Alu insertion-Genetic Origins

An Alu element is a short stretch of DNA originally characterized by the action of the Arthrobacter luteus Alu restriction endonuclease. Alu elements are highly conserved within primate genomes and originated in the genome of an ancestor of Supraprimates. Alu insertions have been implicated in several inherited human diseases and in various forms of cancer. The study of Alu elements has also been important in elucidating human population genetics and the evolution of primates , including the evolution of humans. The Alu family is a family of repetitive elements in primate genomes, including the human genome.

Alu insertion

Alu insertion

It is thought that at least isertion other Alu insertion binds the duplex portion of the RNA structure. Bibcode : PNAS Although Alu Alu insertion have long been considered "junk" DNA, scientists are beginning to question whether these elements might serve important biological functions after all. Alu repeats and human disease. Cytogenet Genome Res.

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International Human Genome Sequencing Consortium. However, given the relatively low levels of endogenous Alu transcripts, even upon Alu insertion stimulation, it is not completely clear that the necessary Alu insertion of RNA to achieve these influences Alu insertion made in cells. Novick, Alu insertion. J Clin Oncol. The major subfamily branches J, S, and Y seem to have appeared at different evolutionary times, with J being older than S, and S being older than Jnsertion. Extensive adenosine-to-inosine editing detected in Alu repeats of antisense RNAs reveals scarcity of sense-antisense duplex formation. These polymorphic insertions have been used as genetic markers in human evolution studies due to their particular properties: they are rapid and easy to type, are apparently selectively neutral, and have known ancestral states. Figure 1. Insertion of an Alu exon is likely to introduce a premature termination codon or Alu insertion Bbs kidzilla shift. Figure 4. Genome Med.

Metrics details.

  • An Alu element is a short stretch of DNA originally characterized by the action of the Arthrobacter luteus Alu restriction endonuclease.
  • While retrotransposons can disrupt gene as in some cases of hemophilia , they often land outside of genes or within introns without effect.

Metrics details. They have wide-ranging influences on gene expression. Their contribution to genome evolution, gene regulation and disease is reviewed. They belong to a class of retroelements termed SINEs short interspersed elements and are primate specific. These elements are non-autonomous, in that they acquire trans -acting factors for their amplification from the only active family of autonomous human retroelements: LINE-1 [ 2 ].

They are also a major factor contributing to non-allelic homologous recombination events causing copy number variation and disease. However, the ubiquitous presence of Alu elements throughout the human genome has led to their presence in a large number of genes and their transcripts.

Many individual Alu elements have wide-ranging influences on gene expression, including influences on polyadenylation [ 3 , 4 ], splicing [ 5 — 7 ] and ADAR adenosine deaminase that acts on RNA editing [ 8 — 10 ]. This review focuses heavily on studies generated as a result of the advent of high-throughput genomics providing huge datasets of genome sequences, and data on gene expression and epigenetics.

These data provide tremendous insight into the role of Alu elements in genetic instability and genome evolution, as well as their many impacts on expression of the genes in their vicinity. These roles then influence normal cellular health and function, as well as having a broad array of impacts on human health.

The general structure of an Alu element is presented in Figure 1a. The body of the Alu element is about bases in length, formed from two diverged dimers, ancestrally derived from the 7SL RNA gene, separated by a short A-rich region reviewed in [ 11 ]. The 3' end of an Alu element has a longer A-rich region that plays a critical role in its amplification mechanism [ 12 ].

The entire Alu element is flanked by direct repeats of variable length that are formed by duplication of the sequences at the insertion site. Alu elements have an internal RNA polymerase III promoter that potentially initiates transcription at the beginning of the Alu and produces RNAs that are responsible for their amplification.

However, Alu elements have no terminator for transcription and the transcripts terminate at nearby genomic locations using a TTTT terminator sequence. The structure of an Alu element. The Alu ends with a long A-run, often referred to as the A-tail, and it also has a smaller A-rich region indicated by AA separating the two halves of a diverged dimer structure.

They utilize whatever stretch of T nucleotides is found at various distances downstream of the Alu element to terminate transcription. A typical Alu transcript is shown below the genomic Alu , showing that it encompasses the entire Alu , including the A-tail, and has a 3' region that is unique for each locus.

It is thought that at least one other protein binds the duplex portion of the RNA structure. This creates a cDNA copy of the body of the Alu element.

A nick occurs by an unknown mechanism on the second strand and second-strand synthesis is primed. The new Alu element is then flanked by short direct repeats that are duplicates of the DNA sequence between the first and second nicks.

Each RNA polymerase III generated Alu RNA is unique in terms of: i accumulated mutations in the Alu element itself; ii the length and accumulated sequence heterogeneity in the encoded A-rich region at its 3' end; and iii the unique 3' end on each RNA transcribed from the adjacent genomic site.

Alu RNAs then utilize the purloined ORF2p to copy themselves at a new genomic site using a process termed target-primed reverse transcription Figure 1c ; reviewed in [ 18 , 19 ]. Although Alu is dependent on the L1 ORF2p protein, Alu retrotransposition is not simply an extension of the L1 retrotransposition process.

This may be one of the reasons why Alu causes several times as many diseases as L1 through insertion [ 22 , 23 ] and has twice the copy number of L1 [ 1 ]. Because L1 elements have been shown to have a splice variant that makes only ORF2p [ 24 ], or that may express ORF2p from elements with a mutated ORF1, Alu might be able to amplify in cells that do not effectively amplify L1. This means that Alu may retrotranspose well in the testis, even though L1 retrotransposes poorly.

Alu and L1s have several other differences. Alu elements encode the A-tail separately at each locus rather than through post-transcriptional polyadenylation, as with L1. Thus, Alu A-tails are prone to shrinkage and accumulation of mutations that can affect the amplification process from each particular locus discussed below [ 16 ]. Only a handful of the greater than 1 million genomic Alu elements can amplify [ 29 , 30 ].

It seems highly likely that relatively few polymorphic elements in the population have high amplification capability that maintains Alu amplification within the population. There are many factors that contribute to the relative amplification activity of an Alu locus Figure 2 [ 29 , 31 ]. These include: i the influence of the primary genomic sequence on transcription; ii epigenetic influences on transcription; iii the length, and possibly the specific nature, of the 3' unique region of the Alu RNAs; iv the length and heterogeneity of the A-tail of the Alu ; and v divergence of the body of the Alu element, which seems likely to influence RNA structure and probably relevant protein binding Figure 1b.

Why so few Alu elements are active. Upon insertion in a new locus, the factors that make a very active Alu element are the flanking sequences influencing the promoter, creating a short unique region. Active elements match the consensus Alu element fairly closely and they have a long and fairly perfect A-tail. Active elements degrade rapidly on an evolutionary time scale by A-tail shortening, heterogeneous base interruptions accumulating in the A-tail, and eventually by the accumulation of random mutations in the Alu element.

At least some of these changes alter Alu activity through disruption of the various proteins binding to the RNA in the ribonucleoprotein Figure 1b.

These mechanistic features all contribute to the observed paucity of actively amplifying 'master' or 'source' Alu elements in the human genome. The internal RNA polymerase III promoter is not strong unless it fortuitously lands near appropriate flanking sequences [ 32 ]. Thus, there are generally very low levels of RNA polymerase III transcribed Alu RNAs in a cell and it is transcribed by a number of dispersed loci, including many loci that are incapable of active retrotransposition [ 33 ].

However, because each new insert lands in a different genomic environment, the new loci will vary tremendously in their transcription potential owing to the influences of flanking sequences [ 32 ] and epigenetics. In addition, the 3' flanking sequence will provide the RNA polymerase III terminator, and those with longer 3' unique regions will be poor at retrotransposition [ 29 ]. Following insertion, those elements that are initially capable of retrotransposition will gradually lose that capability by a series of sequence changes.

In addition, the A-tails will rapidly accumulate mutations and often form variant microsatellite-like sequences at their ends that will also impair the activity [ 29 ]. Large-scale sequencing studies of primate genomes have provided a great deal of detail on the evolution of Alu elements. Because there is no specific mechanism for removal of Alu insertions, Alu evolution is dominated by the accumulation of new Alu inserts.

These new Alu inserts accumulate sequence variation over time and are rarely removed by non-specific deletion processes. Different periods of evolutionary history have given rise to different subfamilies of Alu elements with a very limited and homogeneous group of subfamilies active in any given species because of a very limited number of source, or master, Alu loci Figure 3 [ 38 , 39 ]. The earliest Alu elements were the J subfamily, followed by a very active series of S subfamilies.

The Alu amplification rate peaked with the S subfamilies [ 38 ]. Comparisons between chimpanzee and human genomes have shown that, since their divergence about 6 million years ago, there have been about 2, and 5, lineage-specific insertions fixed, respectively [ 41 , 42 ]. There are , lineage-specific insertions in the Rhesus macaque genome [ 43 ]. However, this estimate was measured over a longer period of time than the estimates for human and chimpanzee insertion rates.

Thus, we are unable to compare rates over the same period of time. The orangutan has only acquired approximately lineage-specific insertions in the last 12 million years [ 44 ], demonstrating a marked decrease in amplification rate in that lineage. L1 elements do not show a significant difference in their lineage-specific insertions between human, chimp and orangutan, and it therefore appears that changes in Alu source elements or other Alu -specific amplification changes have occurred to cause the slow rate in orangutan.

Further studies from incomplete, large-scale analyses of other primate genomes [ 45 ] show that the overall rates of Alu insertion in the marmoset lineage were generally lower than towards the human lineage, supporting the idea that Alu amplification rates vary in a species-specific or lineage-specific manner. Subfamily analysis and these rate studies suggest that the bottleneck events that occur during speciation can result in altered levels of Alu activity, probably through fixation of different numbers or levels of activity of source elements.

Evolutionary impact of Alu elements in primates. An approximate evolutionary tree is shown for various primate species.

The approximate density of Alu elements in the genomes of those species is shown as the number of Alu elements per megabase MB. For specific evolutionary time periods, marked by thicker lines, the number of lineage-specific Alu insertions Lsi is marked. Note that the rate of Alu insertion, as well as recombination, seems to vary with different lineages and different evolutionary time periods. However, studies of the human and chimpanzee genomes show that approximately deletion events have occurred in both genomes Figure 3 [ 47 , 48 ].

It has not been possible to assess the duplication events that are also caused by this type of recombination, but it is likely that there is approximately the same number of events, and these events have also been suggested to contribute to genomic inversions [ 49 ] and segmental duplications [ 50 ].

This is consistent with the relatively short length of the fixed deletions relative to the longer deletions commonly found associated with disease [ 46 ]. Alu elements are preferentially enriched in regions that are generally gene rich, whereas L1 elements are enriched in the gene-poor regions [ 1 ].

Alu elements have continued to insert in the modern human lineage as evidenced by their continued contribution to human genetic disease. It is estimated that there is about one new Alu insert per 20 human births [ 55 ], leading to about one in every 1, new human genetic diseases [ 23 ]. Comparison between two completed human genomes showed that there were approximately polymorphic Alu elements between those two individuals [ 55 ].

Alu insertions contribute to disease by either disrupting a coding region or a splice signal [ 23 , 56 ] Table 1. Fourteen new Alu insertions inactivating the NF1 gene have been reported [ 57 ], representing 0. Similarly, many diseases caused by non-allelic homologous recombination between Alu elements have been discussed previously [ 23 , 57 ].

Thus, the events described above represent only a tiny proportion of the overall genetic instability in the human population caused by such elements. Genomic studies are now beginning to delve into the diversity of Alu elements in the human population.

Several studies involve the resequencing of multiple independent human genomes, resulting in the discovery of many new polymorphic Alu elements [ 59 — 61 ]. These studies largely confirm earlier work on the tremendous amount of diversity contributed to individual genomes by Alu insertions, as well as Alu subfamily types and distribution.

These studies have utilized multiple available human genome sequences, primarily those available with low-to-moderate sequence coverage from the first genomes from the Genomes Project.

Among these approaches is a PCR method to isolate sequences flanking L1 or Alu sequences [ 62 , 63 ]. This approach isolated an additional polymorphic Alu inserts from a number of individuals also see a second method in the section Somatic insertions of Alu elements. The added sensitivity of these directed NGS approaches will aid in studies for detecting rare insertions in germline tissues, as well as for detecting somatic insertions present in only a few cells within an organ or tumor.

However, there is reason to believe that Alu elements are also active in somatic tissues and may continue to contribute to genetic instability throughout the life of an individual, possibly leading to cancer or other age-related degenerations. However, the only way to demonstrate endogenous activity of Alu elements in tissues is by utilizing the power of high-throughput NGS technologies. One NGS approach has claimed detection of somatic Alu elements.

This approach uses hybrid selection with probes to Alu elements to enrich Alu -containing regions prior to NGS. DNA was sequenced from several brain regions, particularly the hippocampus, which has been reported to have higher levels of somatic L1 retrotransposition [ 64 ].

Using very deep sequencing, this study found evidence of thousands of individual Alu insertions. These studies were unable to quantify the relative insertion rate per cell. Each insertion is also extremely low in sequence coverage in these studies as if each one is specific to only a small proportion of cells within the tissue, consistent with insertion very late in the differentiation process.

However, with so many of these rare insertions, these data suggest that there is a significant amount of genetic mosaicism created by the activity of mobile elements. A feature of note for the somatic Alu insertions was that there were apparently a large number of insertions of the older S subfamilies. However, this study needs to be further substantiated, as the NGS reads are short and may have led to some misassignments or misinterpretations. Alu elements are extremely prevalent within RNA molecules, owing to their preference for gene-rich regions Figure 4 [ 1 ].

Zietkiewicz, and E. Taken altogether, these data showed that the million Alu elements present in the human genome could act as a very large reservoir of alternative exons. Alu sequences in the coding regions of mRNA: a source of protein variability. The use of these polymorphisms in a worldwide survey of human populations has confirmed the African origin of modern humans Batzer et al. Alu elements have only relatively weak, cryptic splice sites upon insertion. External link.

Alu insertion

Alu insertion. Navigation menu

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An Alu element is a short stretch of DNA originally characterized by the action of the Arthrobacter luteus Alu restriction endonuclease. Alu elements are highly conserved within primate genomes and originated in the genome of an ancestor of Supraprimates. Alu insertions have been implicated in several inherited human diseases and in various forms of cancer.

The study of Alu elements has also been important in elucidating human population genetics and the evolution of primates , including the evolution of humans. The Alu family is a family of repetitive elements in primate genomes, including the human genome. Expressed another way, it is believed modern Alu elements emerged from a head to tail fusion of two distinct FAMs fossil antique monomers over mya, hence its dimeric structure of two similar, but distinct monomers left and right arms joined by an A-rich linker.

There are over one million Alu elements interspersed throughout the human genome, and it is estimated that about However, less than 0. Dating back 65 million years, the AluJ lineage is the oldest and least active in the human genome. The younger AluS lineage is about 30 million years old and still contains some active elements.

Finally, the AluY elements are the youngest of the three and have the greatest disposition to move along the human genome. The functional retinoic acid response element hexamer sites [12] are in upper case and overlap the internal transcriptional promoter. Alu elements are responsible for regulation of tissue-specific genes. They are also involved in the transcription of nearby genes and can sometimes change the way a gene is expressed.

Alu elements do not encode for protein products. Alu elements replication and mobilization begins by interactions with signal recognition particles SRPs , which aid newly translated proteins reach final destinations. Alu elements in primates form a fossil record that is relatively easy to decipher because Alu elements insertion events have a characteristic signature that is both easy to read and faithfully recorded in the genome from generation to generation.

Therefore, individuals with an element likely descended from an ancestor with one—and vice versa, for those without.

In genetics, the presence or lack thereof of a recently inserted Alu element may be a good property to consider when studying human evolution. Alu elements have been proposed to affect gene expression and been found to contain functional promoter regions for steroid hormone receptors. The Alu insertions that can be detrimental to the human body are inserted into coding regions exons or into mRNA after the process of splicing.

Alu insertions are sometimes disruptive and can result in inherited disorders. The first report of Alu -mediated recombination causing a prevalent inherited predisposition to cancer was a report about hereditary nonpolyposis colorectal cancer. Thus due to their major heritable damage it is important to understand the causes that affect their transpositional activity.

The following human diseases have been linked with Alu insertions: [23] [28]. And the following diseases have been associated with single-nucleotide DNA variations in Alu elements affecting transcription levels: [29]. From Wikipedia, the free encyclopedia. Retrieved 26 June Trends in Genetics. September Nucleic Acids Research.

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R; Futreal, P. A; Wiseman, R. W; Iglehart, J. D; Deininger, P. L; McDonnell, D. P The Journal of Biological Chemistry. W Molecular Genetics and Metabolism. Nature Reviews Genetics.

J; Jiang, P; Kenkel, E. J; Stroik, M. R; Sato, S; Davidson, B. L; Xing, Y Bibcode : PNAS.. Nature Medicine. BMC Genomics. Genome Biology. Sports Medicine. S; von Dornum, M; Mollon, J. D; Hunt, D. M Genetics : repeated sequence. Alu sequence MIR. Pathogenicity island symbiosis island. Hidden categories: All articles lacking reliable references Articles lacking reliable references from December Pages with DOIs inactive as of August All articles with unsourced statements Articles with unsourced statements from December CS1 errors: missing periodical.

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Alu insertion

Alu insertion

Alu insertion