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PubMed2004

The use of Alu-PCR to distinguish between typical pulmonary carcinoids versus classic midgut carcinoids.

Although histologically 'typical' pulmonary and 'classic' midgut carcinoids are similar, the small intestine tumors are more aggressive than their pulmonary counterpart. We believe that in contrast to pulmonary carcinoids arising from Kulchitsky cells, 'classical' midgut carcinoids develop from crypt stem cells that differentiate into endocrine ('classical') or exocrine-endocrine ('non-classical' adenocarcinoid) tumors. The different progenitor cells may determine different malignant potentials between these types of carcinoids. To identify genetic differences between 'classical' midgut and typical pulmonary carcinoids using an Alu-PCR genomic profiling method, we reviewed 54 cases of carcinoid tumors that were surgically removed at Hartford Hospital from 1996 through 2001. Histologically these cases were selected into three groups: i) foregut or pulmonary carcinoids, ii) 'classic' midgut carcinoids of small intestine and iii) multiple typical pulmonary carcinoids. Genomic-profiling of DNA from these cases was performed using an Alu-PCR method. Metastases were observed in 18/20 'classical' intestinal carcinoid tumors, 3/30 pulmonary carcinoids, and 0/4 multiple pulmonary carcinoids. These results confirm that pulmonary carcinoids behave in a more benign fashion than intestinal carcinoid tumors. Using Alu-PCR to profile tumor cell genomic DNA, we showed that 68% of small intestine carcinoids and 58% of pulmonary carcinoids had allelic banding patterns suggestive of either amplification or deletion of gene sequences. Alu-PCR demonstrated loss or gain of genetic sequences that were unique for each examined group. These findings strongly suggest that pulmonary carcinoids differ from their intestinal counterparts.

Alu Elements↗
PubMed1999

[Globin gene mutation is a model of genetic abnormalities].

Hemoglobin has been extensively studied as a prototype of molecular abnormality, and abnormal hemoglobins have disclosed a number of molecular pathogeneses. Genetic analysis of hemoglobin has also contributed to recent advances in molecular biology. Here, thalassemia (thal) is examined. It is a congenital type of hemolytic anemia caused by defective production of either alpha- or beta-globin due to various genetic abnormalities and is referred to as alpha- or beta-thal, respectively. beta-thal is mainly caused by a point mutation, deletion or insertion of a few nucleotides resulting in decreased transcription, inability of initiating translation, abnormal RNA processing, frameshift, premature termination and production of super unstable hemoglobins. In many cases, the amount of mRNA carrying the mutation seems to be decreased. Reduced mRNA would prevent the subsequent formation of an abnormal translational product which is unstable and deleterious to the red cell membrane. Many alpha-thal's, in contrast, have an extensive gene deletion including the alpha-globin genes. Alu reiterative sequence plays an important role in the recombination of alpha-globin gene clusters which give rise to a large deletion or alpha-thal.

Alu Elements↗
PubMed1999

Rapid isolation of chromosomal breakpoints from patients with t(4;11) acute lymphoblastic leukemia: implications for basic and clinical research.

Chromosomal translocations t(4;11)(q21;q23) are associated with a group of acute lymphoblastic leukemias with very poor prognosis. From the complete sequences of the breakpoint cluster regions of the human MLL and AF-4 translocation partner genes, a novel set of 66 oligonucleotides that facilitates the rapid identification of translocation breakpoints by PCR analysis of genomic DNA was designed. For each breakpoint, a pair of optimally snited primers can be assigned, which improves the monitoring of the disease during treatment. Comparison of the breakpoints with the corresponding parental sequences also contributes to our better understanding of the illegitimate recombination events leading to these translocations.

Alu Elements↗
PubMed1999

[Analysis of the Alu insertion polymorphism in urban and rural populations of Siberia].

Polymorphic Alu-repeat loci of human genome are commonly used as effective genetic markers in population and evolution studies. In this work, the data on genetic structure of two Russian populations from Siberia obtained via analysis of five polymorphic Alu repeats are presented. The urban population was characterized by a slightly higher level of genetic diversity compared to the rural population. The value of genetic differentiation coefficient for the populations studied was 0.57%, pointing to the absence of genetic subdivision within the urban and rural populations. Phylogenetic analysis of these populations, together with literature data, shows that, with respect to the markers examined, the gene pool structure of Russian population is similar to that of other Caucasoid populations.

Alu Elements↗
PubMedDate not supplied

[The DNA of recombinant plasmids acquires mutagenic activity in a Bacillus subtilis culture after the insertion of the human genome Alu repeat].

In our previous work the mutagenic activity of recombinant plasmids (pBR322 carrying the human Alu repeat alone or in combination with preproinsulin or apo AI gene) in competent Bacillus subtilis culture was demonstrated. In present work it was shown that among seven tested plasmids only three revealed mutagenic activity (pBR322 and two Alu repeat-containing constructions). It seems that mutagenic activity is not inherent to any recombinant molecule in applied test system but depends on its structure. For example, Alu repeat of human genome may attach mutagenic properties to plasmids which either had no such properties, or lost them after gene engineering manipulations.

Alu Elements↗
PubMed1999

Organization and sequence of the gene for the human mitochondrial dicarboxylate carrier: evolution of the carrier family.

The dicarboxylate carrier (DIC) is a nuclear-encoded protein located in the mitochondrial inner membrane. It catalyses the transport of dicarboxylates such as malate and succinate across the mitochondrial membrane in exchange for phosphate, sulphate and thiosulphate. We have determined the sequences of the human cDNA and gene for the DIC. The gene sequence was established from overlapping genomic clones generated by PCRs by use of primers and probes based upon the human cDNA sequence. It is spread over 8.6 kb of human DNA and is divided into 11 exons. Five short interspersed repetitive Alu sequences are found in intron I. The protein encoded by the gene is 287 amino acids long. In common with the rat protein, it does not have a processed presequence to help to target it into mitochondria. It has been demonstrated by Northern- and Western-blot analyses that the DIC is present in high amounts in liver and kidney, and at lower levels in all the other tissues analysed. The positions of introns contribute towards an understanding of the processes involved in the evolution of human genes for carrier proteins.

Alu Elements↗
PubMed2000

Identification of eight novel single-nucleotide polymorphisms at human tissue-type plasminogen activator (t-PA) locus: association with vascular t-PA release in vivo.

Recently, we reported that an Alu insertion polymorphism of the tissue-type plasminogen activator (t-PA) gene is associated with vascular t-PA release rates in man. In the current study we searched the t-PA gene for putative functional genetic variants in linkage disequilibrium (LD) with this polymorphism. Healthy individuals with different Alu genotypes and contrasting t-PA release rates were studied. Regulatory and coding regions of the t-PA gene were sequenced. Eight single-nucleotide polymorphisms (SNPs) were identified. Three of these were in significant LD with the Alu polymorphism and consequently associated with t-PA release rates; one in the far upstream enhancer, one in exon 6, and one in intron 10. The enhancer SNP resides within a GC box. Electrophoretic mobility shift assay (EMSA) revealed a reduced binding affinity of Sp1 to the T allele, which is the allele associated with a low t-PA release rate. Variations in exon 6 and intron 10 were silent and without apparent effect on splicing, respectively.

Alu Elements↗
PubMed2000

Characteristics of myotonic dystrophy in Istria: molecular genetic approach. Part II: Analysis of genetic polymorphisms.

One of the world highest prevalence estimates of myotonic dystrophy (DM) has been reported in the Croatian region Istria. To analyse the population genetic characteristics of DM locus in Istria, two intragenic and three extragenic polymorphic markers were tested. The Southern blot technique was used for D19S63 locus analysis, whereas PCR analysis was performed for CKMM, Alu polymorphism, DMPK (G/T) intron 9/HinfI polymorphism, and D19S207 genetic markers. The compound haplotypes segregating with DM were established. A complete association between the DM mutation and D19S63, D19S207, intron 9/HinfI polymorphism and Alu polymorphism markers were found. In all DM chromosomes: D19S63 and Alu markers had the allele 1 in common; D19S207 had the allele 3 in common, DMPK (G/T) intron 9/HinfI marker had the allele 2 in common. The analysis of CKMM polymorphism revealed genotype heterogeneity; in DM chromosomes either allele 2 or allele 4 were found. The haplotype analysis in the population of Croatian Istria supports the linkage disequilibrium between the DM mutation and Alu polymorphism, intron 9/HinfI polymorphism, D19S63 and D19S207 markers as reported worldwide. The results of the haplotype analysis suggest a common origin of the mutation in Istrian population.

Adult↗
PubMed2000

Long DOP-PCR of rare archival anthropological samples.

The application of molecular DNA technologies to anthropological questions has meant that rare or archival samples of human remains, including blood, hair, and bone, can now be used as a source of material for genetic analysis. Often, these samples are irreplaceable, and/or yield very small quantities of DNA, so methods for preamplifying as much of the whole genome as possible would greatly enhance their usefulness. DOP-PCR (degenerate oligonucleotide-primed polymerase chain reaction) is an amplification method that uses a degenerate primer and very low initial annealing temperatures to amplify the whole genome. We adapted a published DOP-PCR protocol to long PCR enzyme and amplification conditions. The effectiveness of these modifications was tested by PCR amplification of DOP-PCR products at a mixture of genomic targets including 66 different microsatellites, 11 Alu insertion polymorphisms, and variable-length segments of the human lipoprotein lipase gene (LPL). The selected microsatellite markers were chosen to represent every chromosome, with expected product sizes ranging from 150 base pairs to 8,000 base pairs in length, while the 22 Alu insertion polymorphisms were selected to reveal biases in the recovery of alleles of different sizes. To determine nucleotide sequence variation, 2 kilobases (kb) of the LPL gene in 30 Mongolian individuals were sequenced. All gene-specific targets from DOP-PCR product template were amplified. No unexpected polymorphisms in the sequence results attributable to the DOP-PCR step were found, and 93% to 95% of Alu genotypes that have been amplified from total genomic DNA were replicated. The incorrect typings were all due to the preferential amplification of the shorter of two possible alleles in individuals heterozygous for an Alu insertion and were all correctly typed on subsequent reamplification of the gene-specific PCR products. This method of whole-genome amplification promises to be an efficient way to maximize the genetic use of rare anthropological samples.

Alu Elements↗
PubMed2001

[Genetic differentiation of the Tuva population with respect to the Alu insertions].

Polymorphism of three rural populations of the Tuva Republic was examined using a set of five autosomal Alu insertions at the ACE, PLAT, PV92, APOA1, and F13B loci. The allele frequency distribution patterns revealed in Tuvinians were typical to Mongoloid populations of Asia and were characterized by relatively high frequency of the Alu-repeat insertion at the PV92 and F13B loci along with relatively low insertion frequency at the APOA1 locus. With respect to the test systems used, Tuvinian populations examined displayed high levels of genetic diversity. The mean expected heterozygosity values in the populations of Kugurtug, Toora-Khem, and Teeli were 0.433, 0.407, and 0.437, respectively. The level of genetic diversity in the pooled Tuvinian sample was 0.432. The coefficient of genetic differentiation in the three populations studied was 1.45 pointing to relatively low level of genetic subdivision of the indigenous Tuvinian populations. However, estimates of genetic differentiation of the Tuvinian gene pool made by use of the Alu-repeat system were higher compared to those performed using classical protein systems, mtDNA, or Y-chromosomal haplotypes. Even though Tuvinian populations were characterized by common gene pool, some features specific to Western Tuvinian population could be distinguished. These features could be associated with higher contribution of the Caucasian component to the gene pool of this population. Phylogenetic analysis demonstrated close genetic relationships between the Tuvinian and Altaic ethnic populations.

Alleles↗
PubMed2001

[Analysis of Y-chromosomal diallelic loci polymorphism in populations of the Volga-Ural region].

Three diallelic polymorphisms of human Y chromosome, DYS287 (Y Alu polymorphism, YAP), T/C transition at the RBF5 locus (Tat), and G/A transition at the LLY22 locus, were studied in eight ethnic populations of the Volga-Ural region, representing Turkic (Bashkirs, Tatars, and Chuvashes) and Finno-Ugric (Maris, Mordovians, Udmurts, Komi-Zyryans, and Komi-Permyaks) branches of the Uralic linguistic family, and in the group of Slavic migrants, belonging to the Indo-European linguistic family (Russians). Ethnic populations of the Volga-Ural region were characterized by a low frequency of the Y chromosome Alu insertion. Examination of an association between the Alu polymorphism and Tat mutation revealed absolute C/YAP linkage. Analysis of the haplotype frequency distribution patterns constructed from the data on the DYS287 and RBF5 polymorphisms revealed substantial differences between Udmurts and the other ethnic populations. The differences were also observed between Komi-Zyryans and the populations of Bashkirs, Mordovians, Komi-Permyaks, and Russians. Analysis of the degree of genetic differentiation pointed to high level of genetic differentiation of the male lineages of the Finno-Ugric ethnic groups. The data on the linkage between mutations of the RBF5 and the LLY22 loci indicated the common origin of the Tat mutation in Bashkirs, Mordovians, Udmurts, and Komi-Zyryans, and of a number of ancestral C allele-bearing chromosomes in Tatars, Maris, and Chuvashes.

Alleles↗
PubMed2001

[Regulation of elastin synthesis].

Elastin is the main protein of elastic fibers and confers the property of elastic recoil to the tissues such as arteries, lung, elastic cartilage,... Elastin synthesis goes through several steps: gene transcription, alternative splicing of pre-mRNA, mRNA translation, hydroxylation of some proline residues of the newly synthesized protein-tropoelastin-, association of with a 67 kDa chaperone protein, secretion of tropoelastin molecules in the extracellular space, and their deposition on the microfibrillar scaffold which contains fibrillin 1, fibrillin 2, MAGP 1 and MAGP 2,.... After the synthesis of cross-links-lysinonorleucine, desmosine, isodesmosine-, elastin becomes insoluble and elastic. The elastogenic pathway is regulated at many levels. The most recently described regulatory mechanism of elastin synthesis is the control of elastin mRNA stability. Elastogenesis is well controlled during development and aging but remains responsive to external factors such as soluble compounds-cytokines, vitamins, hormones,...- and hemodynamic stress. In order to ensure its function, both quantity and quality of elastin should be and should remain optimal in elastic tissues.

Alternative Splicing↗
PubMed2001

[Analysis of Alu-polymorphism in Buryat populations].

Polymorphism of three populations of the Buryat Republic and a population from Aginskii Buryat Autonomous okrug of Chita oblast was examined using a set of five autosomal Alu insertions at the ACE, PLAT, PV92, APOA1, and F13B loci. The allele frequency distribution patterns revealed in Buryat populations were typical to other Asian populations. Buryats were characterized by relatively low level of intrapopulation diversity (0.369 in the pooled population sample). Analysis of autosomal Alu insertions suggests the uniformity of the Buryat gene pool. The coefficient of genetic differentiation in the four populations studied was 0.8%.

Alleles↗
PubMed2001

Sequence analysis of HIV-1 insertion sites in peripheral blood lymphocytes.

An essential component of the HIV-1 life cycle involves insertion in the genome of an infected cell. The site of HIV-1 integration has the potential to disrupt a gene and perturb a normal cellular function. To begin to address whether disease pathogenesis may correlate with the site of insertion, flanking cellular sequences at these HIV integrated regions were directly amplified from peripheral blood mononuclear cells DNA from a broad range of infected individuals using an inverse polymerase chain reaction strategy. Amplified flanking regions were sequenced and examined for similarity to the nucleic acid database. In this group of analyzed samples, the HIV-1 provirus was inserted within non-coding regions throughout the genome of the infected host, in which 7/14 sites were positioned in close proximity to different Alu repetitive elements while 2/14 sites were located within intron sequences. Insertions were also detected at sites without a specific gene designation but not within short tandem repetitive sequences, telomeres or centromeric repeat regions. Altogether, it is expected that this approach will yield new information on sites of integration by HIV-1 that may be associated with the pathogenic manifestations of disease progression.

Base Sequence↗
PubMed2002

[Analysis of gene complexes predisposing to coronary atherosclerosis].

The following seven polymorphic marker loci of genes responsible for predisposition to coronary atherosclerosis (CAS) were studied: the ACE locus responsible for angiotensin-converting enzyme insertion/deletion polymorphism for the presence or absence of the Alu insertion in the gene; the F13, PLAT, and APOA1 loci, controlling the clotting factor 13, plasminogen-activating tissue factor, and apolipoprotein A, respectively; the MTHFR and AGT polymorphic loci responsible for point mutations in methylenetetrahydrofolate reductase and those in angiotensinogen, respectively, and the NOS3 locus controlling the number of tandem repeats in the nitric oxide synthase gene. These loci are located on different chromosomes and encode products involved into various metabolic pathways leading to CAS. In the populations studied, significant differences between healthy subjects and patients predisposed to cardiovascular diseases were revealed with regard to the above seven markers. The 174M allele (T174M polymorphism in the ACE gene) was significantly associated with coronary atherosclerosis. It was found that specific gene combinations are involved in the CAS development and determine variation in the pathogenetically important quantitative traits.

Adult↗
PubMed2002

A more sensitive method for the quantitation of genomic DNA by Alu amplification.

Current procedures for human DNA quantitation reach their limit at 150 pg DNA, which is above the limit of the PCR profiling range using Profiler-Plus (Applied Biosystems, CA). This study tested the potential for the use of primate specific Alu sequences in forensic science for the sensitive detection and quantitaion of DNA. A fluorescently labelled primer pair was designed enabling high efficiency amplification of the core Alu sequence within primate DNA. Quantitation was performed by measurement of fluorescence intensity and comparison to a series of standard template DNA amounts via the construction of a standard curve. The new Alu-based quantitation protocol developed has shown its feasibility in more sensitively quantitating (100-2.5 pg) unknown amounts of human DNA for forensic use. The method is compatible with the use and throughput of current forensic procedures.

Alu Elements↗
PubMed2002

[Properties of endoribonuclease activity of proteasomes from K562 cells. II. Analysis of specific mRNA nucleolysis by proteasomes].

The ability of 26S proteasomes from the human proerythroleukaemic cell line K562 to degrade high-molecular-weight cytoplasmic RNAs, particularly specific messenger RNA, has been detected. The addition of hemin to K562 cells in the culture media leads to redistribution of proteasomes and their migration mainly to the cytoplasm. The human wild type p53 gene mRNA was shown to be specifically nucleolized by proteasomes. These particles displayed endoribonuclease activity towards mRNA for Renilla sp. luciferase. Proteasomes also specifically degraded Alu-containing mRNAs. A supposition is made about the involvement of proteasomes in stability control of specific RNA groups.

Alu Elements↗