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Genomics Inform > Volume 14(3); 2016 > Article
Kim, Cho, Han, and Lee: Structural Variation of Alu Element and Human Disease

Abstract

Transposable elements are one of major sources to cause genomic instability through various mechanisms including de novo insertion, insertion-mediated genomic deletion, and recombination-associated genomic deletion. Among them is Alu element which is the most abundant element, composing ~10% of the human genome. The element emerged in the primate genome 65 million years ago and has since propagated successfully in the human and non-human primate genomes. Alu element is a non-autonomous retrotransposon and therefore retrotransposed using L1-enzyme machinery. The 'master gene' model has been generally accepted to explain Alu element amplification in primate genomes. According to the model, different subfamilies of Alu elements are created by mutations on the master gene and most Alu elements are amplified from the hyperactive master genes. Alu element is frequently involved in genomic rearrangements in the human genome due to its abundance and sequence identity between them. The genomic rearrangements caused by Alu elements could lead to genetic disorders such as hereditary disease, blood disorder, and neurological disorder. In fact, Alu elements are associated with approximately 0.1% of human genetic disorders. The first part of this review discusses mechanisms of Alu amplification and diversity among different Alu subfamilies. The second part discusses the particular role of Alu elements in generating genomic rearrangements as well as human genetic disorders.

Introduction

Transposable elements accounts for ~45% of the human genome. They are divided into DNA transposon and retrotransposons, according to their amplification mechanisms. DNA transposons mobilize through a "cut and paste" mechanism while retrotransposons propagate through "copy and paste" mechanism. Retrotransposon transcribes its RNA intermediate, and the RNA intermediate integrates into a new genomic region using a mechanism called target primed reverse transcription (TPRT). Endogenous retroviruses, long interspersed elements (LINEs), and short interspersed elements (SINEs) belong to retrotransposon. Alu element, one of the SINEs, is the most successful retrotransposon in primate genomes. The estimated copy number of the elements is 1.1 million and it is currently retrotranspositionally active in the human genome [1]. The full-length Alu element is 300 bp long and has a dimeric structure. Both of the left and right monomers were derived from 7SL RNA gene and thus they share a high level of sequence identity. Alu elements have an internal RNA polymerase III promoter (A and B boxes) in the 5' region and a poly (A) tail in the 3' end. The transcription of Alu element is initiated by internal RNA polymerase III promoter and terminated at a nearby genomic location having TTTT terminator because the element lacks a transcription terminator (Fig. 1). Alu elements use L1 enzyme machinery for their mobilization. L1 provides Alu elements with endonuclease and reverse transcriptase. L1 endonuclease recognizes consensus oligomer (5'-TTTT/AA-3') and cleaves the genomic region. A-rich region of Alu elements binds to the released consensus site and the elements are reverse-transcribed by L1 reverse transcriptase. The second strand of the Alu element is synthesized by host DNA polymerase using the first strand of the Alu element as a DNA template. The newly inserted Alu element has 7 to 20 bp direct repeats on both sides of the element, termed target site duplications (TSDs) [2,3].
Alu elements are divided into several subfamilies which are determined based on diagnostic nucleotides. During the past 60 million years of the primate genome evolution, old Alu subfamilies became retrotranspositionally dormant while new Alu subfamilies emerged and expanded, leading to the increased number of different Alu subfamilies. The generally accepted canonical mechanism for Alu amplification is master gene model [4] but it could not explain the recent expansion of AluYb subfamily in the human genome: AluYb subfamily was retrotranspositionally dormant for the past 20 million years but it retrieved the ability to retrotranspose and rapidly expanded in the human genome within the past a few million years, which led to a new model of Alu amplification, stealth model, to explain the aberrant amplification of AluYb subfamily [5].
Some of Alu elements amplified and spread in genic regions contributing to human genetic diversity [2,4,6]. Alu element is able to disrupt gene function either by inserting into exonic regions or causing alternative splicing of the genes. In addition, they could cause genomic deletions through insertion-mediated deletion or recombination-associated deletion. The homologous recombination (HR) between Alu elements has associated with genomic duplications, genomic conversion as well as genomic deletions in the human genome. The genomic changes could affect gene expression and lead to abnormal proteins resulting in genetic diseases [7,8,9,10,11].

Amplification and Diversity of Alu Elements

Alu elements emerged in the primate genome, approximately 65 million years ago (mya). Since then, they have successfully amplified and diversified in primate genomes. However, their amplification rate has been fluctuated over the time. The majority of Alu elements were inserted in the primate genome ~40 mya and one new Alu insertion occurred in every birth at the time of the most successful amplification [1], which is much higher than an averaged amplification rate, one insertion every 21 new births during the past 60 million years [10,12]. Alu elements are divided into different subfamilies according to key diagnostic nucleotides on them. Therefore, Alu elements sharing the diagnostic nucleotides are grouped into the same subfamily. Major Alu lineages are AluJ, AluS, and AluY which are distinguished from each other, based on 18 diagnostic nucleotides on their sequences [6]. Among the three major lineages, AluY lineage is the youngest and AluJ lineage is the oldest. During the long time, AluJ subfamilies have accumulated more random mutations on them and thus their mutation rates are much higher than the younger subfamilies [2].
There are four different models suggested for Alu expansion. The first model is master gene model which well explains how new Alu subfamily is created. It suggests that new Alu subfamily is generated by point mutation(s) of retrotranspositionally hyperactive Alu element. During the primate evolution, the master genes accumulated diagnostic nucleotide changes, leading to different subfamilies at different times. Thus, all Alu subfamilies were derived from a series of sequential master genes which accumulated diagnostic base changes, and all members of an Alu subfamily were propagated from a few master genes representing the subfamily. Because Alu element contains a high content of CpG dinucleotide, point mutation frequently occurs on them. In general, the master genes produce a high number of its progenies (Fig. 2A) [4,6]. However, some Alu elements have low retrotranspositional activity and their amplification is not well explained by the master gene model. Unlike the master gene model, transposon model suggests that all elements have a similar capability of generating new copies (Fig. 2C). The third model is intermediate model which is literally the intermediate of master gene and transposon models. The third model suggests that there are much more than a few hyperactive Alu elements (Fig. 2B) [4,13]. Recently, Han et al. [5] introduced the forth model called stealth model. It follows the concept of the master gene model but explains aberrant amplification of Alu elements. Hyperactive Alu elements get mutated and lose its retrotranspositional capability relatively quickly by selection. In contrast, Alu elements with a low retrotransposition activity are able to retain its retrotransposition activity and produce the short-lived hyperactive Alu elements over an extended period of time. It was introduced to explain the recent remarkable expansion of old Alu elements, AluYb lineage, in the human genome (Fig. 2D) [5].

Alu Insertion

Alu element is a primate-specific retrotransposon and has played an important role in primate genomic diversity. During the past six million years, 5,530 Alu elements newly inserted into the human genome [14,15]. Most of them were propagated through classical insertion, in that, Alu elements are inserted into the human genome using TPRT mechanism. The hallmark of the classical Alu insertions is TSDs flanking both ends of an Alu element. However, Alu elements integrated through non-classical insertions are deficient of TSDs but have instead 1 to 7 bp microhomologous sequences on their pre-insertion site. When chromosomal double strand break (DSB) happens, Alu element is able to integrate into the genomic region through the HR between the elements and the chromosomal break site [14,16]. Through the de novo insertion event, Alu elements have modified the human genome in a species-specific manner. In addition, they could disrupt genes by inserting into their exonic regions (Fig. 3A). Alu elements locating in the intronic region could also regulate gene function by promoting alternative splicing of the genes; the elements have multiple splice donor/accept sites (Fig. 3D). The alternative splicing generates Alu exonization or/and intron retention in respective transcripts, which could disrupt or modify the function of the genes (Fig. 3C and 3E) [8,17]. As mentioned above, Alu elements have a relatively high point mutation rate and can obtain splicing sites by the point mutations after the insertion. The Alu elements provide cryptic splicing sites and recognize these sites by splicing factors (Fig. 3C and 3D). Ornithine aminotransferase (OAT) gene encodes mitochondrial enzyme ornithine δ-aminotransferase, which converts ornithine to glutamate. The deficiency of this enzyme results in autosomal recessive eye disease. The third intron of OAT gene contains the right monomer of Alu element which is residues, 279 to 138, of antisense Alu element. The antisense Alu monomer provides cryptic splicing sites by the point mutation, cytosine to guanine. The cryptic splicing site causes an alternative splicing of the gene, disrupting the function of OAT gene. Consequently, patients suffer from gyrate atrophy of the choroid and retina by producing abnormal proteins [18]. Alu elements can influence gene function through RNA editing which is a post-transcriptional alteration. Adenosine deamination by an enzyme, adenosine deaminase acting on RNA (ADAR) results in inosine, which in turn interpreted as guanosine by translation or spliceosome machinery. Adenosine to inosine (A-to-I) is the most frequent RNA editing in humans. A-to-I RNA editing occurs within a long duplex of RNA sequence because ADAR works only on double strand RNA structures. Due to the dimeric structure, Alu element in RNA sequences forms the stem loop structure, leading to A-to-I RNA editing [19]. In addition, two Alu elements located in close to each other can make a stem loop structure, which result in A-to-I editing and the edited Alu element could subsequently bring out novel alternative splicing site [19,20,21,22,23]. On the other hand, the intronic Alu elements could lead to deletion of nascent exons, which is called exon skipping. It therefore disrupts open reading frames of the human genes (Fig. 3A). Ganguly et al. [24] have reported that intronic insertion of AluYb9 causes exon skipping and leads to hemophilia A disease. Hemophilia A is an X-linked disorder caused by exon skipping of exon 19 in Factor VIII gene. AluYb9 locates in the intron 18 of the gene and causes the skipping of the exon19 from the gene transcript.
Alu elements could regulate gene function by providing canonical polyadenylation signal, AATAAA (Fig. 3B) [25,26]. Alu elements contain three potential polyadenylation sites and two of them are active in the human genome. One of the previous studies on Alu elements has reported that ~10,000 Alu elements are identified within the 3' untranslated region (UTR) of protein coding human genes. Among them, 107 Alu elements retain active polyadenylation site. Interestingly, 99% of polyadenylation-active Alu elements locate in the forward direction although the elements exist in the 3' UTR of human genes randomly, regarding the insertion direction. In addition, old Alu subfamily has more active polyadenylation sites than younger subfamilies [27,28]. An example of Alu polyadenylation site affecting gene function is calcium-sensing receptor (CaSR) which is a member of G protein-coupled receptor. The gene involves in regulating extracellular level of calcium ion. Alu element locates in the exon 7 of the gene and pre-terminates transcripts of CaSR by providing a stop codon signal. Patients having the missense mutations show symptoms of familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism [29,30,31].

Recombination between Alu Elements

A total of 515 Alu-mediated deletion events have been identified in the human genome. The deletion events occurred either through Alu insertion-mediated deletions (AIMD) or Alu recombination-mediated deletions (ARMD): 24 AIMDs and 492 ARMDs. AIMDs and ARMDs have deleted 11,206 and 396,420 base pairs of the human genome, respectively, after the divergence of the human and chimpanzee lineages (~6 mya) [14,32,33,34]. Alu element has been frequently involved in the genomic recombination because of its two characteristics: a high level of sequence identity among them and its abundance in the human genome. Among the 492 ARMD events, 197 ARMD events were occurred by the recombination between Alu elements belonging to different subfamilies. Although AluJ subfamily is more abundant than AluY subfamily in the human genome, AluY subfamily is more associated with ARMD events because AluY subfamily retains a higher sequence identity among its members than AluJ subfamily does. Alu element accumulates random mutations over time so that older Alu elements have more mutations than younger elements [33].
DNA DSB is one of the most dangerous events of DNA damage. In the human genome, it could be repaired by retrotransposons using two different mechanisms: nonhomologous end-joining mediated deletion (NHEJ) and HR [34]. NHEJ does not need a homologous template for repair of DSBs while HR requires sequence homologies on either side of the break for the repair (Fig. 4A). DSB repair by NHEJ mechanism is initiated by an enzyme complex including Ku70/80 heterodimer. After the enzyme complex binds to either side of DSB, it functions as a docking site for other NHEJ enzymes such as DNA ligase [35,36]. Nonallelic homologous recombination (NAHR) is one of HRs. It occurs between two DNA sequences which are not alleles but share a high sequence similarity from one another. Major NAHR hotspots for several human diseases locate at repeat elements including Alu element. During meiosis, Alu elements can misalign and the subsequent crossover could lead to genetic rearrangements of duplication, deletion, and translocation [37,38]. NAHR is proceeded either by interchromosomal recombination, in which occurs between different chromosomes or intrachromosomal recombination, in which recombination occurs via crossing over within the same chromosome. Interchromosomal recombination results in a deletion or duplication depending the orientation of the DNA sequences. Intrachromosomal recombination results in a deletion or inversion (Fig. 4B).

Genetic Disorder Caused by Alu Elements

During the past 6 million years, Alu elements have modified the human genome in a species-specific manner and also caused human disease through de novo insertion or the recombination between them. Genomic rearrangements induced by Alu insertion account for approximately 0.1% of human diseases and genomic deletions by ARMD are responsible for approximately 0.3% of human genetic disorders [10,32,33]. There are many Alu elements which are closely related to human diseases (Table 1) [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Alström syndrome is a rare genetic disease which is caused by Alu insertion in ALMS1 gene. ALMS1 is composed of 23 exons and encodes centrosome and basal body-associated protein which plays an important role in microtubule organization, especially form and maintain cilia. The protein is associated with insulin resistance, hypogonadism, and heart disease. Therefore, Alström syndrome has several symptoms such as blindness and obesity. Most mutations causing Alström syndrome occur in exons 8, 10, and 16 of ALMS1 [54]. The mutation of ALMS1 caused by Alu element was first discovered in 2013. AluYa5 element exists in the exon 16 of ALMS1, which disrupts open reading frame, leading to frameshift mutation [40]. Pulmonary arterial hypertension (PAH) is also caused by Alu element, which locates in BMPR2 gene. BMPR2 locates on chromosome 2 and has 13 exons. Exons 1–3 encoding an extracellular domain were deleted by the recombination between two different AluY elements in PAH patients. In another PAH patient, the exon 10 of the gene was deleted by AluSx involved-nonhomologous recombination. The recombination took place between the Alu element in the intron 9 and a unique sequence in the intron 10 of the gene [41]. Fork stalling and template switching/microhomology-mediated break-induced replication model (FoSTeS/MMBIR) has been often proposed in cases where the complexity of the genomic rearrangement is not able to be explained by using classic recombination mechanisms. Recently, Alu element was reported to be associated with a human genomic deletion responsible for Waardenburg syndrome type 4 (WS4). WS4 is a rare neural crest disorder. Three Alu elements are involved in the large deletion within SOX10 regulatory sequences in patients with WS4. The deletion could be explained by a two-step FoSTeS/MMBIR mechanism mediated via the 4-bp and 13-bp microhomology found at the Alu1/Alu3 and Alu3/Alu2 breakpoints, respectively. The deletion of SOX10 regulatory sequences was also identified in patients with Hirschsprung disease and peripheral demyelinating neuropathy–central dysmeylinating leukodystrophy [50].

Conclusion

In this review, we discuss the amplification of Alu elements and its impact on human genomic rearrangements and human disease. Four different models: master gene, intermediate, transposon, and stealth models have been suggested to explain the Alu amplification during primate evolution. Among them, master gene model is generally accepted to explain the diversity of Alu subfamilies. Since the divergence of human and chimpanzee, Alu elements have caused various genetic/genomic rearrangements in the human genome through human-specific insertion, deletion, and recombination. Alu elements could repair DSBs in the human genome using microhomology between the element and the break point, leading to de novo Alu insertion. In spite of the positive effect, Alu element is considered to be one of major factors to cause human genomic instability because many Alu elements are associated with various human diseases. The recombination between Alu elements has deleted human genic regions and subsequently disrupted gene function, leading to human diseases. The abundance of Alu elements in the human genome and a high level of sequence identity among them predispose them to be a tremendous and unpredictable factor to cause genomic instability and the related human diseases. Characterization of Alu amplification in the human genome and elucidating the mechanisms which Alu elements could utilize to cause human diseases may help us understand Alu-associated pathogenesis and predict Alu-associated human diseases.

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Fig. 1

Structural schema of Alu elements. A full-length Alu element is 300 bp in length and composed of left monomer, right monomer, and poly(A) tail. A and B boxes in the left monomer contain RNA polymerase III promoter binding sites. Alu inserts in the host genome using target site duplication (TSD) of flanking region.

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Fig. 2

Mechanisms of Alu amplification. This figure depicts four different mechanisms for Alu amplification. (A) Master gene model is a typical mechanism. All members of the same Alu subfamily are derived from one or a few transpositionally active Alu elements. When the active Alu element mutates but remains the transposition activity, it will produce a new Alu subfamily. (B) Intermediate model is literally an intermediate form of master gene and transposon models. More than a few active Alu elements exist in host genome and each of them actively produces its progenies. (C) Transposon model suggests that all Alu elements including mutated elements have transposition activities. (D) Stealth driver model suggests that old Alu element which stayed transcriptionally dormant for the extended period can produce a new Alu subfamily by retrieving a high transposition activity. Green and blue boxes indicate active and inactive Alu elements, respectively. X indicates a mutation and the mutated Alu elements represent different subfamilies.

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Fig. 3

Impact of Alu insertion on alternative transcription. Alu element inserting in the genic region could alter the expression level of the respective gene. (A) Alu insertion in the exonic region. Exons could be skipped and deleted, called exon skipping. (B) Alu insertion in the genic region, Alu element is able to provide a polyadenylation signal. Thus, Alu element could induce the premature termination of gene transcription. (C–E) Alu element is also able to provide cryptic splicing sites, leading to alternative gene transcripts. Blue and red boxes indicate exon and Alu element. Arrow shows promoter and the dash line indicates alternative splicing form.

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Fig. 4

Mechanisms of Alu recombination-mediated deletions. (A) Nonhomologous end-joining mediated deletion mechanism. After DNA double strand breaks, non-homologous templates are ligated by Alu element. (B) Nonallelic homologous recombination mechanism, interchromosomal recombination occurs between two different Alu elements which locate on different chromosomes and mediates genomic duplication or deletion. Intrachromosomal recombination occurs between two different Alu elements which locate on the same chromosome and mediates genomic deletion. Green and yellow boxes represent Alu elements. The red dot line indicates homologous sequences.

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Table 1.

A list of Alu-mediated genetic disorder in recent studies

Gene Position Subfamily Mechanism Disease Reference
ACE Chr 17 AluYa5 Insertion Alzheimer's disease [39]
ALMS1 Chr 2 AluYa5 Insertion Alström syndrome [40]
BMPR2 Chr 2 AluY ARMD_NAHR Pulmonary arterial hypertension [41]
AluS NHEJ
CDSN Chr 6 AluS ARMD_NHEJ Peeling skin disease [42]
COL4A5 Chr X AluY Insertion Alport syndrome [43]
FA Chr X AluY ARMD_NAHR Fanconi anemia [44]
GBA1 Chr 1 AluSx ARMD_NAHR Gaucher disease [45]
GGA Chr 17 AluS ARMD_NAHR Pomp disease [46]
GLA Chr X Alu Insertion mediated deletion Fabry disease [47]
MUTYH Chr 1 AluYb8 Insertion Breast cancer/gastric cancer [48]
PMP22 Chr 17 AluY/AluSc ARMD_NAHR Charcot-Marie-Tooth disease [49]
SOX10 Chr 22 AluS FoSTes/MMBIR Waardenburg syndrome type 4 [50]
SPAST Chr 2 AluY/AluS FoSTes/MMBIR Hereditary spastic paraplegia [51]
Chr 2 AluY
SPG11 Chr 15 AluY/AluS ARMD_NAHR Spastic paraplegias [52]
Chr 15 AluS
STK11 Chr 19 AluY ARMD_NAHR Peutz-Jeghers syndrome [53]

ARMD, Alu recombination-mediated deletions; NAHR, nonallelic homologous recombination; NHEJ, nonhomologous end-joining mediated deletion; FoSTeS/MMBIR, fork stalling and template switching/microhomology-mediated break-induced replication.

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