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.
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Introduction to mammalian transposable elements
Transposable elements (TEs) occupy almost half, 46%, of the human genome, making the TE content of our genome one of the highest among mammals, second only to the opossum genome with a reported TE content of 52% [1, 2]. The total representation of TE-related sequences in the human genome is probably even higher, as many of the sequences of the most ancient TEs have deteriorated beyond recognition [3]. The human genome contains two major classes of TEs, DNA and RNA transposons, defined by the type of molecule used as an intermediate in their mobilization.
DNA TEs encode a transposase that re-enters the nucleus to specifically recognize transposon sequences in chromosomal DNA. The transposase excises these sequences from their genomic location and inserts them into a new genomic site (reviewed in [4]); this is also referred to as 'cut and paste' transposition. Human DNA TE activity subsided over 37 million years ago [5]; as a result, DNA TEs no longer contribute significantly to the ongoing mutagenesis in humans.
Retrotransposons or retroelements make use of an RNA-mediated transposition process. Retroelements are subdivided into two major groups: those containing long-terminal repeats, LTR retroelements, and all others, lumped into the category of non-LTR retroelements. Although inactive in humans for millions of years, the best known LTR retrotransposons, the endogenous retroviruses, make up approximately 8% of the human genome [1]. This contrasts with rodent genomes, in which LTR elements continue to contribute a high proportion of the germline TE-associated mutations (reviewed in [6]).
Non-LTR retrotransposons include autonomous and non-autonomous members. The autonomous long interspersed element-1 (LINE-1 or L1), and its non-autonomous partners, such as 'SINER, VNTR, and Alu' (SVA) and the short interspersed element (SINE) Alu, are the only mobile elements with clear evidence of current retrotrans-positional activity in the human genome [7] and will therefore be the primary focus of this article.
The human L1 is about 6 kb long and encodes two open reading frames, ORF1 and ORF2, which are both required for L1 retrotransposition (Figure 1a) [8]. ORF2 encodes endonuclease and reverse transcriptase activities that are crucial for the insertion mechanism [8, 9]. SINEs and SVA elements do not encode any proteins [10], instead they depend on the presence of the functional L1s, and they are therefore often referred to as L1 parasites [11]. In contrast to L1, Alu elements require only ORF2 of L1 for their mobilization [11, 12]. Alu elements are transcribed by RNA polymerase III and encode a variable length adenosine-rich region at their 3' end, a critical feature for retro-transposition [10]. SVA is a composite element containing a complex sequence composed of a (CCCTCT)n hexamer repeat region, an Alu-derived region, a variable number tandem repeat (VNTR) region and a retroviral-derived sequence (Figure 1a) [13]. The requirements for SVA mobilization are still poorly understood [13, TE activity can generate a wide-spectrum of genomic mutations, ranging from point mutations to gross rearrangements with gain of genomic information, as well as interference with normal gene processing and expression after insertion. These mutations contribute to idiopathic human disease. Because of the intimate relationship between L1 activity and multiple cellular processes, it is likely that people with genetic backgrounds that produce defects in any of the pathways influencing the L1 lifecycle are more vulnerable to insult from TEs. Thus, to evaluate the impact of these elements on the stability of the human genome and human disease, it is crucial to take into account their cumulative activity in a specific genetic background as well as the potential modulating effects of the extracellular environment. The increasing ease of sequencing genomes is likely to help clarify the extent of the contribution of mobile elements to genetic instability in many human diseases. This information is critical in determining the full spectrum of mutations contributing to human disease. However, the full impact of these ubiquitous, high-copy-number elements on the biology of the cell may remain elusive for some time.Conclusions
Abbreviations
- AML:
-
acute myelogenous leukemia
- BRCA1 :
-
breast cancer-1 gene
- CGH:
-
comparative genomic hybridization
- DSB:
-
double-strand break
- LINE-1:
-
L1, long interspersed element-1
- LTR:
-
long terminal repeat
- NAHR:
-
non-allelic homologous recombination
- NHEJ:
-
non-homologous end joining
- ORF:
-
open reading frame
- SINE:
-
short interspersed element
- SVA:
-
SINE-R, VNTR, and Alu element
- TE:
-
transposable element.
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Acknowledgements
This article was made possible by grants P20RR020152 (PLD, VPB, and AMR-E), R01GM45668 (PLD), and R01GM079709A (AMR-E) from the National Institutes of Health (NIH) and an EPSCOR grant from the National Science Foundation (PLD). VPB is supported by NIH/NIA grant 5K01AG030074 and an Ellison Medical Foundation New Scholar in Aging award (AG-NS-0447-08). The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for Research Resources or the NIH. Competitive Advantage Funds (2006) from the Louisiana Cancer Research Consortium (LCRC) were also awarded to AMR-E.
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Belancio, V.P., Deininger, P.L. & Roy-Engel, A.M. LINE dancing in the human genome: transposable elements and disease. Genome Med 1, 97 (2009). https://doi.org/10.1186/gm97
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DOI: https://doi.org/10.1186/gm97