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 . 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 . 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 ) . 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   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 . some of alu elements amplified and spread in genic regions contributing to human genetic diversity . 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 . alu elements emerged in the primate genome , approximately 65 million years ago ( mya ) . 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 , which is much higher than an averaged amplification rate , one insertion every 21 new births during the past 60 million years . major alu lineages are aluj , alus , and aluy which are distinguished from each other , based on 18 diagnostic nucleotides on their sequences . 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 . 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 . 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 . 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 . it follows the concept of the master gene model but explains aberrant amplification of alu elements . 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 . 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 . 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 . through the de novo insertion event , in addition , they could disrupt genes by inserting into their exonic regions ( fig . 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 . the alternative splicing generates alu exonization or / and intron retention in respective transcripts , which could disrupt or modify the function of the genes ( fig . 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 . ornithine aminotransferase ( oat ) gene encodes mitochondrial enzyme ornithine -aminotransferase , which converts ornithine to glutamate . 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 . 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 . 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 . on the other hand , the intronic alu elements could lead to deletion of nascent exons , which is called exon skipping . ganguly et al .   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 . 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 , an example of alu polyadenylation site affecting gene function is calcium - sensing receptor ( casr ) which is a member of g protein - coupled receptor . 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 . 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 ) . 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 . 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 . 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 . after the enzyme complex binds to either side of dsb , it functions as a docking site for other nhej enzymes such as dna ligase . 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 . 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 . 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 . there are many alu elements which are closely related to human diseases ( table 1 ) . alstrm 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 . most mutations causing alstrm syndrome occur in exons 8 , 10 , and 16 of alms1 . aluya5 element exists in the exon 16 of alms1 , which disrupts open reading frame , leading to frameshift mutation . pulmonary arterial hypertension ( pah ) exons 13 encoding an extracellular domain were deleted by the recombination between two different aluy elements in pah patients . in another pah patient , the recombination took place between the alu element in the intron 9 and a unique sequence in the intron 10 of the gene . 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 ) . 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 . 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 .
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 .