Role Of Transposable Elements Research Articles

The role of Transposable Elements in shaping the combinatorial interaction of Transcription Factors

BackgroundIn the last few years several studies have shown that Transposable Elements (TEs) in the human genome are significantly associated with Transcription Factor Binding Sites (TFBSs) and that in several cases their expansion within the genome led to a substantial rewiring of the regulatory network. Another important feature of the regulatory network which has been thoroughly studied is the combinatorial organization of transcriptional regulation. In this paper we combine these two observations and suggest that TEs, besides rewiring the network, also played a central role in the evolution of particular patterns of combinatorial gene regulation.ResultsTo address this issue we searched for TEs overlapping Estrogen Receptor α (ERα) binding peaks in two publicly available ChIP-seq datasets from the MCF7 cell line corresponding to different modalities of exposure to estrogen. We found a remarkable enrichment of a few specific classes of Transposons. Among these a prominent role was played by MIR (Mammalian Interspersed Repeats) transposons. These TEs underwent a dramatic expansion at the beginning of the mammalian radiation and then stabilized. We conjecture that the special affinity of ERα for the MIR class of TEs could be at the origin of the important role assumed by ERα in Mammalians. We then searched for TFBSs within the TEs overlapping ChIP-seq peaks. We found a strong enrichment of a few precise combinations of TFBS. In several cases the corresponding Transcription Factors (TFs) were known cofactors of ERα, thus supporting the idea of a co-regulatory role of TFBS within the same TE. Moreover, most of these correlations turned out to be strictly associated to specific classes of TEs thus suggesting the presence of a well-defined "transposon code" within the regulatory network.ConclusionsIn this work we tried to shed light into the role of Transposable Elements (TEs) in shaping the regulatory network of higher eukaryotes. To test this idea we focused on a particular transcription factor: the Estrogen Receptor α (ERα) and we found that ERα preferentially targets a well defined set of TEs and that these TEs host combinations of transcriptional regulators involving several of known co-regulators of ERα. Moreover, a significant number of these TEs turned out to be conserved between human and mouse and located in the vicinity (and thus candidate to be regulators) of important estrogen-related genes.

Transposable elements: Instability of genes and genomes

The role of transposable elements as controlling and destabilizing factors of the genome of germ and somatic cells is considered. The ability of various stress factors, both intragenomic (hybrid dysgenesis, inbreeding, and outbreeding) and environmental (heat and ionizing radiation), to induce transposable element transposition is analyzed.

WHAT IS THE IMPACT OF ALLOPOLYPLOIDY ON TRANSPOSABLE ELEMENTS? A STRUCTURAL APPROACH ON NEWLY SYNTHESIZED BRASSICA NAPUS ALLOTETRAPLOIDS

Transposable elements (TEs) represent a major component of plant genomes and may provide the host genome with the necessary plasticity for its adaptative response. Polyploidy has played a major role in the evolution of plants (Wendel, 2000) and its success can be explained by the fact that a polyploid genome is not only the strict addition of the progenitor genomes, but that polyploidisation induces structural and functional modifications which represent important sources of novelty (Adams and Wendel, 2005). Our study aims at evaluating the implication of TEs in the genomic modifications that occur during the formation of a polyploid genome. Our plant model is oilseed rape (Brassica napus, AACC) originating from interspecific hybridization between B. rapa (AA) and B. oleracea (CC), and we dispose of newly synthesized B. napus allotetraploids resulting from independent AA x CC crosses. We developed sequence-specific amplification polymorphism (S-SAP) markers anchored in two different families of Brassica-specific TEs, an Athila-like retrotransposon and a MITE, which are contrasting TEs regarding their genomic organisation, dynamics of evolution, and mode of replication. Comparison of the S-SAP profiles and characterization of the polymorphism identified in the newly synthesized allotetraploids will provide new insights into the putative role of TEs during the creation of an allopolyploid species.

The role of transposable elements in the evolution of non-mammalian vertebrates and invertebrates

BackgroundTransposable elements (TEs) have played an important role in the diversification and enrichment of mammalian transcriptomes through various mechanisms such as exonization and intronization (the birth of new exons/introns from previously intronic/exonic sequences, respectively), and insertion into first and last exons. However, no extensive analysis has compared the effects of TEs on the transcriptomes of mammals, non-mammalian vertebrates and invertebrates.ResultsWe analyzed the influence of TEs on the transcriptomes of five species, three invertebrates and two non-mammalian vertebrates. Compared to previously analyzed mammals, there were lower levels of TE introduction into introns, significantly lower numbers of exonizations originating from TEs and a lower percentage of TE insertion within the first and last exons. Although the transcriptomes of vertebrates exhibit significant levels of exonization of TEs, only anecdotal cases were found in invertebrates. In vertebrates, as in mammals, the exonized TEs are mostly alternatively spliced, indicating that selective pressure maintains the original mRNA product generated from such genes.ConclusionsExonization of TEs is widespread in mammals, less so in non-mammalian vertebrates, and very low in invertebrates. We assume that the exonization process depends on the length of introns. Vertebrates, unlike invertebrates, are characterized by long introns and short internal exons. Our results suggest that there is a direct link between the length of introns and exonization of TEs and that this process became more prevalent following the appearance of mammals.

The role of transposable elements in the regulation of IFN-λ1 gene expression

IFNs lambda1, lambda2, and lambda3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-beta gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-lambda gene expression. Studies of virus induction of IFN-lambda1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-lambda1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-kappaB binding sites. Remarkably, these sites, which bind efficiently to NF-kappaB and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-kappaB RelA protein significantly reduces the level of the IFN-lambda1 gene expression. We conclude that IFN-lambda1 gene expression requires NF-kappaB, and we propose a model for IFN-lambda1 gene regulation, in which IRF and NF-kappaB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-lambda1 and IFN-beta promoters and directly implicate transposable elements in the regulation of the IFN-lambda1 gene by NF-kappaB.

The opossum genome: Insights and opportunities from an alternative mammal

The strategic importance of the genome sequence of the gray, short-tailed opossum, Monodelphis domestica, accrues from both the unique phylogenetic position of metatherian (marsupial) mammals and the fundamental biologic characteristics of metatherians that distinguish them from other mammalian species. Metatherian and eutherian (placental) mammals are more closely related to one another than to other vertebrate groups, and owing to this close relationship they share fundamentally similar genetic structures and molecular processes. However, during their long evolutionary separation these alternative mammals have developed distinctive anatomical, physiologic, and genetic features that hold tremendous potential for examining relationships between the molecular structures of mammalian genomes and the functional attributes of their components. Comparative analyses using the opossum genome have already provided a wealth of new evidence regarding the importance of noncoding elements in the evolution of mammalian genomes, the role of transposable elements in driving genomic innovation, and the relationships between recombination rate, nucleotide composition, and the genomic distributions of repetitive elements. The genome sequence is also beginning to enlarge our understanding of the evolution and function of the vertebrate immune system, and it provides an alternative model for investigating mechanisms of genomic imprinting. Equally important, availability of the genome sequence is fostering the development of new research tools for physical and functional genomic analyses of M. domestica that are expanding its versatility as an experimental system for a broad range of research applications in basic biology and biomedically oriented research.

Chromosomal polymorphism and racial evolution of Sorex uruneus L. in Finland

Halkka, L., Soderlund, V., Skaren, U. and Heikkila, J. 1987. Chromosomal polymorphism and racial evolution of Sorex araneus L. in Finland. —Hereditas 106: 257–275. Lund, Sweden. ISSN 0018–0661. Received October 2, 1986 Karyotypes of 197 Sorex araneus specimens from 26 populations throughout Finland were studied. Six chromosomal races with different combinations of arms, g, h, k, m, n, o, q and r were found to form chromosomes nos 3,5,7 and 8. The races may have evolved from a common ancestral karyotype through a series of reciprocal translocations. Postglacial geological development and distribution routes of Sorex support this hypothesis. Ancestor 3=qg, 5=nh, 7=rk, 8=om (Northern Russia)—race II 3=mg, 5=nh, 7=rk, 8=qo easternmost Finland) — race I 3=mg, 5=nh, 7=qk, 8=ro (Northern Finland and Lapland). Ancestor —race IV 3=qg, 5=nh, 7=ok, 8=rm (Central and Southern Finland, via Salpausselka ridge) — race V13, 5, 7, 8 =g, h, k, m, n, o, q, r (Aland Islands), race IV — race V3=k, g, 5=nh, 7=rm, 8=qo(Rauma, new centric fusion or hybrid). Ancestor — race III 3=qg, 5=kh, 7=om, 8=rn (Southeastern Finland, via Karlelian Isthmus). Chromosomes 3, 5, 7, 8, 4=li and 6=pi form an internal chromosomal polymorphism with two arms being combined to one metacentric chromosome (m) or being separated into two telocentric arms (t). The lowest frequencies of telocentrics were found in Central Finland and the highest, in Southwestern Finland and Aland. The chromosomal phenotypes mm, mt and tt seem to stay in Hardy-Weinberg equilibrium inside populations. The possible role of transposable elements in chromosomal evolution of Sorex araneus is discussed.

Transposon Excision from an Atypical Site: A Mechanism of Evolution of Novel Transposable Elements

The role of transposable elements in sculpting the genome is well appreciated but remains poorly understood. Some organisms, such as humans, do not have active transposons; however, transposable elements were presumably active in their ancestral genomes. Of specific interest is whether the DNA surrounding the sites of transposon excision become recombinogenic, thus bringing about homologous recombination. Previous studies in maize and Drosophila have provided conflicting evidence on whether transposon excision is correlated with homologous recombination. Here we take advantage of an atypical Dissociation (Ds) element, a maize transposon that can be mobilized by the Ac transposase gene in Arabidopsis thaliana, to address questions on the mechanism of Ds excision. This atypical Ds element contains an adjacent 598 base pairs (bp) inverted repeat; the element was allowed to excise by the introduction of an unlinked Ac transposase source through mating. Footprints at the excision site suggest a micro-homology mediated non-homologous end joining reminiscent of V(D)J recombination involving the formation of intra-helix 3′ to 5′ trans-esterification as an intermediate, a mechanism consistent with previous observations in maize, Antirrhinum and in certain insects. The proposed mechanism suggests that the broken chromosome at the excision site should not allow recombinational interaction with the homologous chromosome, and that the linked inverted repeat should also be mobilizable. To test the first prediction, we measured recombination of flanking chromosomal arms selected for the excision of Ds. In congruence with the model, Ds excision did not influence crossover recombination. Furthermore, evidence for correlated movement of the adjacent inverted repeat sequence is presented; its origin and movement suggest a novel mechanism for the evolution of repeated elements. Taken together these results suggest that the movement of transposable elements themselves may not directly influence linkage. Possibility remains, however, for novel repeated DNA sequences produced as a consequence of transposon movement to influence crossover in subsequent generations.

Evolutionary Genetics: Jumping into a New Species

A new study finds a dramatic increase in transposable element numbers in three new sunflower hybrid species, and may suggest a novel role for transposable elements in speciation.

Role of transposable elements in heterochromatin and epigenetic control.

Heterochromatin has been defined as deeply staining chromosomal material that remains condensed in interphase, whereas euchromatin undergoes de-condensation. Heterochromatin is found near centromeres and telomeres, but interstitial sites of heterochromatin (knobs) are common in plant genomes and were first described in maize. These regions are repetitive and late-replicating. In Drosophila, heterochromatin influences gene expression, a heterochromatin phenomenon called position effect variegation. Similarities between position effect variegation in Drosophila and gene silencing in maize mediated by "controlling elements" (that is, transposable elements) led in part to the proposal that heterochromatin is composed of transposable elements, and that such elements scattered throughout the genome might regulate development. Using microarray analysis, we show that heterochromatin in Arabidopsis is determined by transposable elements and related tandem repeats, under the control of the chromatin remodelling ATPase DDM1 (Decrease in DNA Methylation 1). Small interfering RNAs (siRNAs) correspond to these sequences, suggesting a role in guiding DDM1. We also show that transposable elements can regulate genes epigenetically, but only when inserted within or very close to them. This probably accounts for the regulation by DDM1 and the DNA methyltransferase MET1 of the euchromatic, imprinted gene FWA, as its promoter is provided by transposable-element-derived tandem repeats that are associated with siRNAs.

Epigenomics: beyond CpG islands.

Epigenomic studies aim to define the location and nature of the genomic sequences that are epigenetically modified. Much progress has been made towards whole-genome epigenetic profiling using molecular techniques, but the analysis of such large and complex data sets is far from trivial given the correlated nature of sequence and functional characteristics within the genome. We describe the statistical solutions that help to overcome the problems with data-set complexity, in anticipation of the imminent wealth of data that will be generated by new genome-wide epigenetic profiling and DNA sequence analysis techniques. So far, epigenomic studies have succeeded in identifying CpG islands, but recent evidence points towards a role for transposable elements in epigenetic regulation, causing the fields of study of epigenetics and transposable element biology to converge.

Genome evolution in polyploids.

Polyploidy is a prominent process in plants and has been significant in the evolutionary history of vertebrates and other eukaryotes. In plants, interdisciplinary approaches combining phylogenetic and molecular genetic perspectives have enhanced our awareness of the myriad genetic interactions made possible by polyploidy. Here, processes and mechanisms of gene and genome evolution in polyploids are reviewed. Genes duplicated by polyploidy may retain their original or similar function, undergo diversification in protein function or regulation, or one copy may become silenced through mutational or epigenetic means. Duplicated genes also may interact through inter-locus recombination, gene conversion, or concerted evolution. Recent experiments have illuminated important processes in polyploids that operate above the organizational level of duplicated genes. These include inter-genomic chromosomal exchanges, saltational, non-Mendelian genomic evolution in nascent polyploids, inter-genomic invasion, and cytonuclear stabilization. Notwithstanding many recent insights, much remains to be learned about many aspects of polyploid evolution, including: the role of transposable elements in structural and regulatory gene evolution; processes and significance of epigenetic silencing; underlying controls of chromosome pairing; mechanisms and functional significance of rapid genome changes; cytonuclear accommodation; and coordination of regulatory factors contributed by two, sometimes divergent progenitor genomes. Continued application of molecular genetic approaches to questions of polyploid genome evolution holds promise for producing lasting insight into processes by which novel genotypes are generated and ultimately into how polyploidy facilitates evolution and adaptation.

A race-specific insertion of transposable element IS801 in Pseudomonas syringae pv. phaseolicola.

The isolation and cloning of a random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) band specific for Pseudomonas syringae pv. phaseolicola race 1 allowed us to design a pair of primers that amplify 1.2-kb race 1-specific and 2.7-kb race 2-specific fragments, providing a rapid method for the identification of races by standard PCR methods. Restriction analysis revealed identical endonuclease sites in both fragments but the race 2 fragment contains a 1.5-kb insertion, identified as transposable element IS801 by sequence comparison. One complete and one partial open reading frame (ORF), each with a high probability of encoding a protein, have been identified in the 1.2-kb fragment common to both race 1 and race 2 sequences. As IS801 disrupts the partial ORF in the race 2 fragment, the complete sequence of this ORF has been obtained as well as its promoter region. The possibility that it may encode an avirulence gene is discussed as well as the role of transposable elements in pathogen evolution.

Role of transposable elements in age-related genomic instability.

Genetic instability is associated with aging in many species. One of the initiating factors for genetic instability is the movement of transposable elements (TEs), which occur in all prokaryotic and eukaryotic organisms. The hypothesis that TEs could be involved in the aging process is discussed and the correlation between aging and activity of TEs is analysed in a variety of biological systems.

Transposable elements are stable structural components of Drosophila melanogaster heterochromatin.

We determined the distribution of 11 different transposable elements on Drosophila melanogaster mitotic chromosomes by using high-resolution fluorescent in situ hybridization (FISH) coupled with charge-coupled device camera analysis. Nine of these transposable elements (copia, gypsy, mdg-1, blood, Doc, I, F, G, and Bari-1) are preferentially clustered into one or more discrete heterochromatic regions in chromosomes of the Oregon-R laboratory stock. Moreover, FISH analysis of geographically distant strains revealed that the locations of these heterochromatic transposable element clusters are highly conserved. The P and hobo elements, which are likely to have invaded the D. melanogaster genome at the beginning of this century, are absent from Oregon-R heterochromatin but clearly exhibit heterochromatic clusters in certain natural populations. Together these data indicate that transposable elements are major structural components of Drosophila heterochromatin, and they change the current views on the role of transposable elements in host genome evolution.

Population consequences of mutagenesis and antimutagenesis.

Although the progress in basic understanding of mutagenesis and in techniques for precise measurement of mutation rates in test systems has been enormous, there has been very little progress in applying this information to estimates of germline mutation in humans, and even less in translating such estimates into quantitative assessments of the impact on future generations. This doesn't mean that new information about the mutation process, and antimutagens in particular, is not useful. Lowering the human mutation rate would be good, even if we can't say how good. Some simple population kinetics of a change of mutation are discussed, and it is shown that future environmental changes can be ignored if we assume that the impact of a disease on human welfare is changed by the environment in the same proportion as its effect on fitness. Since the human mutation rate appears to be much higher in males than in females, it would be especially important to find ways of reducing the male rate. The role of transposable elements in determining human spontaneous mutation rates is unknown, but unless data from experimental organisms are grossly misleading, this role may be substantial. It is sometimes argued that such responses as error-prone repair systems may be an evolutionary strategy to allow the population to try a larger repertoire of mutations in times of environmental change. They may also be a survival strategy. I suggest that, although such an evolutionary strategy may possibly be adopted in asexual organisms with a very high reproductive rate, it is very unlikely in Mendelian species with limited reproduction such as most higher animals. The amount of existing variability in a large population is so great relative to that which arises in a few generations by mutation that segregation and recombination of existing alleles would appear to be a better way of coping with changing environment. As the human age of reproduction has increased in the recent evolutionary past, it is possible that the compensatory adjustment of mutation rates has not been fast enough to keep up. Perhaps evolution of mutation rates is more determined by selection to reduce somatic mutation than by selection to reduce germinal mutation. Regardless of the answer to the question of the optimum mutation rate for long-time evolution, in my view, the optimum mutation rate from the standpoint of human welfare for the foreseeable future is zero.

Speculation on the role of transposable elements in human genetic disease with particular attention to achondroplasia and the fragile X syndrome.

We suggest that mutations for fragile X-positive Martin-Bell syndrome, and perhaps also for achondroplasia, may result from the insertion of transposable elements (TE's). Loss of genetic function could result from either the insertion of TE's within or adjacent to a normal chromosomal gene or, in the case of fragile X, from the loss of genes distal to the site of TE insertion following subsequent TE excision without ligation of the resulting discontinuity. The phenotypically and often cytogenetically normal transmitting males in fragile X pedigrees are interpreted not as "nonpenetrant" transmitters of a fully formed fragile X but rather as transmitters of some or all of the factors necessary for TE insertion at Xq27. We consider it likely that such insertion frequently first occurs, both in soma and especially in the germline, in their daughters. Our models predict that father to son transmission of causative factors would be a common occurrence in fragile X pedigrees. The absence of documented father to son transmission either points to a flaw in the models or reflects systematic bias in the collection of pedigree information.

PλCM System: Observations on the Roles of Transposable Elements in Formation and Breakdown of Plasmids Derived from Bacteriophage Lambda Replicons

Transduction with phage derived from a 2-year-old lysate of lambda cam105 (lambda::Tn9) gave rise to chloramphenicol-resistant (Cm(r)) transductants harboring a plasmid (plambdaCM1) formed from lambda cam105 by a Tn9-mediated adjacent deletion to position 36.07 kilobases in the N cistron of lambda. The plambdaCM element can replicate as a plasmid, insert into the bacterial genome, or reproduce lytically as a phage on cells that provide N function. The feasibility of obtaining high titers in encapsidated form and the ease of synchronous introduction into and recovery from bacterial populations make plambdaCM very suitable for quantitative studies of recombination involving transposable elements. Replicon fusions between plambdaCM1 and RSF1596 (pMB8::Tn3Delta596) occur by duplication of either IS1 (at low rate in the absence of TnpA activity) or Tn3Delta596 (in the presence of TnpA activity). At 24 or 32 degrees C, the rate of increase of TnpA-mediated fusions per plambdaCM is about 2% per cell doubling. RSF103 contains the deleted Tn1DeltaAp (which lacks intact beta-lactamase and TnpR resolvase coding sequences) adjacent to a streptomycin resistance (Sm(r)) determinant. We observed that Tn1DeltaAp mediates insertions of external RSF103 sequences into the R388 plasmid. R388::Tn1DeltaAp plasmids show transposition immunity in cells lacking TnpR activity. Using the plambdaCM system, we isolated adjacent transpositions of the RSF103 Sm(r) determinant. The resulting plambdaCM-Sm cosmids contain Sm(r) genetic material flanked by direct repeats of Tn1DeltaAp, and all are deleted for some RSF103 or plambdaCM sequences. The plambdaCM-Sm constructs will fuse into R388 by duplication of a single Tn1DeltaAp element. In the presence of tnpR(+) (but not tnpR) Tn1 or Tn3 elements, all Tn1DeltaAp-mediated complex replicons break down completely and rapidly to simple Tn1DeltaAp inserts. The equilibrium for resolution is at least 10(5):1, and resolution is more than 90% complete after 40 min of exposure to a tnpR(+) cytoplasm. In the absence of TnpR, Rec, and Red activities, Tn1DeltaAp-mediated complex replicons yield simple Tn1DeltaAp inserts at a lower rate. The presence of intact RSF103 replication determinants between direct Tn1DeltaAp repeats appears to accelerate this precise TnpR- and Rec-independent breakdown.