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PubMed1994

Human casein kinase II: structures, genes, expression and requirement in cell growth stimulation.

Casein kinase II (CKII) is an ubiquitous Ser/Thr protein phosphotransferase in control of a variety of crucial cellular functions including metabolism, signal transduction, transcription, translation and replication. CKII levels are consistently higher in neoplastic tissues. The human CKII is composed of subunits alpha, alpha', and beta with molecular masses of 43, 38 and 28 kDa, respectively, that form heterotetrameric holoenzymes (alpha 2 beta 2; alpha alpha' beta 2, alpha'2 beta 2) showing autophosphorylation particularly at subunit beta and hence suspected to play a regulatory role. The amino acid sequences of subunits indicate high evolutionary conservation. Employing the complete set of tissue-derived (placenta) and recombinant (expressed in E. coli) subunits and CKII holoenzymes, the catalytic function of alpha and alpha' and the several-fold stimulation by beta is shown to occur comparably in tissue-derived and recombinant CKII and the autophosphorylation of beta is shown by site-directed mutagenesis to be not decisive for the tuning of CKII activity. The human genome contains two genes encoding CKII alpha. First, there is a processed (pseudo)gene which is 99% homologous to the CKII alpha cDNA and which possesses a promoter-like region adjacently upstream with TATA and CAAT boxes so that transcription cannot be excluded. Second, there is an active gene of which we have characterized so far a 18.9 kb long central fragment which contains 8 exons comprising bases 102-824 of the CKII alpha coding region. The gene fragment contains repetitive elements, most prominently 16 Alu repeats. The genome further contains one as yet uncharacterized CKII alpha' gene and one gene encoding CKII beta. The CKII beta gene has been characterized as a 4.2 kb spanning gene composed of seven exons which possesses three transcription start sites and the translation start site in the second exon. The first intron harbors an Alu repeat also. The promoter region of the CKII beta gene contains elements such as multiple GC boxes, a CpG island, and nonstandard-positioned CAAT boxes but lacks a TATA box thus characterizing the gene as a housekeeping gene. The CKII genes are not clustered at a certain chromosome but rather are distributed over the whole human genome. Using the genomic clones as the probes for in situ hybridization, the active CKII alpha gene was mapped to chromosome 20p13, the processed CKII alpha (pseudo)gene to chromosome 11p15, and the CKII beta gene to chromosome 6p21. (The CKII alpha' gene has been localized on chromosome 16 with a cDNA probe.).(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1987

Analysis of a human gene cluster coding for tRNA(GAAPhe) and tRNA(UUULys).

A 13.8-kb fragment of human DNA isolated from a human lambda Charon-4A DNA library was found to contain four human tRNA genes. Nucleotide sequence analysis of approx. 3.7 kb of this segment of human DNA identified two lysine tRNA(UUU) genes identical in coding sequence to a previously reported human lysine tRNA gene [Roy et al., Nucl. Acids Res. 10 (1982) 7313-7322]. The other two tRNA genes were phenylalanine tRNA(GAA) genes, the first to be isolated from a mammalian source. These phenylalanine tRNA(GAA) genes were identical in sequence with the exception of a G/A polymorphism at coordinate 57. None of these tRNA genes contains introns. The tRNA(UUULys) and tRNA(GAAPhe) genes are organized in alternating order and are irregularly spaced, by intergenic regions of approx. 1.0, 2.6 and 5.0 kb, and randomly oriented. There was no evidence to indicate that any of these genes arose by gene duplication, since flanking sequence homology was limited to the putative RNA polymerase III termination signals in the 3'-flanking regions. A mature tRNA-sized product was identified following the transcription of each tRNA gene in a homologous in vitro transcription system. Interestingly, different levels of transcriptional activity of the three identical lysine tRNA genes were observed, suggesting modulation of tDNA expression by extragenic sequences. In addition, a minimum of eight regions of homology to Alu-type repetitive elements were detected in this human DNA fragment, one of which was located 53 bp upstream from a tRNA(GAAPhe) gene.

Base Sequence↗
PubMed1993

Genomic structure of rat liver aryl sulfotransferase IV-encoding gene.

This report contains the first description of the genomic structure for a sulfotransferase (ST). The gene (ASTIV) encodes rat hepatic aryl ST IV, also known as tyrosine-ester ST (EC 2.8.2.9). A phage genomic clone containing 70% of the 3' AST gene coding sequence was isolated after screening a rat genomic library with an ASTIV cDNA. The remaining 5' sequence was determined from a PCR product obtained from rat genomic DNA and ASTIV cDNA-specific primers. ASTIV spans 3.5 kb and contains eight exons and seven introns. The fourth intron of this gene contains sequences homologous to rodent B1 repetitive elements and an Alu repeat found in rat. An alignment of the primary structures of ten different ST revealed several conserved regions, as well as a putative binding site for the cofactor for enzymatic sulfation reactions, 3'-phosphoadenosine-5'-phosphosulfate.

Amino Acid Sequence↗
PubMed1989

The human growth hormone locus: nucleotide sequence, biology, and evolution.

The human chromosomal growth hormone locus contained on cloned DNA and spanning approximately 66,500 bp was sequenced in its entirety to provide a framework for the analysis of its biology and evolution. This locus evolved by a series of duplications and contains in its present form five genes which display a remarkably high degree of sequence identity (approximately 95%) in all their domains. The DNA sequence of the locus reveals the presence of 48 middle repetitive sequence elements of the Alu type and one member of the KpnI family, all located in the intergenic regions. The expression of each gene was examined by screening pituitary and placental cDNA libraries by using gene-specific oligonucleotides. According to this analysis, the hGH-N gene is transcribed exclusively in the pituitary, whereas the other four genes (hCS-L, hCS-A, hGH-V, hCS-B) are expressed only in placental tissue, at levels characteristic for each gene. Particular DNA sequences found upstream of the individual promoter regions might account for the observed tissue specificity and different transcriptional activity of the genes. The hCS-L gene carries a G to A transition in a sequence used by the other four genes as an intronic 5' splice donor site. This mutation results in a different splicing pattern and, hence, in a novel sequence of the hCS-L gene mRNA and the deduced polypeptide.

Amino Acid Sequence↗
PubMed1991

Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The gene responsible for cystic fibrosis, the most common severe autosomal recessive disorder, is located on the long arm of human chromosome 7, region q31-q32. The gene has recently been identified and shown to be approximately 250 kb in size. To understand the structure and to provide the basis for a systematic analysis of the disease-causing mutations in the gene, genomic DNA clones spanning different regions of the previously reported cDNA were isolated and used to determine the coding regions and sequences of intron/exon boundaries. A total of 22,708 bp of sequence, accounting for approximately 10% of the entire gene, was obtained. Alignment of the genomic DNA sequence with the cDNA sequence showed perfect colinearity between the two and a total of 27 exons, each flanked by consensus splice signals. A number of repetitive elements, including the Alu and Kpn families and simple repeats, such as (GT)17, (GATT)7, and (TA)14, were detected in close vicinity of some of the intron/exon boundaries. At least three of the simple repeats were found to be polymorphic in the population. Although an internal amino acid sequence homology could be detected between the two halves of the predicted polypeptide, especially in the regions of the two putative nucleotide-binding folds (NBF1 and NBF2), the lack of alignment of the nucleotide sequence as well as the different positions of the exon/intron boundaries does not seem to support the hypothesis of a recent gene duplication event. To facilitate detection of mutations by direct sequence analysis of genomic DNA, 28 sets of oligonucleotide primers were designed and tested for their ability to amplify individual exons and the immediately flanking sequences in the introns.

Amino Acid Sequence↗
PubMed1992

Genomic organization, sequence analysis, and chromosomal localization of the human carboxyl ester lipase (CEL) gene and a CEL-like (CELL) gene.

The gene encoding human carboxyl ester lipase (CEL), including 1628 bp of the 5'-flanking region, has been isolated and characterized from two overlapping lambda phage clones. The gene spans 9832 bp and contains 11 exons interrupted by 10 introns. The exons range in size from 88 to 204 bp, except for the last exon, which is 841 bp. A major and a minor transcription initiation site were determined 13 and 7 bp, respectively, upstream of the initiator methionine. The nucleotide sequence is identical with that of the previously reported cDNA, except for the third nucleotide in the 5'-untranslated sequence, a C, which in the cDNA is a T. A TAAATA sequence is present 26 nt upstream from the major CAP site, and within the 5'-flanking region there are several putative transcription factor binding sites. Seven Alu repetitive sequence elements are present in the region analyzed. The organization of the human CEL gene is similar to that of the recently reported rat pancreatic cholesterol esterase gene. The CEL gene was assigned to chromosome 9q34-qter, which confirms the recently reported results of Tayler et al. (1991, Genomics 10: 425-431). A previously unknown gene with a striking homology to the human CEL gene, here called the CEL-like gene (CELL), has also been isolated and characterized, including 1724 bp of the 5'-flanking region. The CELL gene, which most likely is a psuedogene, spans 4846 bp, and due to the absence of a 4.8-kb segment, the CEL gene exons 2-7 are not present in the CELL gene. Despite these differences, the CELL gene is transcribed. We have also assigned the CELL gene to a separate locus at chromosome 9q34-qter.

Animals↗
PubMed1995

Isolation of 115 human chromosome 8-specific expressed-sequence tags by exon amplification.

Exon-amplification experiments were undertaken to isolate potentially transcribable sequences from cosmid clones that previously had been mapped to subchromosomal bands of human chromosome 8 by fluorescence in situ hybridization. From 253 cosmids subjected to this procedure so far, we isolated 169 fragments and confirmed that they had been derived from the original cosmid clones. Among them, 38 revealed homology to repetitive DNA sequences such as Alu and L1 elements. The other 131 were unique sequences, but of these only 115 contained discernible open reading frames. Among these 115 sequences, 15 were identical to parts of six known genes listed in the public database. On the basis of information derived from mapping the original cosmid clones, we were able to localize two of these known genes, zinc finger protein 7 and heat shock transcription factor 1, to 8q24.3. Furthermore, we have proven that some of these clones are parts of the transcribed products by an exon connection method or by isolation of a novel cDNA that is homologous to murine clathrin-associated protein. The expressed-sequence tags isolated here will be useful resources for a transcriptional map of chromosome 8 and for isolation of new genes.

Adaptor Proteins, Vesicular Transport↗
PubMed2006

The human myeloperoxidase gene is regulated by LXR and PPARalpha ligands.

Myeloperoxidase (MPO) is an oxidant-generating enzyme expressed in macrophages and implicated in atherosclerosis and cholesterol homeostasis. LXRalpha and PPARalpha regulate genes involved in cholesterol metabolism and the inflammatory response in macrophages. Here, we examine the effect of LXR and PPARalpha ligands on MPO expression. LXR and PPARalpha, as heterodimers with RXR, are shown to bind overlapping sites in an Alu receptor response element (AluRRE) in the MPO promoter. The LXR ligand T0901317 suppresses MPO mRNA expression in primary human macrophages, and in bone marrow cells and macrophages from huMPO transgenic mice. The PPARalpha ligand GW9578 downregulates MPO expression in GMCSF-macrophages, while upregulating in MCSF-macrophages. In contrast, the mouse MPO gene, which lacks the primate-specific AluRRE, is not regulated by LXR or PPARalpha ligands. These findings identify human MPO as a novel LXR and PPARalpha target gene, consistent with the role of these receptors in regulation of proinflammatory genes in macrophages.

Animals↗
PubMed1998

Subtracted, unique-sequence, in situ hybridization: experimental and diagnostic applications.

Nonrandom chromosomal aberrations, particularly in cancer, identify pathogenic biological pathways and, in some cases, have clinical relevance as diagnostic or prognostic markers. Fluorescence and colorimetric in situ hybridization methods facilitate identification of numerical and structural chromosome abnormalities. We report the development of robust, unique-sequence in situ hybridization probes that have several novel features: 1) they are constructed from multimegabase contigs of yeast artificial chromosome (YAC) clones; 2) they are in the form of adapter-ligated, short-fragment, DNA libraries that may be amplified by polymerase chain reaction; and 3) they have had repetitive sequences (eg, Alu and LINE elements) quantitatively removed by subtractive hybridization. These subtracted probes are labeled conveniently, and the fluorescence or colorimetric detection signals are extremely bright. Moreover, they constitute a stable resource that may be amplified through at least four rounds of polymerase chain reaction without diminishing signal intensity. We demonstrate applications of subtracted probes for the MYC and EWS oncogene regions, including 1) characterization of a novel EWS-region translocation in Ewing's sarcoma, 2) identification of chromosomal translocations in paraffin sections, and 3) identification of chromosomal translocations by conventional bright-field microscopy.

Burkitt Lymphoma↗
PubMed2001

Identification of a novel retina-specific gene located in a subtelomeric region with polymorphic distribution among multiple human chromosomes.

The human retina is comprised of a large number of cell types with highly specialized functions that depend on the action of countless genes, many of which are exclusively expressed in the retina. We have isolated a novel retinal gene, termed F379. The transcript was initially identified as a cluster of ESTs derived predominantly from retinal cDNA libraries and its retinal transcription confirmed by Northern blot and RT-PCR. Screening of retinal cDNA libraries yielded four clones that were assembled into a 1188 bp consensus sequence. The putative open reading frame includes an unusual configuration of Alu and MIR repeats and encodes a putative 85 aa peptide with no significant homology to any known protein sequence outside of the Alu and MIR elements. Comparison with genomic sequence determined that F379 consists of three exons and maps to multiple locations throughout the genome, a finding confirmed by PCR screening of a somatic cell hybrid mapping panel. F379 appears to be contained within a region of subtelomeric DNA that is duplicated in a polymorphic distribution to multiple chromosomes. Comparison of interchromosomal sequence variation with the sequences of expressed transcripts suggests that the gene is transcribed in the human retina from at least four different chromosomes.

Amino Acid Sequence↗
PubMed1998

Polymorphism in the 5' flanking region of the human somatostatin receptor subtype 5.

The human somatostatin receptor subtype 5 (hSSTR5) gene has previously been cloned and localized to chromosome 16 p13.3. This region is evolutionarily conserved in all vertebrate genomes from the puffer fish (Fugu rubripes) to human, and also contains loci for genes associated with two common multisystemic disorders, adult polycystic kidney disease (PKD1) and tuberous sclerosis (TSC2). Analysis of the 5' flanking region of the hSSTR5 gene has revealed consensus sequences for a number of transcription factors as well as Alu-like repeat elements. In the present study, genomic DNA from 53 unrelated individuals was analysed by PCR and Southern blots probed with radiolabeled fragments generated from different segments of the hSSTR5 gene. We have identified two restriction fragment length polymorphisms (RFLP) with high heterozygosity values at the 5' flanking region of the hSSTR5 gene. These RFLP markers will be useful for determining the allelic loss of genetic material from this region. The observed polymorphism in the promoter region may affect the function of the hSSTR5 gene.

Adult↗
PubMed2003

Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.

Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery. Screening genes in the region of overlap identified mutations in a novel predicted gene in three mouse jittery alleles, including the first mouse mutation caused by an Alu-related (B1 element) insertion. We found two mutations exclusively in all individuals with Cayman ataxia. The gene ATCAY or Atcay encodes a neuron-restricted protein called caytaxin. Caytaxin contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia. Three-dimensional protein structural modeling predicts that the caytaxin ligand is more polar than vitamin E. Identification of the caytaxin ligand may help develop a therapy for Cayman ataxia.

Amino Acid Sequence↗
PubMed1989

DNA sequences of a bovine gene and of two related pseudogenes for the proteolipid subunit of mitochondrial ATP synthase.

The dicyclohexylcarbodi-imide-reactive proteolipid is a membrane subunit of mitochondrial ATP synthase. In cows it is encoded by two different nuclear genes known as P1 and P2. These genes are expressed in a tissue-specific fashion which reflects the embryonic origin of the tissues. The proteins that they encode are synthesized in the cytosol, and are precursors of the proteolipid that have different mitochondrial import sequences of 61 and 68 amino acids respectively. By use of gene-specific probes derived from the bovine P2 cDNA, regions containing corresponding parts of the bovine P2 gene have been isolated from a bovine genomic library, and their DNA sequences and those of flanking and intervening regions have been determined. The sequence contains four exons, which represent the cDNA sequence, spread over 3.8 kb of the bovine genome. Two of the introns are in the DNA sequence coding for the mitochondrial import sequence, and a third intron is in a sequence encoding an extramembranous structure between the two putative transmembrane alpha-helical domains of the mature proteolipid. An Alu-type repetitive element was detected at the extreme 5' end of the sequence. The bovine P1 and P2 genes for the dicyclohexylcarbodimide-reactive proteolipid of ATP synthase are members of a multiple gene family that also contains many pseudogenes. The bovine P1 gene has not been isolated, but two distinct P1 pseudogenes have been cloned and their DNA sequences have been determined. Both of them contain 'in-phase' stop codons and frame-shift mutations, and one of them bears the hallmarks of retroposition; it has no introns, it contains a poly(A) tract at its 3' end and it is flanked by direct DNA sequence repeats. The second P1 pseudogene is very unusual. It appears to be derived from a partially processed transcript and contains an intervening DNA sequence of 861 bp that corresponds in position with an intron in the human P1 gene. This pseudogene also could have been introduced by retroposition since its sequence is flanked by short direct repeats. However, it does not contain a poly(A) tract at its 3' end. An alternative, but less likely, explanation is that rather than being a retroposon, this sequence arose by duplication of an expressed gene at a time when it had only one intron.

ATP Synthetase Complexes↗
PubMed1983

The human growth hormone gene family: structure and evolution of the chromosomal locus.

The structure of the human growth hormone gene cluster has been determined over a 78 kilobase region of DNA by the study of two overlapping cosmids. There are two growth hormone genes interspersed with three chorionic somatomammotropin genes, all in the same transcriptional orientation. One of the growth hormone genes lies in an active chromatin conformation in the pituitary and at least one of the chorionic somatomammotropin genes lies in an active chromatin conformation in the placenta. The two groups of genes are highly homologous throughout their 5' flanking and coding sequences, but diverge in their 3' flanking regions which raises the paradox of how genes so similar in structural and flanking sequences can be so differentially regulated. Analysis of the sequences of the genes and identification of at least three different classes of duplication units interspersed throughout the five gene cluster suggests that the cluster evolved quite recently and that the mechanism of gene duplication involved homologous but unequal exchange between middle repetitive elements of the Alu family.

Chromatin↗
PubMed2004

MaGIC: a program to generate targeted marker sets for genome-wide association studies.

High-throughput genotyping technologies such as DNA pooling and DNA microarrays mean that whole-genome screens are now practical for complex disease gene discovery using association studies. Because it is currently impractical to use all available markers, a subset is typically selected on the basis of required saturation density. Restricting markers to those within annotated genomic features of interest (e.g., genes or exons) or within feature-rich regions, reduces workload and cost while retaining much information. We have designed a program (MaGIC) that exploits genome assembly data to create lists of markers correlated with other genomic features. Marker lists are generated at a user-defined spacing and can target features with a user-defined density. Maps are in base pairs or linkage disequilibrium units (LDUs) as derived from the International HapMap data, which is useful for association studies and fine-mapping. Markers may be selected on the basis of heterozygosity and source database, and single nucleotide polymorphism (SNP) markers may additionally be selected on the basis of validation status. The import function means the method can be used for any genomic features such as housekeeping genes, long interspersed elements (LINES), or Alu repeats in humans, and is also functional for other species with equivalent data. The program and source code is freely available at http://cogent.iop.kcl.ac.uk/MaGIC.cogx.

Algorithms↗
PubMed2000

Growth regulation, acid sphingomyelinase gene and genomic imprinting: lessons from an experiment of nature.

The author investigated the possible role of acid sphingomyelinase (ASM) gene (SMPD1) in the regulation of growth, in connection with an experiment of nature. The association of a decreased ASM activity and an overgrowth disorder, Beckwith-Wiedemann Syndrome (BWS) with hemihypertrophy has been described at a 23 months old boy in a recent case report (Réthy et al, in this issue). ASM catalyses the production of ceramide, a key molecule of apoptosis, from sphingomyelin. Based on these data it is suggested that the ASM gene (SMPD1) can suppress/counterbalance the anti-apoptotic effects of BWSrelated growth-promoters, like IGF-II, under normal circumstances. Recent literary data support this view. ASM deficient lymphoblasts derived from patients with Niemann-Pick disease (NPD) fail to undergo apoptosis in response to external signals and Fas cross-linking. BWS-related genes are considered to be regulated by genomic imprinting. Therefore the author compared some characteristics of both SMPD1 and imprinted genes. The analyzed features of SMPD1 gene (few and small introns, Alu 1 repeat element, CC-rich regulatory region, alternative splicing) are characteristic to imprinted genes. Hemihypertrophy, mentioned in the referred BWS-case, is distinctive to the involvement of the maternal allele of the second BWS chromosomal region (BWSCR2) at 11p15.3. The SMPDI gene has been localized just distal to the B05 breakpoint of BWSCR2. Furthermore, in BWS-associated tumors, the loss of heterozygosity (LOH) found on 11p15 was always maternal. Thus, in the case referred to with ASM deficiency the maternal allele has certainly been effected. These conclusions are in accordance with the 'cluster-model of imprinting' as well as with the conflict theory of imprinting. Taken together, the above mentioned clinical and experimental data suggest that SMPD1, most likely at 11p15.4, is an imprinted, maternally expressed, BWS- and apoptosis-related growth suppressor gene. Further studies are necessary to prove this hypothesis.

Beckwith-Wiedemann Syndrome↗
PubMed1995

Y chromosomal DNA variation and the peopling of Japan.

Four loci mapping to the nonrecombining portion of the Y chromosome were genotyped in Japanese populations from Okinawa, the southernmost island of Japan; Shizuoka and Aomori on the main island of Honshu; and a small sample of Taiwanese. The Y Alu polymorphic (YAP) element is present in 42% of the Japanese and absent in the Taiwanese, confirming the irregular distribution of this polymorphism in Asia. Data from the four loci were used to determine genetic distances among populations, construct Y chromosome haplotypes, and estimate the degree of genetic diversity in each population and on different Y chromosome haplotypes. Evolutionary analysis of Y haplotypes suggests that polymorphisms at the YAP (DYS287) and DXYS5Y loci originated a single time, whereas restriction patterns at the DYS1 locus and microsatellite alleles at the DYS19 locus arose more than once. Genetic distance analysis indicated that the Okinawans are differentiated from Japanese living on Honshu. The data support the hypotheses that modern Japanese populations have resulted from distinctive genetic contributions involving the ancient Jomon people and Yayoi immigrants from Korea or mainland China, with Okinawans experiencing the least amount of admixture with the Yayoi. It is suggested that YAP+ chromosomes migrated to Japan with the Jomon people > 10,000 years ago and that a large infusion of YAP- chromosomes entered Japan with the Yayoi migration starting 2,300 years ago. Different degrees of genetic diversity carried by these two ancient chromosomal lineages may be explained by the different life-styles (hunter-gatherer versus agriculturalist). of the migrant groups, the size of the founding populations, and the antiquities of the founding events.

Alleles↗
PubMed1993

Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema.

Mutations in one C1 INH allele result in the autosomal dominant disease, hereditary angioedema. The plasma antigenic level of C1 INH in this disease may be low, normal, or high, while the functional level is uniformly depressed. Investigation of the mutations in the C1 INH gene reveal several key features about the DNA itself as well as protein structure-function relationships. The largest single group of mutations with a defined mechanism are recombinations associated with Alu repetitive DNA elements. Current data suggest that there may be an increased number of mutations within the region encoding the reactive center which, like some other serpins, contains both primary and secondary structure DNA polymerase pause sites. These sites may enhance the rates of mutation and evolution in the reactive center region. Some of the dysfunctional C1 INH proteins that result from hinge region mutations support models for reactive center loop interaction with beta sheet A during complex formation. The analysis of the dysfunctional mutants, therefore, suggest regions of the molecule that are important for inhibitor function.

Amino Acid Sequence↗