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[Mitochondrial ceruloplasmin of mammals].

Using immunoblotting method it was found out that ceruloplasmin (Cp) polypeptides are revealed in mitochondria of rats, isolated from brain, liver, testicles and mammary gland. Cp is localized in matrix and inner membranes of mitochondria. Its molecular weight corresponds to the non-glycosilated form of the protein. Computer analysis did not reveal any sequences homologous to the signal peptide for mitochondria protein import (SPMPI) in the rat chromosomal Cp gene. However the analysis of homologous to Cp sequences, presented in databases, detected SPMPI in the human processed Cp pseudogene. Cp pseudogene region of 984 nucleotides long is translated in the only reading frame to the polypeptide of 328 a.a. long including 66 a.a of SPMPI at N-terminus. The predicted protein with the exception of SPMPI is identical to the corresponding Cp fragment at 92%, it has 20 amino acid substitutions, 8 of which are significant. His-X-His motif, typical for copper containing ferroxidases, is located in the centre of a molecule. Potential copper-binding site appears as a result of proline to histidine substitution at 923 position along Cp sequence. The product of Cp pseudogene transcription was detected in the human cultured cells of HepG2 and HuTu 80 cell lines using RT-PCR strategy. 30 kDa polypeptide that interacts with human Cp antibodies was found in mitochondria of HuTu 80 cells. The possible biological role of mitochondrial Cp is under discussion.

Amino Acid Sequence↗
PubMed1994

The origin of the primate Mhc-DRB genes and allelic lineages as deduced from the study of prosimians.

MHC class II genes of the DRB family were partially sequenced from 10 individuals representing six species of prosimians: Galago senegalensis, G. moholi, Otolemur garnetti, Loris tardigradus, Petterus (Lemur) fulvus, and Lemur catta. Altogether, 41 different genes were discerned, all distinct from genes identified previously. Comparative analysis of the sequences has led to the following conclusions. First, the DRB loci present in human populations diverged from one another before the divergence of prosimian and anthropoid primates. Second, major allelic lineages of the DRB1 locus, such as DRB1*03 (DRB1*13) and DRB1*04, were established more than 85 million years ago. Third, the DRB6 gene was inactivated before the separation of prosimians and anthropoids, and has remained a pseudogene for more than 85 million years. Fourth, the primate DRB region is structurally and functionally unstable. In Lemur catta, for example, all DRB genes have apparently been lost and their function taken over by DOB and/or DPB genes. DRB genes are, however, present in a related species, Petterus (Lemur) fulvus. Fifth, the prosimian DRB3 genes are all inactive; their function seems to have been taken over by new genes. Sixth, several of the prosimian DRB genes and pseudogenes have recently been duplicated. In Otolemur garnetti, for example, one chromosome carries at least three copies of the DRB3 pseudogene.

Alleles↗
PubMed1996

Molecular basis for secretor type alpha(1,2)-fucosyltransferase gene deficiency in a Japanese population: a fusion gene generated by unequal crossover responsible for the enzyme deficiency.

About 20%-25% of Caucasian individuals are nonsecretors who fail to express soluble A, B, H, and Lewis b histo-blood group antigens in secretory organs and secretory fluids because of the absence of the Secretor gene (FUT2)-encoded alpha(1,2)-fucosyltransferase (Se enzyme) activity. Recently, the FUT2 and a pseudogene have been isolated, and an Se enzyme-deficient allele (se) caused by a nonsense mutation (G428A, se1) in Caucasians has also been reported. Although we were unable to find the se1 allele, we have found a missense mutation (A385T, se2) and two nonsense mutations (C571T, se3 and C628T, se4) in the Japanese Se enzyme-deficient alleles. In addition, we have found a fusion gene, which consisted of the 5'-region of the pseudogene and the 3'-region of the functional FUT2, as a Se enzyme-deficient allele (se5). The DNA sequence analysis of the fusion gene indicated that the crossover region corresponded to regions between bases 253 and 313 of the pseudogene and between bases 211 and 271 of the FUT2. This finding suggested that the fusion gene was generated by homologous but unequal crossover. A population study on 141 randomly selected Japanese has indicated that the se2 is a common Se enzyme-deficient allele in the Japanese population. The results suggest that Se enzyme-deficient alleles are race specific.

ABO Blood-Group System↗
PubMed2000

The 5' part of the mouse immunoglobulin kappa locus as a continuously cloned structure.

Five contigs of the 5' part of the immunoglobulin kappa locus (F. Röschenthaler et al., Eur. J. Immunol. 1999. 29: 2065 - 2071) have been linked by cosmid clones prepared from bacterial artificial chromosomes (BACs) and by PCR. One of the previously defined contigs which contains three pseudogenes (Z7) was shown by fluorescence in situ hybridization to be located near the kappa locus on chromosome 6, but not within the locus; the three Vkappa genes are therefore now classified as orphons. A Vkappa9 / 10 gene, which was sequenced previously, was now localized within the locus, and two additional Vkappa genes were identified, a potentially functional Vkappa24 gene and a pseudogene of the Vkappa9 / 10 family. This brings the number of localized and sequenced Vkappa genes in the locus to 140; 75 of them are functional, 21 potentially functional and 44 pseudogenes. The 5' part of the kappa locus is now one contig of 1.88 megabase (Mb); it comprises 82 Vkappa genes. Other contigs of the locus are 65 kb, 105 kb and 1.04 Mb in size and contain 2, 5 and 51 Vkappa genes, respectively. The contigs are separated by three gaps of 10 - 40 kb each. Detailed restriction maps and other structural details of the kappa locus are deposted in the Internet at http://www.med. uni-muenchen.de / biochemie / zachau / kappa.htm.

Animals↗
PubMed2006

Isolation of the feline alpha1,3-galactosyltransferase gene, expression in transfected human cells and its phylogenetic analysis.

The enzyme alpha 1,3-galactosyltransferase (alpha1,3-GT), which catalyzes synthesis of terminal alpha-galactosyl epitopes (Gal alpha1,3Gal beta1-4GlcNAc-R), is produced in non-primate mammals, prosimians and new-world monkeys, but not in old-world monkeys, apes and humans. We cloned and sequenced a cDNA that contains the coding sequence of the feline alpha1,3-GT gene. Flow cytometric analysis demonstrated that the alpha-galactosyl epitope was expressed on the surface of a human cell line transduced with an expression vector containing this cDNA, and this alpha-galactosyl epitope expression subsided by alpha-galactosidase treatment. The open reading frame of the feline alpha1,3-GT cDNA is 1,113 base pairs in length and encodes 371 amino acids. The nucleotide sequence and its deduced amino acid sequence of the feline alpha1,3-GT gene are 88-90% and 85-87%, respectively, similar to the reported sequences of the bovine, porcine, marmoset and cebus monkey alpha1,3-GT genes, while they are 88% and 82-83%, respectively, similar to those of the orangutan and human alpha1,3-GT pseudogenes, and 81% and 77%, respectively, similar to the murine alpha1,3-GT gene. Thus, the alpha1,3-GT genes and pseudogenes of mammals are highly similar. Ratios of non-synonymous nucleotide changes among the primate pseudogenes as well as the primate genes are still higher than the ratios of non-primates, suggesting that the primate alpha1,3-GT genes tend to be divergent.

Amino Acid Sequence↗
PubMed1998

Diagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood.

Mitochondrial DNA (mtDNA) mutations are an important cause of neurological disease. The identification of causative mtDNA mutations may be particularly troublesome in blood where there are often low levels of mutant mtDNA. This is evident from a recent study in which heteroplasmic mtDNA mutations in cytochrome c oxidase genes were incorrectly thought to be linked to Alzheimer's disease. We wished to explore whether analysis of blood mtDNA, prepared by a number of DNA extraction procedures, influenced the diagnosis of mtDNA disease. DNA was extracted by different procedures from 4 patients with heteroplasmic mtDNA mutations, and the level of heteroplasmy investigated by radioactive PCR-RFLP analysis. Whilst there was no consistent decrease in the level of mtDNA heteroplasmy, we observed the coamplification of a novel mtDNA pseudogene from DNA samples extracted by a simple 'boiling' procedure using primers designed to screen for the tRNALeu(UUR) A3243G mutation. This pseudogene was readily amplified from DNA extracted from rho degrees (mtDNA-less) cells, confirming its nuclear location. We believe that mtDNA pseudogenes may therefore present significant difficulties in the accurate identification of pathogenic heteroplasmic mtDNA mutations in blood.

DNA, Mitochondrial↗
PubMed1998

A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease.

Gaucher disease, the most prevalent inherited sphingolipidosis, is characterized by lipid laden histiocytes in the spleen, liver and bone marrow sinusoids of affected individuals. It results from deleterious mutations in the functional gene of glucocerebrosidase (acid beta-glucosidase, EC. 3.2.1.45) and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: Type 1 non-neuronopathic, type 2 acute neuronopathic, and type 3 subacute neuronopathic. In this report, we describe the identification and characterization of three novel mutations from two patients who died with type 2 Gaucher disease. Two heterozygous missense point mutations, one at cDNA nucleotide 238A (E41L) and the other at cDNA nucleotide 508T (R131C) were identified, both in the context of a cDNA nucleotide 1448C (L444P) mutation in the second allele. One of these L444P mutations was identified as a novel complex allele resulting from a crossover involving the glucocerebrosidase functional gene and pseudogene beginning between genomic nucleotides 5689 and 5723 and extending through the rest of the coding sequence. Based on the recent identification and sequence analysis of the metaxin gene and pseudogene contiguous with the glucocerebrosidase pseudogene and functional gene respectively, we have developed a PCR-based method for the analysis of the origin and extent of this recombination.

Adult↗
PubMed1993

The human glutamate dehydrogenase gene family: gene organization and structural characterization.

Glutamate dehydrogenase is a mitochondrially located, key metabolic enzyme. In addition to its general metabolic role, GLUD is important in neurotransmission. Significant alterations in GLUD enzymatic activity have been associated with certain neurodegenerative human disorders. Although a single species of human GLUD cDNA molecule has been identified so far, both genomic DNA Southern and cytogenetic analyses have indicated the presence of a GLUD gene family. Screening of a human genomic lambda-phage library with the GLUD cDNA, led us to the isolation of several clones divided into five structurally distinct contigs. We have confirmed the presence of all GLUD-specific sequences in the human genome by detailed genomic Southern analysis. This study allowed the identification of the entire functional GLUD gene, named GLUD1. The GLUD1 gene is about 45 kb long and it is organized into 13 exons. Its nucleotide sequence, exon-intron boundaries, and transcription start sites were determined. Potential binding sites for various regulatory factors such as Sp1, AP-1, and AP-2 were recognized at the promoter region of the gene. The members of the other contigs showed an organization clearly different from GLUD1. Two distinct GLUD-specific gene loci, termed GLUDP2 and GLUDP3, possibly represent truncated pseudogenes. Their high degree of similarity to GLUD1 is limited to the region surrounding exons 2, 3, and 4. Finally, two additional GLUD-specific genomic sequences, termed GLUDP4 and GLUDP5, are structurally similar with the 3' part of the GLUD cDNA sequence. These loci probably represent truncated GLUD pseudogenes generated by retrotransposition. The data presented here suggest that all human GLUD pseudogenes have diverged recently in evolution.

Amino Acid Sequence↗
PubMed1996

Localization of chi1-related helicase genes to human chromosome regions 12p11 and 12p13: similarity between parts of these genes and conserved human telomeric-associated DNA.

The helicase enzymes are essential components of a number of multi-protein complexes, including those that regulate transcription, splicing, translation, and DNA repair. These enzymes assist in the unwinding of double-stranded DNA and RNA as an essential part of their function. The yeast Chl1 gene encodes a putative helicase that appears to be essential for normal chromosome transmission. Human cDNAs related to this yeast gene, hCHLR1 and hCHLR2, were recently isolated and shown to encode products that localize to the nucleus. Two corresponding genes have now been partially characterized and localized to human chromosome regions 12p11 and 12p13, indicating that this gene is contained within a duplicated region localized to 12p. In addition, a comparison of the hCHLR gene sequences with available databases indicates that a large portion of these genes, including exons encoding two functional domains of the carboxyl-terminal region of these proteins, has been duplicated as part of a larger human telomeric repeat sequence found on many human chromosomes. Our results suggest that duplication of a relatively large region of chromosome 12p containing this putative helicase gene has resulted in the creation of numerous pseudogenes as part of a subtelomeric repeat. The presence of these helicase pseudogenes, as well as pseudogenes for other genes such as the interleukin-9 receptor, within many subtelomeric regions support the possibility that the spread of this region is subject to exchange between different chromosomes and may have implications for elucidation of the mechanism of intra- and interchromosomal duplication events.

Base Sequence↗
PubMed1999

A genomic region encompassing a cluster of olfactory receptor genes and a myosin light chain kinase (MYLK) gene is duplicated on human chromosome regions 3q13-q21 and 3p13.

The olfactory receptor (OR) multigene family is widely distributed in the human genome. We characterize here a new cluster of four OR genes (HGMW-approved symbols OR7E20P, OR7E6P, OR7E21P, and OR7E22P) on human chromosome 3p13 that is contained in an approximately 250-kb region. This region has been physically mapped, and a 106-kb portion containing the OR genes has been sequenced. All the OR sequences are disrupted by frameshifts and stop codons and appear to have arisen through local duplications. A myosin light chain kinase pseudogene (HGMW-approved symbol MYLKP) lies at one end of the OR gene cluster. Sequences spanning the entire region are also present at 3q13-q21, the site of the functional MYLK gene. This region duplicated locally before the divergence of primates, and the two paralogous copies were later separated to sites on either side of the centromere. This study increases our understanding of the evolution of the human genome. The 3p13 cluster is the first example of a tandem array of OR pseudogenes, and duplications of such clusters may account for the accumulation of a large number of pseudogenes in the human genome.

Amino Acid Sequence↗
PubMed1999

Cloning, expression, and physical mapping of the 3beta-hydroxysteroid dehydrogenase gene cluster (HSD3BP1-HSD3BP5) in human.

Seven members of the human 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene family (HGMW-approved symbols HSD3BP1-HSD3BP5) have been cloned and physically mapped. HSD3B1 and 2 express 3beta-HSD enzymes; HSD3Bpsi1-5 are unprocessed pseudogenes that are closely related to HSD3B1 and 2 but contain no corresponding open reading frames. mRNA is expressed from psi4 and psi5 in several tissues, but with altered splice sites that disrupt reading frames. A 0.5-Mb contig of 3 yeast artificial chromosome and 32 bacterial artificial chromosome genomic clones contained no additional members of the gene family. The seven genes and pseudogenes mapped within 230 kb in the order HSD3Bpsi5-psi4-psi3-HSD3B1-psi1-psi2 -HSD3B2. HSD3B1 and 2 are in direct repeat, 100 kb apart. Six HSD3B2 mutations involve substitutions that are present in several of the pseudogenes. In four cases, mutations arose in CpG sites that are conserved within the gene cluster. The tendency for CpG sites to mutate by transition provides an adequate explanation for these HSD3B2 mutations, which are unlikely to be due to recombination or conversion within the gene family.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Phylogenetic studies of marsupials based on phosphoglycerate kinase DNA sequences.

Phosphoglycerate kinase sequences were obtained for 313 aligned bases of 41 individuals from 39 marsupial species. In contrast to previous molecular analyses, the relationships suggested by these data show a high level of congruence with morphologically defined orders and families. Four main monophyletic lineages are recognizable. These are the monogeneric orders Microbiotheria (Dromiciops australis) and Notoryctemorphia (Notoryctes typhlops), a grouping of the American orders Didelphimorphia and Paucituberculata, and the Australasian species other than N. typhlops. Within the Australasian lineage, there are again four main monophyletic groups; the Dasyuridae, two peramelemorph (bandicoot) lineages (one comprised of pseudogene sequences) and the Diprotodontia. This topology is not greatly affected by the exclusion of pseudogenes except that a clade of syndactylous species (Peramelemorphia plus Diprotodontia) is recovered. Two other peramelemorph pseudogenes have inserts of about 1 kb with high levels of similarity to LINE 1 elements. The Diprotodontia is notable for its relative lack of intersequence variation in comparison to the Dasyuromorphia.

Animals↗
PubMed1991

The nucleotide sequence and evolution of ovine MHC class II B genes: DQB and DRB.

The nucleotide sequences of one Ovar-DQB gene, excluding exon 1 and parts of the introns, and one Ovar-DRB pseudogene are presented. The structure of the Ovar-DQB gene is typical of a major histocompatibility complex (MHC) class II B gene and demonstrates considerable sequence similarity with that of humans including such characteristics as the less common polyadenylation signal, ATTAAA. The ovine sequence has a typical 5' acceptor splice signal for exon 5, thus potentially encoding a full length cytoplasmic tail. The Ovar-DRB gene identified in this study was found to be a pseudogene, lacking a defined exon 2 and containing premature termination codons in both exons 3 and 4. The 3' donor splice site of exon 3 is also atypical. A purine-pyrimidine microsatellite repeat, (dC.dA)15, in the 3' region of the pseudogene may be a hotspot for recombination within the ovine DR subregion.

Amino Acid Sequence↗
PubMed1989

The primary structure of a feline class I gene: striking similarity to HLA-A.

The sequence of a feline class I pseudogene and its comparison with class I genes from other species is presented. The gene isolated is a pseudogene because of the presence of four stop codons and two frame shift mutations in the first- and second-domain encoding exons, as well as a mutation in a splice acceptor site in the third intron. By sequence comparison with the other class I sequences determined to date, the FLA pseudogene is most closely related to the HLA-A locus products (88% nucleotide identity.

Amino Acid Sequence↗
PubMed1996

Structure and organization of pig MHC class II DRB genes: evidence for genetic exchange between loci.

The pig major histocompatibility complex DRB genes were studied by polymerase chain reaction (PCR) amplification of exon 2 from eight domestic pigs and two European wild boars. Sequence comparisons together with a phylogenetic analysis showed the existence of at least three DRB genes of which only one appears to be expressed. The two putative DRB pseudogenes contained deletions in exon 2, making it possible to confirm the presence of three non-allelic DRB genes by analyzing the length polymorphism of the amplified PCR products. The expressed gene shows allelic polymorphism at the same positions as in the human DRB1 gene. In addition, this pig gene shows extensive allelic polymorphism at positions 84-88, whereas, e.g., human DRB genes do not. Surprisingly, the two putative DRB pseudogenes also display a considerable amount of allelic polymorphism, albeit of a different character as compared with the expressed DRB gene. Short stretches of sequences are shared between individual alleles at different loci. These sequence similarities cannot be due to natural selection, since two of the three DRB genes involved are polymorphic pseudogenes constituting allelic series that have diverged after the inactivation event. Instead, the results indicate that the sequences have been exchanged between the DRB genes by intergenic recombination.

Animals↗
PubMed2003

Molecular population genetics of the beta-esterase gene cluster of Drosophila melanogaster.

We have investigated nucleotide polymorphism at the beta-esterase gene cluster including the Est-6 gene and psiEst-6 putative pseudogene in four samples of Drosophila melanogaster derived from natural populations of southern Africa (Zimbabwe), Europe (Spain), North America (USA: California), and South America (Venezuela). A complex haplotype structure is revealed in both Est-6 and psiEst-6. Total nucleotide diversity is twice in psiEst-6 as in Est-6; diversity is higher in the African sample than in the non-African ones. Strong linkage disequilibrium occurs within the beta-esterase gene cluster in non-African samples, but not in the African one. Intragenic gene conversion events are detected within Est-6 and, to a much greater extent, within psiEst-6; intergenic gene conversion events are rare. Tests of neutrality with recombination are significant for the beta-esterase gene cluster in the non-African samples but not significant in the African one. We suggest that the demographic history (bottleneck and admixture of genetically differentiated populations) is the major factor shaping the pattern of nucleotide polymorphism in the beta-esterase gene cluster. However there are some 'footprints' of directional and balancing selection shaping specific distribution of nucleotide polymorphism within the cluster. Intergenic epistatic selection between Est-6 and psiEst-6 may play an important role in the evolution of the beta-esterase gene cluster preserving the putative pseudogene from degenerative destruction and reflecting possible functional interaction between the functional gene and the putative pseudogene. Est-6 and psiEst-6 may represent an indivisible intergenic complex ('intergene') in which each single component (Est-6 or psiEst-6) cannot separately carry out the full functional role.

Animals↗
PubMed2002

A DNA sequence evolution analysis generalized by simulation and the markov chain monte carlo method implicates strand slippage in a majority of insertions and deletions.

To study the mechanisms for local evolutionary changes in DNA sequences involving slippage-type insertions and deletions, an alignment approach is explored that can consider the posterior probabilities of alignment models. Various patterns of insertion and deletion that can link the ancestor and descendant sequences are proposed and evaluated by simulation and compared by the Markov chain Monte Carlo (MCMC) method. Analyses of pseudogenes reveal that the introduction of the parameters that control the probability of slippage-type events markedly augments the probability of the observed sequence evolution, arguing that a cryptic involvement of slippage occurrences is manifested as insertions and deletions of short nucleotide segments. Strikingly, approximately 80% of insertions in human pseudogenes and approximately 50% of insertions in murids pseudogenes are likely to be caused by the slippage-mediated process, as represented by BC in ABCD --> ABCBCD. We suggest that, in both human and murids, even very short repetitive motifs, such as CAGCAG, CACACA, and CCCC, have approximately 10- to 15-fold susceptibility to insertions and deletions, compared to nonrepetitive sequences. Our protocol, namely, indel-MCMC, thus seems to be a reasonable approach for statistical analyses of the early phase of microsatellite evolution.

Base Sequence↗
PubMed2002

Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism.

The human insulin resistance syndromes---type 2 diabetes, obesity, combined hyperlipidemia, and essential hypertension---are genetically complex disorders whose molecular basis is largely unknown. The spontaneously hypertensive rate (SHR) is a model of these human syndromes. In the SHR/NCrlBR strain, a chromosomal deletion event that occurred at the Cd36 locus during the evolution of this SHR strain has been proposed as a cause of defective insulin action and fatty acid metabolism. In this study, three copies of the Cd36 gene, one transcribed copy and two pseudogenes, were identified in normal rat strains, but only a single gene in SHR/NCrlBR. Analysis of SHR genomic sequence localized the chromosomal deletion event between intron 4 of the normally transcribed copy of the gene and intron 4 of the second pseudogene. The deletion led to the creation of a single chimeric Cd36 gene in SHR/NCrlBR. The boundaries of the recombination/deletion junction identified within intron 4 were surrounded by long interspersed nuclear elements (LINEs) and DNA topoisomerase I recognition sequences. An 8-bp deletion at the intron 14/exon 15 boundary of the second pseudogene abolishes the putative splice acceptor site and is the cause of an aberrant 3' UTR previously observed in SHR/NCrlBR. We conclude that in SHR/NCrlBR, the complex trait of insulin resistance and defective fatty acid metabolism is caused by Cd36 deficiency, resulting from a chromosomal deletion caused by unequal recombination. This demonstrates that chromosomal deletions caused by unequal recombination can be a cause of quantitative or complex mammalian phenotypes.

Animals↗