Mobilizing diversity: transposable element
insertions in genetic variation and disease
Kathryn A O’Donnell1,2*, Kathleen H Burns3,4
Transposable elements (TEs) comprise a large fraction of mammalian genomes. A number of these elements are
actively jumping in our genomes today. As a consequence, these insertions provide a source of genetic variation
and, in rare cases, these events cause mutations that lead to disease. Yet, the extent to which these elements
impact their host genomes is not completely understood. This review will summarize our current understanding of
the mechanisms underlying transposon regulation and the contribution of TE insertions to genetic diversity in the
germline and in somatic cells. Finally, traditional methods and emerging technologies for identifying transposon
insertions will be considered.
In the 60 years since Barbara McClintock first discov-
ered transposable elements (TEs), it has become increas-
ingly recognized that these mobile sequences are
important components of mammalian genomes and not
merely ‘junk DNA’. We now appreciate that these ele-
ments modify gene structure and alter gene expression.
Through their mobilization, transposons reshuffle
sequences, promote ectopic rearrangements and create
novel genes. In rare cases, TE insertions which cause
mutations and lead to diseases both in humans and in
mice have also been documented. However, we are at
the very earliest stages of understanding how mobile
element insertions influence specific phenotypes and to
the extent to which they contribute to genetic diversity
and human disease.
TEs are categorized into two major classes based on
their distinct mechanisms of transposition. DNA trans-
posons, referred to as Class II elements, mobilize by a
‘cut-and-paste’ mechanism in which the transposon is
excised from a donor site before inserting into a new
genomic location. These elements are relatively inactive
in mammals, although one notable exception is a piggy-
Bac element recently identified to be active in bats (,
R Mitra and N Craig, personal communication). In
humans, DNA transposons represent a small fraction
(3%) of the genome . Retrotransposons, also known
as Class I elements, mobilize by a ‘copy-and-paste’
mechanism of transposition in which RNA intermedi-
ates are reverse transcribed and inserted into new geno-
mic locations. These include long terminal repeat (LTR)
elements such as endogenous retroviruses, and non-LTR
retrotransposons. Endogenous retroviruses are remnants
of viruses that have lost the ability to re-infect cells.
These elements, which comprise 8% of the human gen-
ome, perform reverse transcription in cytoplasmic virus-
like particles . In contrast, non-LTR retrotransposons
undergo a distinct mechanism of transposition whereby
their RNA copies undergo reverse transcription and
integration through a coupled process that occurs on
target genomic DNA in the nucleus [3-5].
Of all mobile element families, only the retrotranspo-
sons remain actively mobile in the human and primate
genomes and serve as ongoing sources of genetic varia-
tion by generating new transposon insertions. LINEs
(long interspersed nucleotide elements) represent the
most abundant autonomous retrotransposons in
humans, accounting for approximately 18% of human
DNA. Non-autonomous elements such as SINEs (short
interspersed nucleotide elements) and SVAs [hybrid
SINE-R-VNTR (variable number of tandem repeat)-Alu
elements] require LINE-1 (L1) encoded proteins for
their mobilization [2,6-9]. Together, SINEs and SVA ele-
ments occupy ~13% of the human genome.
It is both impressive and puzzling that almost half of
our genome is composed of these repeat sequences.
* Correspondence: email@example.com
1Department of Molecular Biology and Genetics, The Johns Hopkins
University School of Medicine, Baltimore, MD, USA
Full list of author information is available at the end of the article
O’Donnell and Burns Mobile DNA 2010, 1:21
© 2010 O’Donnell and Burns; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Evolutionary paradigms dictate that useless elements
and harmful TE insertions events should be selected
against, while beneficial insertions should gain a selec-
tive advantage and thus be retained. Indeed, the most
successful transposons have co-evolved with their hosts.
Most transposable element insertions are expected to
have few consequences for the host genome and, there-
fore, have little to no impact on gene function .
Rarely, transposon insertions will have a deleterious
effect on their host genome, resulting in human disease.
To date, approximately 65 disease-causing TE insertions
(due to L1, SVA and Alus) have been documented in
humans . Less frequently recognized are instances in
which transposons have made innovative contributions
to the human genome. In these cases, mobile element
sequences have been co-opted by the host genome for a
new purpose. For example, approximately 150 human
genes have been derived from mobile genetic sequences
[2,12,13]. Perhaps the best studied example of a domes-
ticated transposon is the RAG1 endonuclease, which
initiates V(D)J recombination leading to the combinator-
ial generation of antigen receptor genes. The RAG
endonucleases have been demonstrated to function as
transposases in vitro, providing strong support for the
idea that the V(D)J recombination machinery evolved
from transposable elements [14-16].
In this review, we examine mechanisms of transposon
regulation and discuss how TE insertions account for
genetic diversity in the germline and in somatic cells.
Traditional methods and recently developed techno-
logies for identifying these insertions will also be
Mechanisms of TE regulation
Expansion of mobile elements occurs when de novo
insertions are transmitted through the germline to sub-
sequent generations. Indeed, successful metazoan trans-
posons often show germline-restricted expression. As
TEs pose a significant threat to genome integrity,
uncontrolled activation of these elements would imperil
both the host and the element. It appears that, as a con-
sequence, metazoan genomes have evolved sophisticated
mechanisms to limit the mobilization of these elements.
DNA methylation is, perhaps, the most well under-
stood mechanism involved in the regulation of TEs in
the germline of plants, fungi and mammals [17-20].
Cytosine methylation silences LTR and non-LTR ele-
ments by blocking transcription of retrotransposon
RNA. Host suppression mechanisms appear to function
post-transcriptionally as well. For example, the prema-
ture termination of transcription and alternative splicing
inhibits expression of LINE-1 elements [21,22]. A family
of RNA/DNA editing enzymes with cytosine deaminase
activity known as APOBECs (apolipoprotein B mRNA
editing enzyme, catalytic polypeptide) has been found to
inhibit LINE-1, Alu, and mouse IAP (intracisternal A
particle) elements . Interestingly, suppression of ret-
rotransposons by APOBECs does not require any editing
activity, suggesting that these proteins may carry out a
novel function in addition to their ability to act as cyto-
sine deaminases. Several groups have proposed that
APOBECs may sequester retrotransposon RNA in cyto-
plasmic complexes, although additional studies are war-
ranted in order to prove this hypothesis [24,25]. RNA
interference is believed to control retrotransposition
, although the observed effect in mammalian cells
in vitro is modest [27,28].
Recently, a novel form of mobile element control has
emerged that involves small RNAs in germ cells . At
the heart of this pathway is a class of small RNAs [piwi-
interacting RNA (piRNAs)] that bind to the germline-
restricted Piwi subclass of the Argonaute family of RNA
interference effector proteins. In Drosophila, piRNAs are
enriched in sequences containing retrotransposons and
other repetitive elements. Disruption of Piwi proteins
results in the reduction in piRNA abundance and trans-
poson derepression [30,31]. A series of elegant studies
in Drosophila and zebrafish directly implicated Piwi pro-
teins in piRNA biogenesis to maintain transposon silen-
cing in the germline genome [32-34]. These findings
have led to the idea that piRNAs might immunize the
Drosophila germline against potentially sterilizing trans-
position events [32,35].
Mutations in two mouse Piwi orthologues (Mili and
Miwi2) result in the loss of TE methylation in the testes,
transposon derepression and meiotic arrest during sper-
matogenesis [36,37]. Interestingly, the mouse MAEL-
STROM (MAEL) protein was found to interact with
MILI and MIWI in the germline-specific structure
nuage , suggesting that MAEL may also function in
this pathway. Nuage (French for ‘cloud’) is a perinuclear
electron-dense structure found in the germ cells of
many species . In flies, Mael is required for the
accumulation of repeat-associated small interfering
RNAs (siRNAs) and repression of TEs . Soper et al.
demonstrated that loss of Mael leads to germ cell
degeneration (at the same point in meiosis as Mili and
Miwi2 mutants) and male sterility in mice . In addi-
tion, they provided evidence that the mammalian MAEL
protein is essential for the silencing of retrotransposons
and determined that early meiosis is a critical timepoint
when transposon control is established in the male
germline. More recently, a similar role for another germ
cell protein, GASZ, has been uncovered . Given that
MAEL, MILI, MIWI and GASZ all localize to nuage
(chromatoid body in mammals), this structure is likely
where the piRNA pathway defends the germline genome
from the invasion of unchecked transposable elements.
O’Donnell and Burns Mobile DNA 2010, 1:21
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Cite this article as: O’Donnell and Burns: Mobilizing diversity:
transposable element insertions in genetic variation and disease. Mobile
DNA 2010 1:21.
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