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PubMed1997

Interethnic polymorphism of EWS intron 6: genome plasticity mediated by Alu retroposition and recombination.

The EWS gene has been identified as being systematically translocated in Ewing's sarcoma. In order to ascertain the basis of a marked interethnic difference in the incidence of Ewing's sarcoma, intron 6 of EWS, which is located near the translocation breakpoint region (EWSR1), was characterized. Sequence analysis of the entire intron 6 region revealed a very high density of Alu elements. Most of these Alu sequences could be classified in previously described subfamilies, facilitating delineation of an evolutionary model that involves successive retroposition events. According to this model, the EWS intron 6 region progressively expanded until about 5 million years ago. More recently (10(5) years ago), in part of the human population, the size of this region decreased by over 50% as the result of a homeologous recombination between two Alu sequences, which removed 2480 bp. This rare allele has only been observed in individuals of African origin, a population that is characterized by the lowest incidence of Ewing's sarcoma.

Alleles↗
PubMed2002

PROGINS Alu insertion and human genomic diversity.

A polymorphic Alu element belonging to the young Ya5 subfamily of Alu repeats located in the progesterone receptor gene has been characterized. Using a polymerase chain reaction (PCR)-based assay, the genetic diversity associated with the PROGINS Alu repeat was determined in a diverse array of human populations. The level of insertion polymorphism associated with PROGINS suggests that it will be a useful marker for the study of human evolution. In addition, we determined the distribution of the PROGINS Alu insertion in two groups of women from greater New Orleans, LA with breast cancer. The PROGINS Alu insertion was not associated with breast cancer in the populations tested.

Alu Elements↗
PubMed2004

Expansion of GAA triplet repeats in the human genome: unique origin of the FRDA mutation at the center of an Alu.

Friedreich ataxia is caused by expansion of a GAA triplet repeat (GAA-TR) in the FRDA gene. Normal alleles contain <30 triplets, and disease-causing expansions (66-1700 triplets) arise via hyperexpansion of premutations (30-65 triplets). To gain insight into GAA-TR instability we analyzed all triplet repeats in the human genome. We identified 988 (GAA)(8+) repeats, 291 with >or=20 triplets, including 29 potential premutations (30-62 triplets). Most other triplet repeats were restricted to <20 triplets. We estimated the expected frequency of (GAA)(6+) repeats to be negligible, further indicating that GAA-TRs have undergone significant expansion. Eighty-nine percent of (GAA)(8+) sequences map within G/A islands, and 58% map within the poly(A) tails of Alu elements. Only two other (GAA)(8+) sequences shared the central Alu location seen at the FRDA locus. One showed allelic variation, including expansions analogous to short Friedreich ataxia mutations. Our data demonstrate that GAA-TRs have expanded throughout primate evolution with the generation of potential premutation alleles at multiple loci.

Algorithms↗
PubMed2006

The length of CpG islands is associated with the distribution of Alu and L1 retroelements.

Alu and L1 retroelements have been suggested to initiate the spread of CpG methylation. In this study, the spread of CpG methylation was estimated based on the distance between the CpG islands and the nearest retroelements. All human genes (23,116) were examined and the correlations between the length of the CpG islands and the distance and density of the confronting retroelements were examined using nonoverlapping 5-kb windows. There was a linear relationship between the length of the CpG islands and the density of the Alu elements and an inverse relationship between the CpG islands and the L1 elements located more distantly, suggesting a suppressive effect of the Alu's on the spread of L1 methylation. Methylation analysis of the transitional CpG sites between the CpG islands and the nearest retroelements upstream of 16 genes was then carried out using DNA preparations from 11 different human tissues. Methylation-variable transitional CpGs were observed for the selected genes and the different tissues.

Alu Elements↗
PubMed1999

Origin and phylogenetic distribution of Alu DNA repeats: irreversible events in the evolution of primates.

Over the past 60 million years, or so, approximately one million copies of Alu DNA repeats have accumulated in the genome of primates, in what appears to be an ongoing process. We determined the phylogenetic distribution of specific Alu (and other) DNA repeats in the genome of several primates: human, chimpanzee, gorilla, orangutan, baboon, rhesus, and macaque. At the population level studied, the majority of the repeats was found to be fixed in the primate species. Our data suggest that new Alu elements arise in unique, irreversible events, in a mechanism that seems to preclude precise excision and loss. The same insertions did not arise independently in two species. Once inserted and genetically fixed, the DNA elements are retained in all descendant lineages. The irreversible expansion of Alu s introduces a vector of time into the evolutionary process, and provides realistic (rather than statistical) answers to questions on phylogenies. In contrast to point mutations, the present distribution of individual Alu s is congruent with just one phylogeny. We submit that only irreversible and taxonomically relevant events are at the molecular basis of evolution. Most point mutations do not belong to this category.

Alu Elements↗
PubMed2005

Tracking Alu evolution in New World primates.

BACKGROUND: Alu elements are Short INterspersed Elements (SINEs) in primate genomes that have proven useful as markers for studying genome evolution, population biology and phylogenetics. Most of these applications, however, have been limited to humans and their nearest relatives, chimpanzees. In an effort to expand our understanding of Alu sequence evolution and to increase the applicability of these markers to non-human primate biology, we have analyzed available Alu sequences for loci specific to platyrrhine (New World) primates. RESULTS: Branching patterns along an Alu sequence phylogeny indicate three major classes of platyrrhine-specific Alu sequences. Sequence comparisons further reveal at least three New World monkey-specific subfamilies; AluTa7, AluTa10, and AluTa15. Two of these subfamilies appear to be derived from a gene conversion event that has produced a recently active fusion of AluSc- and AluSp-type elements. This is a novel mode of origin for new Alu subfamilies. CONCLUSION: The use of Alu elements as genetic markers in studies of genome evolution, phylogenetics, and population biology has been very productive when applied to humans. The characterization of these three new Alu subfamilies not only increases our understanding of Alu sequence evolution in primates, but also opens the door to the application of these genetic markers outside the hominid lineage.

Alu Elements↗
PubMed2002

Phylogenetics of worldwide human populations as determined by polymorphic Alu insertions.

Alu elements, the largest family of interspersed repeats, mobilize throughout the genomes of primates by retroposition. Alu are present in humans in an excess of 500 000 copies per haploid genome. Since some of the insertion alleles have not reached fixation, they remain polymorphic and can be used as biallelic DNA marker systems in investigations of human evolution. In this study, six polymorphic Alu insertional (PAI) loci were used as genetic markers. These markers are thought to be selectively neutral. The presence of these six PAIs was determined by a polymerase chain reaction (PCR)-based assay in 1646 individuals from 47 populations from around the world. Examination of the populations by plotting the first and second principal components, shows the expected segregation of populations according to geographical vicinity and established ethnic affinities. Centroid analysis demonstrated that sub-Sahara populations have experienced higher than average gene flow and/or represent larger populations as compared to groups in other parts of the globe and especially to known inbreed populations. This is consistent with greater heterogeneity and diversity expected of source groups. In addition, maximum likelihood (ML) analyses were performed with these 47 populations and a hypothetical ancestral group lacking the insertion in all six loci. Analysis of our data supports the Out of Africa hypothesis. African populations and admixed groups of African descent formed a single monophyletic group with a basal placement on the tree, which grouped closest to the hypothetical ancestor.

Alu Elements↗
PubMed2006

APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination-independent mechanism.

The most common transposable genetic element in humans, long interspersed element 1 (L1), constitutes about 20% of the genome. The activity of L1 and related transposons such as Alu elements causes disease and contributes to speciation. Little is known about the cellular mechanisms that control their spread. We show that expression of human APOBEC3B or APOBEC3F decreased the rate of L1 retrotransposition by 5-10-fold. Expression of two related proteins, APOBEC3D or APOBEC3G, had little effect. The mechanism of L1 inhibition did not correlate with an obvious subcellular protein distribution as APOBEC3B appeared predominantly nuclear and APOBEC3F was mostly cytosolic. Two lines of evidence indicated that these APOBEC3 proteins use a deamination-independent mechanism to inhibit L1. First, a catalytically inactive APOBEC3B mutant maintained L1 inhibition activity. Second, cDNA strand-specific C --> T hypermutations were not detected among L1 elements that had replicated in the presence of APOBEC3B or APOBEC3F. In addition, lower levels of retrotransposed L1 DNA accumulated in the presence of APOBEC3B and APOBEC3F. Together, these data combined to suggest a model in which APOBEC3B or APOBEC3F provide a preintegration barrier to L1 retrotransposition. A particularly high level of APOBEC3F protein in human testes and an inverse correlation between L1 activity and APOBEC3 gene number suggest the relevance of this mechanism to mammals.

Alu Elements↗
PubMed2005

Alu-associated enhancement of single nucleotide polymorphisms in the human genome.

Identifying features shaping the architecture of sequence variations is important for understanding genome evolution and mapping disease loci. In this study, high-resolution scanning of Alu-centered alignments of the human genome sequences has revealed a striking elevation of the frequency of single nucleotide polymorphisms (SNP) in the body and tail of Alu sequences compared to flanking regions. This enhancement in SNP density is evident for all twenty-four chromosomes, and in both the Alu-body and Alu-tail, which together may be referred to as the Alu-SNPs. Reduced levels of Alu-SNPs in the sex chromosomes, especially in the non-recombining NRY region of the Y chromosome, are consistent with recombination events playing an important role in the enhancement. The Alu elements are unstable recombination-mutation hotspots in the human genome, and it is suggested that the Alu-SNPs represent a key manifestation of this instability. Variations in Alu-SNPs among the HapMap populations of northern and western European ancestry (CEU), Han Chinese from Beijing (CHB), Japanese from Tokyo (JPT), and Yoruba from Ibadan, Nigeria (YRI) indicate that the Alu-SNPs provide useful sequence markers, in addition to the Alu-insertion polymorphisms themselves, for the delineation of human genome evolution. That Alu-SNP levels are highest in the youngest Alu-Y, intermediate in the Alu-S of intermediate age, and lowest in the oldest Alu-J is consistent with the occurrence of not only genetic drift but also natural selection on the Alu-SNPs. Such evolutionary selection in turn suggests that Alu-SNPs might include potential sites of disease association, and therefore deserve detailed investigation.

Alu Elements↗
PubMed2025

Correlation of extracellular vesicle Alu RNA with brain aging and neuronal injury: a potential biomarker for brain aging.

BACKGROUND: Extracellular vesicles (EVs) are promising biomarkers for neurodegeneration. Alu elements are retrotransposons increasingly expressed with age and may be involved in aging-related diseases. OBJECTIVE: To determine the potential of Alu RNA in plasma-derived EVs as a biomarker for brain aging and neuronal injury. METHODS: EVs were isolated from plasma samples across different age groups. EV Alu RNA levels were measured and their associations with biomarkers of brain aging, including plasma neurofilament light chain (NfL), plasma amyloid-beta (A&#x3b2;42 and A&#x3b2;40), and plasma phosphorylated tau (p-Tau181), were analyzed. RESULTS: EV Alu RNA levels were increased significantly with age and were strongly correlated with plasma NfL, suggesting a strong association between EV Alu RNA and neuronal injury. Significant correlations were also found between EV Alu RNA and plasma amyloid-beta levels, while no significant association was observed with tau pathology. CONCLUSIONS: EV Alu RNA levels are elevated with age and associated with neuronal injury, highlighting their potential as a novel, non-invasive biomarker for brain aging and neurodegeneration.

Humans↗
PubMed2004

Differential alu mobilization and polymorphism among the human and chimpanzee lineages.

Alu elements are primate-specific members of the SINE (short interspersed element) retroposon family, which comprise approximately 10% of the human genome. Here we report the first chromosomal-level comparison examining the Alu retroposition dynamics following the divergence of humans and chimpanzees. We find a twofold increase in Alu insertions in humans in comparison to the common chimpanzee (Pan troglodytes). The genomic diversity (polymorphism for presence or absence of the Alu insertion) associated with these inserts indicates that, analogous to recent nucleotide diversity studies, the level of chimpanzee Alu diversity is approximately 1.7 times higher than that of humans. Evolutionarily recent Alu subfamily structure differs markedly between the human and chimpanzee lineages, with the major human subfamilies remaining largely inactive in the chimpanzee lineage. We propose a population-based model to account for the observed fluctuation in Alu retroposition rates across primate taxa.

Alu Elements↗
PubMed1991

Generation of novel sequence tagged sites (STSs) from discrete chromosomal regions using Alu-PCR.

Human DNA segments from discrete chromosomal regions were generated by utilizing Alu-element-based polymerase chain reaction (Alu-PCR) of an irradiation-fusion hybrid containing approximately 10 to 15 Mb of human DNA. Following cloning into a plasmid vector, a subset of the clones was used to generate sequence tagged sites (STSs) de novo. By means of a panel of hybrids containing portions of the human X chromosome, the STSs were shown to localize to two chromosomal regions, Xq24-Xq26 and Xcen-Xq13, reflecting the presence in the irradiation-fusion hybrid of two human chromosome fragments. These results demonstrate that high densities of STSs can be rapidly and efficiently generated from defined regions of the human genome using Alu-PCR.

Animals↗
PubMed2001

Differential stress induction of individual Alu loci: implications for transcription and retrotransposition.

While human Alu repeats can be considered to be members of an extremely large, globally regulated, multigene family, each member of this family resides within a different sequence context that might uniquely modulate its transcription. Unique 3' flanking sequences for several transcriptionally active human Alu elements were identified by cDNA cloning and used for primer extension analysis to compare the basal and stress-induced expression of the corresponding Alu loci. Each of six Alu loci investigated exhibits a unique pattern of expression in three different human cell lines and in response to stress induction. The sequence context surrounding each Alu member uniquely determines its transcriptional regulation. In many cases, the individual Alu loci and total Alu RNA exhibit opposing patterns of expression implying that local rather than global regulation ultimately determines the expression of individual members. Some of the stresses, which induce Alu transcription, increase co-expression of LINE1 RNA, another requirement for Alu retrotransposition.

Alu Elements↗
PubMed1992

A random STS strategy for construction of YAC contigs spanning defined chromosomal regions.

Sequence tagged sites (STSs) that were generated via Alu-element-mediated polymerase chain reaction (Alu-PCR) and mapped to human Xq26 were used to isolate and overlap yeast artificial chromosomes (YACs). By collating the results of primary pool screening, the order of STSs and YACs was postulated directly. Subsequent isolation of 11 key YACs from 75 positive pools confirmed the proposed contig. Although only a small subset of the available Alu-PCR fragments was used, the STSs were generated at sufficient density to isolate all the YACs required and to identify all except one overlap directly. The results confirmed physical linkage of HPRT to DXS86 and DXS144E. Long-range continuity was determined purely by analysis of the 11 YAC colonies and required no end-rescue. This strategy is therefore an effective approach for the construction of YAC contigs spanning discrete chromosomal regions contained within somatic cell hybrids, with minimal prior knowledge of the region.

Base Sequence↗
PubMed1995

Human signal recognition particle (SRP) Alu-associated protein also binds Alu interspersed repeat sequence RNAs. Characterization of human SRP9.

Nearly 1 million interspersed Alu elements reside in the human genome. Alu retrotransposition is presumably mediated by full-length Alu transcripts synthesized by RNA polymerase III, while some polymerase III-synthesized Alu transcripts undergo 3'-processing and accumulate as small cytoplasmic (sc) RNAs of unknown function. Interspersed Alu sequences also reside in the untranslated regions of some mRNAs. The Alu sequence is related to a portion of the 7SL RNA component of signal recognition particle (SRP). This region of 7SL RNA together with 9- and 14-kDa polypeptides (SRP9/14) regulates translational elongation of ribosomes engaged by SRP. Here we characterize human (h) SRP9 and show that it, together with hSRP14 (SRP9/14), forms the activity previously identified as Alu RNA-binding protein (RBP). The primate-specific C-terminal tail of hSRP14 does not appreciably affect binding to scAlu RNA. Kd values for three Alu-homologous scRNAs were determined using Alu RBP (SRP9/14) purified from HeLa cells. The Alu region of 7SL, scAlu, and scB1 RNAs exhibited Kd values of 203 pM, 318 pM, and 1.8 nM, respectively. Finally, Alu RBP can bind with high affinity to synthetic mRNAs that contain interspersed Alus in their untranslated regions.

Amino Acid Sequence↗
PubMed1997

MLL self fusion mediated by Alu repeat homologous recombination and prognosis of AML-M4/M5 subtypes.

Fifty-six patients with de novo acute myeloid leukemia M4/M5 subtypes were studied for rearrangements of the mixed lineage leukemia gene, MLL (also called HRX, Htrx-1, or ALL-1). Ten patients (18%) showed rearrangements of the MLL gene, 9 in a major breakpoint cluster region within a centromeric 8.3-kb BamHI fragment, whereas rearrangement in one patient was the result of a direct tandem duplication of exons 2-6 of MLL. Analysis of sequences at the duplication junction revealed that the points of MLL fusion within introns 6 and 1 both lie within Alu elements. This suggests the involvement of Alu repeat mediated homologous recombination in MLL self fusion. For the 10 rearranged samples, cytogenetics analysis revealed a normal karyotype in 3, and 3 had abnormalities other than 11q23. Survival analysis of patients revealed no difference between those with rearrangement of MLL and those showing the germ-line configuration.

Adult↗
PubMed2001

The Basques according to polymorphic Alu insertions.

Polymorphic Alu insertions provide a set of DNA markers of interest in human population genetics. Approximately 1000-2000 of these insertions have not reached fixation within the human genome. Each one of these polymorphic loci most probably resulted from a unique insertional event, and therefore all individuals possessing the insertion are related by descent not just state. In addition, the direction of mutational change is toward the gain of the Alu element at a particular locus. Therefore, the improved knowledge of both the ancestral state and the direction of mutational change greatly facilitates the analysis of population relationships. As a result, Alu insertion polymorphisms represent a significant tool for population genetic studies. In this study, polymorphic Alu insertions have been employed to ascertain phylogenetic relationships among Basque groups and worldwide populations. The Basques are considered to be a geographic isolate with a unique language and customs. They may be direct descendants of Cro-Magnon enclaves from the upper Paleolithic (38,000 to 10,000 years). The Basques are distributed among narrow valleys in northeastern Spain with little migration between them until recently. This characteristic may have had an effect on allelic frequency distributions. With the aim of studying this possible effect, we have analyzed six autosomal polymorphic Alu loci from four different sites within the Spanish Basque region in order to ascertain any genetic heterogeneity among the Basques. The results are consistent with a lack of homogeneity among these four autochthonous Basque groups.

Alu Elements↗
PubMed2001

Hierarchical assembly of the Alu domain of the mammalian signal recognition particle.

The mammalian signal recognition particle (SRP) catalytically promotes cotranslational translocation of signal sequence containing proteins across the endoplasmic reticulum membrane. While the S-domain of SRP binds the N-terminal signal sequence on the nascent polypeptide, the Alu domain of SRP temporarily interferes with the ribosomal elongation cycle until the translocation pore in the membrane is correctly engaged. Here we present biochemical and biophysical evidence for a hierarchical assembly pathway of the SRP Alu domain. The proteins SRP9 and SRP14 first heterodimerize and then initially bind to the Alu RNA 5' domain. This creates the binding site for the Alu RNA 3' domain. Alu RNA then undergoes a large conformational change with the flexibly linked 3' domain folding back by 180 degrees onto the 5' domain complex to form the final compact Alu ribonucleoprotein particle (Alu RNP). We discuss the possible mechanistic consequences of the likely reversibility of this final step with reference to translational regulation by the SRP Alu domain and with reference to the structurally similar Alu RNP retroposition intermediates derived from Alu elements in genomic DNA.

Alu Elements↗