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PubMed2002

Isolation and characterization of annexin 2 pseudogene in Rattus norvegicus.

Annexin 2 is a calcium-regulated, phospholipid-binding protein present in endothelial cells, macrophages and some tumor cells. Annexin 2 is a substrate for a variety of protein kinases, and plays roles in the regulation of endocytosis, exocytosis and thrombolysis. We have determined the nucleotide sequence of a rat genomic DNA fragment that hybridized to a rat annexin 2 DNA complementary to RNA (cDNA) probe. Sequence analysis revealed that it was an intronless rat annexin 2, consisting of a start-to-stop-codon-length copy of the processed transcript. This pseudogene contained 33 point mutations and two deletion sites in the coding region as compared with the cDNA, and thus displayed typical features of a retroposon. Transitions were more frequent than transversions, and the most frequent type of mutation was G to A transition. We isolated a phage clone that contained a functional rat annexin 2 genomic fragment including coding exons 3 and 4. Polymerase chain reaction and subsequent sequence analysis revealed an intron of approximately 4 kbp at the same site as in humans and mice. Whereas the annexin 2 gene or its cDNA homologues have been detected in various species from Xenopus to humans, its pseudogene has been reported only in humans. In the present study, we demonstrated the presence of an annexin 2 pseudogene in rats.

Animals↗
PubMed2002

Human mitochondrial transcription factor A (mtTFA): gene structure and characterization of related pseudogenes.

Mitochondrial transcription factor A (mtTFA or Tfam) is a 25 kDa protein encoded by a nuclear gene and imported to mitochondria, where it functions as a key regulator of mammalian mitochondrial (mt) DNA transcription and replication. The coding sequence of the human mtTFA gene is reported in the literature and the sizes of few introns are known. In this paper we present the genomic structure of the human mtTFA gene along with the complete sequence of its six intronic regions. Three of the introns (I, III, VI) have been found to be less than 600 bp, while the other three were greater than 1.8 kb. In the course of this work, we discovered that, in addition to the active copy, different homologous sequences identified as processed pseudogenes psi h-mtTFA have been isolated and sequenced. Using an 'in silico' mapping approach we determined their locations on chromosomes 7, 11 and X. psi h-mtTFA locations are different from that of the gene, previously reported on chromosome 10. Transcription analysis by means of reverse transcriptase-polymerase chain reaction has shown that other than the RNA corresponding to the full-length transcript, an isoform lacking 96 bp is also present. Among the three sequenced pseudogenes only one of them located on chromosome 11 has been found to be transcribed in Jurkat cells under these culture conditions, even though transcription initiation and binding sites for different transcription factors have also been found upstream from the other two pseudogenes.

Chromosome Mapping↗
PubMed1997

Cloning and characterization of two processed pseudogenes and the cDNA for the murine U1 snRNP-specific protein C.

Genes for the snRNP proteins U1-70K, U1-A, Sm-B'/B, Sm-D1 and Sm-E have been isolated from various metazoan species. The genes for Sm-D1 and Sm-E, which were isolated from a murine and human source respectively, appear to belong to a multigene family. It has been suggested that also for the mammalian U1-C protein such a multigene family exists. With the human U1-C cDNA as a probe, two genes containing sequences homologous to the probe sequence were isolated from a mouse genomic library. Simultaneously, a murine U1-C cDNA was isolated from a mouse cDNA library. This 0.74 kb cDNA contains an open reading frame (ORF) of 477 bp encoding a polypeptide of 159 amino acids (aa) which differs at only one position (position 65) from the human U1-C protein. One of the isolated U1-C genes contains an ORF as well and shares 92% nucleotide sequence identity with the mouse U1-C cDNA. The features of this gene, in particular the absence of introns, the acquisition of a 3' poly(A) tail and flanking direct repeats, indicate that it represents a processed pseudogene. At the predicted aa sequence level, substitutions of conserved residues at functionally important positions are observed, strongly suggesting that expression of this gene would not lead to a functional polypeptide. The second U1-C gene appeared to be a pseudogene as well because it is also intronless and contains a frameshift mutation compared to the ORF in the mouse U1-C cDNA. The characterization of these two pseudogenes points to the existence of a U1-C multigene family in mice. Furthermore, comparison of aa sequences of the murine, human and Xenopus U1-C shows that the protein is highly conserved through evolution. Since the Xenopus U1-C differs from the two mammalian counterparts solely at a number of positions in the C-terminal region, it can be concluded that aa changes are less well tolerated in the N-terminal region of U1-C than in the rest of the protein.

Animals↗
PubMed1997

Molecular cloning of the human methylthioadenosine phosphorylase processed pseudogene and localization to 3q28.

Human methylthioadenosine phosphorylase (MTAP) is a purine and methionine metabolic enzyme present ubiquitously in all normal tissues, but often deleted in many types of cancer. The gene for this enzyme maps to chromosome 9 at band p21 where the cyclin-dependent kinase inhibitor genes for p16 and p15 also reside. During our efforts to clone this gene we also isolated a phage clone containing a processed pseudogene of MTAP. The sequence is 92% homologous to the MTAP cDNA, is flanked at its 3' end by a repetitive element, but does not possess a poly(A) stretch. We localized this processed pseudogene to band 28 on the long arm of chromosome 3 by fluorescence in situ hybridization. All 22 malignant cell lines with deletions at 9p21 screened possessed the pseudogene.

Amino Acid Sequence↗
PubMed1997

A phosphoglycerate mutase brain isoform (PGAM 1) pseudogene is localized within the human Menkes disease gene (ATP7 A).

We have identified a phosphoglycerate mutase brain isoform (PGAM 1, PGAM B) cDNA that is localized between exons 1 and 2 of the Menkes disease gene (ATP7 A, MNK) at Xq13.3. The cDNA shows 98% identity to the previously identified PGAM 1 cDNA (Sakoda et al., J. Biol. Chem. 263 (1988) 16899-16905) and probably represents a recent retroposition of this parent PGAM 1 mRNA. Although the typical features of a processed pseudogene are present, the open reading frame (ORF) of this PGAM cDNA is potentially expressed. There are 11 bp changes in the 765 bp ORF, none of which are nonsense mutations or deletions. The region upstream from the ORF shows some features of a possible promoter region, although it lacks a CpG island often associated with functional promoters. We analyzed the expression of this PGAM 1 cDNA using RT-PCR followed by restriction enzyme digestion based on a 1 bp missmatch in this cDNA to distinguish it from normal PGAM 1 gene expression. With this sensitive method, we could not find expression in any of the tissues examined. Taken together, we conclude that the PGAM 1 cDNA upstream from exon 2 of the Menkes gene is likely to be a processed pseudogene originating from a very recent retroposition of a PGAM 1 transcript. To our knowledge this is the first report of a pseudogene located within a gene.

Adenosine Triphosphatases↗
PubMed1997

The mouse Plk gene: structural characterization, chromosomal localization and identification of a processed Plk pseudogene.

The Plk gene encodes a serine/threonine protein kinase believed to be important for the normal progression of mammalian cells through the cell cycle. In this paper, we report the genomic organization of the mouse Plk gene. The mouse Plk gene encompasses 16 kb of the mouse genome and is organised into 10 exons. Based on homology with the human PLK1 promoter region, the putative mouse promoter region includes a CCAAT motif but lacks the conventional TATA motif. The proposed promoter region contains consensus binding sites for several transcriptional regulators, including Sp1 and AP2. In addition to the active copy of Plk, Plk exists as a processed pseudogene. Using RFLP analysis, we have localized the active Plk gene to mouse Chromosome 7 and the processed pseudogene to mouse Chromosome 5. Southern blot analysis of DNA from a limited number of other mammalian species suggests that the duplication is confined to the mouse. Parsimony analysis suggests that the gene duplication leading to the mouse Plk pseudogene occurred after the rat-mouse split.

Animals↗
PubMed1998

Molecular cloning and characterization of a highly conserved human 67-kDa laminin receptor pseudogene mapping to Xq21.3.

A highly conserved laminin receptor processed pseudogene (LAMRL5) that has been isolated from a fetal brain cDNA library is described. The pseudogene is a complete copy (97.9% identical) of the transcribed laminin receptor (LAMR1) with all the introns precisely removed. The sequence has direct repeats of 18 bp at either end. It has an 885 nucleotide open reading frame from the start methionine codon to the stop codon that contains no deletions, additions or premature stop codons relative to the expressed LAMR1 gene and has the coding potential for a protein of 295 amino acids. Although TATA and CAAT boxes exist in the region 5' to the open reading frame and a polyadenylation signal is present in the 3' region, no evidence could be obtained either by reverse transcriptase-polymerase chain reaction (RT-PCR) or in the expressed sequence tag (EST) database that LAMRL5 is expressed in vivo. If not expressed, it is estimated that this LAMRL5 pseudogene was incorporated into the human genome approximately 3.5-5 million years ago.

Amino Acid Sequence↗
PubMed1998

The gene and processed pseudogenes of the rat mitochondrial single-strand DNA-binding protein: structure and promoter strength analyses.

The gene for the rat mitochondrial single-stranded DNA-binding protein (mtSSB) was amplified by PCR and isolated as several overlapping genomic clones. The clones encompassed the 5' untranslated sequence and all intron/exon junctions. The gene contained seven exons and six introns. The first exon contained only 5' untranslated sequence. The 16-amino acid mitochondrial targeting presequence, encoded by the second and third exons, was precisely bisected by intron 2. All intron donor and acceptor sites were consistent with the GT/AG consensus. The transcription start site was determined by primer-extension analysis to be 69bp upstream of the translation start codon. The upstream sequence lacked TATA and CCAAT boxes at the expected locations, but did contain several other potential regulatory elements including a GC box (Sp1-binding site) and three NRF-2 sites, one of which was located precisely beside the transcription start site. A 10 out of 12 imperfect NRF-1 site was located within the first exon. The 5' flanking sequence (-546 to +30) was shown to have strong promoter activity in transient transfection assays in primary rat hepatocytes and HepG2 cells. In addition, evidence for the existence of several mtSSB processed pseudogenes was obtained. These pseudogenes lacked introns and contained substitution and deletion mutations compared to the cDNA sequence. The 5' upstream region of one of the pseudogenes was analyzed and found to contain negligible promoter activity.

Animals↗
PubMed1998

The human elk-1 gene family: the functional gene and two processed pseudogenes embedded in the IgH locus.

Elk-1 is a transcription factor whose activation by several mitogen-activated protein kinases (MAPKs) mediates the immediate early responses of the c-fos promoter to growth factors and other stimuli. Here, we report the structure of the human elk-1 gene, which we have localized about 6.5kb upstream of the properdin gene on the X chromosome. The coding sequence is interrupted by four introns; two additional introns lie within the 5' untranslated region. We have also found two elk-1-related processed pseudogenes in the human immunoglobulin heavy chain (IgH) locus, accounting for 'elk-2' previously visualized by in-situ hybridization at 14q32. A processed pseudogene evidently inserted downstream of a primordial immunoglobulin Calpha gene and was duplicated along with part of the IgH locus. Gene/pseudogene sequence comparisons and Southern blots of primate DNAs suggest that both the pseudogene insertion and the locus duplication occurred between about 30 and 60 million years ago.

Amino Acid Sequence↗
PubMed1999

Cloning, mRNA localization and evolutionary conservation of a human 5-HT7 receptor pseudogene.

Initial experiments designed to clone novel serotonin receptor subtypes in the substantia nigra have led to the discovery of a transcribed human 5-HT7 receptor pseudogene that is expressed in a wide range of tissues. The original clone (S771) possessed greater than 90% homology to the 5-HT7 receptor sequence and was identified by a degenerate PCR approach. Expression of the pseudogene transcript was detected throughout the brain and peripheral tissues in general agreement with 5-HT7 mRNA localization. Interestingly, the transcript was detected in tissues not known to express the 5-HT7 receptor (i.e. liver and kidney). Analysis of genomic DNA explained the genesis of the human pseudogene via a processed parental transcript (retrotransposition) and led to the discovery of a species homologue in the rhesus monkey.

Amino Acid Sequence↗
PubMed1999

The human genome has only one functional hsp47 gene (CBP2) and a pseudogene (pshsp47).

Among all the species investigated to date, only in humans is hsp47 reported to exist as two separate genes. Here we examined whether hsp47 forms a gene family, and if so, how many genes constitute the family. Cloning and sequencing of human hsp47 cDNA revealed that only one gene, identical to CBP2, was transcribed. No transcript corresponding to colligin, which was reported to be a human homologue of hsp47, was found. Genomic southern hybridization using the exon III fragment of mouse hsp47 as a probe, however, showed two bands for several restriction enzyme digests. We cloned and sequenced the gene corresponding to the extra band and found that a pseudogene (pshsp47) existed in the human genome. We have mapped this pseudogene to chromosome 9p12-p13 by fluorescent in situ hybridization (FISH) using a 3.5kb genomic fragment containing the entire pshsp47 sequence as a probe. These results suggested that functional hsp47 exists as CBP2, not as colligin, and a highly conserved pseudogene is present in the human genome.

Base Sequence↗
PubMed1999

Characterization and localization to chromosome 7 of psihGABPalpha, a human processed pseudogene related to the ets transcription factor, hGABPalpha.

GABP is a heteromeric transcription factor complex which consists of the ets related protein, GABPalpha, and the Notch-related protein, GABPbeta. We isolated a human genomic DNA fragment which is highly homologous and colinear with human GABPalpha cDNA, but which lacks introns. This processed pseudogene, psihGABPalpha, is expressed as RNA in U937 human myeloid cells, but a mutation at the site that corresponds to the ATG start methionine codon prevents its translation into protein. The pseudogene was localized to chromosome 7 using a somatic cell hybrid mapping panel and it is not syntenic with authentic GABPalpha, which was localized to chromosome 21. We have identified psihGABPalpha, a novel, GABPalpha-related processed pseudogene which is expressed as a RNA transcript in human myeloid cells.

Base Sequence↗
PubMed2001

Human glycosaminoglycan glucuronyltransferase I gene and a related processed pseudogene: genomic structure, chromosomal mapping and characterization.

Here we describe the characterization of the human glycosaminoglycan glucuronyltransferase I gene (GlcAT-I) and a related pseudogene. The GlcAT-I gene was localized to human chromosome 11q12-q13 by in situ hybridization of metaphase chromosomes. GlcAT-I spanned 7 kb of human genomic DNA and was divided into five exons. Northern blot analysis showed that GlcAT-I exhibited ubiquitous but markedly different expressions in the human tissues examined. The GlcAT-I promoter was approx. 3-fold more active in a melanoma cell line than in a hepatoma cell line, providing evidence for the differential regulation of the gene's expression. Stepwise 5' deletions of the promoter identified a strong enhancer element between -303 and -153 bp that included binding motifs for Ets, CREB (cAMP-response-element-binding protein) and STAT (signal transducers and activators of transcription). Screening of a human genomic library identified one additional distinct genomic clone containing an approx. 1.4 kb sequence region that shared an overall 95.3% nucleotide identity with exons 1-5 of GlcAT-I. However, a lack of intron sequences, as well as the presence of several nucleotide mutations, insertions and deletions that disrupted the potential GlcAT-I reading frame, suggested that the clone contained a processed pseudogene. The pseudogene was localized to chromosome 3. The human genome therefore contains two related GlcAT-I genes that are located on separate chromosomes.

Base Sequence↗
PubMed2002

Remarkable compartmentalization of transposable elements and pseudogenes in the heterochromatin of the Tetraodon nigroviridis genome.

Tetraodon nigroviridis is among the smallest known vertebrate genomes and as such represents an interesting model for studying genome architecture and evolution. Previous studies have shown that Tetraodon contains several types of tandem and dispersed repeats, but that their overall contribution is >10% of the genome. Using genomic library hybridization, fluorescent in situ hybridization, and whole genome shotgun and directed sequencing, we have investigated the global and local organization of repeat sequences in Tetraodon. We show that both tandem and dispersed repeat elements are compartmentalized in specific regions that correspond to the short arms of small subtelocentric chromosomes. The concentration of repeats in these heterochromatic regions is in sharp contrast to their paucity in euchromatin. In addition, we have identified a number of pseudogenes that have arisen through either duplication of genes or the retro-transcription of mRNAs. These pseudogenes are amplified to high numbers, some with more than 200 copies, and remain almost exclusively located in the same heterochromatic regions as transposable elements. The sequencing of one such heterochromatic region reveals a complex pattern of duplications and inversions, reminiscent of active and frequent rearrangements that can result in the truncation and hence inactivation of transposable elements. This tight compartmentalization of repeats and pseudogenes is absent in large vertebrate genomes such as mammals and is reminiscent of genomes that remain compact during evolution such as Drosophila and Arabidopsis.

Animals↗
PubMed2002

Identification of a syndecan 4 pseudogene.

The syndecan family of heparan sulfate proteoglycans participates in cellular activation through interactions with growth factors, extracellular matrix, and other molecules. The family consists of four proteins that share sequence homology within their cytosolic domains. Here we report that a 5.8 kb region of human chromosome 22q12.2 contains multiple segments that share greater than 80% sequence homology to the syndecan 4 transcript, including homology to 443 nucleotides of the syndecan 4 coding region. Three pieces of evidence indicate that the chromosome 22 sequences are a syndecan 4 pseudogene. First, single nucleotide gaps need to be inserted into the chromosome 22 sequence in order to maintain maximal alignment to the syndecan 4 coding sequence, and this introduces stop codons into a deduced amino acid sequence. Second, the total length of chromosome 22 containing the homologous sequences is compressed when compared to the genomic organization of the complementary syndecan 4 sequences. Third, the 5.8 kb chromosome 22 sequence contains multiple Alu and other repetitive sequences, and this is a property of pseudogenes. Both RT-PCR and RNase protection assays indicated that the syndecan 4 pseudogene is transcribed in human umbilical vein endothelial cells.

Amino Acid Sequence↗
PubMed2004

Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.

We investigated a family with an autosomal recessive syndrome of cafe-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previously unrecognized PMS2 pseudogene, corresponding to exons 9-15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. This information allowed a redesigned sequence analysis, identifying a homozygous mutation (R802X) in PMS2 exon 14. Furthermore, in the family with Turcot syndrome, in which the first inherited PMS2 mutation (R134X) was described, a further truncating mutation was identified on the other allele, in exon 13. Further whole-genome analysis shows that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms are, in fact, pseudogene sequence variants. Although PMS2 mutations may be rare in colorectal cancer, they appear, for the most part, to behave as recessive traits. For technical reasons, their involvement in childhood cancer, particularly in primitive neuroectodermal tumor, may have been underestimated.

Adenosine Triphosphatases↗
PubMed2000

Absence of PTEN/MMAC1 pseudogene in mice.

The PTEN gene encodes a phosphatase that acts as a tumor-suppressor gene and is mutated in a variety of human cancers. Alterations of the PTEN gene in these tumor samples were identified using exon-by-exon analysis of the gene using single-stranded conformational polymorphism or direct sequencing of PTEN cDNA. However, in humans, mutational analysis of a PTEN cDNA template can produce false results because of a highly conserved PTEN processed pseudogene that shares more than 98% homology with the coding region of functional PTEN. PTEN-knockout mice develop tumors, suggesting that mouse tumor models are useful in vivo model systems to study PTEN function. Any mutational analysis of mouse PTEN cDNA may also produce false results if mice contain a highly conserved PTEN pseudogene. In this paper, we demonstrate the absence of any PTEN pseudogene in the mouse and discuss the significance of this observation for the mutational studies of the PTEN gene in mouse tumor models.

Animals↗
PubMed2004

Presence of a human Hyaluronan binding protein 1 (HABP1) pseudogene-like sequence in Methanosarcina barkeri suggests its linkage in evolution.

The gene encoding Hyaluronan binding protein 1 (HABP1) and its homologs have been reported across eukaryotes, from yeast to human. We have reported the presence of processed pseudogenes in several human chromosomes, along with the location of the HABP1 gene on chromosome 17p12-p13. In this study, we report not only the presence of HABP1 pseudogene in other animal species, but also the presence of a homologous sequence in Methanosarcina barkeri, an ancient life form. This sequence has 44.8% homology to the human HABP1 cDNA and 45.3% homology with the HABP1 pseudogene in human chromosome 21. This sequence has a high G + C content (57%), characteristic of archaea, a family to which M. barkeri belongs. The presence of this HABP1 cDNA like fragment in M. barkeri might enable us to shed light on the evolution of the HABPl gene and whether it was present in a common ancestral organism before the lineages separated.

Animals↗