LINE dancing in the human genome: transposable elements and disease

Abstract

Transposable elements (TEs) have been consistently underestimated in their contribution to genetic instability and human disease. TEs can cause human disease by creating insertional mutations in genes, and also contributing to genetic instability through non-allelic homologous recombination and introduction of sequences that evolve into various cis-acting signals that alter gene expression. Other outcomes of TE activity, such as their potential to cause DNA double-strand breaks or to modulate the epigenetic state of chromosomes, are less fully characterized. The currently active human transposable elements are members of the non-LTR retroelement families, LINE-1, Alu (SINE), and SVA. The impact of germline insertional mutagenesis by TEs is well established, whereas the rate of post-insertional TE-mediated germline mutations and all forms of somatic mutations remain less well quantified. The number of human diseases discovered to be associated with non-allelic homologous recombination between TEs, and particularly between Alu elements, is growing at an unprecedented rate. Improvement in the technology for detection of such events, as well as the mounting interest in the research and medical communities in resolving the underlying causes of the human diseases with unknown etiology, explain this increase. Here, we focus on the most recent advances in understanding of the impact of the active human TEs on the stability of the human genome and its relevance to human disease.

Comprehensive oligonucleotide array-comparative genomic hybridization analysis: new insights into the molecular pathology of the DMD gene

“…In our study, microhomology was present in 60.6% of breakpoints being comparable to the findings of Mitsui et al (2010) 5 for the DMD gene. There were no breakpoint clustering noticed and different families of known repetitive sequences, whose role has already been demonstrated 8,9 in other diseases, were found in 48.5% of the junctions. However, this frequency does not differ significantly from that of transposable repetitive elements in the human genome (46%) 9 and could explain our findings.…”

“…There were no breakpoint clustering noticed and different families of known repetitive sequences, whose role has already been demonstrated 8,9 in other diseases, were found in 48.5% of the junctions. However, this frequency does not differ significantly from that of transposable repetitive elements in the human genome (46%) 9 and could explain our findings. Finally, no low-copy repeats with extensive homology that could participate in DNA secondary structure formation was evidenced except in the 120-kb deletion junction involving exons 48-50.…”

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

“…6 Although Alu-mediated NAHR contributes to a large variety of genetic disorders, L1-mediated NAHR and human endogenous retrovirus-mediated NAHR are very rare causes of human diseases. [9][10][11][12] Only three human diseasesglycogen storage disease type IXb, Alport syndrome-diffuse leiomyomatosis, and Ellis-van Creveld syndrome -have been reported to be caused by L1-mediated NAHR. [13][14][15] To our knowledge, this is the fourth NAHR event to cause human disease, in this case Perlman syndrome.…”

Alu elements and DNA double-strand break repair

“…7 and extensive DNA rearrangements associated with human disease. 8,9 It is estimated that about 0.3% of new human genetic diseases are caused by homeologous Alu/Alu recombination and it is likely that they also represent an important form of somatic instability, particularly in tumors. This type of secondary genomic instability has a much bigger impact on gene disruption than the initial insertion of Alu elements.…”

“…The explanations for these recurrently affected genes include the relative Alu density within the genes as well as the potential for more regional chromatin influences on recombination. 4,9 There have also been a number of suggestions that in addition to Alu/Alu Figure 1. Alu/Alu-mediated genomic deletion mechanisms.…”