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PubMed2002

[Study of hybridization in four species of ground squirrels (spermophilus: Rodentia, Sciuridae) by molecular genetic methods].

Four species of ground squirrel--yellow (Spermophilus fulvus), russet (S. major), small (S. pygmaeus), and spotted (S. suslicus)--occur in the Volga region. Between S. major and S. pigmaeus, S. major and S. fulvus, and S. major and S. suslicus, sporadic hybridization was reported. Using sequencing and restriction analysis, we have examined the mtDNA C region in 13 yellow, 60 russet, 61 small, 45 spotted ground squirrels, and 9 phenotypic hybrids between these species. It was shown that 43% of S. major individuals had "alien" mitotypes typical of S. fulvus and S. pygmaeus. Alien mitotypes occurred both within and outside sympatric zones. No alien mitotypes were found in 119 animals of the other three species, which suggests that only one parental species (S. major) predominantly participates in backcrosses. Phenotypic hybrids S. fulvus x S. major and S. major x S. pygmaeus) were reliably identified using RAPD-PCR of nuclear DNA. However, we could find no significant traces of hybridization in S. major with alien mitotypes. Analysis of p53 pseudogenes of S. major and S. fulvus that were for the first time described in the present study produced similar results: 59 out of 60 individuals of S. major (including S. major with S. fulvus mitotypes) had only the pseudogene variant specific for S. major. This situation is possible even at low hybridization frequencies (less than 1% according to field observations and 1.4 to 2.7% according to nuclear DNA analysis) if dispersal of S. major from the sympatric zones mainly involved animals that obtained alien mtDNA via backcrossing. The prevalence of animals with alien mitotypes in some S. major populations can be explained by the founder effect. Further studies based on large samples are required for clarifying the discrepancies between mitochondrial and nuclear DNA data.

Animals↗
PubMed1992

HLA-J, a second inactivated class I HLA gene related to HLA-G and HLA-A. Implications for the evolution of the HLA-A-related genes.

Ragoussis and co-workers (Genomics 4:301) previously described a class I HLA gene (now designated HLA-J) that maps to within 50 kb of HLA-A. The nucleotide sequences of three HLA-J alleles are reported here. Comparison of the nucleotide sequences of HLA-J alleles shows this gene is more related to HLA-G, A, and H than to HLA-B, C, E, and F. All four alleles of HLA-J are pseudogenes because of deleterious mutations that produce translation termination either in exon 2 or exon 4. Apart from these mutations, the predicted proteins have structures similar to those of HLA-A, B, and C molecules. There is, however, little polymorphism at HLA-J and none at functional positions of the Ag-recognition site. The polymorphism is less than found for HLA-H another HLA-A-related pseudogene. HLA-J appears, like HLA-H, to be an inactivated gene that result from duplication of an Ag-presenting locus related to HLA-A. Nucleotide sequence comparisons show that the HLA-A, H, J, and G genes form a well defined group of "HLA-A-related" loci. Evolutionary relationships as assessed by construction of trees suggest the four modern loci: HLA-A, G, H, and J were formed by successive duplications from a common ancestral gene. In this scheme one intermediate locus gave rise to HLA-A and H, the other to HLA-G and J.

Alleles↗
PubMed2006

Comparative analysis of human masculinity.

To study rapidly evolving male specific Y (MSY) genes we retrieved and analyzed nine such genes. VCY, HSFY and RBMY were found to have functional X gametologs, but the rest did not. Using chimpanzee orthologs for XKRY, CDY, HSFY, PRY, and TSPY, the average silent substitution is estimated as 0.017 +/- 0.006/site and the substitution rate is 1.42 x 10(-9)/site/year. Except for VCY, all other loci possess two or more pseudogenes on the Y chromosome. Sequence differences from functional genes show that BPY2, DAZ, XKRY, and RBMY each have one pseudogene for each one that is human specific, while others were generated well before the human-chimpanzee split, by means of duplication, retro-transposition or translocation. Some functional MSY gene duplication of VCY, CDY and HSFY, as well as X-linked VCX and HSFX duplication, occurred in the lineage leading to humans; these duplicates have accumulated nucleotide substitutions that permit their identification.

Animals↗
PubMed1990

CYP21B gene conversion and complete CYP21A gene deletion in congenital adrenal hyperplasia.

We studied a family in which one out of two children presented a non-salt wasting form of CAH. Genomic DNA of the patient, his brother, his parents and a normal control were digested by the Taq I and Bgl II restriction enzymes. The fragments were electrophoresed, transferred onto a nitrocellulose membrane and hybridized with two specific probes: pC21a for the CYP21 genes and pAT-A for the C4 genes. We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films. The affected child had a CYP21B gene conversion in the CYP21A pseudogene on one chromosome inherited from his mother and a mutated CYP21B gene on the second chromosome inherited from his father. The second maternal chromosome, inherited by the unaffected brother, presented an unusual CYP21A gene deletion without a C4A or C4B gene deletion. Although CYP21A is a pseudogene, this type of complete CYP21A gene deletion associated with a CYP21B gene conversion has never been previously described.

Adrenal Hyperplasia, Congenital↗
PubMed1990

Structure of the gene for rat nucleolar protein B23.

Protein B23 is an abundant RNA-associated nucleolar phosphoprotein involved in the ribosome assembly process. Previous studies showed that two forms of the protein (B23.1 and B23.2) are generated from a single gene via alternative splicing of 3' exons at the mRNA level (Chang, J. H., and Olson, M. O. J. (1989) J. Biol. Chem. 264, 11732-11737). We now report the structure of the complete B23 gene which spans 11-kilobases of DNA and contains 12 exons coding for the 294 amino acid residues. B23.1 mRNA is encoded by exons 1-9, 11, and 12, whereas exons 1-10 code for the B23.2 mRNA. Each exon codes for a relatively short segment of the protein (2-40 amino acid residues). The exons, which are distributed unevenly over the length of the gene, are separated by introns varying in size between 122 base pairs and 2.2 kilobases. Southern blot analyses using a probe derived from the untranslated segment of exon 10 suggests that a single expressed gene is present in the rat genome. Additional genomic clones contained apparent processed pseudogenes for protein B23. Primer extension studies and comparison with a processed pseudogene reveal a probable transcription initiation site at position -96 from the first ATG. The 5' region of the gene contains several possible regulatory elements. Three GC boxes which are potential binding sites for transcription factor Sp1 were found, including one within the first intron. A segment of about 1500 base pairs in the 5' region is unusually rich in the dinucleotide CpG. Although no CCAAT box was found a well-defined TATA box is present at position -126. The latter feature suggests that the B23 gene has some properties of tissue-specific genes in addition to the predominant characteristics of housekeeping genes.

Amino Acid Sequence↗
PubMed1989

A family with an apparent HLA-DR triplet: evidence for exchange of functional HLA-DR beta-genes between different haplotypes.

Serological and protein analysis showed that HLA-DR1 and DR2 short (s) segregated together as one haplotype, resulting in a HLA-DR triplet as found in a family study. Both DR1 and DR2 molecules were coordinately expressed and were shown to function as restriction elements in antigen presentation assays. This unique HLA-DR1, 2s haplotype was further studied by Southern blot analysis. Based upon well-known restriction fragment length polymorphisms for the involved gene sets, i.e. DR1 and DR2 along with the DR type from the other haplotype, the genes as identified by restriction fragment length polymorphism of the triplet could be established. Pseudogenes, which are included in the previously described gene sets of HLA-DR1 and DR2 are apparently lacking in the triplet. We therefore postulate that during an unequal crossing-over event the DR beta-pseudogene of DR2 could be exchanged by a functional DR1 beta-gene.

Crossing Over, Genetic↗
PubMed1995

Evolution of the bovine lysozyme gene family: changes in gene expression and reversion of function.

Recruitment of lysozyme to a digestive function in ruminant artiodactyls is associated with amplification of the gene. At least four of the approximately ten genes are expressed in the stomach, and several are expressed in nonstomach tissues. Characterization of additional lysozymelike sequences in the bovine genome has identified most, if not all, of the members of this gene family. There are at least six stomachlike lysozyme genes, two of which are pseudogenes. The stomach lysozyme pseudogenes show a pattern of concerted evolution similar to that of the functional stomach genes. At least four nonstomach lysozyme genes exist. The nonstomach lysozyme genes are not monophyletic. A gene encoding a tracheal lysozyme was isolated, and the stomach lysozyme of advanced ruminants was found to be more closely related to the tracheal lysozyme than to the stomach lysozyme of the camel or other nonstomach lysozyme genes of ruminants. The tracheal lysozyme shares with stomach lysozymes of advanced ruminants the deletion of amino acid 103, and several other adaptive sequence characteristics of stomach lysozymes. I suggest here that tracheal lysozyme has reverted from a functional stomach lysozyme. Tracheal lysozyme then represents a second instance of a change in lysozyme gene expression and function within ruminants.

Animals↗
PubMed1991

The human immunoglobulin kappa locus. Characterization of the duplicated O regions.

Two large regions of the human immunoglobulin kappa locus, the so-called O regions, have been characterized on cosmid and phage lambda clones. The two regions are very similar but not identical duplicates belonging to the C kappa proximal (p) and the distal (d) copies of the kappa locus. The Op and Od regions comprise contigs of 90 and 120 kb, respectively, and contain 20 V kappa genes and pseudogenes which have been sequenced. Three pairs of V kappa genes were found to be practically identical in the duplicates while allotypic differences, at least for two of the genes, are considerable. The similarities between the duplicate genes may be related to the fact that the two copies of the kappa locus are arranged in a palindrome-like fashion with the 5' sides of the O regions pointing towards each other (C kappa J kappa B Lp Ap Op-Od Ad Ld). This may have contributed to equalizing the sequences. Beyond Op and Od no further V kappa genes were found within about 80 kb. Instead, repetitive DNA sequences have been localized there, the structures of which suggest that they may have been involved in the evolution of the V kappa gene-containing regions. The V kappa pseudogene containing W regions, that had been transposed in evolution from the short to the long arm of chromosome 2 by a pericentric inversion, may have been derived from the O regions according to structural homologies between defined sections of the O and W regions.

Base Sequence↗
PubMed1992

The human immunoglobulin kappa locus. Characterization of the duplicated A regions.

The central regions of the kappa locus, the so-called A regions, have been fully characterized on cosmid and phage lambda clones. The regions, which are parts of the C kappa-proximal and -distal copies of the locus and are, therefore, called Ap and Ad regions, comprise about 140 kb each and contain together 30 V kappa genes and pseudogenes. The A regions have been linked on their 5' sides to the O regions and on their 3' sides to the L regions. Chromosomal walking has eliminated a previous gap in the Ap region. Detailed restriction maps of the Ap and Ad regions and the sequences of 9 V kappa genes are reported. Four events, which have occurred in evolution probably after the duplication of the A region, were identified: the insertion of an Alu element in Ad; the insertion of part of a LINE element in Ap; the deletion of a 17.5-kb fragment including one V kappa gene from Ap; the sequence divergence of duplicated V kappa gene regions which ranges among the five pairs studied here from 0 to 14 bp per kb and converted two genes to pseudogenes while their duplicates stayed functional. An analysis of the A regions of the lymphoid cell lines RPMI 6140 and GM607 confirmed the previous finding that the V kappa-J kappa rearrangement in these cell lines had occurred by deletion and inversion mechanisms, respectively. Thus, the structural data contribute to the understanding of the evolution and the functioning of the A regions of the kappa locus.

Amino Acid Sequence↗
PubMed1993

The human immunoglobulin VH7 gene family consists of a small, polymorphic group of six to eight gene segments dispersed throughout the VH locus.

In this report we describe the analysis and mapping of members of the human immunoglobulin VH7 gene family. VH7 and VH1 gene segments are closely related, with individual gene segments sharing between 78% and 82% sequence identity. Divergence from VH1 gene sequence occurs as an abrupt event at the boundary between framework region (FR) 2 and complementarity-determining region (CDR) 2 and continues through a major portion of FR 3. We used polymerase chain reaction amplification to create a 162-base pair probe spanning the family-specific region of CDR 2 and FR 3 that proved suitable for standard Southern analysis of genomic DNA. The VH7 gene family was found to be a small but discrete VH gene family consisting of five to eight germ-line elements, of which at least three are polymorphic. Four different VH7 gene segments were cloned from the germ line of a single individual, and assigned to specific restriction fragments by sequence-specific hybridization. Two of the four VH7 elements were pseudogenes. The pattern of sequence variation in these and other known pseudogenes suggests that these nonfunctional elements may play a role in the evolution of novel VH families. A combination of one and two-dimensional pulsed field gel electrophoresis was employed to map the chromosomal location of all of these VH7 elements. Individual VH7 gene segments were found to be dispersed over a region of at least 940 kb of DNA, and interspersed with members from other VH gene families. The polymorphism of the VH7 gene segments and their scattered location throughout the VH locus makes them potentially useful markers for mapping and linkage studies.

Amino Acid Sequence↗
PubMed1993

The V kappa genes of the L regions and the repertoire of V kappa gene sequences in the human germ line.

Only 14 of the 25 V kappa genes and pseudogenes had been found before as parts of the L regions. The cloning and linking described in the accompanying report allowed us now to assign to Lp or Ld some V kappa genes which had been found before on scattered clones. In addition the sequences of several still unknown genes are reported here, thus completing the publication of the V kappa genes of the kappa locus as far as they are potentially functional or have only one or two 1-bp defects. Of the V kappa genes of the kappa locus, 32 are potentially functional, 16 have minor defects, 3 have both potentially functional and slightly defective alleles and 25 are pseudogenes which amounts to a repertoire of 76 V kappa-related gene sequences. The V kappa genes of the L regions are, within the subgroups, particularly similar to each other, which is in part due to common evolutionary origins and in part caused by gene conversion-like events. One donor-acceptor pair could be clearly identified, since converted and not-converted alleles of the acceptor gene were found. In other cases the duplicates of the converted genes served as non-converted controls.

Alleles↗
PubMed1994

T cell receptor gamma cDNA in human fetal liver and thymus: variable regions of gamma chains are restricted to V gamma I or V9, due to the absence of splicing of the V10 and V11 leader intron.

Although complete in-frame transcripts of the human T cell receptor gamma V10 and V11 genes have been described, the corresponding gamma chains have never been found in gamma delta T cell receptors. In this study, we show that the leader intron of all V10 and V11 cDNA isolated from fetal thymus, fetal liver and adult peripheral blood lymphocytes are unspliced. We demonstrate that, due to the absence of splicing, V10 and V11 are pseudogenes and cannot be expressed in gamma chains. They are the first pseudogenes of this type described in a rearranging T cell receptor/immunoglobulin locus. Therefore the gamma repertoire at the protein level is limited to subgroup V gamma I and to V9. By analysis of the gamma polymerase chain reaction products from total cDNA, we find that the gamma locus is active in early ontogeny (8 weeks), as shown by the presence of rearranged V9 and V10 gene transcripts in the liver. At 13 weeks, the V gamma I genes as well as V9 and V10 have undergone productive rearrangements in the liver, and in the thymus. Most rearrangements, if not all, involve the T cell receptor gamma C1 region (JP1, JP, J1 segments) in both tissues, confirming the accessibility of the C1 region in early stages of development.

Amino Acid Sequence↗
PubMed1993

How much do we know about spontaneous human mutation rates?

The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes of the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane [Ann Eugen 13:262-271, 1947] in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm, and may be considerably higher. The great mutation load implied by a rate of approximately 1 per zygote can be greatly ameliorated by quasi-truncation selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10(2) new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophila shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations.

Age Factors↗
PubMed2006

Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox protein. Most (>97%) CGD patients without p47phox (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psiNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psiNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psiNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psiNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis.

Adolescent↗
PubMed2002

The SSX gene family: characterization of 9 complete genes.

Human SSX genes comprise a gene family with 6 known members. SSX1, 2 and 4 have been found to be involved in the t(X;18) translocation characteristically found in all synovial sarcomas. Four (SSX1, 2, 4 and 5) are known to be expressed in a subset of tumors and testis, and anti-SSX antibodies have been found in sera from cancer patients. SSX antigens are thus typical cancer-testis (CT) antigens. To identify additional SSX family members, we isolated and characterized human genomic clones homologous to a prototype SSX cDNA. We also searched public databases for sequences similar to SSX. This identified 3 additional SSX genes, SSX7, 8, 9, and also completed the sequence of the formerly partially defined SSX6 gene. In addition to these novel SSX genes, several SSX pseudogenes were identified. With the exception of 1 pseudogene, all SSX genomic SSX sequences map to chromosome X. Among normal tissues, SSX7 mRNA was present only in testis, whereas SSX6, 8 and 9 were not detected in any normal tissue. SSX6 and 7 were expressed in 1 of 9 melanoma cell lines tested, whereas SSX8 and 9 expression was not detected in any tumor tissue or cell lines tested. SSX1, 2, 4 and 5 mRNA expression can be induced in cell lines by 5-aza-2-deoxycytidine or Trichostatin A. These agents also induce SSX6, but not SSX3, 7, 8 or 9 in the tumor cell lines tested, indicating that mechanisms other than methylation or histone acetylation may be responsible for the repressed state of some SSX genes.

Amino Acid Sequence↗
PubMed1983

Structure of two human beta-actin-related processed genes one of which is located next to a simple repetitive sequence.

From a human gene library we have isolated and sequenced a beta-actin-like pseudogene, H beta Ac-psi 2, which lacks intervening sequences and contains several mutations resulting in frame-shifts, stop codons and in a departure from the known beta-actin protein sequence. We have also extended our sequence work on the intronless human beta-actin-related pseudogene H beta Ac-psi 1 described previously and we find that both genes are processed genes ending in a poly(dA) tract and flanked by direct repeats. The gene H beta Ac-psi 2 is preceded by a 230-bp region in which the simple sequence 5'-GAAA-3' is repeated greater than 40 times. This satellite-like sequence is highly repetitive in the human genome.

Actins↗
PubMed1996

Cloning and expression of a cDNA encoding uridine kinase from mouse brain.

Uridine kinase is the rate-limiting enzyme in the pyrimidine salvage pathway of all mammalian cells. A cDNA for uridine kinase from mouse brain has been isolated, sequenced, and characterized. This is the first report of a complete nucleotide sequence for mammalian uridine kinase. The isolated cDNA is only 95% complete, missing the first 17 codons. The correct 5'-terminus sequence was obtained from high-stringency screening of a mouse liver genomic DNA library. The translated cDNA sequence encodes a protein of 277 amino acids (Mr 31,068). A truncated form of the cDNA was expressed in Escherichia coli. The expressed protein displayed uridine kinase activity and readily formed a tetramer, the most active form of the wild-type enzyme. Analysis of the amino acid sequence identified the three ATP-binding site consensus motifs. The predicted secondary structure for uridine kinase and the sequence comparison with three kinases having known crystal structures are consistent with uridine kinase having an alpha/beta core structure of the nucleotide-binding fold found in many kinases. We have also isolated and cloned a nonfunctional, processed pseudogene from mouse genomic DNA. This pseudogene sequence is 94% identical with the coding DNA.

Amino Acid Sequence↗
PubMed1997

Loss of calcyphosine gene expression in mouse and other rodents.

Calcyphosine-for calcium binding and regulated by cyclic AMP through phosphorylation protein-is a target of both the cyclic AMP and the Ca(+2)-phophatidylinositol cascades first isolated from dog thyroid, and then from rabbit and human brain. Although the exact function of this 24kD protein is unknown, calcyphosine could be implicated in the cross-signaling between these cascades to coordinate cellular proliferation and differentiation. Here, we report the sequence of a pseudogene which is the murine calcyphosine homologue, and demonstrate that it represents the unique sequence homologous to the dog calcyphosine gene in the murine genome. The lack of expression of this murine pseudogene in brain and thyroid-two major sites of dog calcyphosine expression-was extended to 5 other rodents, and suggest the existence of alternative pathway(s) to fill the function of calcyphosine in rodents.

Animals↗