A1 allele of CYP19 may have an increased risk of developing breast cancer, OR 2.42 (95% confidence interval [CI] 1.03-5.80). The higher frequency was observed in both sporadic and familial patients, although when each of the groups was compared to the control group only a borderline significance was seen. A higher frequency of A1 allele carriers was also found in the group of patients with positive estrogen receptor and progesterone receptor positive tumors. These data suggest that the CYP19 gene may be involved as a low penetrance gene in breast cancer susceptibility.

Adult↗
PubMed1999

Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A.

Human herpesvirus 6 variants A and B (HHV-6A and HHV-6B) are closely related viruses that can be readily distinguished by comparison of restriction endonuclease profiles and nucleotide sequences. The viruses are similar with respect to genomic and genetic organization, and their genomes cross-hybridize extensively, but they differ in biological and epidemiologic features. Differences include infectivity of T-cell lines, patterns of reactivity with monoclonal antibodies, and disease associations. Here we report the complete genome sequence of HHV-6B strain Z29 [HHV-6B(Z29)], describe its genetic content, and present an analysis of the relationships between HHV-6A and HHV-6B. As sequenced, the HHV-6B(Z29) genome is 162,114 bp long and is composed of a 144,528-bp unique segment (U) bracketed by 8,793-bp direct repeats (DR). The genomic sequence allows prediction of a total of 119 unique open reading frames (ORFs), 9 of which are present only in HHV-6B. Splicing is predicted in 11 genes, resulting in the 119 ORFs composing 97 unique genes. The overall nucleotide sequence identity between HHV-6A and HHV-6B is 90%. The most divergent regions are DR and the right end of U, spanning ORFs U86 to U100. These regions have 85 and 72% nucleotide sequence identity, respectively. The amino acid sequences of 13 of the 17 ORFs at the right end of U differ by more than 10%, with the notable exception of U94, the adeno-associated virus type 2 rep homolog, which differs by only 2.4%. This region also includes putative cis-acting sequences that are likely to be involved in transcriptional regulation of the major immediate-early locus. The catalog of variant-specific genetic differences resulting from our comparison of the genome sequences adds support to previous data indicating that HHV-6A and HHV-6B are distinct herpesvirus species.

Base Sequence↗
PubMed1988

A family study of multiple mutations of alpha and delta glycophorins (glycophorins A and B).

Glycophorins alpha and delta are the carriers of the antigens of the MNSs blood system; this report documents the presence of three glycophorin mutations in two individuals of a 16 member family. Erythrocytes were examined by serology, sodium dodecyl sulfate electrophoresis, and immunoblotting. The inheritance pattern and immunoblot profile revealed: (1) A variant Dantu glycophorin showed properties consistent with a delta-alpha glycophorin hybrid structure, previously noted in other individuals. The gene responsible for the Dantu glycophorin in this family is linked to a gene coding for an M-specific alpha glycophorin. (2) Another variant glycophorin, Mi-III glycophorin, was first revealed by immunoblotting and subsequently confirmed by erythrocyte antigen typing. This autosomal dominant trait is associated with N blood group activity and the inheritance pattern indicates that it could be a variant of delta glycophorin. (3) In the individuals with both Dantu and Mi-III glycophorins a delta glycophorin deficiency was observed suggesting that a deletion or alteration of delta gene may exist cis to the Dantu gene. Our findings that document clustering of multiple mutations in MNSs gene loci in the propositus family are very unusual as such variants are relatively rare.

Female↗
PubMed1984

Genome analysis of epidemic influenza virus strains isolated in 1979-1983.

Comparative studies on the electrophoretic mobility of double-stranded RNA segments constructed of the genome of isolates under study and of reference influenza virus strains of respective serotypes are suggestive for the evolution of majority of the genes of both A and B influenza viruses, including their genes coding for non-glycosylated proteins. Among influenza A and B virus strains which were circulating during the same epidemic, there were variants differing from each other in a number of genes including those coding for virion internal proteins. A recombinant (reassortant) detected among the influenza virus strains, which circulated in Moscow in 1979, contained the genes 4, 6, 7 and 8 identical with those of the reference H1N1 strain, and the genes 1, 2, 3 and 5 identical with those of the reference H3N2 strain. Comparative analysis of reference influenza virus strains, both the H3N2 serotype (being isolated from 1968 to 1979) and the H1N1 serotype (being isolated from 1977 to 1980) differing in the antigenic specificity of their haemagglutinin (HA) suggested the increasing variability of either genes coding for glycoproteins as well as for non-glycosylated proteins.

Disease Outbreaks↗
PubMed2005

Defective DNA mismatch repair and XRCC2 mutation in uterine carcinosarcomas.

OBJECTIVES: A frameshift mutation in the double-strand breakage repair gene XRCC2 was identified in a mismatch repair (MMR) deficient cell line derived from a uterine carcinosarcoma. The frameshift mutation occurred in a mononucleotide run (poly-T tract), a target for strand-slippage mutation in MMR deficient tumors. We sought to determine if XRCC2 mutation is important to uterine carcinosarcoma tumorigenesis and whether the XRCC2 poly-T tract is a target for mutation in cells lacking MMR. METHODS: MSI-typing was used to assess the MMR status of 30 primary carcinosarcomas. The entire XRCC2 coding region was sequenced in all tumors. Single strand conformational variant (SSCV) analysis was used to screen for poly-T tract mutation in 50 endometrioid adenocarcinomas with defective MMR. RESULTS: Seven of 30 (23.3%) primary carcinosarcomas had an MSI-H phenotype. No XRCC2 coding mutations were identified in the 30 carcinosarcomas, and only one of the fifty MSI-H endometrioid adenocarcinomas had an XRCC2 poly-T tract mutation. CONCLUSIONS: Despite the high frequency of mismatch repair deficiency in carcinosarcomas, no XRCC2 poly-T tract frameshift mutations were identified in these tumors. The fact that only one of 50 additional MSI-H tumors had a frameshift mutation suggests that the XRCC2 poly-T tract is not a frequent target for defective MMR. The absence of coding sequence mutations in primary carcinosarcomas suggests that XRCC2 defects are unlikely to play a significant role in carcinosarcoma tumorigenesis.

Base Pair Mismatch↗
PubMed2000

Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.

UGT2B7 catalyses the glucuronidation of a diverse range of drugs, environmental chemicals and endogenous compounds. Hence, coding region polymorphisms of UGT2B7 are potentially of pharmacological, toxicological and physiological significance. Two variant UGT2B7 cDNAs encoding enzymes with either His or Tyr at residue 268 have been isolated. The variants, referred to as UGT2B7*1 and UGT2B7*2, respectively, arise from a C to T transversion at nucleotide 802 of the UGT2B7 coding region. Analysis of genomic DNA from 91 unrelated Caucasians and 84 unrelated Japanese demonstrated the presence of the variant alleles encoding UGT2B7*1 and UGT2B7*2 in both populations. However, while there was an approximately equal distribution of subjects homozygous for each allele in the Caucasian population, subjects homozygous for the UGT2B7*1 allele were over 10-fold more prevalent than UGT2B7*2 homozygotes in Japanese. The frequencies of the UGT2B7*1 and UGT2B7*2 alleles were 0.511 and 0.489, respectively, in Caucasians, and 0.732 and 0.268, respectively, in Japanese. The 95% confidence intervals for the two alleles did not overlap between Caucasians and Japanese. Rates of microsomal androsterone, menthol and morphine (3-position) glucuronidation were determined for genotyped livers from Caucasian donors. Statistically significant inter-genotypic differences were not apparent for any of the three substrates. Although the UGT2B7 polymorphism characterized here is probably not associated with altered enzyme activity, the results highlight the need to consider ethnic variability in assessing the consequences of UGT polymorphisms.

Adolescent↗
PubMed2006

Polymorphic variants of the multidrug resistance gene Mdr1a and response to antiepileptic drug treatment in the kindling model of epilepsy.

Allelic variants of the human P-glycoprotein encoding gene MDR1 (ABCB1) are discussed to be associated with different clinical conditions including pharmacoresistance of epilepsy. However, conflicting data have been reported with regard to the functional relevance of MDR1 allelic variants for the response to antiepileptic drugs. To our knowledge, it is not known whether functionally relevant genetic polymorphisms also occur in the two genes (Mdr1a/Abcb1a, Mdr1b/Abcb1b) coding for P-glycoprotein in the brain of rodents. Therefore, we have started to search for polymorphisms in the Mdr1a gene, which governs the expression of P-glycoprotein in brain capillary endothelial cells in rats. In the kindling model of temporal lobe epilepsy, subgroups of phenytoin-sensitive and phenytoin-resistant rats were selected in repeated drug trials. Sequencing of the Mdr1a gene coding sequence in the subgroups revealed no general differences between drug-resistant and drug-sensitive rats of the Wistar outbred strain. A comparison between different inbred and outbred rat strains also gave no evidence for polymorphisms in the Mdr1a coding sequence. However, in exon-flanking intron sequences, four genetic variants were identified by comparison between these rats strains. In conclusion, the finding that Wistar rats vary in their response to phenytoin, while having the same genetic background, argues against a major impact of Mdr1a genetics on pharmacosensitivity to antiepileptic drugs in the amygdala kindling model.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

LST1: a gene with extensive alternative splicing and immunomodulatory function.

The gene of the leukocyte-specific transcript (LST1) is encoded within the TNF region of the human MHC. The LST1 gene is constitutively expressed in leukocytes and dendritic cells, and it is characterized by extensive alternative splicing. We identified 7 different LST1 splice variants in PBMC; thus, 14 LST1 splice variants (LST1/A-LST1/N) have been detected in various cell types. These isoforms code for transmembrane as well as soluble LST1 proteins characterized by two alternative open reading frames at their 3' end. We demonstrate the presence of the transmembrane variant LST1/C on the cell surface of the monocytic cell lines U937 and THP1. Recombinant expression of LST1/C permitted its profound inhibitory effect on lymphocyte proliferation to be observed. In contrast, the alternative transmembrane variant LST1/A, the extracellular domain of which shows no amino acid sequence homology to LST1/C exerted a weaker but similar inhibitory effect on PBMC. These data demonstrate the protein expression of LST1 on the cell surface of mononuclear cells, and they show an inhibitory effect on lymphocyte proliferation of two LST1 proteins although they have only a very short amino acid homology.

Adjuvants, Immunologic↗
PubMed2005

Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer.

Evolutionary sequence conservation is now a relatively common approach for the prediction of functional DNA sequences. However, the fraction of conserved non-coding sequences with regulatory potential is still unknown. In this study, we focus on elucidating the regulatory landscape of RET, a crucial developmental gene within which we have recently identified a regulatory Hirschsprung disease (HSCR) susceptibility variant. We report a systematic examination of conserved non-coding sequences (n=45) identified in a 220 kb interval encompassing RET. We demonstrate that most of these conserved elements are capable of enhancer or suppressor activity in vitro, and the majority of the elements exert cell type-dependent control. We show that discrete sequences within regulatory elements can bind nuclear protein in a cell type-dependent manner that is consistent with their identified in vitro regulatory control. Finally, we focused our attention on the enhancer implicated in HSCR to demonstrate that this element drives reporter expression in cell populations of the excretory system and central nervous system (CNS) and peripheral nervous system (PNS), consistent with expression of the endogenous RET protein. Importantly, this sequence also modulates expression in the enteric nervous system consistent with its proposed role in HSCR.

Animals↗
PubMed1991

mRNA variants encoding multiple forms of the high-affinity IgE receptor alpha subunit in transformed and nontransformed mast cells.

Multiple mRNA species encoding several predicted forms of the high-affinity IgE receptor alpha subunit (Fc epsilon RI-alpha) have been previously characterized from rat basophilic leukemia cells. Using the polymerase chain reaction procedure, we have extended these findings to show that one Fc epsilon RI-alpha mRNA variant, characterized by a 163-bp deletion within the coding sequence, exists in normal rat connective tissue mast cells as well as in both transformed and non transformed murine mast cell lines. In addition, a partial murine Fc epsilon RI-alpha genomic clone, spanning the internal-deletion sequence, has been identified, and from analysis of this sequence a mechanism of alternative pre-mRNA splicing is proposed. Finally, mRNA variants have been translated in a cell-free system and the protein products partially characterized.

Amino Acid Sequence↗