Transposable elements (TEs) are sequences of DNA that can move or transpose themselves to new positions within the genome of a single cell. The mechanism of transposition can be either "copy and paste" or "cut and paste". Transposition can create phenotypically significant mutations and alter the cell's genome size. Barbara McClintock's discovery of these jumping genes early in her career earned her a Nobel prize in 1983.[1]
TEs make up a large fraction of the C-value of eukaryotic cells. They are often considered "junk DNA". In Oxytricha, which has a unique genetic system, they play a critical role in its development.[2] They are also very useful to researchers as a means to alter DNA inside a living organism.
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Transposable elements are only one of several types of mobile genetic elements. They are assigned to one of two classes according to their mechanism of transposition, which can be described as either "copy and paste" (for class I TEs) or "cut and paste" (for class II TEs).[3]
Class I (Retrotransposons): They copy themselves in two stages, first from DNA to RNA by transcription, then from RNA back to DNA by reverse transcription. The DNA copy is then inserted into the genome in a new position. Reverse transcription is catalyzed by a reverse transcriptase, which is often coded by the TE itself. Retrotransposons behave very similarly to retroviruses, such as HIV.
There are three main orders of retrotransposons (other orders are less abundant):
Retroviruses can be considered as TEs. Indeed, after entering a host cell and converting their RNA into DNA, retroviruses integrate this DNA into the DNA of the host cell. The integrated DNA form (provirus) of the retrovirus is viewed as a particularly specialized form of eukaryotic retrotransposon, which is able to encode RNA intermediates that usually can leave the host cells and infect other cells. The transposition cycle of retroviruses also has similarities to that of prokaryotic TEs. The similarities suggest a distant familial relationship between these two TEs types.
Class II (DNA transposons): By contrast, the cut-and-paste transposition mechanism of class II TEs does not involve an RNA intermediate. The transpositions are catalyzed by various types of transposase enzymes. Some transposases can bind non-specifically to any target site, while others bind to specific sequence targets. The transposase makes a staggered cut at the target site producing sticky ends, cuts out the DNA transposon and ligates it into the target site. A DNA polymerase fills in the resulting gaps from the sticky ends and DNA ligase closes the sugar-phosphate backbone. This results in target site duplication and the insertion sites of DNA transposons may be identified by short direct repeats (a staggered cut in the target DNA filled by DNA polymerase) followed by inverted repeats (which are important for the TE excision by transposase). The duplications at the target site can result in gene duplication, which plays an important role in evolution[4]:284.
Not all DNA transposons transpose through a cut-and-paste mechanism. In some cases a replicative transposition is observed in which transposon replicates itself to a new target site (e.g. Helitron (biology)).
Cut-and-paste TEs may be duplicated if transposition takes place during S phase of the cell cycle when the "donor" site has already been replicated, but the "target" site has not.
Both classes of TEs may lose their ability to synthesise reverse transcriptase or transposase through mutation, yet continue to jump through the genome because other TEs are still producing the necessary enzymes. Hence, they can be classified as either "autonomous" or "non-autonomous". For instance for the class II TEs, the autonomous ones have an intact gene that encodes an active transposase enzyme; the TE does not need another source of transposase for its transposition. In contrast, non-autonomous elements encode defective polypeptides and accordingly require transposase from another source. When a TE is used as a genetic tool, the transposase is supplied by the investigator, often from an expression cassette within a plasmid.[5]
TEs are mutagens. They can damage the genome of their host cell in different ways [15]:
Diseases that are often caused by TEs include hemophilia A and B, severe combined immunodeficiency, porphyria, predisposition to cancer, and Duchenne muscular dystrophy.[16][17]
Additionally, many TEs contain promoters which drive transcription of their own transposase. These promoters can cause aberrant expression of linked genes, causing disease or mutant phenotypes.
One study estimated the rate of transposition of a particular retrotransposon, the Ty1 element in Saccharomyces cerevisiae. Using several assumptions, the rate of successful transposition event per single Ty1 element came out to be about once every few months to once every few years.[18]
Cells defend against the proliferation of TEs in a number of ways. These include piRNAs and siRNAs[19] which silence TEs after they have been transcribed.
Some TEs contain heat-shock like promoters and their rate of transposition increases if the cell is subjected to stress,[20] thus increasing the mutation rate under these conditions, which might be beneficial to the cell.
The evolution of TEs and their effect on genome evolution is currently a dynamic field of study.
TEs are found in many major branches of life. They may have originated in the last universal common ancestor, or arisen independently multiple times, or perhaps arisen once and then spread to other kingdoms by horizontal gene transfer.[21] While some TEs may confer benefits on their hosts, most are regarded as selfish DNA parasites. In this way, they are similar to viruses. Various viruses and TEs also share features in their genome structures and biochemical abilities, leading to speculation that they share a common ancestor.
Since excessive TE activity can destroy a genome, many organisms have developed mechanisms to inhibit this activity. Bacteria may undergo high rates of gene deletion as part of a mechanism to remove TEs and viruses from their genomes while eukaryotic organisms use RNA interference (RNAi) to inhibit TE activity. Nevertheless, some TEs generated large families often associated with speciation events.
Evolution has been particularly harsh on DNA transposons. In vertebrate animal cells nearly all >100,000 DNA transposons per genome have genes that encode inactive transposase polypeptides.[22] In humans, all of the Tc1-like transposons are inactive. As a result the first DNA transposon used as a tool for genetic purposes, the Sleeping Beauty transposon system, was a Tc1/mariner-like transposon that was resurrected from a long evolutionary sleep.[23]
Interspersed Repeats within genomes are created by transposition events accumulating over evolutionary time. Because interspersed repeats block gene conversion, they protect novel gene sequences from being overwritten by similar gene sequences and thereby facilitate the development of new genes.
TEs may have been co-opted by the vertebrate immune system as a means of producing antibody diversity: The V(D)J recombination system operates by a mechanism similar to that of some TEs.
TEs contain many type of genes- including those conferring antibiotic resistance and ability to transpose to conjugative plasmid. Some TEs also contain integrons(genetic elements that can capture and express genes from other sources) that contain integrase enzyme which can integrate gene cassettes. over 40 antibiotic resistance genes identified on cassettes: also virulance genes.
The first TE was discovered in the plant maize (Zea mays, corn species), and is named dissociator (Ds). Likewise, the first TE to be molecularly isolated was from a plant (Snapdragon). Appropriately, TEs have been an especially useful tool in plant molecular biology. Researchers use them as a means of mutagenesis. In this context, a TE jumps into a gene and produces a mutation. The presence of such a TE provides a straightforward means of identifying the mutant allele, relative to chemical mutagenesis methods.
Sometimes the insertion of a TE into a gene can disrupt that gene's function in a reversible manner, in a process called insertional mutagenesis; transposase-mediated excision of the DNA transposon restores gene function. This produces plants in which neighboring cells have different genotypes. This feature allows researchers to distinguish between genes that must be present inside of a cell in order to function (cell-autonomous) and genes that produce observable effects in cells other than those where the gene is expressed.
TEs are also a widely used tool for mutagenesis of most experimentally tractable organisms. The Sleeping Beauty transposon system has been used extensively as an insertional tag for identifying cancer genes [24]
The Tc1/mariner-class of TEs Sleeping Beauty transposon system, awarded as the Molecule of the Year 2009[25] is active in mammalian cells and are being investigated for use in human gene therapy.[26][27][28]
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