The impact of transposable elements in environmental adaptation
Transcript of The impact of transposable elements in environmental adaptation
INVITED REVIEWS AND META-ANALYSES
The impact of transposable elements in environmentaladaptation
ELENA CASACUBERTA and JOSEFA GONZ �ALEZ
Institute of Evolutionary Biology (CSIC-Universitat Pompeu Fabra), Passeig Maritim de la Barceloneta 37-49, Barcelona 08003,
Spain
Abstract
Transposable elements (TEs) play an important role in the responsive capacity of their
hosts in the face of environmental challenges. The variety of mechanisms by which
TEs influence the capacity of adaptation of the host is as large as the variety of TEs
and host genomes. For example, TEs might directly affect the function of individual
genes, provide a mechanism for rapidly acquiring new genetic material and dissemi-
nate regulatory elements that can lead to the creation of stress-inducible regulatory
networks. In this review, we summarize recent examples that are part of an increasing
body of evidence suggesting a significant role of TEs in the host response to an ever-
changing environment, both in prokaryote and in eukaryote organisms. We argue that
in the near future, the increasing availability of genome sequences and the develop-
ment of new tools to discover and analyse TE insertions will further show the relevant
role of TEs in environmental adaptation.
Keywords: bursts of transposition, environmental adaptation, gene expression, horizontal
transfer, transposable elements
Received 21 November 2011; revision received 1 November 2012; accepted 2 November 2012
Introduction
Organisms are continuously challenged by their chang-
ing environments. Variation in climatic factors such as
temperature and humidity, interactions with other
organisms, resource availability, and presence of toxins
or other chemicals, among other biotic and abiotic fac-
tors, are likely to produce new selective pressures on
populations that can challenge their survival. Organ-
isms can respond to these changing environmental con-
ditions by shifting their geographical distribution,
through phenotypic plasticity or undergoing adaptive
evolution to the new local conditions (Chevin et al.
2010; Hoffmann & Sgr�o 2011). Of these three mecha-
nisms, adaptative evolution is argued to play the most
important role in determining the fate of species chal-
lenged by changing environmental conditions (Visser
2008).
Adaptive evolution occurs by natural selection when
individuals better able to survive and reproduce
pass on more genes to the next generation. As a
consequence, the genetic variants that confer a fitness
advantage increase in frequency in the population.
Mutation is the ultimate source of genetic variation and
different types of mutations, such as point mutations or
whole genome duplications, play a major role in adap-
tation. Transposable elements (TEs; see Box 1) are also
likely to play a relevant role in adaptation because of
their ability to generate mutations of great variety and
magnitude, and their capacity to be responsive and sus-
ceptible to environmental changes (Biemont & Vieira
2006; Schmidt & Anderson 2006; Oliver & Greene 2009;
Hua Van et al. 2011).Correspondence: Josefa Gonz�alez, Fax: +34 93 2211011;
E-mail: [email protected]
© 2013 Blackwell Publishing Ltd
Molecular Ecology (2013) 22, 1503–1517 doi: 10.1111/mec.12170
Box 1
Types of eukaryotic transposable elements
Transposable Elements (TEs) are DNA sequences that have the ability to move around in the genome by generat-
ing new copies of themselves. TEs are abundant, ancient, and active components of genomes. They are classified in
class I and class II elements according to the presence or absence of an RNA transposition intermediate. Within
each class, TEs are further subdivide in orders, based on their insertion mechanism, structure, and encoded pro-
teins; in superfamilies, based on their replication strategy; and in families, based on sequence conservation (Wicker
et al. 2007; Kapitonov & Jurka 2008).
Class II
Class I
Class II
SINEs (Alu)
AAAAA
Class I
MavericksIntegrase ATPase Protease Polymerase
DNA transposonTransposase
MITEs
HelitronsReplicase helicase
LTR retrotransposonGAG POL
Dark blue arrows represent direct or inverted repeats, blue boxes represent coding sequences and white boxes represent non-coding sequences.
Non-LTR retrotransposon
AAAAA
TEs can also be classified according to their self-sufficiency. TEs that are capable of producing the proteins neces-
sary for their transposition are classified as autonomous elements, while TEs that depend on other TEs to trans-
pose, such as SINEs and MITEs, are classified as nonautonomous elements. Nonautonomous elements are often
deletion derivates of autonomous elements although sometimes they have only limited sequence similarity to their
autonomous counterparts.
Transposable element-induced mutations range from
subtle regulatory mutations to gross genomic rear-
rangements often having complex phenotypic effects.
Box 2 includes a detailed description of the different
types of mutations generated by TEs, actively by de
novo insertion and retrotranposition, and passively by
Class I elements (retrotransposons) replicate using a RNA intermediate and areverse transcriptase. Each complete replication cycle produces new TE copies.As a consequence, retrotransposons are often the major contributors to therepetitive fraction in large genomes. Types of Class I elements include longterminal repeat (LTR) elements and non-LTR elements, such as LongInterspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements(SINEs). LTR elements have partly overlapping open reading frames (ORFs),GAG and POL closely related to retroviral proteins, flanked in both ends byLTRs with promoter capability. LINE elements consist of a 50 UntranslatedRegion (UTR) with promoter activity, two ORFs and a 30 UTR with a poly-A tail,a tandem repeat or merely an A-rich region. SINEs are nonautonomous elements,they rely on LINEs for transposition, that originate from accidental retrotrans-position of various polymerase III (Pol III) transcripts. Unlike retro-pseudogenes,SINEs possess an internal Pol III promoter allowing them to be expressed. Alus,the most common SINE in the human genome, consist of two CG-rich fragments,the left and right Alu, connected by an A-rich linker and ended in a poly-A tail.Class II elements do not require a reverse-transcription step to integrate into thegenome. DNA transposons encode a transposase that recognizes the terminalinverted repeats (TIRs) excises the TE out and then integrates the TE into a newsite in the genome. The gap that is left at the position where the TE was originallyinserted can be filled with a copy of the transposon by gap repair mechanisms.Alternatively, DNA transposons can increase in number by transposing duringchromosome replication from a position that has already been replicated toanother that has not been replicated yet. Miniature Inverted Repeats (MITEs)have no ORFs and also have TIRs. Two newly identified DNA transposons,Helitrons and Mavericks duplicate differently. Helitrons used a rolling-circlemechanism and do not have TIRs, while Mavericks, also known as polytons,probably replicate using a self-encoded DNA polymerase and have TIRs.Helitrons often carry gene fragments that have been captured from the hostgenome.
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1504 E. CASACUBERTA and J . GONZ �ALEZ
acting as substrates for ectopic recombination. As well
as being vertically transferred, from parent to off-
spring, TEs can also be horizontally transferred, from
one species to another, potentially causing the multi-
tude of effects summarized in Box 2 in the new host
species. Additionally, TEs can also act as vectors facili-
tating the horizontal transfer of new genetic content
(Ochman et al. 2000; Frost et al. 2005). Whether they
do or do not transfer genes, horizontal transfer of TEs
is a source of raw genomic variation, and at times of
biological innovation, that influences the ability of the
organism to adapt to changes in its environment, and
to colonize new ecological niches (Schaack et al. 2010).
Box 2TEs generate a great variety of mutations
TEs can have a myriad of effects when they insert into new locations (Feschotte 2008; Goodier & Kazazian 2008;
Gogvadze & Buzdin 2009). These effects vary depending on where exactly the TE inserts and on the sequence of
the TE itself. When a TE inserts into the 5′ region of a gene, it can add new regulatory regions leading for example
to gene overexpression (a) or can disrupt existing regulatory regions and inactivate the gene in a particular tissue
or developmental stage (b). When a TE jumps into an exon it can disrupt the gene for example by altering the
reading frame, or by introducing a stop codon (c). A TE that inserts in the 3′UTR of a gene can disrupt the regula-
tory sequences in that UTR and/or it can add new ones, for example it can add miRNA-binding sites (d). A TE
can disrupt the 5′UTR of a gene leading to, for example, gene inactivation (e). When a TE inserts into an intron it
can: (f) be incorporated as a new exon, (g) introduce a STOP codon leading to a truncated transcript, (h) introduce
new splice sites creating new alternative spliced variants, (i) drive antisense transcription that could interfere with
the sense transcript of the same gene, (j) spread epigenetic silencing leading to gene inactivation.
(j) Gene silencing
(h) Alternative splicing
(g) Premature end
(i) Anti-sense transcription
(f) Exonization
Gene silencing
Cis disruption
5’ UTR disruption
Gene disruption
miRNA targeting
Alternative splicing
Premature end
Anti-sense transcription
Cis addition Exonization
gene structure mRNA
Pentagons represent cis-regulatory regions, grey boxes are UTRs, red boxes represent exons and blue boxes represent TEs.
(a) (f)
(g)
(h)
(i)
(j)
(b)
(c)
(d)
(e)
TEs are also involved in the duplication of genes and exons that may contribute to the generation of new genes
(Marques et al. 2005; Xing et al. 2006). TE-encoded genes can be exapted to perform cellular functions (Volff 2006).
Finally, TEs are also passive generators of mutations. TEs that belong to the same family of elements and are
located in different regions of the genome can act as substrates for ectopic recombination events generating rear-
rangements such as inversions, translocations or duplications (Schwartz et al. 1998; Hill et al. 2000; Bailey et al.
2003).
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TEs IN ENVIRONMENTAL ADAPTATION 1505
TEs are also responsive and susceptible to environ-
mental changes. Stress-activated TEs might generate the
raw diversity that species require over evolutionary time
to survive stressful situations. The first person to present
this idea was Barbara McClintock through her extensive
work in the maize transposons Ac and Ds (McClintock
1984). This idea seemed overly optimistic for other
researchers that thought that activation of TEs is due to
the disruption of the host mechanisms that suppress
transposition in normal conditions. One of the clearest
cases of TE activation due to the breaking down of
repression mechanisms is hybrid dysgenesis in
Drosophila. Hybrid dysgenesis is a sterility syndrome
caused by very high rates of transposition of normally
inactive TE families (Bingham et al. 1982; Bucheton et al.
1984; Petrov et al. 1995). Activation of TEs could be the
consequence of the relaxation of epigenetic control
induced by environmental changes (Slotkin &
Martienssen 2007; Zeh et al. 2009; Rebollo et al. 2010).
However, the many examples providing solid grounds
for the activation of specific TEs in response to some
specific stress conditions indicates that the link between
TE activation and stress response is by far more complex
than the simple release of regulation (Wessler 1996;
Grandbastien et al. 1997; Capy et al. 2000; Schmidt &
Anderson 2006; Fablet & Vieira 2011).
In this review, we investigate the evidence for the role
of TEs in environmental adaptation. Because the litera-
ture on this topic is extensive, we do not attempt to
review every known case of environment-related
TE-induced adaptation, but rather focus on the most
recent examples from diverse organisms that illustrate
the variety of molecular mechanisms and phenotypic
effects of TE-induced mutations. We start with site-spe-
cific insertions of TEs that result in adaptation to the
environment. We then focus on the most recent evidence
for environmental adaptation mediated by horizontal
transfer of TEs. Finally, we review cases in which TEs are
activated by, or in response to, environmental stresses.
TE-induced mutations involved inenvironmental adaptation
TE-induced mutations have been frequently associated
with adaptation to the environment. Below, we briefly
describe some of the most compelling examples of indi-
vidual TE-induced environmental adaptations docu-
mented recently. These examples highlight the variety
of molecular mechanisms and adaptive phenotypic
effects of TEs, from bacteria to mammals.
Bacteria insertion sequences (IS) have long been associ-
ated with environmental adaptation. In early studies, it
was unclear whether the IS element was the causal muta-
tion responsible for the adaptive phenotypic change (e.g.
Naas & Nordmann 1994; Schneider et al. 2000; de Visser
et al. 2004). In recent years, however, a cause–effect rela-
tionship has been established between IS elements and
adaptation to several environmental challenges such as
adaptation to high osmolarity (Stoebel et al. 2009; Stoebel
& Dorman 2010), tolerance to toxic organic solvents (Sun
et al. 2009), metal-limited conditions (Chou et al. 2009)
and nutrient-limited conditions (Gaff�e et al. 2011). The
molecular mechanisms underlying these IS-induced
adaptive mutations are diverse, some insertions affect
gene expression (up-regulation, down-regulation, and
inactivation of nearby genes) while other insertions gen-
erate rearrangements leading to deletions. Although the
same adaptive phenotypes may arise in strains lacking IS
elements (Stoebel & Dorman 2010), the studies men-
tioned previously show that IS elements play an impor-
tant role in environmental adaptation.
In plants, adaptation to local environments has been
repeatedly associated with TE-induced mutations. For
example, in soybean, the disruption by a TE insertion
of GmphyA2, one of the two paralogs encoding phyto-
crom A, is associated with adaptation to high latitudes
as showed by phenotypic experiments and allelic distri-
bution analyses (Liu et al. 2008; Kanazawa et al. 2009).
In Arabidopsis, light-regulation of gene expression is
associated with FAR1 and FHY3 that have been co-
opted from an ancient Mutator-like transposase (Lin
et al. 2007). Lin et al. (2007) experimentally showed that
these proteins increase gene expression by directly
binding to the promoter regions of target genes. The
authors argue that the domestication of FAR1 and
FHY3 might have contributed to Arabidopsis adapta-
tion to changing light environments. In wheat, several
TE-induced mutations in vernalization genes are
responsible for changes in the growth habit that enables
wheat to adapt to a wide range of environments (Yan
et al. 2006; Chu et al. 2011).
Adaptation to local environments is also linked to
TE-induced mutations in Drosophila (Gonz�alez et al.
2008, 2010; Gonz�alez & Petrov 2009a). We carried out
the first genome-wide screen for recent adaptive TE
insertions in Drosophila melanogaster and we discov-
ered several TE insertions involved in local adaptation
(Gonz�alez et al. 2008, 2009b). In a follow-up study, we
showed that a substantial proportion of the identified
TE insertions are specifically adaptive to temperate
environments, and that the frequency of some of
these insertions correlates with environmental vari-
ables such as temperature and rainfall (Gonz�alez et al.
2010). We estimated that the already identified muta-
tions only represent a subset of the total number of
TE-induced adaptive mutations suggesting a wide-
spread role of TEs in environmental adaptation in
Drosophila.
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1506 E. CASACUBERTA and J . GONZ �ALEZ
Besides adaptation to local environments, TE inser-
tions in Drosophila have also been involved in
resistance to viral infection and resistance to insecti-
cides. Resistance to viral infection has been associated
with a TE insertion in the protein coding sequence of
CHKov1 (Magwire et al. 2011). The TE insertion trun-
cates CHKov1 creating four different altered transcripts,
none of which contain all four exons of the wild-type
gene. This insertion was previously shown to confer
resistance to insecticides, although the authors already
noted that the allele containing the insertion had been
evolving in the populations for a long time before insec-
ticides started to be used (Aminetzach et al. 2005). It
turns out that the allele carrying the insertion would
initially have played a role in defending flies against
viral infection. However, flies carrying this particular
TE insertion found themselves pre-adapted to the intro-
duction of insecticides in the middle of last century.
Magwire et al. (2011) also provide evidence that
CHKov1 alleles carrying duplications of the gene region
containing the insertion, resulted in further resistance to
viral infection. Similar to the CHKov1 allelic series, the
region containing a Cyp6g1 allele previously shown to
confer resistance to pesticides (Daborn et al. 2002), has
also suffered duplications and additional TE insertions
that increased resistance to pesticides (Schmidt et al.
2010). These two examples support the view that alleles
of large effect may sometimes reflect the accumulation
of multiple mutations of small effect at key genes. Other
than in Drosophila, a clear role for TE insertions in
insecticide resistance has also been demonstrated in
mosquitos (Darboux et al. 2007). The binary toxin pro-
duced by Bacillus sphaericus is used as an insecticide
against the mosquito Culex pipiens. Resistance to this
toxin is due to the insertion of a TE into the coding
sequence of the toxin receptor. The insertion induces a
new mRNA splicing event that creates a shorter tran-
script. This new transcript encodes an altered receptor
unable to interact with the toxin resulting in resistance
to this insecticide (Darboux et al. 2007).
Our last example connecting individual TE-induced
mutations and environmental adaptation comes from
paleogenomic studies in mammals (Santangelo et al.
2007; Franchini et al. 2011). Pomc, a gene involved in
stress response and regulation of food intake and
energy balance, has two functionally overlapping enh-
ancers that originated from ancient unrelated TE inser-
tions. In multicellular organisms, the presence of two
enhancers capable of guiding similar patterns in spatio-
temporal expression is common to several developmen-
tal genes. Rather than being redundant, the presence of
the two enhancers is required to overcome the chal-
lenges imposed by critical environmental conditions
such as changes in temperature (Frankel et al. 2010;
Perry et al. 2010). Possibly, the presence of these two
enhancers has been key to evolution of mammals
through the periods of abrupt climate change. Given
the abundance of TEs in mammalian genomes, the
authors concluded that it is conceivable that sequential
exaptation of TEs leading to analogous cell-specific
enhancers could be a more generalized phenomenon
than previously anticipated (Franchini et al. 2011).
Horizontal Transfer of TEs (HTT) and horizontalgene transfer (HGT) mediated by TEs
Besides being transferred from parent to offspring, TEs
can also be horizontally transferred between species. A
horizontally transferred TE (HTT) can generate in the
new host species the same battery of mutations
described for vertically transferred TEs (see Box 2).
Additionally, TEs can also act as vectors facilitating the
horizontal transfer of new genetic content (Ochman
et al. 2000; Frost et al. 2005). This phenomenon has
been extensively demonstrated in prokaryotes. In
eukaryotes, although TEs are capable of capturing and
transferring genes at a high frequency within a species
(Jiang et al. 2004; Morgante et al. 2005; Schaack et al.
2010) they have not yet been found to transfer host
genes between different species. Although horizontal
gene transfer (HGT) can also occur independent of TE
movement, in this review, we focus on TE-mediated
HGT events.
HTT and HGT in prokaryote environmentaladaptation
There is no doubt that prokaryotes increase their
genetic variation by HGT (Ochman et al. 2000; Aminov
2011). This mechanism rapidly integrates ‘foreign’ DNA
that gives the new host the opportunity to acquire new
functions, and to colonize extremely diverse habitats
(Wiedenbeck & Cohan 2011). This phenomenon is of
such importance in bacteria that the vast majority of
species-specific DNA sequences that differ between two
given species have been the result of different events of
horizontal transfer (Levin & Bergstrom 2000). The
mechanisms by which TE- induced HGT can take place
in prokaryotes are diverse and depend on which TE is
involved. HGT events often involve operons and gene
cassettes because horizontally transferred genes have a
better chance to be functional in the new host genome
if they are transferred with their flanking sequences.
Box 3 briefly describes the main TE sequences often
involved in HGT between prokaryote organisms. Addi-
tionally, a recent review is available to the readers inter-
ested in the mechanistic details of HGT in prokaryotes
(Toussaint & Chandler 2012).
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TEs IN ENVIRONMENTAL ADAPTATION 1507
Box 3Horizontal transfer in prokaryotes
The genetic content of an organism is received by vertical inheritance, leaving most organisms with a finite toolbox
to face all eventualities along their life and limiting their possibilities to explore new ecological niches. Neverthe-
less, in some occasions, evolution provides an alternative mechanism for rapidly acquiring new genetic material:
horizontal gene transfer. Below, we briefly described several types of prokaryotic transposons that have facilitated
the horizontal transfer of genes.
tpase
TIR
IS IS Structural genes
Composite transposon Insertion Sequence: IS
TIR: Terminal Inverted Repeat. tpase: transposase
TIR
Conjugative transposition Donor
Acceptor
Excision of circular intermediate
Transfer of a single strand of the circular intermediate
Replication
Integration
Composite transposons. In a composite transposon, two Insertion Sequences (ISs) flank one or more genes such as
Tn10 composed of two IS10 elements flanking the tetracycline resistance gene, or Tn5, two IS50 elements flanking a
three-resistance gene operon: streptomycin, bleomycin and kanamycin (Ochman et al. 2000). Composite transposons
can be mobilized between distantly related bacteria having a great impact on the adaptive capacity of the genome
that hosts them. ISs are also involved in creating modular assemblies of genes, the simplest being concatenation
within compound transposons. A good example is the 221 kb virulence megaplasmid of Shigella flexneri, pW100;
(Buchrieser et al. 2000; Venkatesan et al. 2001). In this megaplasmid, ISs represents 46% of the DNA content includ-
ing 26 full-length ISs and an extensive array of IS fragments indicative of ancestral rearrangements.
Insertion Sequence Common Regions (ISCR). ISCR are often associated with resistance and virulence genes. ISCR
resemble ISs but lack terminal inverted repeats and are thought to transpose by a rolling-circle mechanism. ISCR
impact on shuffling antibiotic resistance genes among bacteria is remarkable: they have been involved in horizontal
transfer events of resistance genes of every single class (Toleman et al. 2006).
© 2013 Blackwell Publishing Ltd
1508 E. CASACUBERTA and J . GONZ �ALEZ
Box 3 Continued
Conjugative transposons. Conjugative transposons encode their own ability to move from one bacterial cell to another
via cell-to-cell contact. Conjugative transposons have a surprisingly broad host range, and they probably contribute
as much as plasmids to the spread of antibiotic resistance genes in some genera of disease-causing bacteria. Many
conjugative transposons can mobilize co-resident plasmids, and some of them can even excise and mobilize
unlinked integrated elements.
Mobile Integrons (‘quantum leap’ evolution). Integrons are genetic elements able to acquire and rearrange open read-
ing frames (ORFs) embedded in gene cassette units and convert them to functional genes by ensuring their correct
expression. An Integron by itself is nonmobile and its basic functional units are the intI gene and the attI recombina-
tion site. intI encodes a site-specific tyrosine recombinase that recognizes the attI site (Collis et al. 1993; Collis & Hall
1995). intI is responsible for the integration and excision of the different genetic cassettes that compose the Integron.
A promoter often embedded inside the intI gene or the attI sequence drives the expression of the Integron.
When Integrons are associated with transposons they can be mobilized in conjugative plasmids and can be trans-
ferred to individuals of the same or different species. Through their life in different genomes, integrons can acquire
gene cassettes from different origin and be successful in different species thanks to the flexibility of the codon usage
of the harboured genes. Intriguingly, most gene cassettes associated with mobile integrons are composed by antibi-
otic resistance genes (Naas et al. 2001), although a few genes of unknown function have also been identified (Cam-
bray et al. 2010). Integrons have the capacity to harbour many gene cassettes as in the famous case of the Vibrio
cholerae super-integron with 179 gene cassettes (Mazel 2006). The impact of the integration of a mobile unit with
such high number of genes could be considered as a ‘quantum leap’ for the evolution of the new host.
int attI
Pc P2
Pint
Constant Variable
Int
int: integrase gene. attI: sequencesinvolved in recombinationPc, P2: Promoters for the acquired genes Pint: integrase promoter
Integron with exogenous genes
Integron basic structure to acquire genes and build gene cassettes:
.
Several instances of TE-induced HGT are related to
adaptation to different environmental conditions (Och-
man et al. 2000; Hacker & Carniel 2001; Toleman et al.
2006; Cambray et al. 2010; Aminov 2011). In this section,
we will focus on recent examples of HTT and HGT that
play a role in (i) the acquisition of new catabolic and
metabolic properties, (ii) detoxification, and (iii) patho-
genicity and virulence.
1 New catabolic and/or metabolic properties: We have
chosen a recently described example that illustrates
how the acquisition of new catabolic capacities has
allowed a host bacterium to better adapt to harsh
environmental conditions. Cupriavidus metallidurans is
a b-proteobacterium adapted to live in environments
that contain heavy metal pollution (Mijnendonckx
et al. 2011). A recent genome-wide analysis revealed
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TEs IN ENVIRONMENTAL ADAPTATION 1509
that there are 57 IS elements in this species, three of
which show 100% identity with IS elements of a
number of other bacteria: Ralstonia pickettii, Burkholde-
ria vietnamiensis, Delftia acidovorans and Comamonas
testosteroni. All these bacteria live in similar environ-
ments suggesting recent interactions and HTT events
between these strains. These horizontally transferred
TEs have been associated with genomic islands and
with gene inactivation that affect the autotrophic
growth capacity of C. metallidurans. Furthermore, one
of the horizontally transferred TEs is also associated
with stress response (Mijnendonckx et al. 2011). The
previous example demonstrates the crucial role that
TEs can have both directly and indirectly in the adap-
tive capacity of bacteria to harsh and polluted envi-
ronments.
2 Detoxification: The catabolic capacities of bacteria are
not only directly linked to their own chances to sur-
vive in a changing environment, but also often con-
tribute to the survival of other organisms that share
the same, often contaminated, environment. Wei and
collaborators showed that the gene methyl parathion
hydrolase, mph, involved in the degradation of organo-
phosphorus compounds, was part of a typical com-
posite transposon (Tnmph; see Box 3) flanked by two
IS6100 sequences in Pseudomonas sp (Wei et al. 2009).
The Tnmph composite transposon was successfully
transferred in the laboratory to a wide range of bacte-
rial species, including some phylogenetically distant
ones. These results suggest that Tnmph may contrib-
ute to the wide distribution of mph-like genes and the
adaptation of bacteria to organophosphorus com-
pounds (Wei et al. 2009). The possibility of manipu-
lating bacteria that live in our everyday environments
with composite transposons including genes like the
mph, expands the already available possibilities to
counteract some of the effects of contamination using
microorganisms (Wu et al. 2012).
3 Pathogenicity: Clostridium perfringens is a pathogenic
bacterium that causes serious illness in different live-
stock animals. The different isolates of C. perfringens
are classified based on which of four lethal toxins
they produce (Sayeed et al. 2010). Type B isolates are
the most virulent because they are able to produce
two different toxins: beta-toxin and epsilon-toxin.
Molecular characterization of type B isolates, demon-
strated that these isolates contain not just one, but
three different plasmids with virulence genes. The
identification of IS elements (IS1151) as well as genes
involved in conjugative transposition (tcp; see Box 3),
strongly suggested that both circular and conjugative
transposition may have been involved in the HGT of
these large virulence platforms (Sayeed et al. 2010).
This is another example of a case in which a series of
HGT caused by HTT has resulted in a better adapta-
tion. In this case, pathogenicity may increase the
chances of wider spread and therefore increase the
likelihood of survival of the host bacterium.
HTT and HGT in eukaryote environmental adaptation
Horizontal Transfer of TE events have been reported in
eukaryotic species as diverse as Drosophila, yeast and
fungi (Hall et al. 2005; Loreto et al. 2008; Gilbert et al.
2010; Schaack et al. 2010). These events may have evolu-
tionary relevance only if the newly inserted TE is able to
transpose, increase in copy number, or provide a new
cellular function. The capacity to transpose and increase
in copy number in a new invaded genome has been
reported for Helitrons (Box 1) in several organisms
including mammals, reptiles, fish, invertebrates and
insect viruses (Thomas et al. 2010). There is also evidence
for the generation of new cellular functions after an HTT
event for P-elements in Drosophila (Pinsker et al. 2001)
and SPIN elements in mouse (Pace et al. 2008). Therefore,
HTT could be an important evolutionary force shaping
eukaryotic genomes, although evidence for a specific role
in environmental adaptation has yet to be found.
As in prokaryotes, HGT has had an important role in
eukaryote genome evolution (Keeling & Palmer 2008;
Syvanen 2012). The evidence for HGT in diverse
eukaryotes is expanding rapidly in organisms such as
nematodes (Haegeman et al. 2011) and fungi (Fitzpa-
trick 2012). Many of the reported HGT events are
related to environmental adaptation. For example, the
ability of distantly related unicellular eukaryotes to live
in anaerobic environments (Loftus et al. 2005) or the
transfer of antifreeze proteins in fish (Graham et al.
2008) are due to HGT events. Although there is no evi-
dence yet of HGT mediated by TEs (Schaack et al.
2010), some authors predict that it will be soon discov-
ered (Keeling & Palmer 2008). For example, Helitrons
have a rolling-circle mechanism of transposition that
makes them especially prone to take adjacent 3′ unre-
lated DNA along (Feschotte & Wessler 2001) and there-
fore are strong candidates to play a major role in HGT
between eukaryotic species.
TE activation triggered by or in response toenvironmental stress
As we mentioned in the introduction, Barbara McClin-
tock was the first to propose that the activation of TEs
in response to stress induces mutations that could help
the organism adapt to new environmental conditions
(McClintock 1984). TEs would therefore play a key role
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1510 E. CASACUBERTA and J . GONZ �ALEZ
in translating changes in the external environment into
changes at the genomic level. Indeed, TEs respond
directly to some specific stress situations and in some
cases the specific TE sequences responsible for the
stress response have been identified. This is the case of
several Long Terminal Repeat (LTR) retrotransposons
that contain cis-regulatory elements in their 5′ LTR that
trigger transposon expression in response to a particu-
lar stimulus (Kumar and Bennetzen 1999). These regula-
tory sequences are similar to the well-characterized
motifs required for the activation of stress-responsive
genes (Grandbastien et al. 2005). The possibility of
acquiring changes in the cis-regulatory elements entails
the opportunity to respond to new and different envi-
ronmental factors. Examples of TEs containing these
cis-regulatory elements are abundant and are very well
represented in the literature. In Box 4 we describe some
of the classical examples, such as Tnt1 and Bare1 in
tobacco and barley, respectively.
Box 4
The U3 Box of LTR Retrotransposons
The 5′ LTR works as a promoter containing the sequences that drive, specify, and signal for termination of tran-
scription, and the capping signal. The LTR is subdivided in the U3, R and U5 domains. Different specific DNA ele-
ments in the U3 region (B boxes) have been identified in relation to specific molecules that signal for different
stress responses, such as phytohormones and elicitors. See some examples in the table below and text and refer-
ences for further details.
LTR Retrotransposon Specific molecule or stress situation
Tnt1A, N.tabacum (Beguiristain et al. 2001) Jasmonic acid, cryptogein
Tnt1C, N.tabacum (Beguiristain et al. 2001) Salicylic acid and auxin
Tto1, N.tabacum (Takeda et al. 1999) Jasmonic acid (JA)
OARE1, Hordeum vulgare (Kimura Y et al. 2001) Salicylic acid
BARE-1, Hordeum vulgare (Suoniemi et al. 1996) AcidAbscisic (ABA)
Tdt1, Triticum durum L. (Woodrow P. et al. 2010) Light and salinity
Tlc1, Solanum chilense (Salazar et al. 2007) Phytohormones
5’ LTR
U3 R U5
B boxes
.
Although the specific sequence that responds to stress
has not been identified, for other LTR retroelements it
has been shown experimentally that the LTR is suffi-
cient in itself to activate TE transcription in response to
stress. This, for example, is the case of the activation
under nitrate starvation stress of the Blackbeard
retrotransposon in the marine diatom Phaeodactylum
tricornutum (Maumus et al. 2009). Because LTR elements
are very abundant in this diatom genome, the authors
suggest that their massive activation may probably con-
tribute to major genome rearrangements that would
allow this organism to respond rapidly to changing
environmental conditions (Maumus et al. 2009). Further-
more, the authors show that the retroelement is hy-
© 2013 Blackwell Publishing Ltd
TEs IN ENVIRONMENTAL ADAPTATION 1511
pomethylated in response to nitrate starvation, which
provides a link between environmental stress and chro-
matin remodelling in diatoms.
Besides being present in the 50LTR, transcriptional
regulatory sequences are also located in the open read-
ing frames of some LTR retrotransposons (Servant et al.
2008, 2012). This is the case for the LTR retrotransposon
Ty1 of Saccharomyces cerevisiae. The transcription of the
Ty1 retrotransposon is induced, among other specific
stress conditions, by a shortage of adenylic nucleotides
(Todeschini et al. 2005). A recent study by Servant and
collaborators identifies the mechanism of activation of
this TE (Servant et al. 2012). It turns out that severe ade-
nine starvation activates the expression of the transcrip-
tion factor TYE7. TYE7 binds to the E-boxes, located
downstream of the transcription start site of the TYA
gene, and alters Ty1 antisense transcription. As a conse-
quence, there is an increase in sense Ty1 mRNA that
leads to retrotransposition of this element and coactiva-
tion of the expression of genes adjacent to Ty1 inser-
tions (Servant et al. 2008, 2012).
Other than LTR retrotransposons, class II elements
such as Miniature Inverted-repeat Transposable Ele-
ments (MITEs) have also been shown to respond specif-
ically to some stress conditions. This is the case, for
example, for the mPing MITE in rice. In some rice
strains mPing has amplified from c. 50 to 1000 copies
(Naito et al. 2006). The analyses of the insertion sites in
the strains that have undergone this burst of transposi-
tion revealed that under normal growth conditions
mPing elements have a modest impact on the host
because of highly evolved targeting mechanisms that
minimize the effects on host gene expression (Naito
et al. 2009). However, mPing is able to confer a stress-
inducible state to the nearby genes regardless of
whether the TE is inserted at their 5′ or the 3′ region,
suggesting its potential to act as an enhancer element.
Although a specific sequence inside the mPing element
has not been defined, it is clear that mPing is able to
provide the surrounding genes the capacity to respond
to certain stress situations but not others (e.g. cold and
salt but not drought). Because of the high copy number
of mPing in rice genomes, its specific transcription and
transposition could result in new gene regulatory net-
works of coordinated expression that would contribute
to a fine-tuned response of this organism to specific
stress factors. The creation of such regulatory networks
in response to certain stresses could be a widespread
phenomenon in nature since evidence for rapid and
massive amplification of MITEs has been found in
virtually all sequenced eukaryotic genomes and even in
some prokaryote ones (Naito et al. 2009).
The case of mPing illustrates how the integration site
of some TEs may confer stress-inducibility to nearby
genes. However, the opposite is also true: some TEs
specifically integrate close to stress-responsive genes.
Tf1, an LTR retrotransposon from Schizosaccharomyces
pombe, shows a tendency to integrate in a 500 bp win-
dow upstream of ORFs (Behrens et al. 2000; Bowen et al.
2003). Guo & Levin (2010), further demonstrate that in
different activation experiments the newly integrated
Tf1 elements insert close to RNAPol II promoters but
interestingly, there was no correlation with the level of
transcription of the targeted promoters. Instead, Tf1 had
a strong preference for promoters that are induced by
specific stress conditions, such as genes induced by
cadmium and heat. The targeting of Tf1 to stress-
induced promoters represents a unique response that
may function to specifically alter expression levels of
stress response genes (Guo & Levin 2010).
Activation of TEs is not always directly triggered by
a specific stress but the effects that such stress causes
in other cellular mechanisms allow a rapid activation
of some particular TE copies (Dai et al. 2007; Coros
et al. 2009). An interesting example to illustrate this
kind of secondary response is the activation of the Ty5
retrotransposon in Sacharomyces subject to starvation
stress. Ty5 in Sacharomyces preferentially integrates
into heterochromatic regions. This pattern of integra-
tion is directed by the interaction between the Ty5 in-
tegrase targeting domain (TD) and the heterochromatic
protein Sir4 when Ty5 is phosphorylated (Zhu et al.
2003; Dai et al. 2007). When Sacharomyces is faced
with starvation, numerous signal transduction path-
ways, among them the protein kinase A pathway, are
affected. When the TD of Ty5 is not phosphorylated,
there is no interaction with Sir4 and the pattern of
integration of this retrotransposon changes radically.
Under such conditions Ty5 becomes a potent endoge-
nous mutagen that integrates randomly throughout the
genome, including into gene-rich regions. This change
in the pattern of integration of Ty5 is observed in
response to some specific stress conditions (e.g. starva-
tion stress) and not others (e.g. heat-shock, DNA dam-
age, osmotic shock or oxidative stress). The regulation
of Ty5 phosphorylation by stress, demonstrates that
TEs provide the cell with a prewired mechanism to
reorganize the genome in response to environmental
challenge (Dai et al. 2007).
Finally, we will highlight two of the several recent
examples from the literature indicating that noncoding
and small interfering RNAs are also another possible
path by which TEs respond to stress (Hilbricht et al.
2008; Mariner et al. 2008; Lv et al. 2010; Yan et al. 2011;
McCue et al. 2012). Possibly one of the best-studied
stress responses in eukaryotes is the one triggered by
heat-shock. However, the exact mechanisms by which
most organisms subject to a heat-shock manage to
© 2013 Blackwell Publishing Ltd
1512 E. CASACUBERTA and J . GONZ �ALEZ
repress the transcription of most genes are still
unknown. Mariner and collaborators discovered one
mechanism of response to heat-shock involving TEs in
humans (Mariner et al. 2008). Alu elements function as
cell stress genes: different stress conditions cause an
increase in the expression of Alu RNAs, which rapidly
decreases upon recovery from stress (H€asler & Strub
2006). Alu RNA has been implicated in regulating
several aspects of gene expression such as alternative
splicing, RNA editing, translation and miRNA expres-
sion and function (H€asler & Strub 2006; H€asler et al.
2007). In humans, Alu elements but not other Pol III
transcribed genes are activated by heat stress. Mariner
et al. (2008) demonstrated that the mRNA of the Alu
element block transcription by binding RNApol II and
entering the repressor complexes that will be loaded
onto the promoters of the repressed genes. Interestingly,
in mouse cells the SINE B2 element activated upon
heat-shock is also able to repress transcription of many
genes using a similar mechanism. Although the B2
SINE derived from tRNA from mouse, and the human
Alu derived from 7SL-like precursor, do not have
sequence identity or similar RNA secondary structures,
their similar effects on the host heat–shock response
suggest that these two SINE elements have converged
to the same biological function.
An additional example reveals how siRNAs gener-
ated by a retrotransposon confer the capacity to
respond to desiccation to the callus of the plant Cratero-
stigma plantagineum (Hilbricht et al. 2008). CDT-1 was
first identified as a plant desiccation tolerant gene and
later recognized as being a TE, although it is still pend-
ing classification. Hilbright and collaborators reported
that while no translation from this element is needed
for the desiccation tolerance response, the transcription
and the posterior production of related siRNAs from
CDT-1 is essential to induced expression of desiccation-
inducible genes.
Overall, the examples described previously strongly
suggest a role of TEs in the ability of the host to respond
to changes in the environment. The evidence that only
some specific TE families, and not all the TEs in the gen-
ome, are activated in response to stress and the evidence
that these TEs respond to some specific stress conditions
and not others, strongly suggest that activation of TEs
by stress is not only a byproduct of genome deregula-
tion. The consequences of TE activation in response to
stress are diverse. Stress-activated TEs: (i) contribute to
major genomic rearrangements (Maumus et al. 2009), (ii)
confer nearby genes the capacity to respond to stress
(Guo & Levin 2010; Servant et al. 2012), which may lead
to the creation of new regulatory networks (Naito et al.
2009; Ito et al. 2011) and (iii) alter the genome randomly
through insertion of the newly generated copies (Dai
et al. 2007). Therefore, containing a certain number of
potentially active TEs may increase the genome ability
to cope with environmental changes.
Concluding remarks
Given the opportunistic nature of evolution, the capac-
ity of TEs to generate mutations of great variety and
magnitude suggests that TEs are important players in
genome evolution. Some authors may consider that the
capacity of TEs to create genetic diversity that might
result beneficial for the host genome has not been
exploited often, nor has it necessarily been subject to
positive selection. In this review, we argue that there
are many examples that provide solid grounds for the
beneficial effect of TEs in host genome evolution in gen-
eral and in host environmental adaptation in particular.
Note that several of the works summarized in this
review (e.g. Gonz�alez et al. 2008; Naito et al. 2009; Fran-
chini et al. 2011) strongly suggest that the particular
cases described may represent the tip of the iceberg.
Moreover, identifying TE insertions involved in envi-
ronmental adaptation depends ultimately on our ability
to identify a given nucleotide sequence as a TE or a TE
remnant. As such, we are still likely underestimating
the role of TEs in environmental adaptation just because
of our limitations to identify TE insertions. We antici-
pate that in the next years increased availability of gen-
ome sequences, the development of new tools to
accelerate the discovery of TE insertions (Fiston-Lavier
et al. 2011; Flutre et al. 2011; Makalowski et al. 2012)
and the increased knowledge about which genes and
traits are relevant for adaptation will further support
the prevalent role of TEs in environmental adaptation.
Acknowledgements
We thank Anna-Sophie Fiston-Lavier, Lain Guio, Ruth Hersh-
berg, Lidia Mateo, Dmitri A. Petrov and Alfredo Ruiz for
critically reading the manuscript. This work was supported by a
grant from the Spanish Ministry of Science and Innovation
BFU2009-08318/BMC awarded to E.C. and by a Ramon y Cajal
grant (RYC-2010-07306), a Marie Curie CIG grant (PCIG-GA-
2011-293860) and a National Programme for Fundamental
Research Projects grant (BFU-2011-24397) awarded to J. G.
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E.C. is a functional evolution researcher interested in
the role of TEs in the evolution of eukaryote genomes.
J.G. leads the Evolutionary and Functional Genomics
research group which focuses on elucidating the
molecular process and the functional consequences of
adaptation.
© 2013 Blackwell Publishing Ltd
TEs IN ENVIRONMENTAL ADAPTATION 1517