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PubMed2025

Mitochondrial Impostors: Prevalence and Impacts of NUMTs on Genetic and Evolutionary Studies in Carnivora.

Nuclear mitochondrial pseudogenes are mitochondria-derived DNA sequences integrated into the nuclear genome, which can introduce errors in species identification, phylogenetic inference, and population genetics. Although nuclear mitochondrial pseudogene contamination has been reported in some Carnivora species, a systematic investigation into the prevalence and impacts of nuclear mitochondrial pseudogenes across an order is still lacking. In this study, 22,102 mitochondrial DNA sequences of 80 Carnivora species from 14 families and 54 genera were retrieved from the public National Center for Biotechnology Information database and further analyzed. Using alignment-based methods, 158 problematic sequences/sequence groups were identified and categorized into four types: nuclear mitochondrial pseudogenes, species misidentification or mislabeling, sequence errors, and anomalous sites. Among families, Felidae exhibited the highest rate of nuclear mitochondrial pseudogene contamination, particularly in species of the genus Panthera. In contrast, no nuclear mitochondrial pseudogene contamination was detected in members of Ursidae and Ailuridae. Phylogenetic analysis revealed multiple independent origins of nuclear mitochondrial pseudogene, with some tracing back to the common ancestor of Carnivora. To mitigate nuclear mitochondrial pseudogene-related errors, rigorous sequence verification strategies, such as sequence alignment and phylogenetic validation, should be implemented. In conclusion, our findings highlight the necessity of nuclear mitochondrial pseudogene awareness in genetic and evolutionary studies of Carnivora and other taxa.

Animals↗

PubMed2000

The olfactory receptor gene repertoire in primates and mouse: evidence for reduction of the functional fraction in primates.

Olfactory receptors (ORs) located in the cell membrane of olfactory sensory neurons of the nasal epithelium are responsible for odor detection by binding specific odorant ligands. Primates are thought to have a reduced sense of smell (microsmatic) with respect to other mammals such as dogs or rodents. We have previously demonstrated that over 70% of the human OR genes have become nonfunctional pseudogenes, leading us to hypothesize that the reduced sense of smell could correlate with the loss of functional genes. To extend these results, we sampled the OR gene repertoire of 10 primate species, from prosimian lemur to human, in addition to mouse. About 221 previously unidentified primate sequences and 33 mouse sequences were analyzed. These sequences encode ORs distributed in seven families and 56 subfamilies. Analysis showed a high fraction ( approximately 50% on average) of pseudogenes in hominoids. In contrast, only approximately 27% of OR genes are pseudogenes in Old World monkeys, and New World monkeys are almost free of pseudogenes. The prosimian branch seems to have evolved differently from the other primates and has approximately 37% pseudogene content. No pseudogenes were found in mouse. With the exception of New World monkeys, we demonstrate that primates have a high fraction of OR pseudogenes compared with mouse. We hypothesize that under relaxed selective constraints, primates would have progressively accumulated pseudogenes with the highest level seen in hominoids. The fraction of pseudogenes in the OR gene repertoire could parallel the evolution of the olfactory sensory function.

Animals↗

PubMed1992

The evolutionary origin of the HLA-DR3 haplotype.

The human HLA-DR3 haplotype consists of two functional genes (DRB1*03 and DRB3*01) and one pseudogene (DRB2), arranged in the order DRB1...DRB2...DRB3 on the chromosome. To shed light on the origin of the haplotype, we sequenced 1480 nucleotides of the HLA-DRB2 gene and long stretches of two other genes, Gogo-DRB2 from a gorilla, "Sylvia" and Patr-DRB2 from a chimpanzee, "Hugo". All three sequences (HLA-DRB2, Gogo-DRB2, Patr-DRB2) are pseudogenes. The HLA-DRB2 and Gogo-DRB2 pseudogenes lack exon 2 and contain a twenty-nucleotide deletion in exon 3, which destroys the correct translational reading frame and obliterates the highly conserved cysteine residue at position 173. The Patr-DRB2 pseudogene lacks exons 1 and 2; it does not contain the twenty-nucleotide deletion, but does contain a characteristic duplication of that part of exon 6 which codes for the last four amino acid residues of the cytoplasmic region. When the nucleotide sequences of these three genes are compared to those of all other known DRB genes, the HLA-DRB2 is seen as most closely related to Gogo-DRB2, indicating orthologous relationship between the two sequences. The Patr-DRB2 gene is more distantly related to these two DRB2 genes and whether it is orthologous to them is uncertain. The three genes are in turn most closely related to HLA-DRBVI (the pseudogene of the DR2 haplotype) and Patr-DRB6 (another pseudogene of the Hugo haplotype), followed by HLA-DRB4 (the functional but nonpolymorphic gene of the DR4 haplotype). These relationships suggest that these six genes evolved from a common ancestor which existed before the separation of the human, gorilla, and chimpanzee lineages. The DRB2 and DRB6 have apparently been pseudogenes for at least six million years (myr). In the human and the gorilla haplotype, the DRB2 pseudogene is flanked on each side by what appear to be related genes. Apparently, the DR3 haplotype has existed in its present form for more than six myr.

Animals↗

PubMed2001

Gene-scan method for the recognition of carriers and patients with p47(phox)-deficient autosomal recessive chronic granulomatous disease.

OBJECTIVE: We devised a method to recognize carriers and patients with p47(phox)-deficient chronic granulomatous disease (A47 CGD), the most common autosomal form of the disease. CGD is characterized by the inability of phagocytic leukocytes to kill microorganisms, due to a defective NADPH oxidase system. The predominant genetic defect leading to p47(phox)-deficient CGD is a GT deletion at the beginning of exon 2 in the p47(phox) gene NCF1, most likely caused by recombination events between the NCF1 and one of its pseudogenes. It is hardly possible to investigate sequences of patients, carriers, and normal individuals using standard PCR/sequencing techniques, due to greater than 99% homology between NCF1 and its pseudogenes. METHODS: In our gene-scan method, a 198-bp region of genomic DNA around exon 2 of NCF1 is amplified by nonspecific PCR with one fluorochrome-labeled primer. The mixture of NCF1 and pseudogene product, which differs by two nucleotides in length, is separated according to size. The ratio between the peak heights indicates the relative number of NCF1 genes and pseudogenes within an individual's genome. RESULTS: The method is highly reproducible (SD = 4%) and sensitive (r = 0.998). Of the 16 healthy individuals, 15 had a 2:4 ratio (2 genes, 4 pseudogenes), 10/12 A47 CGD carriers had a 1:5 ratio, and 34 patients had only pseudogenes. In addition, gene-scans including a 20-bp duplication in intron 2 of the pseudogenes revealed insight in the crossing-over events between NCF1 and pseudogenes. CONCLUSIONS: Our method distinguishes individuals with one NCF1 gene (carriers) from controls and from NCF1-deficient patients.

Adult↗

PubMed2005

Retropseudogenes derived from the human Ro/SS-A autoantigen-associated hY RNAs.

We report the characterization in the human genome of 966 pseudogenes derived from the four human Y (hY) RNAs, components of the Ro/SS-A autoantigen. About 95% of the Y RNA pseudogenes are found in corresponding locations on the chimpanzee and human chromosomes. On the contrary, Y pseudogenes in mice are both infrequent and found in different genomic regions. In addition to this rodent/primate discrepancy, the conservation of hY pseudogenes relative to hY genes suggests that they occurred after rodent/primate divergence. Flanking regions of hY pseudogenes contain convincing evidence for involvement of the L1 retrotransposition machinery. Although Alu elements are found in close proximity to most hY pseudogenes, these are not chimeric retrogenes. Point mutations in hY RNA transcripts specifically affecting binding of Ro60 protein likely contributed to their selection for direct trans retrotransposition. This represents a novel requirement for the selection of specific RNAs for their genomic integration by the L1 retrotransposition machinery. Over 40% of the hY pseudogenes are found in intronic regions of protein-coding genes. Considering the functions of proteins known to bind subsets of hY RNAs, hY pseudogenes constitute a new class of L1-dependent non-autonomous retroelements, potentially involved in post-transcriptional regulation of gene expression.

Animals↗

PubMed2006

Gene losses during human origins.

Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the "less-is-more" hypothesis). However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the "less-is-more" hypothesis.

Animals↗

PubMed2002

Discovery of a functional retrotransposon of the murine phospholipid hydroperoxide glutathione peroxidase: chromosomal localization and tissue-specific expression pattern.

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), a selenoprotein capable of reducing toxic hydroperoxy ester lipids, has been implicated in antioxidative defense and spermatogenesis. Screening a murine genomic library, we isolated two recombinants (pseudogenes 1 and 2) containing retrotransposons for this enzyme. On comparison with the paralogous cDNA, pseudogene 1 contained only two silent nucleotide exchanges, and the 3'-untranslated region (3'-UTR) carrying the functionally important selenocysteine insertion sequence was free of mutations. This retrotransposon was found in various mouse strains and could be mapped to the region B2-B3 of chromosome 10. In vitro studies indicated significant promoter activity in the 5'-flanking region of pseudogene 1, and we observed a tissuespecific expression of this retrotransposon. In the submandibular gland. Most PHGPx transcripts originated from pseudogene 1. In contrast, pseudogene 2, containing numerous mutations in all parts of the retrotransposon, was not expressed in any tissue. It was mapped to region E3-E4 of chromosome 17, and we did not detect any promoter activity in its 5'-flanking region. These data indicate the existence of two retrotransposed PHGPx pseudogenes, one of which encodes a functional enzyme. This retrotransposon belongs to the rare group of pseudogenes that are tissue-specifically expressed under the control of captured regulatory elements, and it constitutes an example of evolutionarily acquired redundancy in gene expression. The results are important for the design of future knockout strategies aimed at investigating the biological role of this enzyme.

5' Flanking Region↗

PubMed1993

The emergence of new DNA repeats and the divergence of primates.

We have identified four genetic novelties that are fixed in specific primate lineages and hence can serve as phylogenetic time markers. One Alu DNA repeat is present in the human lineage but is absent from the great apes. Another Alu DNA repeat is present in the gorilla lineage but is absent from the human, chimpanzee, and orangutan. A progenitor Xba1 element is present in the human, chimpanzee, gorilla, and orangutan, but only in the human lineage did it give rise to a transposed progeny, Xba2. The saltatory appearance of Xba2 is an example of a one-time event in the evolutionary history of a species. The enolase pseudogene, known to be present as a single copy in the human, was found to be present in four other primates, including the baboon, an Old World monkey. Using the accepted value of 5 x 10(-9) nucleotide substitutions per site per year as the evolutionary rate for pseudogenes, we calculated that the enolase pseudogene arose approximately 14 million years ago. The calculated age for this pseudogene and its presence in the baboon are incongruent with each other, since Old World monkeys are considered to have diverged from the hominid lineage some 30 million years ago. Thus the rate of evolution in the enolase pseudogene is only about 2.5 x 10(-9) substitutions per site per year, or half the rate in other pseudogenes. It is concluded that rates of substitution vary between species, even for similar DNA elements such as pseudogenes. We submit that new DNA repeats arise in the genomes of species in irreversible and punctuated events and hence can be used as molecular time markers to decipher phylogenies.

Animals↗

PubMed1994

An in vivo assay for the reverse transcriptase of human retrotransposon L1 in Saccharomyces cerevisiae.

L1 elements constitute a highly repetitive human DNA family (50,000 to 100,000 copies) lacking long terminal repeats and ending in a poly(A) tail. Some L1 elements are capable of retrotransposition in the human genome (Kazazian, H. H., Jr., C. Wong, H. Youssoufian, A. F. Scott, D. G. Phillips, and S.E. Antonarakis, Nature (London) 332:164-166, 1988). Although most are 5' truncated, a consensus sequence of complete L1 elements is 6 kb long and contains two open reading frames (ORFs) (Scott, A. F., B. J. Schmeckpeper, M. Abdelrazik, C. T. Comey, B. O'Hara, J. P. Rossiter, T. Cooley, P. Health, K. D. Smith, and L. Margolet, Genomics 1:113-125, 1987). The protein encoded by ORF2 has reverse transcriptase (RT) activity in vitro (Mathias, S. L., A. F. Scott, H. H. Kazazian, Jr., J. D. Boeke, and A. Gabriel, Science 254:1808-1810, 1991). Because L1 elements are so numerous, efficient methods for identifying active copies are required. We have developed a simple in vivo assay for the activity of L1 RT based on the system developed by Derr et al. (Derr, L. K., J. N. Strathern, and D. J. Garfinkel, Cell 67:355-364, 1991) for yeast HIS3 pseudogene formation. L1 ORF2 displays an in vivo RT activity similar to that of yeast Ty1 RT in this system and generates pseudogenes with unusual structures. Like the HIS3 pseudogenes whose formation depends on Ty1 RT, the HIS3 pseudogenes generated by L1 RT are joined to Ty1 sequences and often are part of complex arrays of Ty1 elements, multiple HIS3 pseudogenes, and hybrid Ty1/L1 elements. These pseudogenes differ from those previously described in that there are base pairs of unknown origin inserted at several of the junctions. In two of three HIS3 pseudogenes studied, the L1 RT appears to have jumped from the 5' end of a Ty1/L1 transcript to the poly(A) tract of the HIS3 RNA.

Base Sequence↗

PubMed1985

Human U1 small nuclear RNA genes: extensive conservation of flanking sequences suggests cycles of gene amplification and transposition.

The DNA immediately flanking the 164-base-pair U1 RNA coding region is highly conserved among the approximately 30 human U1 genes. The U1 multigene family also contains many U1 pseudogenes (designated class I) with striking although imperfect flanking homology to the true U1 genes. Using cosmid vectors, we now have cloned, characterized, and partially sequenced three 35-kilobase (kb) regions of the human genome spanning U1 homologies. Two clones contain one true U1 gene each, and the third bears two class I pseudogenes 9 kb apart in the opposite orientation. We show by genomic blotting and by direct DNA sequence determination that the conserved sequences surrounding U1 genes are much more extensive than previously estimated: nearly perfect sequence homology between many true U1 genes extends for at least 24 kb upstream and at least 20 kb downstream from the U1 coding region. In addition, the sequences of the two new pseudogenes provide evidence that class I U1 pseudogenes are more closely related to each other than to true genes. Finally, it is demonstrated elsewhere (Lindgren et al., Mol. Cell. Biol. 5:2190-2196, 1985) that both true U1 genes and class I U1 pseudogenes map to chromosome 1, but in separate clusters located far apart on opposite sides of the centromere. Taken together, these results suggest a model for the evolution of the U1 multigene family. We speculate that the contemporary family of true U1 genes was derived from a more ancient family of U1 genes (now class I U1 pseudogenes) by gene amplification and transposition. Gene amplification provides the simplest explanation for the clustering of both U1 genes and class I pseudogenes and for the conservation of at least 44 kb of DNA flanking the U1 coding region in a large fraction of the 30 true U1 genes.

Base Sequence↗

PubMed2000

Programmed DNA under-amplification in Paramecium primaurelia.

Ciliates are unicellular eukaryotic organisms that contain two types of nuclei throughout their vegetative life, transcriptionally active macronuclei governing the cell phenotype, and transcriptionally inert micronuclei. Following sexual reproduction, new macronuclear genomes regularly develop from micronuclear genomes through programmed DNA rearrangements that include DNA splicing, DNA fragmentation and DNA amplification. In the course of characterization of the micronuclear version of the 9.0 kb G gene, which encodes the G surface antigen in Paramecium primaurelia, we characterized a G gene duplicate. Compared with the G gene, the G gene duplicate displays features identifying it as a psi G pseudogene. About 1.6 kb upstream from the G gene, we characterized a new gene, the P gene. A related psi P putative pseudogene lies 1.6 kb upstream from the psi G pseudogene, showing that the duplicated region extends over > 15 kb and putatively defining it as a pseudogene region. Within macronuclear genomes, this region is highly under-amplified; its level never exceeds 20% of that of the corresponding G gene/P gene region in the 11 cell clones we tested. Under-amplification of the psi G pseudogene/psi P putative pseudogene region could be due to its distal position on macronuclear chromosomes, the use of alternative DNA fragmentation domains being frequent in Paramecium species, or to intrinsically lower amplification of a large genomic region. Therefore, the psi G pseudogene/psi P putative pseudogene region presented in this study provides a useful tool for the analysis of DNA fragmentation and/or amplification in eukaryotic genomes.

Amino Acid Sequence↗

PubMed1997

The nuclear autoantigen La/SS-B: mapping and sequencing of the gene and the three retropseudogenes.

One target of autoantibodies in sera of patients with systemic lupus erythematosus or primary Sjögren's syndrome is the nuclear autoantigen La/SS-B. Lambda clones and cosmids were isolated, which contained the sequences of the La gene and the three La pseudogenes. They were used for preparation of a physical map. Finally, the La gene and pseudogenes were sequenced. The pseudogenes were characterized as retropseudogenes. Their evolutionary ages were estimated to be approx. 4, 4.5 and 5 million years. Inserts of 4, 16 and 24 nucleotides, which were mostly A-residues, were found in exon 7 of the respective pseudogene. The oldest pseudogene contained the longest insert, the youngest pseudogene contained the smallest insert. The oligonucleotides seem to be the result of repeated inserts of A-residues in a hot spot region of the La genes. Two La cDNAs were isolated which contained either a deletion or an insert of an A-residue at the same position.

Autoantigens↗

PubMed1991

Molecular analysis of the hot spot region related to length mutations in wheat chloroplast DNAs. I. Nucleotide divergence of genes and intergenic spacer regions located in the hot spot region.

The nucleotide divergence of chloroplast DNAs around the hot spot region related to length mutation in Triticum (wheat) and Aegilops was analyzed. DNA sequences (ca. 4.5 kbp) of three chloroplast genome types of wheat complex were compared with one another and with the corresponding region of other grasses. The sequences region contained rbcL and psaI, two open reading frames, and a pseudogene, rpl23' (pseudogene for ribosomal protein L23) disrupted by AT-rich intergic spacer regions. The evolution of these genes in the closely related wheat complex is characterized by nonbiased nucleotide substitutions in terms of being synonymous/nonsynonymous, having A-T pressure transitions over transversions, and frequent changes at the third codon position, in contrast with the gene evolution among more distant plant groups where biased nucleotide substitutions have frequently occurred. The sequences of these genes had diverged almost in proportion to taxonomic distance. The sequence of the pseudogene rpl23' changed approximately two times faster than that of the coding region. Sequence comparison between the pseudogene and its protein-coding counterpart revealed different degrees of nucleotide homology in wheat, rice and maize, suggesting that the transposition timing of the pseudogene differed and/or that different rates of gene conversion operated on the pseudogene in the cpDNA of the three plant groups in Gramineae. The intergenic spacer regions diverged approximately ten times faster than the genes. The divergence of wheat from barley, and that from rice are estimated based on the nucleotide similarity to be 1.5, 10 and 40 million years, respectively.

Base Sequence↗

PubMed1986

An analysis of replacement and synonymous changes in the rodent L1 repeat family.

L1 is a family of long interspersed repetitive sequences in mammals that includes the BamHI family in rodents and the KpnI family in primates. Previous studies have shown that L1 repeats contain a long open reading frame and that the family evolves in concert. Working with 32 rodent elements for which DNA sequence is available, we used the distribution of replacement and synonymous changes to determine which L1 lineages had been expressing their reading frame. The evidence obtained is consistent with there having been a small number of L1 genes that have been expressing a functional protein. Much of the concerted evolution in L1 is accounted for by the tendency of these functioning L1 genes to continually create nonfunctional pseudogenes by reinsertion into the genome of sequences derived from their transcripts. The gain of new pseudogenes is balanced by the loss of old pseudogenes with a half-life of 2 Myr. Therefore, most of the observed L1 repeats are at a dead end with respect to either the expression of the L1 protein or the potential to elaborate further copies of themselves. However, the turnover of L1 pseudogenes is sufficient to constitute a vast flux of sequences into and then out of the flanking regions of all cellular genes. If the presence of flanking L1 pseudogenes affects the expression of other genes in even a subtle fashion, this process should represent a major source of genetic variation. A second level of concerted evolution occurs within the functional L1 sequences in a pattern that did not meet our expectations for selfish DNA. Also, in spite of the marked suppression of replacement relative to synonymous changes in functioning L1 genes, they evolve at an overall rate accelerated to the level of their own pseudogenes.

Animals↗

PubMed2000

Decay of mutualistic potential in aphid endosymbionts through silencing of biosynthetic loci: Buchnera of Diuraphis.

Buchnera, the primary bacterial endosymbiont of aphids, is known to provision essential amino acids lacking in the hosts' diet of plant sap. The recent discovery of silenced copies of genes for tryptophan biosynthesis (trpEG) in certain Buchnera lineages suggests a decay in symbiotic functions in some aphid species. However, neither the distribution of pseudogenes among lineages nor the impact of this gene silencing on amino-acid availability in hosts has been assessed. In Buchnera of the aphid Diuraphis noxia, tandem repeats of these pseudogenes have persisted in diverse lineages, and thpEG pseudogenes have originated at least twice within this aphid genus. Measures of amino-acid concentrations in Diuraphis species have shown that the presence of the pseudogene is associated with a decreased availability of tryptophan, indicating that gene silencing decreases nutrient provisioning by symbionts. In Buchnera of Diuraphis, rates of nonsynonymous substitutions are elevated in functional trpE copies, supporting the hypothesis that pseudogene origin and persistence reflect a reduced selection for symbiont biosynthetic contributions. The parallel evolution of trpEG pseudogenes in Buchnera of Diuraphis and certain other aphid hosts suggests that either selection at the host level is not effective or that fitness in these aphids is not limited by tryptophan availability.

Animals↗

PubMed2005

Structural basis for segmental gene conversion in generation of Anaplasma marginale outer membrane protein variants.

Bacterial pathogens in the genus Anaplasma generate surface coat variants by gene conversion of chromosomal pseudogenes into single-expression sites. These pseudogenes encode unique surface-exposed hypervariable regions flanked by conserved domains, which are identical to the expression site flanking domains. In addition, Anaplasma marginale generates variants by recombination of oligonucleotide segments derived from the pseudogenes into the existing expression site copy, resulting in a combinatorial increase in variant diversity. Using the A. marginale genome sequence to track the origin of sequences recombined into the msp2 expression site, we demonstrated that the complexity of the expressed msp2 increases during infection, reflecting a shift from recombination of the complete hypervariable region of a given pseudogene to complex mosaics with segments derived from hypervariable regions of different pseudogenes. Examination of the complete set of 1183 variants with segmental changes revealed that 99% could be explained by one of the recombination sites occurring in the conserved flanking domains and the other within the hypervariable region. Consequently, we propose an 'anchoring' model for segmental gene conversion whereby the conserved flanking sequences tightly align and anchor the expression site sequence to the pseudogene. Associated with the recombination sites were deletions, insertions and substitutions; however, these are a relatively minor contribution to variant generation as these occurred in less than 2% of the variants. Importantly, the anchoring model, which can account for more variants than a strict segmental sequence identity mechanism, is consistent with the number of msp2 variants predicted and empirically identified during persistent infection.

Amino Acid Sequence↗

PubMed1995

Characterisation of a second, apparently inactive, copy of the bovine beta-lactoglobulin gene.

A bovine cosmid clone was isolated which contains the previously characterised beta-lactoglobulin gene and, in addition, a related sequence which appears to be a beta-lactoglobulin pseudogene. The total length of the pseudogene, as determined by DNA sequencing, is 4.8 kb, similar to that of beta-lactoglobulin. Both genes are in the same orientation and are separated by approximately 14 kb intergenic sequence. Although most of introns I-V are extremely divergent, the exon sequences are clearly related, exons I-V exhibiting nucleotide sequence similarities in the range 60-87%. Exons VI and VII, together with the final intron, comprise a region of sequence extending over 730 bp, which displays 92.5% identity to the corresponding beta-lactoglobulin sequence. It is suggested that this is the result of a recent gene conversion event involving conversion of the pseudogene by the authentic beta-lactoglobulin gene. Identification of the new lactoglobulin sequence as a pseudogene is based on the occurrence of a stop codon in exon V. Comparison of the inferred translation product encoded by the pseudogene before its mutational inactivation, with the sequences of equine and feline beta-lactoglobulins I and II, indicates that the bovine pseudogene is more closely related to these type-II lactoglobulin sequences than to the type-I sequences.

Amino Acid Sequence↗

PubMed2002

Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal duplication of 15q.

Clinical cytogenetic laboratories frequently identify an apparent duplication of proximal 15q that does not involve probes within the PWS/AS critical region and is not associated with any consistent phenotype. Previous mapping data placed several pseudogenes, NF1, IgH D/V, and GABRA5 in the pericentromeric region of proximal 15q. Recent studies have shown that these pseudogene sequences have increased copy numbers in subjects with apparent duplications of proximal 15q. To determine the extent of variation in a control population, we analysed NF1 and IgH D pseudogene copy number in interphase nuclei from 20 cytogenetically normal subjects by FISH. Both loci are polymorphic in controls, ranging from 1-4 signals for NF1 and 1-3 signals for IgH D. Eight subjects with apparent duplications, examined by the same method, showed significantly increased NF1 copy number (5-10 signals). IgH D copy number was also increased in 6/8 of these patients (4-9 signals). We identified a fourth pseudogene, BCL8A, which maps to the pericentromeric region and is coamplified along with the NF1 sequences. Interphase FISH ordering experiments show that IgH D lies closest to the centromere, while BCL8A is the most distal locus in this pseudogene array; the total size of the amplicon is estimated at approximately 1 Mb. The duplicated chromosome was inherited from either sex parent, indicating no parent of origin effect, and no consistent phenotype was present. FISH analysis with one or more of these probes is therefore useful in discriminating polymorphic amplification of proximal pseudogene sequences from clinically significant duplications of 15q.

Adult↗