in this article we will use the term variable number tandem repeat ( vntr ) to encompass both microsatellites and minisatellites however not all tandem repeat domains are polymorphic in repeat copy number .
sva elements only represent 0.13% of the genome , representing ~2700 elements , constituting the youngest of the retrotransposable elements in the human genome and are hominid specific .
they consist of a hexamer repeat ( ccctct ) , an alu - like sequence , a gc - rich vntr , a sine and a poly a - tail as with other retrotransposons much effort has been expended on the retrotransposition event itself giving rise to disease .
this has resulted in the identification of at least 8 well characterized diseases in which the retrotransposition event has caused the disease , in the majority of cases by affecting alternative slicing
our hypothesis is that the sva element could impart a hominid specific regulatory twist on regulation of the gene in which they have inserted ( assuming that insertion is not in an exon or destroys intron / exon boundaries etc ) . in the promoter they would act as classical mediators of gene expression .
analysis of human genome release 19 ( hg19 ) indicates that of the 2676 sva elements in the human genome , 433 are present within 10 kb 5 of the main transcriptional start site 1 .
sva elements are functional in conventional reporter gene assay both in vitro ( cell line ) and in vivo ( chick embryo ) 2 .
sva elements are polymorphic , most clearly via vntr domains ( flanking and internal ) a. we have previously shown in other genes ( as have many others ) that vntrs are both polymorphic biomarkers associated with disorders and transcriptional regulatory domains in vivo and in vitro b. vntrs are common regulatory domains in viruses ; i. they in part control hsv-1 virus latency in dorsal root ganglia ( via a similar cccctc repeat to that found in the flanking sequence of the sva element ) ii .
sva elements can be associated with active chromatin adjacent to : a. positive affymetrix probe arrays in the human cns b. encode active histone marks 4 .
sva elements have the potential to form structures which may be strong modulators of genome structure / function : a. potential g4 quadruplex b. strong cpg component approaching the classical requirements to be defined as cpg islands , which is consistent with their differential methylation in tumors
in our analysis of the fus sva element we generated reporter gene constructs that were analyzed in both the neuroblastoma cell line , sk - n - as and a chicken embryo model the distance of the sva element from its site of action on a specific promoter or transcriptional start site can be quite large .
it has been demonstrated by us and others when attempting to reproduce endogenous gene expression in transgenic models , that regulatory domains utilized by a locus can be 100kb+ away from the gene itself .
our own studies on the endogenous expression of the neuropeptide , substance p encoded by the tac1 gene demonstrated that although the gene itself from 5 to 3 utr was 8 kb , we required a dna fragment of 350 kb to reproduce the appropriate expression patterns the recent evolution of sva elements has imposed restricted sequence variation in each of the sva subclasses ; this may allow a concerted response to challenge by groups of sva elements with similar primary sequence based on sequence specific dna binding proteins . in this manner
it might be possible for sva elements containing similar primary sequence such as is present in the hexamer repeat or central vntrs to bind similar transcription factors based on shared consensus dna binding domains .
thus alterations in active transcription factor complement in the cell might modulate several sva elements by the same signal transduction pathways .
the frequency of sva element retrotransposition is estimated to be 1:916 births which would correspond to 7  10
our recent work suggests that sva elements can in part modulate genome function via their action as a transcriptional or epigenetic modulator .
polymorphism in the vntrs within these retrotransposons demonstrates a mechanism not only for differential regulatory function associated with genotype but a way to rapidly integrate polymorphism in the sva element as a potential biomarker for disease association without the requirement for retrotransposition .
 endogenous mobile genetic elements can give rise to de novo germline or somatic mutations that can have dramatic consequences for genome regulation both local and possibly more globally based on the site of integration . 
 however if we consider them as  normal genetic  components of the reference genome then they are likely to modify local chromatin structure which would have an effect on gene regulation irrelevant of their ability to further transpose . as such 
 they can be treated as any other domain involved in a gene  environment interaction . 
 similarly their evolutionary appearance in the reference genome would supply a driver for species specific responses / traits . 
 our recent data would suggest the hominid specific subset of retrotransposons , sine - vntr - alu ( sva ) , can function as transcriptional regulatory domains both in vivo and in vitro when analyzed in reporter gene constructs . 
 of particular interest in the sva element , were the variable number tandem repeat ( vntr ) domains which as their name suggests can be polymorphic . 
 we and others have previously shown that vntrs can be both differential regulators and biomarkers of disease based on the genotype of the repeat . here , we provide an overview of why polymorphism in the sva elements , in particular the vntrs , could alter gene expression patterns that could be mechanistically associated with different traits in evolution or disease progression in humans . 