The contributions of transposable elements to the structure, function, and evolution of plant genomes.

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Annu. Rev. Plant Biol. 2014.65. Downloaded from www.annualreviews.org by National Chung Hsing University on 03/27/14. For personal use only.

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The Contributions of Transposable Elements to the Structure, Function, and Evolution of Plant Genomes Jeffrey L. Bennetzen and Hao Wang Kunming Institute of Botany, Kunming 650201, China Department of Genetics, University of Georgia, Athens, Georgia 30602; email: [email protected], [email protected]

Annu. Rev. Plant Biol. 2014. 65:19.1–19.26

Keywords

The Annual Review of Plant Biology is online at plant.annualreviews.org

epigenetics, gene regulation, genome rearrangement, genome size, transposon domestication

This article’s doi: 10.1146/annurev-arplant-050213-035811 c 2014 by Annual Reviews. Copyright All rights reserved

Abstract Transposable elements (TEs) are the key players in generating genomic novelty by a combination of the chromosome rearrangements they cause and the genes that come under their regulatory sway. Genome size, gene content, gene order, centromere function, and numerous other aspects of nuclear biology are driven by TE activity. Although the origins and attitudes of TEs have the hallmarks of selfish DNA, there are numerous cases where TE components have been co-opted by the host to create new genes or modify gene regulation. In particular, epigenetic regulation has been transformed from a process to silence invading TEs and viruses into a key strategy for regulating plant genes. Most, perhaps all, of this epigenetic regulation is derived from TE insertions near genes or TE-encoded factors that act in trans. Enormous pools of genome data and new technologies for reverse genetics will lead to a powerful new era of TE analysis in plants.

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Contents


INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2 PLANT TE TYPES AND ORIGINS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.2 TE SPECIFICITIES AND REGULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.3 TEs AND THE SELFISH:USEFUL:PARASITIC:CO-OPTED DNA DEBATE . . . 19.7 TE EFFECTS ON GENOMES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.8 Genome Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19.8 Genome Rearrangement: Ectopic Recombination and Chromosome Breakage . . . . .19.10 Other Effects of TE Presence on Genome Structure and/or Function . . . . . . . . . . . . .19.10 TE EFFECTS ON GENES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.11 Gene Mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.11 Gene Structural Modification After Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.11 Gene Movement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.11 Gene Creation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.12 Pseudogene Creation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.14 Gene Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.14 Epigenetic Gene Regulation and TE Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.16 Differences in TE Qualitative and Quantitative Activities Across Generations: Random or a Selected Trait? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.18 CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19.20

INTRODUCTION Ever since the discovery of transposable elements (TEs) by the cytogeneticist Barbara McClintock during her investigations of chromosome breakage in maize (88), the origins, roles, specificities, and regulation of these mobile DNAs have been subjects of great interest. McClintock originally named the maize transposons “controlling elements” because of her observation that they could alter the expression of genes near or at the site of TE insertion (90). The generality of TE distribution and activities was recognized only after the discoveries of TEs in bacteria (reviewed in 122). The first cloning of TEs from plants, in the early 1980s, brought plant TE research into the realm of molecular genetics, leading to a rebirth of what had become a rather quiescent research area. Hundreds of articles are now published every year that describe various aspects of plant TE biology. This review briefly discusses the biology of TEs, including their origins, specificities, regulation, and transmission; because there have been several recent reviews on these subjects (36, 39, 103, 120, 124), we concentrate on the effects TEs have on the structure, function, and evolution of the plant genes and genomes that they inhabit.

PLANT TE TYPES AND ORIGINS As in all other eukaryotes, TEs in plants are categorized as class I (retroelement) or class II (DNA element) transposons. The class I elements transpose through an RNA intermediate, wherein the RNA transcript of a chromosomally integrated copy is used as a template to make DNA (by reverse transcriptase, with RNaseH), and then the integrase or endonuclease component allows insertion of the double-stranded DNA back into the host genome (111). Hence, retroelements do

TE: transposable element

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not excise during transposition. The class II elements transpose through a DNA intermediate, with the majority excising from the chromosome using the transposase enzyme and then integrating elsewhere in the genome by the action of this same transposase. In most cases, the repair of the donor site for these cut-and-paste TEs occurs by conversion using the sister chromatid or homolog as a template, such that no net excision is detected. The other category of plant class II DNA elements is exemplified by the Helitrons. These TEs have structural and coding similarities to specific transposons of bacteria that exhibit a rolling-circle transposition process, which should not yield an excision outcome, although a recent report has uncovered evidence of somatic Helitron excision in maize (73). Individual classes of TEs can be further categorized into families, which differ in their transposase specificity and/or their degree of sequence homology (for a description of the families of TEs and how these different families are defined, see 139). Most TE families have fully intact (autonomous) copies that encode all of the element-specific activities, such as transposase for cut-and-paste elements, replicase/helicase for Helitrons, and GAG packaging proteins and reverse transcriptase for retroelements. In any genome where TEs of a particular family exist in multiple copies, the majority are usually defective elements that do not encode some or any of the TE-specific genes. These defective TEs utilize the proteins encoded by autonomous elements in trans. In a particularly well-studied case, the short interspersed (retro)elements (SINEs) in the human genome can become major parasites on the long interspersed (retro)elements (LINEs) that provide their trans-acting functions because the SINEs are selected exclusively for the potential to make new copies (99). TEs are nearly ubiquitous in eukaryotes, with only a few tiny-genome species exhibiting an apparent complete absence (reviewed in 108). All TE classes exhibit an ancient lineage, with clear prokaryotic origins and a general history of vertical descent (140). However, many prokaryotic TEs exhibit frequent horizontal transmission, and some eukaryotic lineages exhibit horizontal transfer of a few TE families (22, 34; reviewed in 115). Such conclusions have also been reached in plants (39). However, specific TE families can easily and repeatedly become extinct in particular lineages owing to high rates of DNA removal (84, 137), so presence/absence differences per se are not a reliable indicator of horizontal transfer. As exemplified by SINEs, a non-TE sequence can sometimes turn into a defective TE merely by randomly mutating to a structure that is recognized and mobilized by transposition enzymes (see, for instance, 71).

SINE: short interspersed element LINE: long interspersed element LTR: long terminal repeat

TE SPECIFICITIES AND REGULATION Most, perhaps all, TE families show strong insertion biases. For instance, the high-copy-number retroelements called long terminal repeat (LTR) retrotransposons, which contribute the majority of the maize genome, have never been detected to generate a de novo insertion mutation in any maize gene, yet lower-copy-number TEs of this type are often found as de novo gene mutagens. Kakutani and coworkers (126) recently found de novo insertions of an LTR retrotransposon from the Arabidopsis lyrata genome that preferentially targets centromeric regions. Studies of LTR retrotransposon distribution in maize indicate that copy number inversely correlates with genic insertion bias (3). Similarly, low-copy-number DNA elements like Mutator in maize show preferential insertion into open chromatin (82). The abundant nonautonomous DNA elements known as miniature inverted-repeat TEs (MITEs) preferentially insert near, but not into, genes (60, 97), especially into the matrix attachment regions that are predicted to provide buffers between genes and adjacent seas of epigenetically silenced TEs (125). There is an obvious ecological logic to this generalized behavior. If a TE family’s copy number is low, then it is appropriate to maintain activity as efficiently as possible, which can be accomplished by inserting into an active part of the www.annualreviews.org • TE Contributions to Plant Genome Biology


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Genes Copias Gypsys Other class I TEs CACTAs MITEs Other class II TEs

Figure 1


A heat map showing the distributions of genes and different classes of TEs in a typical grass genome. The genomic region shown is chromosome 1 of Setaria italica (12). High concentrations of a particular sequence feature are indicated by red and low concentrations by blue, with gradations between these two extremes. The triangles indicate the approximate position of the centromere on this chromosome. Gypsy and Copia are two superfamilies of long terminal repeat (LTR) retrotransposons; CACTAs and miniature inverted-repeat TEs (MITEs) are two categories of DNA (class II) transposons (see 139).

genome (e.g., in or near genes). If a TE family has thousands of copies scattered across the genome, however, then transmission to subsequent generations is guaranteed, but genic insertions need to be avoided because thousands of insertional mutations would be highly deleterious to the TE host (7). TE distribution in a genome is a function of both specificity of insertion and possible differential rates of removal in different genomic regions (81, 85). Figure 1 shows an example of standard nonrandom accumulation patterns, depicting the different TE classes in the Setaria italica genome (12). Because the same mechanisms act similarly to remove all LTR retrotransposon families (28, 84, 85, 129), the differences in the distribution of LTR retrotransposons of the Gypsy and Copia superfamilies appear to be determined largely by different insertion specificities. How TE insertion specificities are generated in plants is unknown, but the LTR retrotransposon specificities of yeast are an outcome of different families showing specific integrase interactions with unique chromatin proteins (66, 148). Given the enormous differentiation potential resulting from the many variations in histone modification and DNA methylation (reviewed in 127), it is likely that there are thousands or even millions of different types of chromatin, each with the potential for attracting a novel TE family with a novel transposase or integrase (6). In fact, Baucom et al. (3) proposed that each TE family might provide a unique reagent to isolate each unique class of heterochromatin. One interesting type of specificity is exhibited by maize Helitrons. These elements preferentially insert near each other, in the same orientation (142). This specificity is not an outcome of nearby transposition specificity, like that seen for Ac/Ds in maize (18), because the resultant adjacent Helitrons are usually not as closely related in sequence to each other as they are to other Helitrons in the same genome. Instead, we propose that the Helitron replicase/helicase protein may be the sole source of the insertion specificity (Figure 2). The majority of all proteins that act on DNA, a twofold-symmetric molecule, are functional as multimers. McClintock’s demonstration of the suppressor function of the Suppressor/Mutator (Spm) TEs (90) indicates that transposases are often bound to a TE even when the TE is not being mobilized. Hence, with a rolling-circle replication process, it is possible that an integrated Helitron would have a replicase/helicase protein bound to its 5 end, and a mobilized Helitron would have 5 to 3 DNA synthesis that would yield a replicase/helicase protein at its 3 end. If these 5 and 3 replicase/helicase proteins found each 19.4

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Helicase/replicase protein

Helitron Gene

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Binding


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Insertion

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Figure 2 A model to explain the insertion specificity observed for Helitron TEs in maize. Helitrons are often found near each other, in a direct tandem orientation. The model shows a replicating Helitron free in the nucleus (upper right), which has its helicase/replicase protein ( puzzle piece) at the 3 end of the element. This helicase/replicase finds a second protein of the same type to form a homodimer, and this second helicase/ replicase is sitting on the 5 end of an already-inserted Helitron. This association now places the inserting TE near the already-inserted TE, in the same orientation, facilitating its targeting to this region.

other to form a multimer, then this would position the mobilized Helitron for insertion near the already-inserted Helitron and in the same orientation. The distributions of TEs across a genome are not exclusively an outcome of insertion specificity. TE sequences can be rapidly removed (see below), and so differences across the genome in the relative rates of removal could also fully or partly explain TE distribution profiles. For instance, it has long been predicted and observed that TE insertions into genes are usually detrimental (as is true of most mutations of all types), thereby leading to their eventual removal by natural selection. More generally, unequal homologous recombination and gene conversion are also efficient processes for DNA removal and are most active in genic (euchromatic) regions (40, 85, 147), thus generally explaining why TEs tend to accumulate in recombination-poor regions like pericentromeric heterochromatin or the Y chromosome in humans. The regulation of plant TEs is almost as poorly understood as their insertion specificities. TEs cannot transpose, of course, if they are found in a nucleus that does not contain intact TE transposition genes, like those encoding transposase or integrase. Because TEs move about, an autonomous element in a lineage is often heterozygous for presence/absence at any particular location, and thus it can be lost by simple segregation. Moreover, epigenetic silencing of TEs results in a higher rate of point mutation owing to the higher transition rate of 5-methylcytosine (113), so any silenced TE is soon permanently inactivated by mutation. It is therefore likely that many TE families do not contain any potentially active autonomous element in a genome, leading to zero chance for reactivation in a derived lineage. Analysis of TE activational history across panicoid grasses suggested that vertical transmission of a potentially active system is rare but can be traced to particular branches of a phylogenetic tree (35). In fact, because of this very rapid rate of permanent inactivation, it seems likely that the only reason active TEs can be found in any www.annualreviews.org • TE Contributions to Plant Genome Biology


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species is the very high level of polymorphic distribution across any population that is generated by their initial activity, thus leading to the rare individual where activity is retained, largely by chance and/or by rare activation/amplification. Different TEs show different expression patterns, commonly associated with different transcription factor binding sites in their promoters (reviewed in 15). These expression patterns can be quite different for orthologous TEs even in closely related species (51). In plants, activation of LTR retrotransposons by tissue wounding (e.g., insect feeding) is particularly common (46), suggesting a viral etiology where the LTR retrotransposons are recognizing the presence of a vector to the next plant. However, despite this common transcriptional activation mode, horizontal LTR retrotransposon transmission is rare at best (39), so the actual value (if any) of this somatic activation remains unknown. Other TEs show different transcriptional activation specificities whose usefulness to the TE or host is equally obscure. Some TE expression patterns appear to have been co-opted or “exapted” by the host to allow a whole suite of genes to acquire a coordinated set of expression patterns (97; reviewed in 15), as discussed below. Some TEs encode negative self-regulators, presumably to maintain their copy number at manageable levels in the genome. The negative dosage effect of the Ac transposase provides an especially interesting case where a single gene product is both activator and repressor (89). The most dramatic negative regulation of TEs in eukaryotes is by epigenetic processes that appear to have evolved from similar phenomena in bacteria (2; reviewed in 13, 16). Epigenetic silencing of a TE may be initiated by the presence of double-stranded RNA derived from senseantisense transcription either of internally rearranged elements (119) or across nested element insertions (114). These double-stranded TE RNAs are recognized as foreign by enzymes that create DICER targets, leading to small interfering RNAs (siRNAs) that induce the full suite of heterochromatin-creating, RNA-cleaving, and translational-suppression outcomes (reviewed in 118). The packaging of TEs into heterochromatin both decreases their expression and inhibits unequal homologous recombination because heterochromatic regions tend to generally be recombination poor. The importance of this ectopic recombinational suppression by heterochromatin seems to be underappreciated. If ectopic recombination of each pair of related TE sequences in maize, for instance, occurred at the same rates as ectopic recombination of tandemly duplicated gene families (e.g., approximately once in a few thousand gametes) (96, 110), then there would be hundreds of chromosomal rearrangements per cell per meiosis, yielding gametic gene imbalances that would guarantee zero-percent fertility. The best-understood case of how an active TE is recognized as a target for silencing comes from the research of Lisch and coworkers (119) in maize. In this case, a defective transposon called Mu killer (Muk), a dominant inhibitor that creates epigenetic silencing of the autonomous MuDR element, was found to have been derived from the autonomous MuDR by partial deletion and internal duplication/inversion, leading to a hairpin structure whose transcripts are processed into small RNAs, presumably by the standard epigenetic machinery. Lisch and coworkers postulated that this may be a standard aspect of TE silencing for any family, particularly as these defective (zombie) TEs are expected to accumulate with greater likelihood as TE copy numbers increase, thus eventually leading to a self-induced suppression that would limit TE activity (80) as these zombies kill off their closest living relatives. McCue et al. (92) recently found that some TEs encode siRNAs that target genes involved in the establishment of an epigenetically silenced state. This suggests an arms-race scenario, where these epigenetic silencers would now be selected for their ability to escape targeting by these TE-encoded siRNAs. Although many genomes appear to lack any autonomous element of specific families, despite abundant defective TEs of that family, many plants do contain autonomous TEs that are quiescent


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because of their epigenetic state. Relief from this silencing can occur by such dramatic stresses as repeated chromosome breakage (reviewed in 91), mutation in a silencing gene (24), passage through tissue culture (1, 20, 47), and, in some cases, formation of an allopolyploid genome (64, 87). All of these scenarios can be explained by an altered epigenetic balance and/or promotion of extensive chromatin remodeling owing to exceptional DNA repair demands. However, such activation is not necessarily dependable (for instance, many initiated polyploidies do not lead to general TE activation) and would also not explain a high level of persistence once TEs are reactivated (given that their silencing siRNAs and the full epigenetic machinery are still present). One interesting aspect of this story is that a highly expressed autonomous TE can overcome the presence of high levels of silencing components, including siRNAs (80).


TEs AND THE SELFISH:USEFUL:PARASITIC:CO-OPTED DNA DEBATE It is surprising to us that there continues to be a debate on whether TEs are selfish/parasitic or useful. An overinterpretation of the McClintock (91) model that TEs can remodel genomes in response to genomic stress suggested that, after a major stress and monstrous genome rearrangement, a rare individual would survive because it had so greatly rearranged its genome and altered its gene transcription patterns that it had created the novelty to survive the severe stress. This seems unlikely, given that the great majority of TE-induced changes are detrimental, and it certainly goes well beyond what McClintock proposed. If the possibility to create rare, massively rearranged individuals to escape extinction were the reason for TEs’ existence, then one would expect common instances of new species having very narrow genetic foundations, with genomes that looked very unlike their closely related species in gene content, gene order, and gene regulation. However, different species in closely related taxa are found to have gene content, gene order, gene structure, and gene expression patterns that are quite similar to those of their sister species (reviewed in 8). Moreover, a process that is used only once every few million years for a vital function would not be able to be maintained in the face of genetic drift unless it had some second vital function that was needed on a more routine basis. McClintock (91) stated that the diversity generated by TE action should be useful in the evolution of novelty, but she gave no time frame for this value. Of course, genetic diversity per se contributes to long-term adaptation, so there is every reason to believe that TEs will be a significant part of that mix. However, current usefulness does not in any way negate the possibility of selfish origins. Additionally, it is difficult to see how Darwinian natural selection would not lead to selfish or parasitic DNAs (30, 102). If one believes that an enhanced ability to be transmitted into the next generation is a valid basis for selection, and/or if one believes in the existence of transmissible viruses and other microbes, then it is difficult to understand why one would not believe in vertically transmitted TEs as parasites or commensals. Of course, there is no shortage of examples of TEs that have become useful or even essential to their host genome (see below). Once again, basic Darwinian theory indicates that anything heritable in a genome can evolve and that this evolution might lead to an unexpected emergent property (such as, for a TE, usefulness to its host). Once such a chance mutation occurs, it would undergo natural selection based on its effects on host fitness, probably including selection against its natural TE-derived instability. Hence, examples of useful TE-derived genes or other genome components in no way refute the selfish or parasitic DNA model, and it remains odd that some scientists continue to support an either fully useful or fully selfish/parasitic paradigm. www.annualreviews.org • TE Contributions to Plant Genome Biology


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LTR retrotransposon

Gene

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The standard structure of a gene-rich region of a medium-to-large angiosperm genome. The mean flowering plant genome is over 5.5 Gb, and species with genomes larger than 2 Gb have so far always had this standard genome structure, with nested long terminal repeat (LTR) retrotransposons inserted between genes. Older LTR retrotransposons are generally found at the bottoms of these stacks, indicating that the nested structures are caused by multiple rounds of independent transposition (113). Gene-poor regions like pericentromeric heterochromatin have this same structure, but with fewer genes and larger LTR retrotransposon blocks.

TE EFFECTS ON GENOMES Genome Size Angiosperm nuclear genomes vary enormously in overall DNA content, from the 63 Mb of two carnivorous species of the genus Genlisea (48) to a predicted 148,852 Mb in Paris japonica (105). Some of this variation is due to differences in ploidy (121), but differences in TE content are severalfold more important (55, 65, 98). Although it has been clear for some time that differences in TE content, especially the LTR retrotransposons that make up the majority of most plant genomes, are the major players in angiosperm genome size variation (112), the mechanistic and/or regulatory reasons for these differences have not been clear. Although not enough cases have been investigated, it generally appears that very large angiosperm genomes are derived from the massive amplification of a small number of LTR retrotransposon families in that genome (76, 114, 144), and the majority of these LTR retrotransposons are found as nested series of insertions, with the older elements at the bottom of each nest (113) (Figure 3). Smaller genomes usually have this same sort of LTR retrotransposon structure in their pericentromeric heterochromatin, but genic regions are mostly free of large TE assemblages. For instance, a comparison of LTR retrotransposon family content between the ∼400-Mb rice genome and the ∼2,400-Mb maize genome shows that approximately the same number of TE families are present in each, but the larger maize genome has some LTR retrotransposon families with thousands of copies per genome, whereas copy numbers do not exceed hundreds per nucleus for any LTR retrotransposon family in rice (3, 4). In some cases, a very few elements have become very active in one lineage and then given rise to a major genome size increase in just a few million years (32, 106). In a detailed comparison of Zea mays with Zea luxurians, numerous LTR retrotransposon families were seen to have greatly increased only in Z. luxurians, whereas a few families increased in both Zea species (35). The sum of all these changes was an approximately twofold-larger Z. luxurians genome, accomplished in 50 base pairs) are present in a genome, it is clear that unequal recombination between TEs will be a major factor in chromosome rearrangement in any case where the TEs are not in a heterochromatic state that severely suppresses homologous recombination (see below). McClintock (90) observed numerous chromosomal rearrangements in maize that were caused by the presence of an unusual (“breaker Ds”) TE with specific chromosome breakage activities. The actions of such an element, and particularly two in the same nucleus, can lead to all categories of chromosomal rearrangement, including deletions, duplications, inversions, and translocations.

Other Effects of TE Presence on Genome Structure and/or Function One of the primary characteristics of centromeres is their repetitive nature. In plants, many of these repeats are provided by LTR retrotransposons, some of which accumulate primarily at 19.10

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centromeric locations (41, 72, 126, 132, 133). Centromeres exhibit exceptional haplotype polymorphism, much of it derived from unequal homologous recombination between TEs and other repeats (85; reviewed in 86). TEs appear to be the origins of at least some of the short tandem repeats most closely associated with centromere function (117), and their rearrangement may generate the raw material for meiotic drive selection (25). In this regard, LTR retrotransposons may provide the promoters for transcription into flanking repeats and other sequences that yield a double-stranded RNA product sufficient to create the epigenetic structural outcome that is argued to be one basis of centromere function (78). Additional genome-level TE effects should be discovered as more genomes are investigated. Anything present in a genome has the potential to evolve a new (emergent) function, and TEs are a major presence. It seems likely that some truly interesting cases will be discovered, perhaps at the same level of novelty as seen in the genus Drosophila, where three LINE-like transposons have evolved to replace standard telomere structures, thus allowing the telomerase gene to be lost from this lineage (reviewed in 104).

TE EFFECTS ON GENES Gene Mutation Of all the activities of TEs, their inactivation of genes by insertion is the best characterized. In some species, the majority of mutations identified in a screen of “natural” inactivations turn out to be associated with TEs, although some species show more inactivations by point mutations or other sources of insertions or deletions (indels) (100). Regulatory mutations are even more likely to be caused by TEs, partly because TEs routinely carry regulatory modules of their own and partly because the small target size and redundancy in gene regulation components for the average gene lead to a rarity of point mutations or small indels that yield a detectable regulatory effect. Insertions in genes are not always inactivational, as exemplified by cases where insertions in introns, 5 leaders, or 3 trailers can affect the sites of RNA processing or polyadenylation. The following sections describe specific aspects of the mutation of genes by TEs.

Gene Structural Modification After Insertion Many TEs, especially class II elements, tend to be self-mutagenic, perhaps as an outcome of DSB misrepair after attempted excision (146). Hence, a TE inserted into or near a gene provides ample subsequent variation to evolve new gene properties. Particularly interesting aspects of this kind of modification are the short indel legacies of the TE insertion that are left behind when a cut-and-paste element excises (44, 61, 116). When in frame, these TE footprints could be significant factors in the evolution of the protein sequence within any gene, especially in a genome like that of maize, where genes have gone through many cycles of TE insertion and excision.

Gene Movement When comparing the genomes of closely related organisms, the TEs are commonly found in different locations, particularly in angiosperms, where TE turnover/removal rates often have halflives of much less than 2 million years (84, 130, 137). Genes, in contrast, are fairly well conserved in number, order, and orientation (reviewed in 8). Recent evidence suggests that the exceptions to local genomic microcolinearity are caused mostly by TEs (135). One proven source of mobility is through TEs that acquire fragments of genomic DNA, including genes (3, 31, 33, 59, 62, 69, www.annualreviews.org • TE Contributions to Plant Genome Biology


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94, 136, 142). On very rare occasions, entire genes are acquired, amplified, and scattered about the genome (58). However, the most important process disrupting microcolinearity is associated with larger fragments (up to 50 kb) containing one or several genes that appear to be moved as an outcome of ectopic template choice in DSB repair, at acceptor sites where TEs may have been responsible for the DSB (135).

Gene Creation


Many studies in many organisms have demonstrated the “domestication” of transposon genes, often via the fusion of a TE with the regulatory and/or coding regions of a host gene (reviewed in 38). Numerous cases are known in plants, including the Daysleeper transcription factor gene, which regulates morphogenetic development (14); the FAR1 and FHY3 transcription factor genes, which appear to regulate aspects of the light response (54, 77); and the Mustang gene, which is associated with regulation of hormonal homeostasis (63). All of these “new” plant genes are derived from the transposases of class II elements, so they were poised to be involved in host DNA binding and gene regulatory activities. Lockton & Gaut (83) recently scanned Arabidopsis genes for fragments of TE genes within their coding regions. They estimated that >1.2% of known Arabidopsis protein-encoding genes contain some TE-related protein-encoding segments, with an overrepresentation of Copia LTR retrotransposons and CACTA class II TEs relative to their current abundances. Further studies along these lines are needed, particularly if they employ a phylogenetic perspective where the lineages and timings of acquisitions can be ascertained. Many of the candidate “new” genes in plants are derived from a more complex process, however. Class II TEs like Helitrons and Pack-MULEs (59, 69, 94, 142) commonly acquire multiple gene fragments in a single TE. The chimeric genes inside elements are often transcribed and can be alternatively processed into numerous final products (1, 59, 94). For instance, Lal and coworkers (1) identified a minimum of 11,000 different transcripts in a single maize line that were derived from differential processing of transcripts from Helitron-created chimeric genes, many showing tissue-specific alternate processing. The acquired fragments in Helitrons are primarily (∼93% of the time in maize) in the same orientation as the TE promoter, thus decreasing their antisense contributions and increasing their chance to encode a functioning protein (142). Despite the abundance of these chimeric gene candidates in many plant species [for instance, >20,000 gene fragments inside Helitrons in maize line B73 and segments from ∼1,500 genes captured by Pack-MULEs in the rice variety Nipponbare (59, 142)], no case has been found where one of these genes has acquired a confirmed function. That is, there is no case of a known mutation affecting any aspect of plant biology that can be tied to a chimeric protein-encoding gene inside an intact TE. We do not think that this is at all surprising. As all previous genetic studies have shown, mutation usually leads to neutral or deleterious outcomes. A favorite analogy is that a mutation in a gene is about as likely to improve that gene as driving a nail through a watch is likely to improve the function of that watch (Figure 4a). For gene fragments picked up by a TE, the analogy morphs into taking pieces chopped off from several different watches, welding them together, and then seeing how often this yields something that keeps better time (Figure 4b). This latter scenario is particularly unlikely to create anything useful, but, in those outlandishly rare cases where something of value is created, it is likely to be very novel. That is, it is unlikely to even be a watch. The gene fragment fusion process inside TEs is otherwise known as exon shuffling, the intron-early model that suggests how genes with multiple protein-encoding domains were created by fusion of single-domain genes (43). However, exon shuffling was meant to describe a very early process in the origin of life, when these newly created gene candidates were in competition only 19.12

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Figure 4 A watch analogy for creating new genes by standard mutation or by randomly shuffling bits of genes. (a) A classic analogy for how a mutation in a gene is like a nail through a watch. The point is that the vast majority of mutations are detrimental or neutral, and very few can possibly yield a better watch. Those few that do improve the watch are more likely to be retained by the watch owner and, in the case of a gene, increase its chance of transmission owing to natural selection. (b) A variation on this analogy for random shuffling of bits of genes. Capturing bits of several genes and expressing them together, as seen for numerous TEs, is analogous to chopping up several watches and then more or less randomly gluing them together. The chance of this process making a better watch, or a better gene, is extremely small. Yet if the process succeeds (and millions of iterations on a perhaps daily basis across the biosphere says that it sometimes will), then it is likely that a product quite different from the starting materials will be produced.

with primitive (e.g., monodomain) genes that had not been through hundreds of millions of years of selection. Despite arguments that gene fragments acquired by TEs yield mostly candidate chimeric genes that have no useful function, it is interesting that the first gene fragment acquisition seen by a TE in plants, the plasma membrane proton ATPase (PMPA) gene inside the Bs1 LTR retrotransposon, has exhibited only conservative mutations since its acquisition, including a 183-base-pair in-frame deletion and 81 point mutations that combined to remove the ATPase function but left the plasma membrane–association activity intact (62). Two other host gene fragments were also found to be inside Bs1 and fused to the PMPA fragment, with evidence suggesting that the gene fusion product is involved in ear development and/or fertility (33). In addition, ∼4% of the gene fragments inside Helitrons in maize exhibited strong purifying selection and ∼4% exhibited strong diversifying selection, suggestive of roles for these chimeric genes (142). It will be fascinating to see how often protein-encoding gene fragments inside Helitrons, Pack-MULEs, or other TEs acquire a useful host function. With recent impressive advances in reverse genetic technologies (72), precise experiments to test this possibility could begin www.annualreviews.org • TE Contributions to Plant Genome Biology


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immediately. Of course, as discussed below, there are already numerous cases known of TEs that encode RNAs that regulate plant genes.

Pseudogene Creation


Although we have few confirmed novel gene creations in plants that can be associated with any process, including TE activity, we have no shortage of pseudogenes. Many of these pseudogenes, like those derived from retroposition (131), are clear in their origin. One of the most abundant categories of pseudogenes is actually the candidate chimeric genes described above that are caused by TE gene fragment acquisition. Scanning the genome of any plant reveals large numbers of pseudogenes. Many of these, like TE genes from low-copy-number elements, are often annotated as novel or species-specific genes in full genome annotations because their small (e.g., truncated) size and/or extensive sequence divergence gives rise to high EXPECT values in BLAST comparisons (9). However, this artifact now accounts for a few percent of gene calls in recent genome annotations rather than the ∼50% error rates seen in some early complete genome analyses in plants. The primary mechanisms of pseudogene origin are just now beginning to be understood in plants. Because LINEs are not usually very active in plants, it is not surprising that intronless pseudogenes are rare. Moreover, given the very high frequency of polyploidy in angiosperms (121), it is also not surprising that gene duplication followed by decay is a common culprit (56, 70). Careful annotation of sequenced genomic bacterial artificial chromosomes from wheat has shown that pseudogenes are particularly common in this species and that many appear to be derived from the action of TEs, often associated with inaccurate DSB repair (138).

Gene Regulation Because TEs routinely carry their own regulatory modules that determine the different expression patterns for TE genes, it is not surprising that TE insertion near a gene often alters its regulation (36, 37, 50, 109). At the evolutionary level, White et al. (134) noted early on that many plant gene promoters contain fragments of TEs that may be involved in gene regulation. This is such a common observation that one could argue that all plant gene regulation is derived from TE contributions. However, this may be both true and false at the same time. TE insertions into or near genes in plants are so routine that one expects dozens of such events per gene in any period of a few million years for a species with a high level of TE activity (113, 130). Many such insertions, like any mutation, will be selected against and thus not seen in subsequent generations. Figure 5 illustrates a situation where a TE with a new expression specificity is inserted into the promoter of a plant gene (Figure 5a), and this change is detrimental, so the inserted allele will be lost by selection. However, if the TE contains a regulatory module that has the same specificity as a module already present, then this will lead to a duplication of functional properties that could be neutral. If one of the regulatory modules is subsequently lost (Figure 5b), approximately half the time it will be the one from the starting gene. Hence, over time, the odds favor TEs becoming the source of all gene regulatory components, even if they were not the source of the original expression specificity. Of course, demonstrated changes in gene regulation by promoters or other components coming from TEs are not rare. Figure 6 broadly depicts this regulation. If these precise types of regulation could be initiated for many genes at once, a novel gene network could be created (reviewed in 38, 109). Recent studies in rice by Wessler and coworkers (97) have provided an exciting example of an alteration in gene regulation for many genes concurrently. In this particular case, multiple insertions in rice of the small class II element mPing, which shows a promoter-specific 19.14

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Figure 5 Likely outcomes of acquisitions by a gene of promoter elements from a TE. (a) Insertion of a TE (dark blue rectangle) with gene regulatory elements (orange and green ovals) into the promoter of a gene that is regulated by incompatible regulatory elements ( purple, blue, yellow, and red ovals). Like any other mutation, this altered regulatory capacity will probably be deleterious, and thus the allele will eventually be lost owing to natural selection. (b) Insertion of a different TE into the same gene, this one with regulatory domains that duplicate those already found in the gene. This insertion is more likely to be neutral than the case shown in panel a. Over time, if this duplication serves no gain-of-function role, there is a 50% chance that the regulatory regions from the TE will be lost or that the earlier regulatory regions of the same type from the gene will be lost. As more and more TE insertions occur, the promoter will (by chance) be likely to eventually lose the original regulatory domains, so a subsequent investigator would erroneously conclude that a TE had created the regulatory properties of this gene’s promoter.

insertion bias, led to several genes now coordinately regulated by a stress-responsive transcriptional regulator within mPing. Although it seems unlikely that such a process would ever be sufficiently efficient to create a surviving rare individual out of a highly stressed population in a single generation, because more of the changes would be needed to increase fitness than to decrease it (in contrast to all standard mutagenesis outcomes, where the great majority of changes are detrimental or neutral), standing variation arising from these changes would distribute across segregants to yield a few individuals with several useful changes and few or no detrimental changes. Despite the great enthusiasm for the idea of co-option or exaptation of TEs to usefully regulate genes and gene networks (see, for instance, 109), there is very little evidence that this commonly happens with de novo events (27). Similarly, evidence from Arabidopsis indicates that TE insertions near genes, particularly those that bring the potential for epigenetic silencing, are strongly selected against (52). It is interesting that active mPing lines seem to have good fitness in the absence of any stress (97), suggesting that they are mainly minor promoter alterations that position a set of genes for later expression optimization while being largely neutral mutations in the short term. Once again, this is fully compatible with the logic of selfish DNA (30, 102), wherein a TE’s effects on its host would be optimally neutral or beneficial so that the plant genome can survive as a dependable www.annualreviews.org • TE Contributions to Plant Genome Biology


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Figure 6 Rapid TE-driven creation of altered gene regulation or a network of similarly regulated genes. (a) A single TE inserts into or near the promoter (or other regulatory region) of a gene and brings a new set of expression characteristics by bringing in a new regulatory domain (white oval ). This could alter the level, developmental timing, and/or environmental response of a gene. (b) Five genes with quite different gene regulatory patterns all receive insertions of the same TE and now share some expression characteristics because they all contain a related regulatory region (white oval ). These genes now have the potential to work together to deal with a particular biological need in the host plant, whereas their different expression patterns prior to TE insertion made this cooperation unlikely or impossible. Because TEs often show preferential insertion into regulatory regions, and because many can be activated in a very short time for transposition/insertion, this creation of a potential new gene network could occur in a single generation (97; reviewed in 109).

host. In this regard, studies in numerous organisms, including in the genus Arabidopsis (53), have shown that TEs contribute to evolved differences in expression patterns for numerous genes, even in close relatives. In summary, there is no doubt that the TEs of plants and other organisms contribute many of the factors that determine the regulation of plant gene expression. How frequently TE changes in adjacent gene regulation contribute positively, neutrally, or negatively to plant fitness is not clear. This is a particularly interesting question with TEs because all other mutational processes yield primarily the latter two categories, but it would be useful to the TEs if their mutagenic outcomes fell into the first two categories. Hence, TEs are the only mutagen that is predisposed to provide an advantage to the host, perhaps partly explaining why they are so frequently domesticated.

Epigenetic Gene Regulation and TE Biology It is now generally accepted that epigenetic gene regulation in eukaryotes evolved from bacterial processes meant to inhibit the pathogenicity of viruses and other sources of foreign DNA 19.16

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Figure 7 A TE insertion creating the potential for epigenetic regulation to now be acquired by a standard host gene and how gene fragments inside a TE can mutate into a candidate microRNA gene. (a) Using the Mu1 TE of the maize Mutator system as an example, the TE is shown inserting into the promoter (red region) of a gene (transcribed regions shown in gray and by purple arrows). The lower gene can now be regulated by the epigenetic status (shown by asterisks) of the TE. (b) A Helitron has acquired fragments from three different genes, with colored boxes representing exons and the thin lines between them representing either introns or acquired fragment junctions. The stem-loop structure to the right is a standard feature of the 3 end of a Helitron. At the lower right, expression across the Helitron from 5 to 3 will create chimeric transcripts (1) that can lead to sense (genes 1 and 2) or antisense (gene 3) repression of host genes 1, 2, and 3. At the lower left, mutations in the Helitron (including here at least one deletion, a duplication, and an inversion) have created a structure for a portion of gene 1 that has the properties of a microRNA gene that can now be selected for its detrimental, neutral, or positive effects on the expression of gene 1.

(2; reviewed in 13, 16). In fact, plant TEs are affected by every form of epigenetic regulation that has been described (80), and it can be argued that every known case of plant gene regulation by epigenetic forces is traceable to TE involvement (78). One common type of TE involvement in the epigenetic regulation of host genes is through insertion of a TE into or near a gene, followed by acquired regulation of that gene’s expression by epigenetic silencing targeted on the TE component of the new host allele (reviewed in 36) (Figure 7a). The average plant genome is likely to have hundreds or thousands of genes epigenetically controlled by regulators originally derived from TEs. A more recent observation relates to TE involvement in the trans epigenetic regulation of many plant genes. TEs are epigenetically silenced by the small siRNAs derived from their own coding sequences (reviewed in 79). Recent studies have shown that TEs can encode small RNAs that regulate normal host genes (92, 93, 141). Given the self-mutagenic properties of at least some TEs (146) and their acquisition of gene fragments, it is not surprising that this might lead to an outcome where TEs generate siRNAs and other small regulatory RNAs. In fact, evidence now www.annualreviews.org • TE Contributions to Plant Genome Biology


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suggests that plant and other eukaryotic TEs are rapidly creating microRNA (miRNA) genes with the potential to regulate host genes (74, 107, 123, 143) (Figure 7b). Given that miRNA genes are so abundant and so many are species specific, a simple model suggests that most or all candidate miRNAs are created by TEs, and only the most recently generated still show the flanking legacies of TE structure (80). Out of these millions of miRNA candidate genes independently created every day across the plant kingdom, the vast majority will be detrimental or neutral in their effects and thus lost by selection or random segregation. The few useful miRNAs can go on to become important trans regulators of gene function. The understanding of TE responses to epigenetic regulation and TE contributions to the evolved regulation of host genes yields dramatic discoveries on a weekly basis. Despite the great advances in this field, there is still much to learn, especially about the degrees of natural selection that act on epigenetic polymorphism (23), on the rates at which epigenetic change both occur and have significant outcomes, and on the degree to which different plant lineages are preconditioned to generate or avoid epigenetic change (53; reviewed in 26).

Differences in TE Qualitative and Quantitative Activities Across Generations: Random or a Selected Trait? Perhaps the most routine observation about TE activity across species is that much more is perceived in some lineages than in others. In fact, TE activity is rarely detected in most plant species unless special screens are used and genomic stresses are employed to activate any quiescent autonomous elements that might be present (47, 91, 95). It was not likely a coincidence that the maize Ac and Ds elements were first found by McClintock in a maize line undergoing recurrent chromosome breakage or that En/Spm was first detected in maize lines derived from materials exposed to a nuclear weapons test at Bikini Atoll. Regardless of the rarity of easily detected TEs, their carcasses are almost everywhere across the kingdoms of life. Modern genome analysis has found only a few cases of organisms that appear to lack TEs or TE remnants in their genomes (reviewed in 108). The near ubiquity of TE presence does not, however, prove any continuity in TE activity. Rather, plant TEs are active in bursts (4, 32, 137). These bursts are associated with transient or long-lived losses of epigenetic silencing within a genome (20, 24). Once reactivated, a TE family may be silenced within a few days or years or may continue to be active for millions of years (4). Perhaps the most dramatic comparison on this point is between maize and gymnosperms (98). The Norway spruce genome has large numbers of very old LTR retrotransposons, whereas most maize LTR retrotransposons are only a few million years old (113). Hence, for reasons unknown, the Norway spruce (and other gymnosperms) has had little LTR retrotransposon activity for many millions of years, and it has maintained its large genome size only because of a very slow rate of DNA removal. Maize, in contrast, has had very high levels of TE activity in recent times (35, 113), which would have led to an enormous genome were it not for very high rates of DNA removal (130). Whether this great difference among lineages in their history of TE activity is stochastic or is itself a selected trait is not known. It has been proposed that lineages with different levels of potential TE activity will have very different abilities to adapt to environmental change (26, 101). Given that TE activity can create new allelic expression patterns, even for concerted sets of genes (97; reviewed in 109), there is every reason to believe that an evolutionary time frame for McClintock’s (91) adaptation-by-TE-activity model is completely true (15, 145). Because TEs will generally create neutral or deleterious mutations in the short term, one expects an optimal balance of TE activity factoring short-term disadvantage versus long-term gain. This topic is frequently covered in numerous discussions of TE population genetics (17, 45) but is not deeply covered in 19.18

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Figure 8 A graphical prediction of the relationship between the frequency of severe unpredicted stresses in a lineage’s evolutionary history versus the optimal TE activity level in that species. Because TEs will generate mostly deleterious mutations, they create a negative genetic load on any population, such that their long-term survival is possible only because of their selfish/parasitic capacity for propagation, perhaps with some contribution from their occasional co-option by the host. The shape of the curve, and its slope, are purely heuristic, given that such factors as population size, mating behavior, perenniality, and the severity of the stresses would all influence the true structure of the data in such an analysis. The upper-right part of the line is meant to end abruptly, because it is likely that no life form could survive if there were a high frequency of events that were each extinction-threatening, even on a million-year timescale.

our review. However, Figure 8 provides a bare-bones depiction of how TE activity might relate to the evolved history of a lineage. Plants have evolved regulated gene networks to deal with any routine stress, including daily fluctuations in light intensity, seasonal variations in heat and moisture, and periodic (or continuous) exposures to severe pathogens or pests. However, some stresses are so rare and so profound, like temperature variation well beyond any seen previously or months without sunlight after some catastrophic event, that these stresses are likely to encounter unprepared genomes. In these cases, a novel set of gene functions (which may have been neutral or even somewhat deleterious) might allow the survival of a species. As Figure 8 indicates, the optimal TE activity level for generating genetic novelty will likely increase with the frequency of this type of unexpected, extinctionthreatening stress. Of course, the shape (or at least slope) of this curve is likely to be affected by many factors, with expected different results for outcrossers versus selfers, small populations versus large populations, seed plants that can withstand very long periods of a problematic environment, and so on. Indirect tests of the model in Figure 8 would involve an investigation of the environmental history of a lineage to determine whether it correlates with past or current TE activity (perhaps as measured by genome size and/or TE age). Has the maize genome experienced so much more TE activity than the average gymnosperm genome because of a more variable environment? If standing variation creates the potential for greater adaptation, as one would expect, then lineages with a recent history of TE activity (e.g., 97) can be compared with lineages that have a similar genetic background but no such history in terms of their ability to thrive or survive under severe stress. In this regard, perhaps the TE-deficient genomes of apicomplexan parasites are not just an indication of selection for a smaller genome, but also an outcome of a parasitic lifestyle within a very homeostatic environment. If de novo genome instability is the source of survival under severe stress, then the comparisons of survival and adaptation could be made with isogenic lines that differ in their epigenetic status (24) or in exposure to “chromosome shock” (91). www.annualreviews.org • TE Contributions to Plant Genome Biology


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CONCLUSIONS


Plants, and the genius of Barbara McClintock, provided the foundation for the discovery and elucidation of TE function. It is surprising that McClintock missed so little, given the very limited tool kit at her disposal. Modern genome analysis gives us gigabases of new TE data weekly, and we are still learning how to mine it efficiently. In some cases, a full genome sequence is needed to look at the great diversity of TEs that might be present in the genome and the full properties of their distribution and evolution. In fact, given the enormous haplotype variation for TEs in many species (130), resequencing large numbers of accessions within the same species will have tremendous value. However, for other purposes, low-intensity sample sequence analysis (35, 81) will be enough to determine the behaviors and history of the most abundant TEs in a genome. One of the great questions in genome biology is why some genomes stay simple and/or small while others become enormous, and why some are so unstable while others seem to show high levels of stability, even with huge genomes (98). For instance, are organisms living in highly stressed and/or unstable environments prone to high levels of TE-driven change? Can the success of a particular family of TEs, or a particular TE burst, be correlated with a specific epigenetic targeting (92) or a genomic crash (91)? Only a broad and deep analysis across taxa can find appropriate genetic and/or environmental correlates with these very different behaviors. Because many plant TEs exhibit exceptional levels of activity, real-time experiments can be performed to investigate genomic outcomes of TE action. The starting point of this work is to find active TEs in natural populations (91, 97), by stressing current populations (47), or by re-creating extinct elements from their degraded parts (57). This last approach is somewhat unsettling, given that TEs have at least some of the properties of infectious agents, so this type of research should be performed at stringent levels of containment. Once active TEs are found in any system, they can be tested for their de novo insertion specificities, mechanisms of transposition, and effects on gene and genome function. Moreover, an active element can be engineered in vitro or in vivo (72) to see what cis or trans components are responsible for specific mechanistic or regulatory outcomes. In this regard, it would be particularly interesting to search for factors that help TEs acquire very high copy numbers, determine how TEs acquire gene fragments, and investigate how often exon shuffling events lead to anything useful to either the TE or the plant host. One of the exciting aspects of studying de novo mutation, especially for the uniquely powerful and many-faceted mutagens called TEs, is that one can compare their natural properties with the evolved structure of current genomes. The differences between de novo mutations and those that persist are primarily chance and natural selection. Hence, study of TEs can give insight into how selection acts on a class of mutagen that can cause all types of gene and genome rearrangement. From the selfish/parasitic perspective, it is fascinating that TEs are the one class of mutagen that is specifically designed to “accentuate the positive and eliminate the negative” in mutational outcomes for its host. Hence, as we begin to more precisely modify genomes for human benefit, perhaps we can learn from some of the tricks TEs have developed to accomplish this same task.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS We thank our many colleagues for helpful discussions and for directing us to important articles. We apologize for being unable to cite hundreds of additional important works owing to the 19.20

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size limitations for this article. The composition of this review was supported by grants from the Chinese Academy of Sciences, the Kunming Institute of Botany, the US National Science Foundation, and the US Department of Agriculture.


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Evolution and Diversity of Transposable Elements in Vertebrate Genomes.

Plant-transposable elements and gene tagging.

Transposable elements: from DNA parasites to architects of metazoan evolution.

The contribution of transposable elements to size variations between four teleost genomes.

Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues.

[Transposable elements reshaping genomes and favouring the evolutionary and adaptive potential of fungal phytopathogens].

In silico analysis of plant and animal transposable elements.

Do larger genomes contain more diverse transposable elements?

The Role of Transposable Elements in the Origin and Evolution of MicroRNAs in Human.

Structure and function of the maize Spm transposable element.

Small repeated sequences and the structure of plant mitochondrial genomes.

Diversity and evolution of mariner-like elements in aphid genomes.

The Tn21 subgroup of bacterial transposable elements.

Phylogenetic and Genomic Analyses Resolve the Origin of Important Plant Genes Derived from Transposable Elements.

Organization and evolution of transposable elements along the bread wheat chromosome 3B.

Highly Conserved Elements and Chromosome Structure Evolution in Mitochondrial Genomes in Ciliates.

Low diversity, activity, and density of transposable elements in five avian genomes.

Contributions of phylogenetically variable structural elements to the function of the ribozyme ribonuclease P.

Transposable elements.

Evolution of the Exon-Intron Structure in Ciliate Genomes.

Impact and insights from ancient repetitive elements in plant genomes.

Making Plants Break a Sweat: the Structure, Function, and Evolution of Plant Salt Glands.

Transposable elements and circular DNAs.

Non-equivalent contributions of maternal and paternal genomes to early plant embryogenesis.