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PubMed1986

The multiple origins of human Alu sequences.

I have analyzed a collection of published human Alu sequences. The compiled sequences show several unexpected features, including a uniform pattern of divergence from their consensus sequence, a mutual divergence that is not correlated with their age, and common features in the genomic DNA flanking the 5' ends of the elements. I suggest that the Alu family of sequences derives from a large pool of precursors and not from a single precursor similar to the family consensus sequence, and that new elements integrate into the genome selectively at oligo-A-rich sites.

Base Sequence↗

PubMed1993

Multiple dispersed loci produce small cytoplasmic Alu RNA.

Alu repeats are short interspersed elements (SINEs) of dimeric structure whose transposition sometimes leads to heritable disorders in humans. Human cells contain a poly(A)- small cytoplasmic transcript of -120 nucleotides (nt) homologous to the left Alu monomer. Although its monomeric size indicates that small cytoplasmic Alu (scAlu) RNA is not an intermediary of human Alu transpositions, a less abundant poly(A)-containing Alu transcript of dimeric size and specificity expected of a transposition intermediary is also detectable in HeLa cells (A. G. Matera, U. Hellmann, M. F. Hintz, and C. W. Schmid, Mol. Cell. Biol. 10:5424-5432, 1990). Although its function is unknown, the accumulation of Alu RNA and its ability to interact with a conserved protein suggest a role in cell biology (D.-Y. Chang and R. J. Maraia, J. Biol. Chem. 268:6423-28, 1993). The relationship between the -120- and -300-nt Alu transcripts had not been determined. However, a B1 SINE produces scB1 RNA by posttranscriptional processing, suggesting a similar pathway for scAlu. An Alu SINE which recently transposed into the neurofibromatosis 1 locus was expressed in microinjected frog oocytes. This neurofibromatosis 1 Alu produced a primary transcript followed by the appearance of the scAlu species. 3' processing of a synthetic -300-nt Alu RNA by HeLa nuclear extract in vitro also produced scAlu RNA. Primer extension of scAlu RNA indicates synthesis by RNA polymerase III. HeLa-derived scAlu cDNAs were cloned so as to preserve their 5'-terminal sequences and were found to correspond to polymerase III transcripts of the left monomeric components of three previously identified Alu SINE subfamilies. Rodent x human somatic cell hybrids express Alu RNAs whose size, heterogeneous length, and chromosomal distribution indicate their derivation from SINEs. The coexpression of dimeric and monomeric Alu RNA in several hybrids suggests a precursor-product relationship.

Animals↗

PubMed2003

A CYP7A promoter binding factor site and Alu repeat in the distal promoter region are implicated in regulation of human CETP gene expression.

The cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport in mediating the transfer of cholesteryl ester from HDL to atherogenic apolipoprotein B-containing lipoproteins (VLDL, IDL, and LDL). Variation in plasma CETP mass in both normolipidemic and dyslipidemic individuals may reflect differences in CETP gene expression. As the 5' flanking sequence up to 3.4 kb of the human CETP gene contributes to transcriptional activity and tissue-specific gene expression, we evaluated the role of the distal promoter region in the modulation of CETP gene expression. In transfection experiments in HepG2 cells, we presently demonstrate that an Alu repeat (-2,153/-2,414) acts as a repressive element, whereas a binding site for the orphan nuclear receptor CYP7A promoter binding factor (CPF), at position -1,042, facilitates activation of human CETP promoter activity. Cotransfection of liver receptor homolog, the mouse homologue of CPF in HEK293 cells that lack CPF, indicated that the -1,042 CPF site is sufficient to induce CPF-mediated activation of CETP promoter activity. Taken together, our results indicate that the distal-promoter region is a major component in the modulation of human CETP promoter activity, and that it may contribute to the liver-specific expression of the CETP gene.

Alu Elements↗

PubMed1994

Emergence of master sequences in families of retroposons derived from 7sl RNA.

The past few years have brought new insight into the evolution of families of retroposons. These are composed of a very small number of master sequences able to duplicate, and a large majority of copies that are inactive for retroposition. During the course of time, successive replacements of master sequences have produced waves of amplification that are recognizable as subfamilies. In the Alu and the B1 families, one can distinguish two evolutionary periods. The first involves only monomeric elements that are now extinguished (fossil elements) and is characterized by deep remodeling of the sequences. This period ends, in primates, with the fusion of a free left and a free right Alu monomer, producing the first modern Alu dimeric element; in rodents it ends with a tandem duplication of 29 bp to create the first modern B1 element. The second period is characterized by a great stability of the master sequences. The observed turn-over of master sequences is still an enigma. However, analysis of the contemporary master sequences and of the oldest master sequences provide some clues. Here, we review the very first stages of the appearance of the Alu and the B1 families in mammalian genomes.

Animals↗

PubMed1997

The SRP9/14 subunit of the human signal recognition particle binds to a variety of Alu-like RNAs and with higher affinity than its mouse homolog.

The heterodimeric subunit, SRP9/14, of the signal recognition particle (SRP) has previously been found to bind to scAlu and scB1 RNAs in vitro and to exist in large excess over SRP in anthropoid cells. Here we show that human and mouse SRP9/14 bind with high affinities to other Alu-like RNAs of different evolutionary ages including the neuron-specific BC200 RNA. The relative dissociation constants of the different RNA-protein complexes are inversely proportional to the evolutionary distance between the Alu RNA species and 7SL RNA. In addition, the human SRP9/14 binds with higher affinity than mouse SRP9/14 to all RNAs analyzed and this difference is not explained by the additional C-terminal domain present in the anthropoid SRP14. The conservation of high affinity interactions between SRP9/14 and Alu-like RNAs strongly indicates that these Alu-like RNPs exist in vivo and that they have cellular functions. The observation that human SRP9/14 binds better than its mouse counterpart to distantly related Alu RNAs, such as recently transposed elements, suggests that the anthropoid-specific excess of SRP9/14 may have a role in controlling Alu amplification rather than in compensating a defect in SRP assembly and functions.

Amino Acid Sequence↗

PubMed2005

Identification of splicing silencers and enhancers in sense Alus: a role for pseudoacceptors in splice site repression.

Auxiliary splicing signals in introns play an important role in splice site selection, but these elements are poorly understood. We show that a subset of serine/arginine (SR)-rich proteins activate a cryptic 3' splice site in a sense Alu repeat located in intron 4 of the human LST1 gene. Utilization of this cryptic splice site is controlled by juxtaposed Alu-derived splicing silencers and enhancers between closely linked short tandem repeats TNFd and TNFe. Systematic mutagenesis of these elements showed that AG dinucleotides that were not preceded by purine residues were critical for repressing exon inclusion of a chimeric splicing reporter. Since the splice acceptor-like sequences are present in excess in exonic splicing silencers, these signals may contribute to inhibition of a large number of pseudosites in primate genomes.

Alternative Splicing↗

PubMed2006

Possible presence and role of the promoter sequence for eukaryotic RNA polymerase III in bacteria.

The bacterial repetitive sequence IS1, is a translocatable DNA segment. The internal region of IS1 acts as a cis-element to stimulate RNA synthesis from the upstream promoter. The product of the bacterial artA gene works with this cis-element to stimulate transcription. Eukaryotic genes for small RNAs and short interspersed repetitive elements (SINEs) have internal promoters, transcribed by RNA polymerase III (RNAP III). RNAP III requires the multisubunit protein factor TFIIIC in transcription initiation. TFIIIC contains the B-block binding subunit which recognizes the internal promoter. Here, I report that the eukaryotic RNAP III promoter-like sequence was found in the cis-element of bacterial IS1. Mutations in the cis-element which affect transcription were present in the RNAP III promoter-like sequence. The RNAP III promoter sequence of Alu, which is a human SINE, was cloned into Escherichia coli, and was shown to stimulate bacterial transcription like the cis-element of IS1. Furthermore, the primary structures of ArtA protein and B-block binding subunits were compared. The amino acid sequence of ArtA appeared to be similar to the N- and C-terminal regions conserved in many B-block binding subunits. Prokaryotes and eukaryotes have been thought to have inherent transcription machineries. The results shown here, however, suggest a new aspect of the evolution of the RNAP III transcription machinery.

Alu Elements↗

PubMed2003

B1 and related SINEs in mammalian genomes.

Although B1 and Alu were the first discovered Short Interspersed Elements (SINEs), the studies of these genomic repeats were mostly limited to mice and humans and little data on their presence in other animals were available. Here we report the presence of these SINEs in a wide range of rodents (in all 15 tested families) as well as primates and tree-shrews and their absence in other mammals. Distribution pattern of these SINEs in mammals supports close relationship between rodents and primates as well as tree-shrews. Sequence analysis of these elements, apparently descending from cellular 7SL RNA indicates their rearrangements such as dimerization (Alu), quasi-dimerization (B1), acquiring a tRNA-related unit (B1-dID), extended deletions, etc., preceding their active expansion in the genomes. The revealed common pattern of microenvironment of some rearrangement hot spots in SINEs (internal duplications and deletions) suggests involvement of short direct repeats in the mechanism of such rearrangements. This hypothesis allows us to explain short rearrangements in these and other short retroposons.

Animals↗

PubMed2005

LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling.

Two major classes of retrotransposons have invaded eukaryotic genomes: the LTR retrotransposons closely resembling the proviral integrated form of infectious retroviruses, and the non-LTR retrotransposons including the widespread, autonomous LINE elements. Here, we review the modeling effects of the latter class of elements, which are the most active in humans, and whose enzymatic machinery is subverted to generate a large series of "secondary" retroelements. These include the processed pseudogenes, naturally present in all eukaryotic genomes possessing non-LTR retroelements, and the very successful SINE elements such as the human Alu sequences which have evolved refined parasitic strategies to efficiently bypass the original "protectionist" cis-preference of LINEs for their own retrotransposition.

Animals↗

PubMed1998

Multiplex polymerase chain reaction of Alu polymorphic insertions.

Alu sequences are present in humans in excess of 500,000 copies per haploid genome and represent the largest family of short interspersed repetitive elements (SINEs). These mobile genetic elements are ancestrally derived from the 7SL RNA gene and move throughout the genomes of primates by retroposition. Polymorphic Alu insertions have proven to be useful for population studies, paternity determinations and forensic applications. Additionally, a simple polymerase chain reaction (PCR)-based assay has been established to examine these polymorphisms. In the present study, we have applied the technique of multiplex polymerase chain reaction to the Alu polymorphic system. Duplex and triplex PCR reactions were performed for the analysis of five different Alu polymorphic loci in different combinations. This study represents a starting point for further experimentation to improve and eventually optimize Alu multiplex PCR.

Alu Elements↗

PubMed1993

A cellular protein binds B1 and Alu small cytoplasmic RNAs in vitro.

B1 and Alu are sequence-homologous interspersed elements of unknown function that have expanded in the genomes of mice and humans, respectively. A minority of B1 and Alu sequences are expressed as small cytoplasmic RNAs. These RNAs have conserved a secondary structure motif also present in signal recognition particle (SRP) RNA despite substantial sequence divergence, whereas random B1 and Alu sequences have not. This RNA structure has also been conserved by the source sequences that gave rise to successive transpositions during B1 and Alu evolution. In the present work small cytoplasmic B1 and Alu RNAs synthesized in vitro were found to bind a cellular protein by mobility shift and UV cross-linking analyses. The mouse and human proteins demonstrate the same specificity to a panel of competitor RNAs. Results using mutated B1 RNA indicate that a single strand loop in the conserved Alu motif is essential for binding. Previous work by Strub et al. (Stub, K., Moss, J. B., and Walter, P. (1991) Mol. Cell. Biol. 11, 3949-3959) demonstrated that the Alu-specific protein SRP 9/14 does not footprint to this region of SRP RNA. This observation coupled with the failure of anti-SRP/9 antibodies to identify SRP 9/14 in the B1 RNA-protein complex as well as the apparent mass and other characteristics of the protein described here suggest that it is a novel B1-Alu RNA-binding protein. Conservation of primary and secondary structure by B1 and Alu small cytoplasmic RNAs as well as features of their specific expression and ability to interact with the conserved binding protein indicate that these RNAs are more homologous than previously appreciated.

Animals↗

PubMed1994

A human Alu RNA-binding protein whose expression is associated with accumulation of small cytoplasmic Alu RNA.

Human Alu sequences are short interspersed DNA elements which have been greatly amplified by retrotransposition. Although initially derived from the 7SL RNA component of signal recognition particle (SRP), the Alu sequence has evolved into a dominant transposon while retaining a specific secondary structure found in 7SL RNA. We previously characterized a set of Alu sequences which are expressed as small cytoplasmic RNAs and isolated a protein that binds to these transcripts. Here we report that biochemical purification of this protein revealed it as the human homolog of the SRP 14 polypeptide which binds the Alu-homologous region of 7SL RNA. The human cDNA predicts an alanine-rich C-terminal tail translated from a trinucleotide repeat not found in the rodent homolog, which accounts for why the human protein-RNA complex migrates more slowly than its rodent counterpart in RNA mobility shift assays. The human Alu RNA-binding protein (RBP) is expressed after transfection of this cDNA into mouse cells. Expression of human RBP in rodent x human somatic cell hybrids is associated with substantial increase in endogenous small cytoplasmic Alu and scB1 transcripts but not other small RNAs. These studies provide evidence that this RBP associates with Alu transcripts in vivo and affects their metabolism and suggests a role for Alu transcripts in translation in an SRP-like manner. Analysis of hybrid lines indicated that the Alu RBP gene maps to human chromosome 15q22, which was confirmed by Southern blotting. The possibility that the primate-specific structure of this protein may have contributed to Alu evolution is considered.

Amino Acid Sequence↗

PubMed1991

Characterization of the transcription unit and two processed pseudogenes of chimpanzee triosephosphate isomerase (TPI).

Three members of the chimpanzee TPI (encoding triosephosphate isomerase) gene family, the transcription unit and two processed pseudogenes, have been characterized by genomic blotting and nucleotide sequence analysis. The bona fide TPI gene spans 3.5 kb with seven exons and six introns, and is the first hominoid TPI gene to be completely sequenced. The chimpanzee gene exhibits a very high degree of sequence identity with human and rhesus TPI genes. For example, the polypeptides of 248 amino acids (aa) encoded by the chimpanzee and human TPI genes are identical, but the codons for five of these aa differ in the third codon wobble position. No alternative splice sites could be identified in the intervening sequences of the gene and, thus, the molecular basis for the synthesis of the proliferation-specific TPI isozyme observed in hominoids remains elusive. An Alu member occurs upstream from one of the processed pseudogenes, and short sequences with significant identity to the primate LINE-1 element flank the region encompassing the Alu member and TPI pseudogene. A solitary endogenous retroviral long terminal repeat occurs within the structural region of the other processed pseudogene. The ages of the processed pseudogenes are estimated to be 2.6 and 10.4 million years, implying that one was inserted into the genome before and one after the divergence of the chimpanzee and human lineages.

Amino Acid Sequence↗

PubMed2006

Evolution of growth hormone in primates: the GH gene clusters of the New World monkeys marmoset (Callithrix jacchus) and white-fronted capuchin (Cebus albifrons).

The GH gene cluster in marmoset, Callithrix jacchus, comprises eight GH-like genes and pseudogenes and appears to have arisen as a consequence of gene duplications occurring independently of those leading to the human GH gene cluster. We report here the complete sequence of the marmoset GH gene locus, including the intergenic regions and 5' and 3' flanking sequence, and a study of the multiple GH-like genes of an additional New World monkey (NWM), the white-fronted capuchin, Cebus albifrons. The marmoset sequence includes 945 nucleotides (nt) of 5' flanking sequence and 1596 nt of 3' flanking sequence that are "unique"; between these are eight repeat units, including the eight GH genes/pseudogenes. The breakpoints between these repeats are very similar, indicating a regular pattern of gene duplication. These breakpoints do not correspond to those found in the much less regular human GH gene cluster. This and phylogenetic analysis of the repeat units within the marmoset gene cluster strongly support the independent origin of these gene clusters, and the idea that the episode of rapid evolution that occurred during GH evolution in primates preceded the gene duplications. The marmoset GH gene cluster also differs from that of human in having fewer and more evenly distributed Alu sequences (a single pair in each repeat unit) and a "P-element" upstream of every gene/pseudogene. In human there is no P-element upstream of the gene encoding pituitary GH, and these elements have been implicated in placental expression of the other genes of the cluster. The GH gene clusters in marmoset and capuchin appear to have arisen as the consequence of a single-gene duplication event, but in capuchin there was then a remarkable expansion of the GH locus, giving at least 40 GH-like genes and pseudogenes. Thus even among NWMs the GH gene cluster is very variable.

Alu Elements↗

PubMed2000

Densities, length proportions, and other distributional features of repetitive sequences in the human genome estimated from 430 megabases of genomic sequence.

The densities of repetitive elements in the human genome were calculated in each GC content class using non-overlapping windows of 50kb. The density of Alu is two to three times higher in GC-rich regions than in AT-rich regions, while the opposite is true for LINE1. In contrast, LINE2 and other elements, such as DNA transposons, are more uniformly distributed in the genome. The number of Alus in the human genome was estimated to be 1.4 million, higher than previous estimates. About 40% of the autosomes and approximately 51% of the X and Y chromosomes are occupied by repetitive elements. In total, the human genome is estimated to contain more than 4 million repetitive elements. The GC contents (%) of repetitive elements and their flanking regions were also calculated. The GC contents of almost all kinds of repeats are positively correlated with the window GC contents, suggesting that a repetitive sequence is subject to the same mutation pressure as its surrounding regions, so it tends to have the same GC content as its surrounding regions. This observation supports the regional mutation hypothesis. The only two exceptions are AluYa and AluYb8, the two youngest Alu subfamilies. The GC content of AluYb8 is negatively correlated with that of its surrounding regions, while AluYa shows no correlation, suggesting different insertion patterns for these two young Alu subfamilies. This suggestion was supported by the fact that the average genetic distance between members of AluYb8 in each GC window class is positively correlated with the GC content of the window, but no correlation was found for AluYa. AluYa is more frequent in Y chromosome than in other chromosomes; the same is true for LTR retroviruses. This pattern might be correlated with the evolutionary history of Y chromosome.

Alu Elements↗

PubMed2006

High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition.

APOBEC3G (A3G) and related deoxycytidine deaminases are potent intrinsic antiretroviral factors. A3G is expressed either as an enzymatically active low-molecular-mass (LMM) form or as an enzymatically inactive high-molecular-mass (HMM) ribonucleoprotein complex. Resting CD4 T cells exclusively express LMM A3G, where it functions as a powerful postentry restriction factor for HIV-1. Activation of CD4 T cells promotes the recruitment of LMM A3G into 5- to 15-MDa HMM complexes whose function is unknown. Using tandem affinity purification techniques coupled with MS, we identified Staufen-containing RNA-transporting granules and Ro ribonucleoprotein complexes as specific components of HMM A3G complexes. Analysis of RNAs in these complexes revealed Alu and small Y RNAs, two of the most prominent nonautonomous mobile genetic elements in human cells. These retroelement RNAs are recruited into Staufen-containing RNA-transporting granules in the presence of A3G. Retrotransposition of Alu and hY RNAs depends on the reverse transcriptase machinery provided by long interspersed nucleotide elements 1 (L1). We now show that A3G greatly inhibits L1-dependent retrotransposition of marked Alu retroelements not by inhibiting L1 function but by sequestering Alu RNAs in cytoplasmic HMM A3G complexes away from the nuclear L1 enzymatic machinery. These findings identify nonautonomous Alu and hY retroelements as natural cellular targets of A3G and highlight how different forms of A3G uniquely protect cells from the threats posed by exogenous retroviruses (LMM A3G) and endogenous retroelements (HMM A3G).

APOBEC-3G Deaminase↗

PubMed1998

Terminator-specific recycling of a B1-Alu transcription complex by RNA polymerase III is mediated by the RNA terminus-binding protein La.

Efficient synthesis of many small abundant RNAs is achieved by the proficient recycling of RNA polymerase (pol) III and stable transcription complexes. Cellular Alu and related retroposons represent unusual pol III genes that are normally repressed but are activated by viral infection and other conditions. The core sequences of these elements contain pol III promoters but must rely on fortuitous downstream oligo(dT) tracts for terminator function. We show that a B1-Alu gene differs markedly from a classical pol III gene (tRNAiMet) in terminator sequence requirements. B1-Alu genes that differ only in terminator sequence context direct differential RNA 3' end formation. These genes are assembled into stable transcription complexes but differ in their ability to be recycled in the presence of the La transcription termination factor. La binds to the nascent RNA 3' UUUOH end motif that is generated by transcriptional termination within the pol III termination signal, oligo(dT). We found that the recycling efficiency of the B1-Alu genes is correlated with the ability of La to access the 3' end of the nascent transcript and protect it from 3'-5' exonucleolytic processing. These results illuminate a relationship between RNA 3' end formation and transcription termination, and La-mediated reinitiation by pol III.

Alu Elements↗

PubMed2002

Characterization of novel Alu- and tRNA-related SINEs from the tree shrew and evolutionary implications of their origins.

We characterized two novel 7SL RNA-derived short interspersed nuclear element (SINE) families (Tu types I and II) and a novel tRNA-derived SINE family (Tu type III) from the tree shrew (Tupaia belangeri). Tu type I contains a monomer unit of a 7SL RNA-derived Alu-like sequence and a tRNA-derived region that includes internal RNA polymerase III promoters. Tu type II has a similar hybrid structure, although the monomer unit of the 7SL RNA-derived sequence is replaced by a dimer. Along with the primate Alu, the galago Alu type II, and the rodent B1, these two families represent the fourth and fifth 7SL RNA-derived SINE families to be identified. Furthermore, comparison of the Alu domains of Tu types I and II with those of other 7SL RNA-derived SINEs reveals that the nucleotides responsible for stabilization of the Alu domain have been conserved during evolution, providing the possibility that these conserved nucleotides play an indispensable role in retropositional activity. Evolutionary relationships among these 7SL RNA-derived SINE families, as well as phylogenetic relationships of their host species, are discussed.

Alu Elements↗