Human Genetics

, Volume 127, Issue 2, pp 135–154 | Cite as

Transposable elements in disease-associated cryptic exons

  • Igor Vorechovsky
Original Investigation


Transposable elements (TEs) make up a half of the human genome, but the extent of their contribution to cryptic exon activation that results in genetic disease is unknown. Here, a comprehensive survey of 78 mutation-induced cryptic exons previously identified in 51 disease genes revealed the presence of TEs in 40 cases (51%). Most TE-containing exons were derived from short interspersed nuclear elements (SINEs), with Alus and mammalian interspersed repeats (MIRs) covering >18 and >16% of the exonized sequences, respectively. The majority of SINE-derived cryptic exons had splice sites at the same positions of the Alu/MIR consensus as existing SINE exons and their inclusion in the mRNA was facilitated by phylogenetically conserved changes that improved both traditional and auxiliary splicing signals, thus marking intronic TEs amenable for pathogenic exonization. The overrepresentation of MIRs among TE exons is likely to result from their high average exon inclusion levels, which reflect their strong splice sites, a lack of splicing silencers and a high density of enhancers, particularly (G)AA(G) motifs. These elements were markedly depleted in antisense Alu exons, had the most prominent position on the exon–intron gradient scale and are proposed to promote exon definition through enhanced tertiary RNA interactions involving unpaired (di)adenosines. The identification of common mechanisms by which the most dynamic parts of the genome contribute both to new exon creation and genetic disease will facilitate detection of intronic mutations and the development of computational tools that predict TE hot-spots of cryptic exon activation.


Splice Site Exon Inclusion Cryptic Exon Branch Point Sequence Exon Definition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Transposable element


Mammalian interspersed repeat


Short interspersed nuclear element


Long interspersed nuclear element


Exonic splicing enhancer


Exonic splicing silencer


Branch point sequence


Polypyrimidine tract






Maximum entropy


Intervening sequence or intron


Neighborhood inference


Exon identity element


Intron identity element



I wish to thank to I. Eperon and F. Major for useful discussions. This work was supported by a grant (47-2008) from the Juvenile Diabetes Research Foundation International.

Supplementary material

439_2009_752_MOESM1_ESM.pdf (4.1 mb)
Supplementary material (PDF 4171 kb)


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© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Division of Human GeneticsUniversity of Southampton School of MedicineSouthamptonUK

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