The Impact of Transposable Elements in Environmental Adaptation

Molecular Ecology (2013) 22, 1503–1517 doi: 10.1111/mec.12170

INVITED REVIEWS AND META-ANALYSES The impact of transposable elements in environmental adaptation

ELENA CASACUBERTA and JOSEFA GONZALEZ 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 development 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

important role in determining the fate of species chal- Introduction lenged by changing environmental conditions (Visser Organisms are continuously challenged by their chang- 2008). ing environments. Variation in climatic factors such as Adaptive evolution occurs by natural selection when temperature and humidity, interactions with other individuals better able to survive and reproduce organisms, resource availability, and presence of toxins pass on more genes to the next generation. As a or other chemicals, among other biotic and abiotic fac- consequence, the genetic variants that confer a ﬁtness tors, are likely to produce new selective pressures on advantage increase in frequency in the population. populations that can challenge their survival. Organ- Mutation is the ultimate source of genetic variation and isms can respond to these changing environmental con- different types of mutations, such as point mutations or ditions by shifting their geographical distribution, whole genome duplications, play a major role in adap- through phenotypic plasticity or undergoing adaptive tation. Transposable elements (TEs; see Box 1) are also evolution to the new local conditions (Chevin et al. likely to play a relevant role in adaptation because of 2010; Hoffmann & Sgro 2011). Of these three mecha- their ability to generate mutations of great variety and nisms, adaptative evolution is argued to play the most magnitude, and their capacity to be responsive and susceptible to environmental changes (Biemont & Vieira Correspondence: Josefa Gonzalez, Fax: +34 93 2211011; 2006; Schmidt & Anderson 2006; Oliver & Greene 2009; E-mail: [email protected] Hua Van et al. 2011).

Box 1 Types of eukaryotic transposable elements Transposable Elements (TEs) are DNA sequences that have the ability to move around in the genome by generating 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 proteins; in superfamilies, based on their replication strategy; and in families, based on sequence conservation (Wicker et al. 2007; Kapitonov & Jurka 2008).

Class I Class I elements (retrotransposons) replicate using a RNA intermediate and a reverse transcriptase. Each complete replication cycle produces new TE copies. LTR retrotransposon GAG POL As a consequence, retrotransposons are often the major contributors to the repetitive fraction in large genomes. Types of Class I elements include long terminal repeat (LTR) elements and non-LTR elements, such as Long Non-LTR retrotransposon Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements AAAAA (SINEs). LTR elements have partly overlapping open reading frames (ORFs),

SINEs (Alu) GAG and POL closely related to retroviral proteins, flanked in both ends by LTRs with promoter capability. LINE elements consist of a 50 Untranslated AAAAA Region (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, Class II they rely on LINEs for transposition, that originate from accidental retrotrans- DNA transposon position of various polymerase III (Pol III) transcripts. Unlike retro-pseudogenes, Transposase 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, MITEs 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 the Helitrons genome. DNA transposons encode a transposase that recognizes the terminal Replicase helicase inverted repeats (TIRs) excises the TE out and then integrates the TE into a new site in the genome. The gap that is left at the position where the TE was originally Mavericks inserted can be filled with a copy of the transposon by gap repair mechanisms. Integrase ATPase Protease Polymerase Alternatively, DNA transposons can increase in number by transposing during chromosome replication from a position that has already been replicated to another that has not been replicated yet. Miniature Inverted Repeats (MITEs) Dark blue arrows represent direct or have no ORFs and also have TIRs. Two newly identified DNA transposons, inverted repeats, blue boxes represent Helitrons and Mavericks duplicate differently. Helitrons used a rolling-circle coding sequences and white boxes mechanism and do not have TIRs, while Mavericks, also known as polytons, represent non-coding sequences. probably replicate using a self-encoded DNA polymerase and have TIRs. Helitrons often carry gene fragments that have been captured from the host genome.

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 transpose, 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 Box 2 includes a detailed description of the different subtle regulatory mutations to gross genomic rear- types of mutations generated by TEs, actively by de rangements often having complex phenotypic effects. novo insertion and retrotranposition, and passively by

© 2013 Blackwell Publishing Ltd TEs IN ENVIRONMENTAL ADAPTATION 1505 acting as substrates for ectopic recombination. As well (Ochman et al. 2000; Frost et al. 2005). Whether they as being vertically transferred, from parent to off- do or do not transfer genes, horizontal transfer of TEs spring, TEs can also be horizontally transferred, from is a source of raw genomic variation, and at times of one species to another, potentially causing the multi- biological innovation, that inﬂuences the ability of the tude of effects summarized in Box 2 in the new host organism to adapt to changes in its environment, and species. Additionally, TEs can also act as vectors facili- to colonize new ecological niches (Schaack et al. 2010). tating the horizontal transfer of new genetic content

Box 2 TEs 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 regulatory 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.

gene structure mRNA

(a) Cis addition (f)(f) ExonizationExonization

(b) Cis disruption (g)(g) PrematurePremature end end

(d) miRNA targeting (i)(i) Anti-senseAnti-sense transcription transcription

(e) 5’ UTR disruption (j)(j) GeneGene silencing silencing

Pentagons represent cis-regulatory regions, grey boxes are UTRs, red boxes represent exons and blue boxes represent TEs.

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 rearrangements such as inversions, translocations or duplications (Schwartz et al. 1998; Hill et al. 2000; Bailey et al. 2003).

TEs are also responsive and susceptible to environ- Naas & Nordmann 1994; Schneider et al. 2000; de Visser mental changes. Stress-activated TEs might generate the et al. 2004). In recent years, however, a cause–effect rela- raw diversity that species require over evolutionary time tionship has been established between IS elements and to survive stressful situations. The first person to present adaptation to several environmental challenges such as this idea was Barbara McClintock through her extensive adaptation to high osmolarity (Stoebel et al. 2009; Stoebel work in the maize transposons Ac and Ds (McClintock & Dorman 2010), tolerance to toxic organic solvents (Sun 1984). This idea seemed overly optimistic for other et al. 2009), metal-limited conditions (Chou et al. 2009) researchers that thought that activation of TEs is due to and nutrient-limited conditions (Gaffe et al. 2011). The the disruption of the host mechanisms that suppress molecular mechanisms underlying these IS-induced transposition in normal conditions. One of the clearest adaptive mutations are diverse, some insertions affect cases of TE activation due to the breaking down of gene expression (up-regulation, down-regulation, and repression mechanisms is hybrid dysgenesis in inactivation of nearby genes) while other insertions gen- Drosophila. Hybrid dysgenesis is a sterility syndrome erate rearrangements leading to deletions. Although the caused by very high rates of transposition of normally same adaptive phenotypes may arise in strains lacking IS inactive TE families (Bingham et al. 1982; Bucheton et al. elements (Stoebel & Dorman 2010), the studies men- 1984; Petrov et al. 1995). Activation of TEs could be the tioned previously show that IS elements play an impor- consequence of the relaxation of epigenetic control tant role in environmental adaptation. induced by environmental changes (Slotkin & In plants, adaptation to local environments has been Martienssen 2007; Zeh et al. 2009; Rebollo et al. 2010). repeatedly associated with TE-induced mutations. For However, the many examples providing solid grounds example, in soybean, the disruption by a TE insertion for the activation of specific TEs in response to some of GmphyA2, one of the two paralogs encoding phyto- specific stress conditions indicates that the link between crom A, is associated with adaptation to high latitudes TE activation and stress response is by far more complex as showed by phenotypic experiments and allelic distri- than the simple release of regulation (Wessler 1996; bution analyses (Liu et al. 2008; Kanazawa et al. 2009). Grandbastien et al. 1997; Capy et al. 2000; Schmidt & In Arabidopsis, light-regulation of gene expression is Anderson 2006; Fablet & Vieira 2011). associated with FAR1 and FHY3 that have been co- In this review, we investigate the evidence for the role opted from an ancient Mutator-like transposase (Lin of TEs in environmental adaptation. Because the litera- et al. 2007). Lin et al. (2007) experimentally showed that ture on this topic is extensive, we do not attempt to these proteins increase gene expression by directly review every known case of environment-related binding to the promoter regions of target genes. The TE-induced adaptation, but rather focus on the most authors argue that the domestication of FAR1 and recent examples from diverse organisms that illustrate FHY3 might have contributed to Arabidopsis adapta- the variety of molecular mechanisms and phenotypic tion to changing light environments. In wheat, several effects of TE-induced mutations. We start with site-spe- TE-induced mutations in vernalization genes are cific insertions of TEs that result in adaptation to the responsible for changes in the growth habit that enables environment. We then focus on the most recent evidence wheat to adapt to a wide range of environments (Yan for environmental adaptation mediated by horizontal et al. 2006; Chu et al. 2011). transfer of TEs. Finally, we review cases in which TEs are Adaptation to local environments is also linked to activated by, or in response to, environmental stresses. TE-induced mutations in Drosophila (Gonzalez et al. 2008, 2010; Gonzalez & Petrov 2009a). We carried out the first genome-wide screen for recent adaptive TE TE-induced mutations involved in insertions in Drosophila melanogaster and we discov- environmental adaptation ered several TE insertions involved in local adaptation TE-induced mutations have been frequently associated (Gonzalez et al. 2008, 2009b). In a follow-up study, we with adaptation to the environment. Below, we briefly showed that a substantial proportion of the identified describe some of the most compelling examples of indi- TE insertions are specifically adaptive to temperate vidual TE-induced environmental adaptations docu- environments, and that the frequency of some of mented recently. These examples highlight the variety these insertions correlates with environmental vari- of molecular mechanisms and adaptive phenotypic ables such as temperature and rainfall (Gonzalez et al. effects of TEs, from bacteria to mammals. 2010). We estimated that the already identified muta- Bacteria insertion sequences (IS) have long been associ- tions only represent a subset of the total number of ated with environmental adaptation. In early studies, it TE-induced adaptive mutations suggesting a wide- was unclear whether the IS element was the causal muta- spread role of TEs in environmental adaptation in tion responsible for the adaptive phenotypic change (e.g. Drosophila.

Besides adaptation to local environments, TE inser- Perry et al. 2010). Possibly, the presence of these two tions in Drosophila have also been involved in enhancers has been key to evolution of mammals resistance to viral infection and resistance to insecti- through the periods of abrupt climate change. Given cides. Resistance to viral infection has been associated the abundance of TEs in mammalian genomes, the with a TE insertion in the protein coding sequence of authors concluded that it is conceivable that sequential CHKov1 (Magwire et al. 2011). The TE insertion trun- exaptation of TEs leading to analogous cell-specific cates CHKov1 creating four different altered transcripts, enhancers could be a more generalized phenomenon none of which contain all four exons of the wild-type than previously anticipated (Franchini et al. 2011). gene. This insertion was previously shown to confer resistance to insecticides, although the authors already Horizontal Transfer of TEs (HTT) and horizontal noted that the allele containing the insertion had been gene transfer (HGT) mediated by TEs evolving in the populations for a long time before insecticides started to be used (Aminetzach et al. 2005). It Besides being transferred from parent to offspring, TEs turns out that the allele carrying the insertion would can also be horizontally transferred between species. A initially have played a role in defending flies against horizontally transferred TE (HTT) can generate in the viral infection. However, flies carrying this particular new host species the same battery of mutations TE insertion found themselves pre-adapted to the intro- described for vertically transferred TEs (see Box 2). duction of insecticides in the middle of last century. Additionally, TEs can also act as vectors facilitating the Magwire et al. (2011) also provide evidence that horizontal transfer of new genetic content (Ochman CHKov1 alleles carrying duplications of the gene region et al. 2000; Frost et al. 2005). This phenomenon has containing the insertion, resulted in further resistance to been extensively demonstrated in prokaryotes. In viral infection. Similar to the CHKov1 allelic series, the eukaryotes, although TEs are capable of capturing and region containing a Cyp6g1 allele previously shown to transferring genes at a high frequency within a species confer resistance to pesticides (Daborn et al. 2002), has (Jiang et al. 2004; Morgante et al. 2005; Schaack et al. also suffered duplications and additional TE insertions 2010) they have not yet been found to transfer host that increased resistance to pesticides (Schmidt et al. genes between different species. Although horizontal 2010). These two examples support the view that alleles gene transfer (HGT) can also occur independent of TE of large effect may sometimes reflect the accumulation movement, in this review, we focus on TE-mediated of multiple mutations of small effect at key genes. Other HGT events. than in Drosophila, a clear role for TE insertions in insecticide resistance has also been demonstrated in HTT and HGT in prokaryote environmental mosquitos (Darboux et al. 2007). The binary toxin pro- adaptation duced by Bacillus sphaericus is used as an insecticide against the mosquito Culex pipiens. Resistance to this There is no doubt that prokaryotes increase their toxin is due to the insertion of a TE into the coding genetic variation by HGT (Ochman et al. 2000; Aminov sequence of the toxin receptor. The insertion induces a 2011). This mechanism rapidly integrates ‘foreign’ DNA new mRNA splicing event that creates a shorter tran- that gives the new host the opportunity to acquire new script. This new transcript encodes an altered receptor functions, and to colonize extremely diverse habitats unable to interact with the toxin resulting in resistance (Wiedenbeck & Cohan 2011). This phenomenon is of to this insecticide (Darboux et al. 2007). such importance in bacteria that the vast majority of Our last example connecting individual TE-induced species-specific DNA sequences that differ between two mutations and environmental adaptation comes from given species have been the result of different events of paleogenomic studies in mammals (Santangelo et al. horizontal transfer (Levin & Bergstrom 2000). The 2007; Franchini et al. 2011). Pomc, a gene involved in mechanisms by which TE- induced HGT can take place stress response and regulation of food intake and in prokaryotes are diverse and depend on which TE is energy balance, has two functionally overlapping enh- involved. HGT events often involve operons and gene ancers that originated from ancient unrelated TE inser- cassettes because horizontally transferred genes have a tions. In multicellular organisms, the presence of two better chance to be functional in the new host genome enhancers capable of guiding similar patterns in spatio- if they are transferred with their flanking sequences. temporal expression is common to several developmen- Box 3 briefly describes the main TE sequences often tal genes. Rather than being redundant, the presence of involved in HGT between prokaryote organisms. Addi- the two enhancers is required to overcome the chal- tionally, a recent review is available to the readers inter- lenges imposed by critical environmental conditions ested in the mechanistic details of HGT in prokaryotes such as changes in temperature (Frankel et al. 2010; (Toussaint & Chandler 2012).

Box 3 Horizontal 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.

Insertion Sequence: IS Composite transposon

TIR TIR tpase IS Structural genes IS

TIR: Terminal Inverted Repeat. tpase: transposase

Conjugative transposition Donor

Excision of circular intermediate

Transfer of a single strand of the circular intermediate

Replication

Integration

Acceptor

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 including 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).

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 reading 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 recombination 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 transferred 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 antibiotic 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.

Integron basic structure to acquire genes and build gene cassettes: Pc P2

int attI Pint

Int .

Constant Variable

Integron with exogenous genes

int: integrase gene. attI: sequences involved in recombination Pc, P2: Promoters for the acquired genes Pint: integrase promoter

Several instances of TE-induced HGT are related to 1 New catabolic and/or metabolic properties: We have adaptation to different environmental conditions (Och- chosen a recently described example that illustrates man et al. 2000; Hacker & Carniel 2001; Toleman et al. how the acquisition of new catabolic capacities has 2006; Cambray et al. 2010; Aminov 2011). In this section, allowed a host bacterium to better adapt to harsh we will focus on recent examples of HTT and HGT that environmental conditions. Cupriavidus metallidurans is play a role in (i) the acquisition of new catabolic and a b-proteobacterium adapted to live in environments metabolic properties, (ii) detoxiﬁcation, and (iii) patho- that contain heavy metal pollution (Mijnendonckx genicity and virulence. et al. 2011). A recent genome-wide analysis revealed

that there are 57 IS elements in this species, three of HGT caused by HTT has resulted in a better adapta- which show 100% identity with IS elements of a tion. In this case, pathogenicity may increase the number of other bacteria: Ralstonia pickettii, Burkholde- chances of wider spread and therefore increase the ria vietnamiensis, Delftia acidovorans and Comamonas likelihood of survival of the host bacterium. testosteroni. All these bacteria live in similar environments suggesting recent interactions and HTT events between these strains. These horizontally transferred HTT and HGT in eukaryote environmental adaptation TEs have been associated with genomic islands and with gene inactivation that affect the autotrophic Horizontal Transfer of TE events have been reported in growth capacity of C. metallidurans. Furthermore, one eukaryotic species as diverse as Drosophila, yeast and of the horizontally transferred TEs is also associated fungi (Hall et al. 2005; Loreto et al. 2008; Gilbert et al. with stress response (Mijnendonckx et al. 2011). The 2010; Schaack et al. 2010). These events may have evolu- previous example demonstrates the crucial role that tionary relevance only if the newly inserted TE is able to TEs can have both directly and indirectly in the adap- transpose, increase in copy number, or provide a new tive capacity of bacteria to harsh and polluted envi- cellular function. The capacity to transpose and increase ronments. in copy number in a new invaded genome has been 2 Detoxification: The catabolic capacities of bacteria are reported for Helitrons (Box 1) in several organisms not only directly linked to their own chances to sur- including mammals, reptiles, fish, invertebrates and vive in a changing environment, but also often con- insect viruses (Thomas et al. 2010). There is also evidence tribute to the survival of other organisms that share for the generation of new cellular functions after an HTT the same, often contaminated, environment. Wei and event for P-elements in Drosophila (Pinsker et al. 2001) collaborators showed that the gene methyl parathion and SPIN elements in mouse (Pace et al. 2008). Therefore, hydrolase, mph, involved in the degradation of organo- HTT could be an important evolutionary force shaping phosphorus compounds, was part of a typical com- eukaryotic genomes, although evidence for a specific role posite transposon (Tnmph; see Box 3) flanked by two in environmental adaptation has yet to be found. IS6100 sequences in Pseudomonas sp (Wei et al. 2009). As in prokaryotes, HGT has had an important role in The Tnmph composite transposon was successfully eukaryote genome evolution (Keeling & Palmer 2008; transferred in the laboratory to a wide range of bacte- Syvanen 2012). The evidence for HGT in diverse rial species, including some phylogenetically distant eukaryotes is expanding rapidly in organisms such as ones. These results suggest that Tnmph may contrib- nematodes (Haegeman et al. 2011) and fungi (Fitzpa- ute to the wide distribution of mph-like genes and the trick 2012). Many of the reported HGT events are adaptation of bacteria to organophosphorus com- related to environmental adaptation. For example, the pounds (Wei et al. 2009). The possibility of manipu- ability of distantly related unicellular eukaryotes to live lating bacteria that live in our everyday environments in anaerobic environments (Loftus et al. 2005) or the with composite transposons including genes like the transfer of antifreeze proteins in fish (Graham et al. mph, expands the already available possibilities to 2008) are due to HGT events. Although there is no evi- counteract some of the effects of contamination using dence yet of HGT mediated by TEs (Schaack et al. microorganisms (Wu et al. 2012). 2010), some authors predict that it will be soon discov- 3 Pathogenicity: Clostridium perfringens is a pathogenic ered (Keeling & Palmer 2008). For example, Helitrons bacterium that causes serious illness in different live- have a rolling-circle mechanism of transposition that stock animals. The different isolates of C. perfringens makes them especially prone to take adjacent 3′ unre- are classified based on which of four lethal toxins lated DNA along (Feschotte & Wessler 2001) and there- they produce (Sayeed et al. 2010). Type B isolates are fore are strong candidates to play a major role in HGT the most virulent because they are able to produce between eukaryotic species. two different toxins: beta-toxin and epsilon-toxin. Molecular characterization of type B isolates, demonstrated that these isolates contain not just one, but TE activation triggered by or in response to three different plasmids with virulence genes. The environmental stress identification of IS elements (IS1151) as well as genes As we mentioned in the introduction, Barbara McClin- involved in conjugative transposition (tcp; see Box 3), tock was the first to propose that the activation of TEs strongly suggested that both circular and conjugative in response to stress induces mutations that could help transposition may have been involved in the HGT of the organism adapt to new environmental conditions these large virulence platforms (Sayeed et al. 2010). (McClintock 1984). TEs would therefore play a key role This is another example of a case in which a series of

© 2013 Blackwell Publishing Ltd TEs IN ENVIRONMENTAL ADAPTATION 1511 in translating changes in the external environment into motifs required for the activation of stress-responsive changes at the genomic level. Indeed, TEs respond genes (Grandbastien et al. 2005). The possibility of directly to some specific stress situations and in some acquiring changes in the cis-regulatory elements entails cases the specific TE sequences responsible for the the opportunity to respond to new and different envi- stress response have been identified. This is the case of ronmental factors. Examples of TEs containing these several Long Terminal Repeat (LTR) retrotransposons cis-regulatory elements are abundant and are very well that contain cis-regulatory elements in their 5′ LTR that represented in the literature. In Box 4 we describe some trigger transposon expression in response to a particu- of the classical examples, such as Tnt1 and Bare1 in lar stimulus (Kumar and Bennetzen 1999). These regula- tobacco and barley, respectively. tory sequences are similar to the well-characterized

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 transcription, and the capping signal. The LTR is subdivided in the U3, R and U5 domains. Different specific DNA elements 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 references for further details.

5’ LTR

B boxes

U3 R U5 . 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

Although the specific sequence that responds to stress tricornutum (Maumus et al. 2009). Because LTR elements has not been identified, for other LTR retroelements it are very abundant in this diatom genome, the authors has been shown experimentally that the LTR is suffi- suggest that their massive activation may probably con- cient in itself to activate TE transcription in response to tribute to major genome rearrangements that would stress. This, for example, is the case of the activation allow this organism to respond rapidly to changing under nitrate starvation stress of the Blackbeard environmental conditions (Maumus et al. 2009). Further- retrotransposon in the marine diatom Phaeodactylum more, the authors show that the retroelement is hy-

© 2013 Blackwell Publishing Ltd 1512 E. CASACUBERTA and J. GONZALEZ pomethylated in response to nitrate starvation, which genes. However, the opposite is also true: some TEs provides a link between environmental stress and chro- specifically integrate close to stress-responsive genes. matin remodelling in diatoms. Tf1, an LTR retrotransposon from Schizosaccharomyces Besides being present in the 50LTR, transcriptional pombe, shows a tendency to integrate in a 500 bp win- regulatory sequences are also located in the open read- dow upstream of ORFs (Behrens et al. 2000; Bowen et al. ing frames of some LTR retrotransposons (Servant et al. 2003). Guo & Levin (2010), further demonstrate that in 2008, 2012). This is the case for the LTR retrotransposon different activation experiments the newly integrated Ty1 of Saccharomyces cerevisiae. The transcription of the Tf1 elements insert close to RNAPol II promoters but Ty1 retrotransposon is induced, among other specific interestingly, there was no correlation with the level of stress conditions, by a shortage of adenylic nucleotides transcription of the targeted promoters. Instead, Tf1 had (Todeschini et al. 2005). A recent study by Servant and a strong preference for promoters that are induced by collaborators identifies the mechanism of activation of specific stress conditions, such as genes induced by this TE (Servant et al. 2012). It turns out that severe ade- cadmium and heat. The targeting of Tf1 to stress- nine starvation activates the expression of the transcrip- induced promoters represents a unique response that tion factor TYE7. TYE7 binds to the E-boxes, located may function to specifically alter expression levels of downstream of the transcription start site of the TYA stress response genes (Guo & Levin 2010). gene, and alters Ty1 antisense transcription. As a conse- Activation of TEs is not always directly triggered by quence, there is an increase in sense Ty1 mRNA that a specific stress but the effects that such stress causes leads to retrotransposition of this element and coactiva- in other cellular mechanisms allow a rapid activation tion of the expression of genes adjacent to Ty1 inser- of some particular TE copies (Dai et al. 2007; Coros tions (Servant et al. 2008, 2012). et al. 2009). An interesting example to illustrate this Other than LTR retrotransposons, class II elements kind of secondary response is the activation of the Ty5 such as Miniature Inverted-repeat Transposable Ele- retrotransposon in Sacharomyces subject to starvation ments (MITEs) have also been shown to respond specif- stress. Ty5 in Sacharomyces preferentially integrates ically to some stress conditions. This is the case, for into heterochromatic regions. This pattern of integra- example, for the mPing MITE in rice. In some rice tion is directed by the interaction between the Ty5 in- strains mPing has amplified from c. 50 to 1000 copies tegrase targeting domain (TD) and the heterochromatic (Naito et al. 2006). The analyses of the insertion sites in protein Sir4 when Ty5 is phosphorylated (Zhu et al. the strains that have undergone this burst of transposi- 2003; Dai et al. 2007). When Sacharomyces is faced tion revealed that under normal growth conditions with starvation, numerous signal transduction path- mPing elements have a modest impact on the host ways, among them the protein kinase A pathway, are because of highly evolved targeting mechanisms that affected. When the TD of Ty5 is not phosphorylated, minimize the effects on host gene expression (Naito there is no interaction with Sir4 and the pattern of et al. 2009). However, mPing is able to confer a stress- integration of this retrotransposon changes radically. inducible state to the nearby genes regardless of Under such conditions Ty5 becomes a potent endoge- whether the TE is inserted at their 5′ or the 3′ region, nous mutagen that integrates randomly throughout the suggesting its potential to act as an enhancer element. genome, including into gene-rich regions. This change Although a specific sequence inside the mPing element in the pattern of integration of Ty5 is observed in has not been defined, it is clear that mPing is able to response to some specific stress conditions (e.g. starva- provide the surrounding genes the capacity to respond tion stress) and not others (e.g. heat-shock, DNA dam- to certain stress situations but not others (e.g. cold and age, osmotic shock or oxidative stress). The regulation salt but not drought). Because of the high copy number of Ty5 phosphorylation by stress, demonstrates that of mPing in rice genomes, its specific transcription and TEs provide the cell with a prewired mechanism to transposition could result in new gene regulatory net- reorganize the genome in response to environmental works of coordinated expression that would contribute challenge (Dai et al. 2007). to a fine-tuned response of this organism to specific Finally, we will highlight two of the several recent stress factors. The creation of such regulatory networks examples from the literature indicating that noncoding in response to certain stresses could be a widespread and small interfering RNAs are also another possible phenomenon in nature since evidence for rapid and path by which TEs respond to stress (Hilbricht et al. massive amplification of MITEs has been found in 2008; Mariner et al. 2008; Lv et al. 2010; Yan et al. 2011; virtually all sequenced eukaryotic genomes and even in McCue et al. 2012). Possibly one of the best-studied some prokaryote ones (Naito et al. 2009). stress responses in eukaryotes is the one triggered by The case of mPing illustrates how the integration site heat-shock. However, the exact mechanisms by which of some TEs may confer stress-inducibility to nearby most organisms subject to a heat-shock manage to

© 2013 Blackwell Publishing Ltd TEs IN ENVIRONMENTAL ADAPTATION 1513 repress the transcription of most genes are still et al. 2007). Therefore, containing a certain number of unknown. Mariner and collaborators discovered one potentially active TEs may increase the genome ability mechanism of response to heat-shock involving TEs in to cope with environmental changes. humans (Mariner et al. 2008). Alu elements function as cell stress genes: different stress conditions cause an Concluding remarks increase in the expression of Alu RNAs, which rapidly decreases upon recovery from stress (Hasler€ & Strub Given the opportunistic nature of evolution, the capac- 2006). Alu RNA has been implicated in regulating ity of TEs to generate mutations of great variety and several aspects of gene expression such as alternative magnitude suggests that TEs are important players in splicing, RNA editing, translation and miRNA expres- genome evolution. Some authors may consider that the sion and function (Hasler€ & Strub 2006; Hasler€ et al. capacity of TEs to create genetic diversity that might 2007). In humans, Alu elements but not other Pol III result beneficial for the host genome has not been transcribed genes are activated by heat stress. Mariner exploited often, nor has it necessarily been subject to et al. (2008) demonstrated that the mRNA of the Alu positive selection. In this review, we argue that there element block transcription by binding RNApol II and are many examples that provide solid grounds for the entering the repressor complexes that will be loaded beneficial effect of TEs in host genome evolution in gen- onto the promoters of the repressed genes. Interestingly, eral and in host environmental adaptation in particular. in mouse cells the SINE B2 element activated upon Note that several of the works summarized in this heat-shock is also able to repress transcription of many review (e.g. Gonzalez et al. 2008; Naito et al. 2009; Fran- genes using a similar mechanism. Although the B2 chini et al. 2011) strongly suggest that the particular SINE derived from tRNA from mouse, and the human cases described may represent the tip of the iceberg. Alu derived from 7SL-like precursor, do not have Moreover, identifying TE insertions involved in envi- sequence identity or similar RNA secondary structures, ronmental adaptation depends ultimately on our ability their similar effects on the host heat–shock response to identify a given nucleotide sequence as a TE or a TE suggest that these two SINE elements have converged remnant. As such, we are still likely underestimating to the same biological function. the role of TEs in environmental adaptation just because An additional example reveals how siRNAs gener- of our limitations to identify TE insertions. We antici- ated by a retrotransposon confer the capacity to pate that in the next years increased availability of gen- respond to desiccation to the callus of the plant Cratero- ome sequences, the development of new tools to stigma plantagineum (Hilbricht et al. 2008). CDT-1 was accelerate the discovery of TE insertions (Fiston-Lavier first identified as a plant desiccation tolerant gene and et al. 2011; Flutre et al. 2011; Makalowski et al. 2012) later recognized as being a TE, although it is still pend- and the increased knowledge about which genes and ing classification. Hilbright and collaborators reported traits are relevant for adaptation will further support that while no translation from this element is needed the prevalent role of TEs in environmental adaptation. for the desiccation tolerance response, the transcription and the posterior production of related siRNAs from Acknowledgements CDT-1 is essential to induced expression of desiccation- inducible genes. We thank Anna-Sophie Fiston-Lavier, Lain Guio, Ruth Hersh- Overall, the examples described previously strongly berg, Lidia Mateo, Dmitri A. Petrov and Alfredo Ruiz for suggest a role of TEs in the ability of the host to respond critically reading the manuscript. This work was supported by a grant from the Spanish Ministry of Science and Innovation to changes in the environment. The evidence that only BFU2009-08318/BMC awarded to E.C. and by a Ramon y Cajal some specific TE families, and not all the TEs in the gen- grant (RYC-2010-07306), a Marie Curie CIG grant (PCIG-GA- ome, are activated in response to stress and the evidence 2011-293860) and a National Programme for Fundamental that these TEs respond to some specific stress conditions Research Projects grant (BFU-2011-24397) awarded to J. G. and not others, strongly suggest that activation of TEs by stress is not only a byproduct of genome deregula- References tion. The consequences of TE activation in response to stress are diverse. Stress-activated TEs: (i) contribute to Aminetzach YT, Macpherson JM, Petrov DA (2005) Pesticide major genomic rearrangements (Maumus et al. 2009), (ii) resistance via transposition-mediated adaptive gene trunca- tion in Drosophila. 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