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PubMed2006

The 5'-end transitional CpGs between the CpG islands and retroelements are hypomethylated in association with loss of heterozygosity in gastric cancers.

BACKGROUND: A loss of heterozygosity (LOH) represents a unilateral chromosomal loss that reduces the dose of highly repetitive Alu, L1, and LTR retroelements. The aim of this study was to determine if the LOH events can affect the spread of retroelement methylation in the 5'-end transitional area between the CpG islands and their nearest retroelements. METHODS: The 5'-transitional area of all human genes (22,297) was measured according to the nearest retroelements to the transcription start sites. For 50 gastric cancer specimens, the level of LOH events on eight cancer-associated chromosomes was estimated using the microsatellite markers, and the 5'-transitional CpGs of 20 selected genes were examined by methylation analysis using the bisulfite-modified DNA. RESULTS: The extent of the transitional area was significantly shorter with the nearest Alu elements than with the nearest L1 and LTR elements, as well as in the extragenic regions containing a higher density of retroelements than in the intragenic regions. The CpG islands neighbouring a high density of Alu elements were consistently hypomethylated in both normal and tumor tissues. The 5'-transitional methylated CpG sites bordered by a low density of Alu elements or the L1 and LTR elements were hypomethylated more frequently in the high-level LOH cases than in the low-level LOH cases. CONCLUSION: The 5'-transitional methylated CpG sites not completely protected by the Alu elements were hypomethylated in association with LOH events in gastric cancers. This suggests that an irreversible unbalanced decrease in the genomic dose reduces the spread of L1 methylation in the 5'-end regions of genes.

5' Flanking Region↗
PubMedDate not supplied

Upstream sequences modulate the internal promoter of the human 7SL RNA gene.

The human genome is rich in sequences which are structurally related to the 7SL RNA component of the signal recognition particle. The 7SL DNA sequence family consists of four 7SL genes, 500 7SL pseudogenes (which are truncated at one or both ends of the 7SL sequence) and 500,000 Alu sequences. Both 7SL genes and Alu elements are transcribed by RNA polymerase III, and we show here that the internal 7SL promoter lies within the Alu-like part of the 7SL gene. Why then does RNA polymerase III transcribe the few 7SL genes so efficiently, while transcripts from the far more abundant Alu elements are not readily detectable? We find that a human 7SL gene and a synthetic Alu sequence derived from it are expressed 50-100-fold more efficiently in vitro than either a representative Alu element or two 7SL pseudogenes. 5' Deletion and insertion mutants of the 7SL gene demonstrate that, in conjunction with the internal promoter, the first 37 nucleotides upstream from the transcription start site are essential for efficient and accurate initiation in vitro. We suggest that the genomic sequences upstream from most Alu elements and 7SL pseudogenes do not contain this element, and consequently that only a small subset of such sequences can be transcribed in vivo. This may help to explain the homogeneity of the Alu family within each mammalian genome, as well as the species-specific differences between mammalian Alu families.

Base Sequence↗
PubMed2001

Alu insertion polymorphisms for the study of human genomic diversity.

Genomic database mining has been a very useful aid in the identification and retrieval of recently integrated Alu elements from the human genome. We analyzed Alu elements retrieved from the GenBank database and identified two new Alu subfamilies, Alu Yb9 and Alu Yc2, and further characterized Yc1 subfamily members. Some members of each of the three subfamilies have inserted in the human genome so recently that about a one-third of the analyzed elements are polymorphic for the presence/absence of the Alu repeat in diverse human populations. These newly identified Alu insertion polymorphisms will serve as identical-by-descent genetic markers for the study of human evolution and forensics. Three previously classified Alu Y elements linked with disease belong to the Yc1 subfamily, supporting the retroposition potential of this subfamily and demonstrating that the Alu Y subfamily currently has a very low amplification rate in the human genome.

Alu Elements↗
PubMed2000

Evolution of alpha 2-fucosyltransferase genes in primates: relation between an intronic Alu-Y element and red cell expression of ABH antigens.

Coding sequences of the paralogous FUT1 (H), FUT2 (Se), and Sec1 alpha 2-fucosyltransferase genes were obtained from different primate species. Analysis of the primate FUT1-like and FUT2-like sequences revealed the absence of the known human inactivating mutations giving rise to the h null alleles of FUT1 and the se null alleles of FUT2. Therefore, most primate FUT1-like and FUT2-like genes potentially code for functional enzymes. The Sec1-like gene encodes for a potentially functional alpha 2-fucosyltransferase enzyme in nonprimate mammals, New World monkeys, and Old World monkeys, but it has been inactivated by a nonsense mutation at codon 325 in the ancestor of humans and African apes (gorillas, chimpanzees). Human and gorilla Sec1's have, in addition, two deletions and one insertion, respectively, 5' of the nonsense mutation leading to proteins shorter than chimpanzee Sec1. Phylogenetic analysis of the available H, Se, and Sec1 mammalian protein sequences demonstrates the existence of three clusters which correspond to the three genes. This suggests that the differentiation of the three genes is rather old and predates the great mammalian radiation. The phylogenetic analysis also suggests that Sec1 has a higher evolutionary rate than FUT2 and FUT1. Finally, we show that an Alu-Y element was inserted in intron 1 of the FUT1 ancestor of humans and apes (chimpanzees, gorillas, orangutans, and gibbons); this Alu-Y element has not been found in monkeys or nonprimate mammals, which lack ABH antigens on red cells. A potential mechanism leading to the red cell expression of the H enzyme in primates, related to the insertion of this Alu-Y sequence, is proposed.

ABO Blood-Group System↗
PubMed2005

Alu-SINE exonization: en route to protein-coding function.

The majority of more than one million primate-specific Alu elements map to nonfunctional parts of introns or intergenic sequences. Once integrated, they have the potential to become exapted as functional modules, e.g., as protein-coding domains via alternative splicing. This particular process is also termed exonization and increases protein versatility. Here we investigate 153 human chromosomal loci where Alu elements were conceivably exonized. In four selected examples, we generated, with the aid of representatives of all primate infraorders, phylogenetic reconstructions of the evolutionary steps presumably leading to exonization of Alu elements. We observed a variety of possible scenarios in which Alu elements led to novel mRNA splice forms and which, like most evolutionary processes, took different courses in different lineages. Our data show that, once acquired, some exonizations were lost again in some lineages. In general, Alu exonization occurred at various time points over the evolutionary history of primate lineages, and protein-coding potential was acquired either relatively soon after integration or millions of years thereafter. The course of these paths can probably be generalized to the exonization of other elements as well.

Alu Elements↗
PubMed1988

Nucleotide sequence and transcription of a rat tRNA(Phe) gene and a neighboring Alu-like element.

A bacteriophage gamma Ch4A clone containing a 22-kb rat DNA insert was isolated and found to contain a solitary tRNA(Phe)GAA gene and, 436 bp downstream of it, an Alu-like element. The nucleotide sequence of a 1141-bp DNA fragment containing these genes was determined. The rat tRNA(Phe)GAA gene, with the exception of an additional A in the extra arm, has a sequence identical to that of a rabbit liver tRNA(Phe). The Alu-like element belongs to the rodent B2 family of short interspersed repetitive nucleotide sequences. This repetitive element, B2Phe, is flanked by 12-bp direct repeats, contains an internal split promoter (block A and block B) for RNA polymerase III and is devoid of an A-rich segment at the 3' end. Like other members of the B2 family, the B2Phe element presents 64% sequence homology with rat serine tRNA and contains a serine (GCT) anticodon. Both tRNA(Phe)GAA gene and B2Phe element were found to be transcriptionally active in HeLa cell and Xenopus oocyte nuclear extracts. The tRNA(Phe) gene transcripts were processed during the course of transcription to form mature-size tRNA(Phe). The transcription efficiency of the B2Phe element was found to be an order of magnitude higher than that of the tRNA(Phe) gene. Competition experiments demonstrate that the B2Phe DNA can form a more stable transcription complex than the tRNA(Phe) gene and compete with it for binding of transcription factors.

Animals↗
PubMed1998

Inactivation of the p53 tumor suppressor gene via a novel Alu rearrangement.

Inactivation of the p53 tumor suppressor gene is a common finding in human cancer. In most cases, inactivation is due to a point mutation in the gene, but rearrangement of the p53 gene is sometimes observed. We analyzed the inactivation of p53 in the human pancreas cancer cell line Hs766T, which harbors a structural alteration in the p53 gene. This inactivation was found to be the result of a complex deletion/insertion event involving at least two different Alu elements. The rearrangement eliminated exons 2-4 from the p53 gene, whereas a 175-bp Alu fragment was inserted between the breakpoints of the deletion. DNA sequence analysis of this Alu fragment revealed that it is identical to an Alu element in intron 1 of the p53 gene. This is the first report of p53 inactivation due to a rearrangement involving Alu elements. This type of inactivation may go unnoticed when only traditional methods to detect p53 alterations are used.

Alu Elements↗
PubMed2004

The origins and implications of Aluternative splicing.

Ten percent of the human genome is composed of highly repetitive DNA sequences called Alu elements. It has recently been found that at least 5% of all human alternative exons are derived from Alu elements. Moreover, single nucleotide mutations can convert either alternative or otherwise silent Alu elements into constitutive exons and this can lead to the development of human disease. These results provide new insights into the function and dangers of 'junk DNA' in the human genome.

Alternative Splicing↗
PubMed1996

Sequence and evolutionary history of the length polymorphism in intron 1 of the human red photopigment gene.

The length of intron 1 of the red pigment gene is dimorphic among Africans but not among Caucasians or Asians. This dimorphism was found to result from the presence or absence of a block of 1,284 bp comprised of three Alu elements and 328 bp of intervening unique-sequence DNA. This additional sequence in the "long" intron 1 of the red pigment gene was shown to have inserted into a fourth and older Alu element present in the "short" from of intron 1. Furthermore, the size and sequence of the "short" intron 1 of the red pigment gene is equivalent to that of the adjacent green pigment gene. The block containing the three Alu elements was not found in intron 1 of the red or green pigment genes of Old World monkeys and orangutans but was present in intron 1 of both the green and red pigment genes of gorillas and chimpanzees. The nucleotide sequence of this block in Old World primates and the estimated ages of the three elements suggest that their insertion occurred sequentially in the Old World monkey lineage prior to duplication of the ancestral X-chromosome-linked pigment gene. After gene duplication, deletion of the entire block containing the three Alu elements from one of the genes created the "short" intron variant. Unequal recombination between the adjacent and highly homologous red and green pigment genes may have resulted in the formation of the "short" intron variant of the other gene.

Animals↗
PubMed2000

Sex chromosomal transposable element accumulation and male-driven substitutional evolution in humans.

We sequenced the genomic region containing the human Y-linked zinc finger gene (ZFY). Comparison of ZFY to the related region on the X chromosome (ZFX) and to autosomal sequences reveals a significant accumulation of transposable elements on the sex chromosomes. In addition, five times as many retroviruslike elements (RLEs) are present in the ZFY region as in the ZFX region. Thus, transposable elements accumulate more rapidly on the sex chromosomes, and the insertion of RLEs may occur more frequently in the male than in the female germ line. When the accumulation of substitutions in Alu elements was analyzed, it was found that the Alu elements at the Y-chromosomal locus diverged significantly faster than those at the X-chromosomal locus, whereas the divergence of autosomal Alu elements was intermediate. The male-to-female mutation rate ratio was estimated to be 2.5.

Alu Elements↗
PubMed1994

Induction of complete segregation of cellular DNA and non-encapsidated viral genomes in herpes simplex virus type 1 infected HeLa cells as revealed by in situ hybridization.

The intranuclear distribution of human Alu elements and herpes simplex virus type 1 (HSV-1) genomes was examined in HeLa cells by post-embedding in situ hybridization using in parallel appropriate biotinylated DNA probes. The bound probes were detected by direct immunogold labeling. In non-infected cells, human Alu elements detected by BLUR 8 were randomly scattered over the masses and strands of chromatin throughout the nucleus. The marked asynchrony of the HSV-1 cycle in individual HeLa cells of 17 h infected cultures allowed us to study the respective distributions of cell and viral DNA during the course of the infectious cycle. Labeling of human Alu elements revealed that cellular DNA had become confined to the border of infected nuclei without extension of cellular DNA fibers into the newly formed electron-translucent regions that occupied the centers of the infected nuclei. Labeling of HSV-1 DNA detected by a viral DNA probe revealed that non-encapsidated viral genomes were present exclusively within this centrally located viral region whereas encapsidated HSV-1 genomes, which were more widely distributed in the infected cell, were seen within the marginated host chromatin as well as the central viral region. Therefore, HSV-1 infection induces a regrouping of human Alu elements, that is, of host chromatin at the nuclear border. Non-encapsidated HSV-1 genomes and cellular DNA do not co-localize. Instead, they always constitute two adjacent compartments without spatial interrelationships.

Cell Nucleus↗
PubMed2002

Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. We report an association between an Alu polymorphism in the angiotensin-converting enzyme (ACE) gene with the dry/atrophic form of AMD. Using the polymerase chain reaction (PCR) on genomic DNA isolated from patients with AMD (n=173), and an age-matched control population (n=189), we amplified a region polymorphic for an Alu element insertion in the ACE gene. The Alu(+/+) genotype occurred 4.5 times more frequently in the control population than the dry/atrophic AMD patient population, (p=0.004). The predominance of the Alu(+/+) genotype within the unaffected control group represents a protective insertion with respect to the human ocular disease, dry/atrophic AMD. This is the first demonstration of an Alu element insertion exerting protective effects against a known human disease.

Age Factors↗
PubMed1990

Negative regulation of the human epsilon-globin gene by transcriptional interference: role of an Alu repetitive element.

The human epsilon-globin gene has a number of alternative transcription initiation sites which correspond with regions of DNase I hypersensitivity upstream of the canonical cap site. Transcripts originating from the promoters located -4.3/-4.5 and -1.48 kilobase pairs (kbp) and -900 and -200 base pairs (bp) upstream of the major epsilon-globin cap site can, at certain stages of erythroid differentiation, extend through the gene and are polyadenylated. The 350-bp PolIII transcripts, originating within the Alu repetitive element -2.2 kbp upstream of the cap site, extend in the opposite direction from the gene, are nonpolyadenylated, nucleus confined, and are detectable only in mature K562 cells or mature embryonic red blood cells where the epsilon-globin major cap site is maximally transcribed. Fragments containing the promoters located between -4.5 and -4.3 kbp upstream of the gene down regulate transcription from the epsilon-globin gene 20- to 30-fold in a transient expression assay in which both erythroid and nonerythroid cell lines were used. This occurs only when the direction of transcription from the -4.3/-4.5-kbp promoters is towards the gene, and we hypothesize that down regulation is caused by transcriptional interference. Fragments containing the Alu repetitive element -2.2 kbp upstream of the gene can overcome down regulation of the epsilon-globin gene by the -4.5-kbp element when interposed in the direct orientation between this element and the epsilon-globin gene.

Cell Line↗
PubMed2005

The Alu Yc1 subfamily: sorting the wheat from the chaff.

Members of the Alu Yc1 subfamily are distinguished from the older Alu Y subfamily by a signature G-->A substitution at base 148 of their 281-bp consensus sequence. Members of the much older and larger Alu Y subfamily could have by chance accumulated this signature G-->A substitution and be misclassified as belonging to the Alu Yc1 subfamily. Using a Mahanalobis classification method, it was estimated that the "authentic" Alu Yc1 subfamily consists of approximately 262 members in the human genome. PCR amplification and further analysis was successfully completed on 225 of the Yc1 Alu family members. One hundred and seventy-seven Yc1 Alu elements were determined to be monomorphic (fixed for presence) in a panel of diverse human genomes. Forty-eight of the Yc1 Alu elements were polymorphic for insertion presence/absence in diverse human genomes. The insertion polymorphism rate of 21% in the human genome is similar to rates reported previously for other "young" Alu subfamilies. The polymorphic Yc1 Alu elements will be useful genetic loci for the study of human population genetics.

Alu Elements↗
PubMed1999

The evolution of trichromatic color vision by opsin gene duplication in New World and Old World primates.

Trichromacy in all Old World primates is dependent on separate X-linked MW and LW opsin genes that are organized into a head-to-tail tandem array flanked on the upstream side by a locus control region (LCR). The 5' regions of these two genes show homology for only the first 236 bp, although within this region, the differences are conserved in humans, chimpanzees, and two species of cercopithecoid monkeys. In contrast, most New World primates have only a single polymorphic X-linked opsin gene; all males are dichromats and trichromacy is achieved only in those females that possess a different form of this gene on each X chromosome. By sequencing the upstream region of this gene in a New World monkey, the marmoset, we have been able to demonstrate the presence of an LCR in an equivalent position to that in Old World primates. Moreover, the marmoset sequence shows extensive homology from the coding region to the LCR with the upstream sequence of the human LW gene, a distance of >3 kb, whereas homology with the human MW gene is again limited to the first 236 bp, indicating that the divergent MW sequence identifies the site of insertion of the duplicated gene. This is further supported by the presence of an incomplete Alu element on the upstream side of this insertion point in the MW gene of both humans and a cercopithecoid monkey, with additional Alu elements present further upstream. Therefore, these Alu elements may have been involved in the initial gene duplication and may also be responsible for the high frequency of gene loss and gene duplication within the opsin gene array. Full trichromacy is present in one species of New World monkey, the howler monkey, in which separate MW and LW genes are again present. In contrast to the separate genes in humans, however, the upstream sequences of the two howler genes show homology with the marmoset for at least 600 bp, which is well beyond the point of divergence of the human MW and LW genes, and each sequence is associated with a different LCR, indicating that the duplication in the howler monkey involved the entire upstream region. [The sequence data described in this paper have been submitted to GenBank under accession nos. AF155218, AF156715, and AF156716.]

Animals↗
PubMed2003

Molecular cladistic markers in New World monkey phylogeny (Platyrrhini, Primates).

Transpositions of primate-specific Alu elements were applied as molecular cladistic markers in a phylogenetic analysis of South American primates. Seventy-four human and platyrrhine loci containing intronic Alu elements were PCR screened in various New World monkeys and the human outgroup to detect the presence of orthologous retrotransposons informative of New World monkey phylogeny. Six loci revealed size polymorphism in the amplification pattern, indicating a shared derived character state due to the presence of orthologous Alu elements confirmed by subsequent sequencing. Three markers corroborate (1) New World monkey monophyly and one marker supports each of the following callitrichine relationships: (2) Callithrix and Cebuella are more closely related to each other than to any other callitrichine, (3) the callitrichines form a monophyletic clade including Callimico, and (4) the next living relatives to the callitrichines are Cebus, Saimiri, and Aotus.

Alu Elements↗
PubMed1986

Multiplicity of glutathione S-transferase genes in the rat and association with a type 2 Alu repetitive element.

Southern blot analysis of rat genomic DNA using glutathione S-transferase Ya and Yc cDNA probes was employed to estimate the size of the Ya/Yc multigene family. A minimum of five to seven Ya/Yc genes were detected; at least two of these are Yc genes. The presence of multiple genes was further supported by the isolation of three nonoverlapping genomic clones from a rat EcoRI library that hybridized to a Ya cDNA clone, pGTB38. However, not all EcoRI bands seen in genomic blots were represented in the clones, suggesting that not all Ya/Yc genes have been isolated. The organization of a Ya gene in one of these EcoRI genomic clones, lambda GTB38-3, and an overlapping clone, lambda GTB45-1, isolated from a HaeIII library, was investigated with 5' and 3' probes prepared from Ya and Yc cDNA clones. Restriction endonuclease mapping and hybridization studies revealed that the gene spans over 10 kilobases and contains at least three introns. Sequences upstream from the 5' untranslated region of the gene, and within an intron in the 5' coding region, were found to contain sequences homologous to a type 2 Alu repetitive element from the rat growth hormone gene [Page, G.S., Smith, S., & Goodman, H.M. (1981) Nucleic Acids Res. 9, 2087-2104]. The repetitive sequences in lambda GTB38-3 were identified by hybridization to a novel Ya cDNA clone, pGTB45. This cDNA clone was isolated from a cDNA library previously described [Telakowski-Hopkins, C.A., Rodkey, J.A., Bennett, C.D., Lu, A.Y.H., & Pickett, C.B. (1985) J. Biol. Chem. 260, 5820-5825] with nick-translated intron sequences as probes. pGTB45 is virtually identical with pGTR261 [Tu, C.-P.D., Lai, H.-C.J., Li, N.-Q., Weiss, M.J., & Reddy, C.C. (1984) J. Biol. Chem. 259, 9434-9439], except that the 3' untranslated region extends 231 base pairs beyond the polyadenylation signal of pGTR261. This elongated 3' untranslated sequence is unique in that it contains a full-length type 2 Alu repetitive element, which includes two additional, overlapping polyadenylation signals.

Animals↗
PubMedDate not supplied

[Alu repeats in the human genome].

Highly repetitive DNA sequences account for more than 50% of the human genome. The L1 and Alu families harbor the most common mammalian long (LINEs) and short (SINEs) interspersed elements. Alu elements are each a dimer of similar, but not identical, fragments of total size about 300 bp, and originate from the 7SL RNA gene. Each element contains a bipartite promoter for RNA polymerase III, a poly(A) tract located between the monomers, a 3'-terminal poly(A) tract, and numerous CpG islands, and is flanked by short direct repeats. Alu repeats comprise more than 10% of the human genome and are capable of retroposition. Possibly, these elements played an important part in genome evolution. Insertion of an Alu element into a functionally important genome region or other Alu-dependent alterations of gene functions cause various hereditary disorders and are probably associated with carcinogenesis. In total, 14 Alu families differing in diagnostic mutations are known. Some of these, which are present in the human genome, are polymorphic and relatively recently inserted into new loci. Alu copies transposed during ethnic divergence of the human population are useful markers for evolutionary genetic studies.

Alu Elements↗