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PubMed2005

Polymorphic Alu insertions and their associations with MHC class I alleles and haplotypes in the northeastern Thais.

Polymorphic Alu insertions (POALINs) are known to contribute to the strong polymorphic nature of the Major Histocompatibility Complex (MHC). Previous population studies on MHC POALINs were limited to only Australian Caucasians and Japanese. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and -B associations, and the three and four locus alpha block POALIN haplotype frequencies in the Northeastern (NE) Thai population. Of the five POALINs, the lowest frequency was 0.018 for AluyHF and the highest frequency was 0.292 for AluyHJ and AluyHG. The strongest positive associations between the POALINs and HLA class I alleles was between AluyMICB and HLA-B*57, AluyHJ and HLA-A*24 and HLA-A*01, and AluyHG and HLA-A*02, supporting previous findings in Caucasians and Japanese. Single POALIN haplotypes were found more frequently than multiple POALIN haplotypes. However, of the seven different POALIN haplotypes within the MHC alpha block, there were only two significant differences between the NE Thais, Caucasians and Japanese. This study confirms that the MHC POALINs are in linkage disequilibrium with HLA-A and -B alleles and that there are significant frequency differences for some of the POALINs when compared between NE Thai, Caucasians and Japanese.

Alu Elements↗
PubMed2005

Chromatin remodeling by DNA bending, not twisting.

Single-stranded regions (gaps) in nucleosomal DNA interfere with action of the RSC chromatin-remodeling complex, monitored by exposure of restriction endonuclease cutting sites. Single-strand breaks (nicks) in the DNA, by contrast, have no effect. Gaps on one side of the cutting site are inhibitory, but gaps on the other side are not. A gap >100 bp from the cutting site is as effective as a gap <20 bp from the site. These findings suggest a remodeling process involving bending, but not twisting, of the DNA and further point to the propagation of a bent region (loop or bulge) from one end of the nucleosome to the other.

Alu Elements↗
PubMed2005

The majority of human genes have regions repeated in other human genes.

Amino acid sequence comparisons have been made between all of 25,193 human proteins with each of the others by using blast software (National Center for Biotechnology Information) and recording the results for regions that are significantly related in sequence, that is, have an expectation of <1 x 10(-3). The results are presented for each amino acid as the number of identical or similar amino acids matched in these aligned regions. This approach avoids summing or dealing directly with the different regions of any one protein that are often related to different numbers and types of other proteins. The results are presented graphically for a sample of 140 proteins. Relationships are not observed for 26.5% of the 12,728,866 amino acids. The average number of related amino acids is 36.5 for the majority (73.5%) that show relationships. The median number of recognized relationships is approximately 3 for all of the amino acids, and the maximum number is 718. The results demonstrate the overwhelming importance of gene regional duplication forming families of proteins with related domains and show the variety of the resulting patterns of relationship. The magnitude of the set of relationships leads to the conclusion that the principal process by which new gene functions arise has been by making use of preexisting genes.

Alu Elements↗
PubMed2005

Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice.

Stem/progenitor cells from bone marrow and other sources have been shown to repair injured tissues by differentiating into tissue-specific phenotypes, by secreting chemokines, and, in part, by cell fusion. Here we prepared the stem/progenitor cells from human bone marrow (MSCs) and implanted athem into the dentate gyrus of the hippocampus of immunodeficient mice. The implanted human MSCs markedly increased the proliferation of endogenous neural stem cells that expressed the stem cell marker Sox2. Labeling of the mice with BrdUrd demonstrated that, 7 days after implantation of the human MSCs, BrdUrd-labeled endogenous cells migrated throughout the dorsal hippocampus (positive for doublecortin) and expressed markers for astrocytes and for neural or oligodendrocyte progenitors. Subpopulations of BrdUrd-labeled cells exhibited short cytoplasmic processes immunoreactive for nerve growth factor and VEGF. By 30 days after implantation, the newly generated cells expressed markers for more mature neurons and astrocytes. Also, subpopulations of BrdUrd-labeled cells exhibited elaborate processes immunoreactive for ciliary neurotrophic factor, neurotrophin-4/5, nerve growth factor, or VEGF. Therefore, implantation of human MSCs stimulated proliferation, migration, and differentiation of the endogenous neural stem cells that survived as differentiated neural cells. The results provide a paradigm to explain recent observations in which MSCs or related stem/progenitor cells were found to produce improvements in disease models even though a limited number of the cells engrafted.

Alu Elements↗
PubMed2002

Genes, pseudogenes, and Alu sequence organization across human chromosomes 21 and 22.

Human chromosomes 21 and 22 (mainly the q-arms) were the first complete parts of the human genome released. Our analysis of genes, pseudogenes (Psig), and Alu repeats across these chromosomes include the following findings: The number of gene structures containing untranslated exons exceeds 25%; the terminal exon tends to be the largest among exons, whereas, the initial intron tends to be the largest among introns; single-exon gene length is approximately the mean gene exon number times the mean internal exon length; processed Psig lengths are on average approximately the same as single-exon gene length; and the G+C content and length of genes are uncorrelated. The counts and distribution of genes, Psig, and Alu sequences and G+C variation are evaluated with respect to clusters and overdispersions. Other assessments concern comparisons of intergenic lengths, properties of Psig sequences, and correlations between Alu and Psig sequences.

Alu Elements↗
PubMed2006

Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons.

Orthologous gene structures in eight vertebrate species were compared on a genomic scale to detect the birth and maturation of new internal exons during the course of evolution. We found that 40% of new human exons are alternatively spliced, and most of these are cassette exons (exons that are either included or skipped in their entirety) with low inclusion rates. This proportion decreases steadily as older and older exons are examined, even as splicing efficiency increases. Remarkably, the great majority of new cassette exons are composed of highly repeated sequences, especially Alu. Many new cassette exons are 5' untranslated exons; the proportion that code for protein increases steadily with age. New protein-coding exons evolve at a high rate, as evidenced by the initially high substitution rates (K(s) and K(a)), as well as the SNP density compared with older exons. This dynamic picture suggests that de novo recruitment rather than shuffling is the major route by which exons are added to genes, and that species-specific repeats could play a significant role in recent evolution.

Alternative Splicing↗
PubMed2000

Plasticity in the organization and sequences of human KIR/ILT gene families.

The approximately 1-Mb leukocyte receptor complex at 19q13.4 is a key polymorphic immunoregion containing all of the natural killer-receptor KIR and related ILT genes. When the organization of the leukocyte receptor complex was compared from two haplotypes, the gene content in the KIR region varied dramatically, with framework loci flanking regions of widely variable gene content. The ILT genes were more stable in number except for ILT6, which was present only in one haplotype. Analysis of Alu repeats and comparison of KIR gene sequences, which are over 90% identical, are consistent with a recent origin. KIR genesis was followed by extensive duplication/deletion as well as intergenic sequence exchange, reminiscent of MHC class I genes, which provide KIR ligands.

Alu Elements↗
PubMed1986

Exon-Alu recombination deletes 5 kilobases from the low density lipoprotein receptor gene, producing a null phenotype in familial hypercholesterolemia.

Among patients with familial hypercholesterolemia, half of the mutant alleles at the low density lipoprotein (LDL) receptor locus produce no immunologically detectable protein. To determine the molecular basis for one such null allele, we have cloned an abnormally short restriction fragment from the genomic DNA of one patient. The DNA sequence revealed a 5-kilobase deletion that joins a coding sequence in exon 13 to an Alu repetitive element in intron 15. The deletion joint is flanked by two inverted repeats that could potentially form a double stem-loop structure that might have predisposed to this deletion. A similar double stem-loop structure can be drawn for a previously described deletion in the LDL receptor gene and for a deletion in the beta-globin gene cluster. We speculate that such double stem-loop structures might contribute to the formation of large deletions in the human genome.

Base Sequence↗
PubMed1987

Structure, expression, and molecular mapping of a divergent member of the class I HLA gene family.

A class I gene distinct from HLA-A, -B, or -C was identified in a cosmid clone and transfected into mouse L cells. The gene, placed adjacent to the polyoma enhancer, produced a full-length class I mRNA and high levels of a 43-kDa protein in the cytoplasm. The surface expression of the gene product required its association with human beta 2-microglobulin. The protein was recognized by a xenoantiserum raised against a mixture of human B- and T-cell lines. The product was also serologically reactive with the HLA framework monoclonal antibodies. The complete nucleotide sequence of the gene was determined and a specific oligonucleotide probe was synthesized. This probe was used to identify a full-length mRNA transcript in a B-lymphoblastoid cell line (JY). The gene was mapped within a 190-kilobase Not I restriction fragment located in the telomeric portion of the human major histocompatibility complex. Distinct features of the gene include the structure of the promoter, the position of the translation initiation site, a frameshift mutation at the carboxyl terminus, the insertion of an Alu repeat element in the eighth exon, divergence in the derived amino acid sequence, and the lack of expression of the gene in some cells.

Amino Acid Sequence↗
PubMed1988

High levels of heterodisperse RNAs accumulate in T cells infected with human immunodeficiency virus and in normal thymocytes.

Infection by human immunodeficiency virus (HIV-1) of a human T leukemia cell line (HUT 78) leads to a rapid accumulation at an elevated level (10- to 20-fold) of heterodisperse RNAs, revealed by their containing repetitive sequences. Sequence data indicate that the repetitive elements (e.g., Alu) are associated with transcripts with no apparent long open reading frame. In contrast, a large increase of such heterodisperse RNAs is not seen in T lymphocytes activated by phytohemagglutinin or in a variety of leukemic cell lines. Examination of several cellular messages showed that the levels of some of their "fully processed" transcripts are reduced late after infection of HUT 78 cells, indicating that the levels of some mRNAs may decrease. Surprisingly, similar heterodisperse transcripts are also seen in great abundance in normal fresh thymocytes. It is possible that in HIV-infected T lymphocytes, the accumulation of high levels of such aberrant RNAs may directly or indirectly contribute to the death of HIV-infected T cells.

Base Sequence↗
PubMed1999

Two major forms of DNA (cytosine-5) methyltransferase in human somatic tissues.

Thus far, only one major form of vertebrate DNA (cytosine-5) methyltransferase (CpG MTase, EC 2.1.1.37) has been identified, cloned, and extensively studied. This enzyme, dnmt1, has been hypothesized to be responsible for most of the maintenance as well as the de novo methylation activities occurring in the somatic cells of vertebrates. We now report the discovery of another abundant species of CpG MTase in various types of human cell lines and somatic tissues. Interestingly, the mRNA encoding this CpG MTase results from alternative splicing of the primary transcript from the Dnmt1 gene, which incorporates in-frame an additional 48 nt between exons 4 and 5. Furthermore, this 48-nt exon sequence is derived from the first, or the most upstream, copy of a set of seven different Alu repeats located in intron 4. The ratios of expression of this mRNA to the expression of the previously known, shorter Dnmt1 mRNA species, as estimated by semiquantitative reverse transcription-PCR analysis, range from two-thirds to three-sevenths. This alternative splicing scheme of the Dnmt1 transcript seems to be conserved in the higher primates. We suggest that the originally described and the recently discovered forms of CpG MTase be named dnmt1-a and dnmt1-b, respectively. The evolutionary and biological implications of this finding are discussed in relation to the cellular functions of the CpG residues and the CpG MTases.

Alternative Splicing↗
PubMed1998

Accurate 3' end processing and adenylation of human signal recognition particle RNA and alu RNA in vitro.

Human signal recognition particle (SRP) RNA is transcribed by RNA polymerase III and terminates with -GUCUCUUUUOH on its 3' end. Our previous studies showed that the three terminal uridylic acid residues of human SRP RNA are post-transcriptionally removed and a single adenylic acid residue is added, resulting in a 3' end sequence of -GUCUCUAOH (Sinha, K. M., Gu, J., Chen, Y., and Reddy, R. (1998) J. Biol. Chem. 273, 6853-6859). In this study we show that the Alu RNA, corresponding to the 5' and 3' ends of SRP RNA, is also accurately processed and adenylated in vitro. Alu RNAs containing 7 or 11 additional nucleotides on the 3' end were accurately processed and then adenylated. Deletion analysis showed that an 87-nucleotide-long motif comprising of the 5' and 3' ends, including stem IV of the Alu RNA, is sufficient and necessary for the 3' end processing and adenylation. A 73-nucleotide-long construct with deletion of stem IV, required for the binding of SRP 9/14-kDa proteins, was neither processed nor adenylated. The adenylated Alu RNA as well as adenylated SRP RNA were bound to the SRP 9/14-kDa heterodimer and were immunoprecipitated by specific antibodies. A significant fraction of SRP RNA in the nucleoli was found to be processed and adenylated. These data are consistent with nascent SRP and/or Alu RNAs first binding to SRP 9/14-kDa protein heterodimer, followed by the removal of extra sequence on the 3' end and then the addition of one adenylic acid residue in the nucleus, before transport into the cytoplasm.

Adenosine Monophosphate↗
PubMed1998

Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion.

A partial physical map has been constructed of the human class Mu glutathione S-transferase genes on chromosome 1p13.3. The glutathione S-transferase genes in this cluster are spaced about 20 kilobase pairs (kb) apart, and arranged as 5'-GSTM4-GSTM2-GSTM1-GSTM5-3'. This map has been used to localize the end points of the polymorphic GSTM1 deletion. The left repeated region is 5 kb downstream from the 3'-end of the GSTM2 gene and 5 kb upstream from the beginning of the GSTM1 gene; the right repeated region is 5 kb downstream from the 3'-end of the GSTM1 and 10 kb upstream from the 5'-end of the GSTM5 gene. The GSTM1-0 deletion produces a novel 7.4-kb HindIII fragment with the loss of 10.3- and 11.4-kb HindIII fragments. The same novel fragment was seen in 13 unrelated individuals (20 null alleles), suggesting that most GSTM1-0 deletions involve recombinations between the same two regions. We have cloned and sequenced the deletion junction that is produced at the GSTM1-null locus; the 5'- and 3'-flanking regions are more than 99% identical to each other and to the deletion junction sequence over 2.3 kb. Because of the high sequence identity between the left repeat, right repeat, and deletion junction regions, the crossing over cannot be localized within the 2.3-kb region. The 2.3-kb repeated region contains a reverse class IV Alu repetitive element near one end of the repeat.

Base Sequence↗
PubMed1999

Post-transcriptional adenylation of signal recognition particle RNA is carried out by an enzyme different from mRNA Poly(A) polymerase.

A fraction of the signal recognition particle (SRP) RNA from human, rat, Xenopus, and Saccharomyces cerevisiae cells contains a single post-transcriptionally added adenylic acid residue on its 3'-end; in the case of human SRP RNA, over 60% of the SRP RNA molecules contain a nontemplated adenylic acid residue on their 3'-ends (Sinha, K. M., Gu, J., Chen, Y., and Reddy, R. (1998) J. Biol. Chem. 273, 6853-6859). In this study, we investigated the enzyme that is involved in this 3'-end adenylation of SRP RNA. A U1A protein peptide conjugated to albumin completely inhibited the polyadenylation of a SV40 mRNA by HeLa cell nuclear extract in vitro; however, the 3'-end adenylation of human SRP RNA or Alu RNA, which corresponds to 5' and 3'-ends of SRP RNA, was not affected by this U1A peptide conjugate. SRP RNA from mutant strains of S. cerevisiae with a temperature-sensitive mRNA poly(A) polymerase grown at a restrictive temperature of 37 degrees C also contained a post-transcriptionally added adenylic acid residue just like SRP RNA from wild-type cells and mutant cells grown at permissive temperature of 23 degrees C. In addition, binding of SRP 9/14-kDa protein heterodimer was required for adenylation of Alu RNA in vitro. These lines of evidence, along with other data, show that post-transcriptional adenylation of SRP and Alu RNAs is carried out by a novel enzyme that is distinct from the mRNA poly(A) polymerase, CCA-adding enzyme, and nonspecific terminal transferase.

Alu Elements↗
PubMedDate not supplied

Alu insertions versus blood group plus protein genetic variability in four Amerindian populations.

BACKGROUND: Do the population relationships obtained using DNA or blood group plus protein markers remain the same or do they reveal different patterns, indicating that the factors which influence genetic variation at these two levels of analysis are diverse? Can these markers shed light on the biological classification of the Aché, a Paraguayan tribe which only recently established more permanent contacts with non-Indians? SUBJECTS AND METHODS: To consider these questions we typed 193 individuals from four Amerindian tribes in relation to 12 Alu polymorphisms (five of them never studied in these populations), while 22 blood group plus protein systems were studied among the Aché. These data were then integrated with those previously available (blood groups plus proteins) for the three other populations. DNA extraction and amplification, as well as the other laboratory procedures, were performed using standard methods currently in use in our laboratory. The genetic relationships were obtained using the D(A) distance, and the trees were constructed by the neighbour-joining method, both developed by M. Nei and collaborators. Reliability of the trees was tested by bootstrap replications. Other population variability values were also determined using Nei's methods. RESULTS: Alu polymorphism was observed in all populations and for most of the loci; in the seven systems from which we could compare our results with those of other Amerindian groups agreement was satisfactory. Unusual findings on the blood group plus protein systems of the Aché were a very low (5%) HP*1 frequency and the presence of the C(W) phenotype in the Rh blood group. The intertribal patterns of relationship and other aspects of their variation were remarkably congruent in the two sets (Alu; blood group plus protein) of systems. CONCLUSIONS: The answer to the first question posed above is affirmative. However, the problem of whether the Aché derived from a Gê group that preceded the Guarani colonization of Paraguay, or are just a differentiated Guarani group, could not be answered with the genetic information available; the second hypothesis seems more likely at present, but the point to be emphasized is the striking genetic distinctiveness of the Aché as compared to other Amerindians.

Alleles↗
PubMedDate not supplied

Molecular genetic variation in the East Midlands, England: analysis of VNTR, STR and Alu insertion/deletion polymorphisms.

BACKGROUND: Short tandem repeats (STRs) and variable number of tandem repeats (VNTRs) have been used successfully in disease analysis and studies of human evolution and population genetic diversity. However DNA-based comprehensive population genetic studies of the East Midlands, England are limited. SUBJECTS AND METHODS: To enlarge our understanding of genetic variation in the East Midlands, a study was conducted on five regional populations: north-west Derbyshire,north-east Derbyshire, south Derbyshire, Nottinghamshire and Leicestershire. Blood samples were collected from donors whose ancestors had lived in the region for at least three generations. Seven VNTRs (MSI (DIS7), MS31 (D7S21), MS43A (D12SII) and YNH24 (D2S44), DIS0, APOB, YNZ22 (D17S5)), six STRs (HumTHOI, HumVWA31A, HumF13AOl1, HumFESFPS, HumCSFIPO, HumTPOX) and six Alu insertion/deletion polymorphisms (TPA25, ACE, PV92, F13B, APO, DI) were analysed in approximately 500 individuals. Allele or bin frequencies were calculated using gene counting and fixed bin methods. The chi-square method and exact tests were used to assess Hardy-Weinberg equilibrium. Genetic distances were calculated using Nei's DA method and correspondence analysis was used to assess population affinities. RESULTS: The overall pattern of allele frequencies was similar to many European and UK populations for a number of genetic systems. Overall heterogeneity was observed for five loci: MS43A, MS31, HumF13A0l, HumFESFPS and HumTHOI. Twenty-three of 190 pairwise population comparisons were also statistically significant at the 5% level. Average molecular genetic system heterozygosity was 1.5 times higher than observed with conventional blood group systems. GsT values for molecular systems were also higher than conventional systems (0.012 vs 0.005) and suggest a low to moderate level of differentiation. CONCLUSION: The allele frequency spectrum and inter-population comparisons show that there is significant genetic variation in the five contiguous regional populations of the East Midlands. Some of this variation may be due to local geographical barriers, genetic drift and possibly the settlement patterns of Continental European invaders.

Alu Elements↗
PubMedDate not supplied

Genetic relationships among Berbers and South Spaniards based on CD4 microsatellite/Alu haplotypes.

BACKGROUND: CD4 STR/Alu haplotype diversity, both for its qualitative and quantitative properties, has been widely used in molecular anthropology to clarify the degree of genetic relationships among human populations. AIM: CD4 STR/Alu variation was studied in two West Mediterranean samples, Andalusians from La Alpujarra region on the north side of the Gibraltar Strait and Berbers from the south, to ascertain the pattern of affinities between them. SUBJECTS AND METHODS: Alu and microsatellite alleles were tested in 99 Andalusians from La Alpujarra region (Southeast Spain) and 124 Middle Atlas Berbers (Morocco). RESULTS: Two new combinations of Alu and STR alleles (75(+) and 80(-)) were found in Berbers. The CD4 STR/Alu haplotype distribution in South Spaniards is similar to that of other Europeans, the only special feature is the slight presence of the 90(+) and 130(+) typical Sub-Saharan haplotypes. The Berber sample is characterized by a high number of different haplotypes (18) with intermediate heterozygosity values (0.846) in comparison with other North African groups, and by a high frequency of the 110(-) combination that has been proposed as representative of an ancient Northwest African population. CONCLUSION: A geographical gradient of Sub-Saharan gene contribution has been detected in North Africa. The Middle Atlas Berbers showed an intermediate value in comparison with the high and low values found in Mauritanians and Moroccan Berbers, respectively. The analysis of the CD4 STR/Alu haplotype variation failed to indicate any particular relationship between South Spaniards and North Africans.

Alu Elements↗
PubMedDate not supplied

Alu insertion polymorphisms in Native Americans and related Asian populations.

BACKGROUND: Alu insertions provide useful markers for the study of inter-population affinities and historical processes, but data on these systems are not numerous in Native Americans and related populations. AIM: The study aimed to answer the following questions: (a) do the population relationships found agree with ethnic, historical and geographical data? and (b) what can heterozygote levels and associated results inform us about the events that led to the colonization of the New World? SUBJECTS AND METHODS: Twelve Alu insertion polymorphisms were studied in 330 individuals belonging to South American Native, Siberian and Mongolian populations. These data were integrated with those from 526 persons, to ascertain the relationships between Asian, Northern Arctic and Amerindian populations. RESULTS: A decreasing trend concerning heterozygosities and amount of gene flow was observed in the three sets, in the order indicated above. Most results indicated the validity of these subdivisions. However, no clear structure could be observed within South American Natives, indicating the importance of dispersive (genetic drift, founder effects) factors in their differentiation. CONCLUSIONS: The answers to the questions are: (a) yes; and (b) an initial moderate bottleneck, intensified by more recent historical events (isolation and inbreeding), can explain the current Amerindian pattern of diversity.

Alu Elements↗