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PubMed1985

Nonrandom integration of human U4 RNA pseudogenes.

Four loci for human U4 RNA have been characterized by DNA sequence analysis. The results show that all four loci represent pseudogenes, which are flanked by direct repeats. Three of the pseudogenes, designated U4/5, U4/6, and U4/8, have very similar structures; they are all truncated and contain the first 67 to 68 nucleotides of the U4 RNA sequence. Their properties suggest that they were created by integration of truncated cDNA copies of the U4 RNA into new chromosomal sites. An interesting observation was that their flanking regions exhibit sequence homology. A purine-rich 5'-flanking sequence 12 to 13 nucleotides long is almost perfectly conserved in all three loci. Boxes of homology were also found on the 3' side when the U4/6 and U4/8 loci were compared. The U4/4 locus has a slightly different structure; the pseudogene matches the first 79 nucleotides of U4 RNA, but contains a greater number of mutations than the other pseudogenes. Taken together, the results suggest that a frequently occurring type of pseudogene for human U4 was created by a RNA-mediated mechanism and that the integration sites have features in common.

Base Sequence↗
PubMed1987

The nontranscribed chicken calmodulin pseudogene cross-hybridizes with mRNA from the slow-muscle troponin C gene.

A chicken calmodulin pseudogene with no introns was previously shown to hybridize under stringent conditions with an mRNA species present in skeletal and cardiac muscles, yet it would not hybridize to calmodulin mRNA (J. P. Stein, R. P. Munjaal, L. Lagace', E. C. Lai, B. W. O'Malley, and A. R. Means, Proc. Natl. Acad. Sci. USA 80:6485-6489, 1983). Using the pseudogene as a probe, we isolated a full-length cDNA corresponding to this mRNA from a chicken breast muscle library and showed by sequence analysis that it encodes slow-muscle troponin C and not the pseudogene product. Hybridization between the calmodulin pseudogene and slow-muscle troponin C cDNA is due to a short region of high homology in those nucleotides that encode helices B and C of troponin C and calmodulin. Genomic Southern analysis showed the calmodulin pseudogene and the gene for slow-muscle troponin C to exist as distinct single copies.

Amino Acid Sequence↗
PubMed1986

Pseudogenes.

Pseudogenes are DNA sequences that bear significant homology to functional genes, yet they lack promoter sequences for their transcription or contain other mutations that preclude formation of a functional product. They appear to be a common feature of many eukaryotic genomes. Pseudogenes were first described among the 5S RNA genes of Xenopus; subsequently, they have been found for a wide range of genes, including globins, snRNAs, immunoglobulins, tubulins, and metallothionein. Some pseudogenes, like those of the beta-globins, lie within the gene cluster of their functional counterparts; they may simply have arisen by accumulation of mutations in a duplicated nonselected gene. Other pseudogenes appear to have arisen by a very different process. Characteristically, they are dispersed in the genome, lack introns, and have oligoA tracts at their 3' ends. Their structure suggests an origin from mRNAs through reverse transcription and integration into the genome. Pseudogenes have no known function. They may represent dead-end byproducts of normal cellular and evolutionary processes, yet they are also potential starting points from which new genes might evolve.

Animals↗
PubMed1987

Opal suppressor phosphoserine tRNA gene and pseudogene are located on human chromosomes 19 and 22, respectively.

An opal suppressor phosphoserine tRNA gene and pseudogene have been isolated from a human DNA library and sequenced (O'Neill, V., Eden, F., Pratt, K., and Hatfield, D. (1985) J. Biol. Chem. 260, 2501-2508). Southern hybridization of human genomic DNA with an opal suppressor tRNA probe suggested that the gene and pseudogene are present in single copy. In this study, we have determined the chromosome location of the human gene and pseudogene by utilizing a 193-base pair fragment encoding the opal suppressor phosphoserine tRNA gene as probe to examine DNAs isolated from human-rodent somatic cell hybrids that have segregated human chromosomes. These studies show that the probe hybridized with two regions in the human genome; one is located on chromosome 19 and the second on chromosome 22. By comparing the restriction sites within these two regions to those previously determined for the human opal suppressor phosphoserine tRNA gene and pseudogene, we tentatively assigned the gene to chromosome 19 and the pseudogene to chromosome 22. These assignments were confirmed by utilizing a 350-base pair fragment which was isolated from the 5'-flanking region of the human gene as probe. This fragment hybridized only to chromosome 19, demonstrating unequivocally that the opal suppressor phosphoserine tRNA gene is located on chromosome 19. The flanking probe hybridized to a single homologous band in hamster and in mouse DNA to which the gene probe also hybridized, demonstrating that the 5'-flanking region of the opal suppressor tRNA gene is conserved in mammals. Restriction analysis of DNAs obtained from the white blood cells of 10 separate individuals demonstrates that the gene is polymorphic. This study provides two additional markers for the human genome and constitutes only the second set of two tRNA genes assigned to human chromosomes.

Animals↗
PubMed2000

Propagation and maintenance of the 119 human immunoglobulin Vlambda genes and pseudogenes during evolution.

We previously determined a contiguous 1,025,415-nucleotide sequence of the entire human immunoglobulin lambda gene locus, in which a total of 36 potentially functional Vlambda genes and 33 pseudogenes were localized. We also identified many more incomplete Vlambda genes to be characterized further. Some of these possessed only a slight sequence homology with the known Vlambda genes, and others possessed a high homology but had severely truncated coding regions. Here, we made extensive characterization of 50 new Vlambda pseudogenes, totaling 119 gene segments in the Vlambda gene locus. Of these 119 Vlambda genes, 118 were localized within the five Vlambda gene-rich clusters that we previously defined. Two of these novel Vlambda pseudogenes possessed the opposite transcriptional polarity to all the other Vlambda genes. The present comprehensive analysis of 119 Vlambda genes validated our previous classification of Vlambda genes and provided a basis for a possible mechanism by which a large number of Vlambda pseudogenes were propagated and maintained as a particular locus during evolution.

Base Sequence↗
PubMed2006

Pseudogenes of the human HPRT1 gene.

Entrez Gene lists four HPRT1 gene pseudogenes (HPRTP1, HPRTP2, HPRTP3, and HPRTP4) mapping to chromosomes 3, 5, 11q, and 11q, respectively, as originally reported by Patel et al. in 1984 (Patel PI, et al. 1984 Somat Cell Mol Genet 10:483-493). However, the Entrez Gene reports for three of the four pseudogenes (HPRTP1, HPRTP3, and HPRTP4) are currently empty. A BLAST search of both GenBank (Homo sapiens) and the human genome found the chromosome 5 associated HPRTP2 sequence and a single chromosome 11q sequence (HPRTP3 or HPRTP4?). This chromosome 11 sequence had a unique 7.2 kb insert, which may explain why it originally appeared to be two separate pseudogenes. No evidence of a chromosome 3 associated sequence was found; however, a sequence highly homologous to HPRT1 was located on chromosome 4. All of these sequences are intronless processed pseudogenes. Lastly, a sequence highly homologous to HPRT1 exon 8 was found on chromosome 10. This homologous sequence was exactly exon 8 of a gene designated PRTFDC1, for phosphoribosyl transferase domain containing 1. This gene with unknown function is almost completely homologous to HPRT1 in exon structure (except for a 21 bp (seven amino acid) insertion in exon 1) and 68% homologous in amino acid sequence.

Animals↗
PubMed1993

Isolation and mapping of human T-cell protein tyrosine phosphatase sequences: localization of genes and pseudogenes discriminated using fluorescence hybridization with genomic versus cDNA probes.

This work reports the isolation, partial characterization, and chromosomal mapping of several human T-cell protein tyrosine phosphatase (PTPase) sequences and provides a direct comparison of the specificity of cDNA versus genomic probes in discriminating the location of genes versus pseudogenes by fluorescence in situ hybridization. In initial attempts to map the T-cell (TC) PTP gene using a 2-kb cDNA, several labeled sites were noted, raising the possibility of multiple related sequences within the genome. To address this, four genomic clones were obtained with homology to the TC PTP cDNA and characterized for their primary structure and their position within the human genome. Based on the presence or absence of an open reading frame and the intron/exon structure, two of these clones were found to be overlapping sequences encoding the true TC PTP gene and two were highly related but distinct processed pseudogenes. The TC PTP gene (gene symbol PTPN2) encoded by clones L17-2 and L5-1 localized to chromosome 18p11.2-p11.3, whereas pseudogenes encoded by clone L17-1, entitled TCPS1 (gene symbol PTPN2P1), and clone L18, entitled TCPS13 (gene symbol PTPN2P2), mapped to chromosomes 1q22-q24 and 13q12-q13, respectively. A direct comparison of the specificity of genomic and cDNA probes demonstrated that under identical conditions the genomic probes (containing both exon and intron sequences) readily identified a single specific site of hybridization, whereas the cDNA identified sites of both the gene and its pseudogenes. While providing mapping and sequencing information on the TC PTPase sequences, this work illustrates a strategy for addressing a recurrent problem in gene mapping studies where highly related sequences exist within the genome.

Amino Acid Sequence↗
PubMed1995

Genomic cloning of mouse MIF (macrophage inhibitory factor) and genetic mapping of the human and mouse expressed gene and nine mouse pseudogenes.

The single functional mouse gene for MIF (macrophage migration inhibitory factor) has been cloned from a P1 library, and its exon/intron structure determined and shown to resemble that of the human gene. The gene was mapped to chromosome 10 using two multilocus crosses between laboratory strains and either Mus musculus musculus or Mus spretus. Nine additional loci containing related sequences, apparently all processed pseudogenes, were also mapped to chromosomes 1, 2, 3, 7, 8, 9, 12, 17, and 19. While most of these pseudogenes were found in inbred mice and M. spretus, some are species specific. This suggests that there have been active phases of pseudogene formation in Mus both before and after the separation of musculus and spretus. The human genome contains no pseudogenes; we assigned the human gene to chromosome 19, consistent with the location of mouse and human functional genes for MIF in a region of conserved linkage.

Amino Acid Sequence↗
PubMed1996

Structure and organization of the human metaxin gene (MTX) and pseudogene.

Metaxin encodes a mitochondrial protein and is an essential nuclear gene in mice. The cDNA sequence and genomic organization of the human metaxin gene (MTX) have now been determined. MTX is 6 kb and consists of eight protein-encoding exons. The gene is contiguous to thrombospondin 3 (THBS3) and to the pseudogene for glucocerebrosidase (psGBA), but it transcribed in a direction opposite to the latter two genes. Thus, MTX and THBS3 share a common promoter region and are transcribed convergently, whereas MTX and psGBA are transcribed convergently and have closed apposed polyadenylation sites. Human metaxin contains 317 amino acids and is 91.5% identical to mouse metaxin. Metaxin is rich in leucine (14.2%) and in basic (12.9%) and acidic (12.0%) amino acids. The predicted protein lacks an amino-terminal signal sequence and N-glycosylation sites, but contains a putative transmembrane domain near its carboxy terminus. A DNA duplication has led to a direct repeat and the evolution of a pseudogene for GBA. A pseudogene for metaxin (psMTX) is also located within the 16 kb of DNA separating GBA from psGBA. The psMTX sequence is nearly identical to the 3' part of exon 2 through exon 8 of MTX, and both the intronic and the 3'-flanking sequences are highly conserved. Thus, there is a 278 amino acid open reading frame that is 97.8% identical to metaxin. However, psMTX lacks the first intron and promoter present in MTX, and at least in liver, the pseudogene is not expressed.

Amino Acid Sequence↗
PubMed2002

Structure and chromosomal distribution of human mitochondrial pseudogenes.

Nuclear mitochondrial pseudogenes (Numts) have been found in the genome of many eukaryote species, including humans. Using a BLAST approach, we found 1105 DNA sequences homologous to mitochondrial DNA (mtDNA) in the August 2001 Goldenpath human genome database. We assembled these sequences manually into 286 pseudogenes on the basis of single insertion events and constructed a chromosomal map of these Numts. Some pseudogenes appeared highly modified, containing inversions, deletions, duplications, and displaced sequences. In the case of four randomly selected Numts, we used PCR tests on cells lacking mtDNA to ensure that our technique was free from genome-sequencing artifacts. Furthermore, phylogenetic investigation suggested that one Numt, apparently inserted into the nuclear genome 25-30 million years ago, had been duplicated at least 10 times in various chromosomes during the course of evolution. Thus, these pseudogenes should be very useful in the study of ancient mtDNA and nuclear genome evolution.

Chromosome Mapping↗
PubMed2001

Recombination among multiple mitochondrial pseudogenes from a Passerine genus.

PCR products of a fragment of the mitchondrial protein coding subunit 5 of NADH-dehydrogenase (ND5) from eight individuals representing five species of the South American bird genus Conirostrum were cloned. The 130 clones, which were subsequently sequenced, constituted 55 different sequences. Due to the observed differences in substitution patterns 58% of the cloned sequences were identified as pseudogenes. Recombination could be traced in 19% of the inferred nuclear pseudogenes, but this figure probably represents a significant underestimation of the factual recombination events. The nonrecombined pseudogenes consisted of multiple haplotypes found to diverge from 1 to 16% from the mitochondrial gene. The number of mitochondrial nuclear copies and their apparent frequent recombination suggest that pseudogenes constitute a serious potential risk in confounding phylogenetic studies and population genetic analysis.

Amino Acid Sequence↗
PubMed1993

Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations through the pseudogene.

Lesions in the gene encoding the adrenal enzyme steroid 21-hydroxylase (P450c21) result in defective adrenal cortisol synthesis, often accompanied by aldosterone deficiency. The symptoms range from severe neonatal disease to inconspicuous symptoms in adulthood depending on the nature of the mutations. The 21-hydroxylase gene is present in close proximity to a highly homologous pseudogene, and both genes show variation in copy number between individuals. For complete DNA sequence characterization, we have applied selective polymerase chain reaction amplification and direct sequencing of all full-length steroid 21-hydroxylase genes present in individuals. Using healthy individuals with only one remaining steroid 21-hydroxylase allele as normal references, a new allele was found in two siblings, in whom clinical and laboratory findings demonstrated moderate enzyme deficiency. Full-length sequencing of this allele displayed an Arg 484 to Pro codon change in exon 10, in the same position as a previously identified GG to C mutation found in a patient with severe 21-hydroxylase deficiency. Arg 484 is located within a stretch of amino acids that are highly conserved between mammalian 21-hydroxylases. The finding of the presently reported 21-hydroxylase allele indicates that the GG to C mutation from the severely affected patient has arisen by a two-step mechanism, consisting of a G to C transversion accompanied by an adjacent G deletion. When sequencing 26 pseudogenes, both these mutations, which are not present in the pseudogenes hitherto reported, were found at low frequency together with a number of other polymorphisms. Thus, also rare mutations can spread via the pseudogene and can therefore be expected to arise independently in unrelated individuals.

Adrenal Hyperplasia, Congenital↗
PubMed1995

Multi-copy nuclear pseudogenes of mitochondrial DNA reveal recent acute genetic changes in the human genome.

Four nuclear pseudogenes homologous to the 10031-10195-bp region of the human mitochondrial genome were detected by constant denaturant capillary electrophoresis. Among them, one pseudogene is present as at least five copies in each cell, in accordance with our previous observations of multi-copy mitochondrial DNA pseudogenes. The presence of multiple identical copies of pseudogenes suggests that the human genome underwent a series of genetic changes, including gene amplifications, very recently in evolutionary history, i.e., within the last 390000 years.

Base Sequence↗
PubMed1993

An rps14 pseudogene is transcribed and edited in Arabidopsis mitochondria.

Sequence analysis of the region upstream of the apocytochrome b (cob) gene in the Arabidopsis mitochondrial genome identifies an open reading frame with homology to ribosomal protein L5, (rpl5), and a pseudogene with similarity to ribosomal protein S14 (rps14) genes. Both cob and rpl5 genes have intact reading frames, but the rps14 homology is disrupted by a stop codon and a deleted nucleotide. The rpl5 gene, the rps14 pseudogene, and the cob gene are separated by one nucleotide and a 1604-nucleotide-long spacer respectively. A plastid-like tRNA(Ser) is encoded downstream from the cob gene. The entire region is transcribed into a 5-kb transcript, containing the rps14 pseudogene and the cob gene. Cob and rpl5 mRNAs are edited in several positions with different frequencies. The rps14 pseudogene is transcribed and edited in one position in common with other plants. Since no intact rps14 gene is found in the mitochondrial genome of Arabidopsis, the functional gene is presumably encoded in the nucleus.

Amino Acid Sequence↗
PubMed1993

Characterization of a porcine glucosephosphate isomerase-processed pseudogene at chromosome 1q1.6-1.7.

A porcine glucosephosphate isomerase-processed pseudogene has been isolated and sequenced. The pseudogene has several base substitutions as well as an insertion and deletions, and is 83% homologous to the corresponding cDNA. It contains an intervening sequence of 565 bp, is truncated at the 3' end, and is flanked by direct repeats of seven nucleotides. Fluorescent in situ hybridization to porcine metaphase chromosomes localized the processed pseudogene to Chromosome (Chr) 1q1.6-1.7. A (GT)14(AT)15 microsatellite was detected close to the processed pseudogene.

Animals↗
PubMed1995

Isolation and characterization of a pseudogene related to human core 2 beta-1,6-N-acetylglucosaminyl-transferase.

In a previous study, we isolated genomic clones encoding core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT) and blood group IGnT and proposed that these two genes were produced from a common ancestral gene by duplication, diversion and intron insertion. In the present study, we have isolated a pseudogene which is highly related to the gene of C2GnT. The sequence analysis of this pseudogene indicated that the pseudogene was produced by duplication of a common precursor gene for C2GnT. These results taken together strongly suggest that the ancestral gene was first duplicated and one of the duplicated genes directly evolved into the IGnT gene. The other duplicated gene was further duplicated to produce the C2GnT gene and the pseudogene.

Amino Acid Sequence↗
PubMed1989

Strong functional GC pressure in a light-regulated maize gene encoding subunit GAPA of chloroplast glyceraldehyde-3-phosphate dehydrogenase: implications for the evolution of GAPA pseudogenes.

The light-regulated nuclear gene encoding subunit A of chloroplast glyceraldehyde-3-phosphate dehydrogenase (subunit GAPA, gene Gpa1) from maize is extremely G + C rich (67% in codons). The genomic surroundings of this gene have been characterized together with the sequences of two strongly conserved Gpa pseudogenes isolated from a genomic maize library by differential cDNA hybridization. The comparisons show that the high G + C content of the maize gene is maintained independently of the surrounding noncoding sequences, which are G + C poor (42%), and only as long as the gene encodes a functional protein. After nonfunctionalization, Gpa pseudogenes rapidly loose G + C mainly due to enhanced turnover of CpG and CpXpG methylation sites. These results suggest that the maize Gpa1 gene is under strong functional GC pressure, due to constraints (CpG island) probably exerted at the transcriptional level. They also indicate that Gpa pseudogenes are methylated and that methylation was either the cause or the immediate consequence of their nonfunctionalization. It can be concluded further that the progenitor of pseudogenes 1 and 2 was a second functional Gpa gene (Gpa'), which, after duplication, accelerated in evolutionary rate due to relaxation of selective constraints. This is in agreement with the neutral theory of evolution. Comparison of Gpa intron sequences reveals a gradient of divergence: the more 3' the position of an intron the more its sequence has diverged between the three Gpa genes. A speculative model is presented explaining these observations in terms of a homologous recombination of genes with their reverse-transcribed pre-mRNAs.

Amino Acid Sequence↗
PubMed1999

Identification of a bovine beta-mannosidosis mutation and detection of two beta-mannosidase pseudogenes.

Beta-mannosidase deficiency results in beta-mannosidosis, a severe neurodegenerative lysosomal storage disease identified in cattle, goats, and humans. To more fully understand the molecular pathology of this disease, the mutation associated with bovine beta-mannosidosis was identified by sequence analysis of cDNA from an affected calf. A transition mutation of G to A at position 2574 of the cDNA coding sequence creates a premature stop codon near the 3' end of the protein coding region. To aid commercial breeders of Salers cattle, a PCR-based test was developed to detect the mutation for beta-mannosidosis carrier screening. Application of this test also revealed the presence of two beta-mannosidase pseudogenes. Portions of the pseudogenes were amplified with allele-specific primers and then sequenced. One pseudogene was highly homologous (>99% sequence identity) to the expressed cDNA sequence over the 1292 bp that were sequenced, while the other showed more divergence (83% sequence identity) in the 477 bp that were sequenced. Both are processed pseudogenes that are not expressed. The severity of the bovine beta-mannosidosis phenotype suggests that the 22 C-terminal amino acids of beta-mannosidase play an important role in the function of this enzyme.

Animals↗