![Composite transposon](https://upload.wikimedia.org/wikipedia/commons/d/dd/Composite_transposon.svg)
A transposable element (TE, transposon, or jumping gene) is a
nucleic acid sequence
A nucleic acid sequence is a succession of Nucleobase, bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequence ...
in
DNA that can change its position within a
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
, sometimes creating or reversing
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s and altering the cell's genetic identity and
genome size
Genome size is the total amount of DNA contained within one copy of a single complete genome. It is typically measured in terms of mass in picograms (trillionths (10−12) of a gram, abbreviated pg) or less frequently in daltons, or as the total ...
. Transposition often results in duplication of the same genetic material.
Barbara McClintock
Barbara McClintock (June 16, 1902 – September 2, 1992) was an American scientist and cytogeneticist who was awarded the 1983 Nobel Prize in Physiology or Medicine. McClintock received her PhD in botany from Cornell University in 1927. There s ...
's discovery of them earned her a
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
in 1983. Its importance in
personalized medicine is becoming increasingly relevant, as well as gaining more attention in
data analytics given the difficulty of analysis in very high dimensional spaces.
Transposable elements make up a large fraction of the genome and are responsible for much of the
mass of DNA in a
eukaryotic cell. Although TEs are
selfish genetic elements, many are important in genome function and evolution. Transposons are also very useful to researchers as a means to alter DNA inside a living organism.
There are at least two classes of TEs: Class I TEs or
retrotransposon
Retrotransposons (also called Class I transposable elements or transposons via RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposon) by converting RNA back into DNA through ...
s generally function via
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, while Class II TEs or
DNA transposons encode the protein
transposase, which they require for insertion and excision, and some of these TEs also encode other proteins.
Discovery by Barbara McClintock
Barbara McClintock
Barbara McClintock (June 16, 1902 – September 2, 1992) was an American scientist and cytogeneticist who was awarded the 1983 Nobel Prize in Physiology or Medicine. McClintock received her PhD in botany from Cornell University in 1927. There s ...
discovered the first TEs in
maize
Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
(''Zea mays'') at the
Cold Spring Harbor Laboratory in New York. McClintock was experimenting with maize plants that had broken chromosomes.
In the winter of 1944–1945, McClintock planted corn kernels that were self-pollinated, meaning that the silk (style) of the flower received pollen from its own anther.
These kernels came from a long line of plants that had been self-pollinated, causing broken arms on the end of their ninth chromosomes.
As the maize plants began to grow, McClintock noted unusual color patterns on the leaves.
For example, one leaf had two albino patches of almost identical size, located side by side on the leaf.
McClintock hypothesized that during cell division certain cells lost genetic material, while others gained what they had lost.
However, when comparing the chromosomes of the current generation of plants with the parent generation, she found certain parts of the chromosome had switched position.
This refuted the popular genetic theory of the time that genes were fixed in their position on a chromosome. McClintock found that genes could not only move but they could also be turned on or off due to certain environmental conditions or during different stages of cell development.
McClintock also showed that gene mutations could be reversed.
She presented her report on her findings in 1951, and published an article on her discoveries in ''Genetics'' in November 1953 entitled "Induction of Instability at Selected Loci in Maize".
At the 1951 Cold Spring Harbor Symposium where she first publicized her findings, her talk was met with dead silence. Her work was largely dismissed and ignored until the late 1960s–1970s when, after TEs were found in bacteria, it was rediscovered. She was awarded a
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
in 1983 for her discovery of TEs, more than thirty years after her initial research.
Classification
Transposable elements represent one of several types of
mobile genetic elements. TEs are assigned to one of two classes according to their mechanism of transposition, which can be described as either ''copy and paste'' (Class I TEs) or ''cut and paste'' (Class II TEs).
Retrotransposon
Class I TEs are copied in two stages: first, they are
transcribed from DNA to
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
, and the RNA produced is then
reverse transcribed to DNA. This
copied DNA is then inserted back into the genome at a new position. The reverse transcription step is catalyzed by a
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, which is often encoded by the TE itself. The characteristics of retrotransposons are similar to
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
es, such as
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
.
Retrotransposons are commonly grouped into three main orders:
* Retrotransposons, with
long terminal repeats (LTRs), which encode reverse transcriptase, similar to retroviruses
* Retroposons,
long interspersed nuclear elements (LINEs, LINE-1s, or L1s), which encode reverse transcriptase but lack LTRs, and are transcribed by
RNA polymerase II
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryoti ...
*
Short interspersed nuclear elements (SINEs) do not encode reverse transcriptase and are transcribed by
RNA polymerase III
Retroviruses can also be considered TEs. For example, after the conversion of retroviral RNA into DNA inside a host cell, the newly produced retroviral DNA is integrated into the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
of the host cell. These integrated DNAs are termed ''
provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these ter ...
es''. The provirus is a specialized form of
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
retrotransposon, which can produce RNA intermediates that may leave the host cell and infect other cells. The transposition cycle of retroviruses has similarities to that of
prokaryotic TEs, suggesting a distant relationship between the two.
DNA transposons
![DNA Transposon](https://upload.wikimedia.org/wikipedia/commons/3/33/DNA_Transposon.png)
The cut-and-paste transposition mechanism of class II TEs does not involve an RNA intermediate. The transpositions are catalyzed by several
transposase enzymes. Some transposases non-specifically bind to any target site in DNA, whereas others bind to specific target sequences. The transposase makes a staggered cut at the target site producing
sticky ends
DNA ends refer to the properties of the ends of linear DNA molecules, which in molecular biology are described as "sticky" or "blunt" based on the shape of the complementary strands at the terminus. In sticky ends, one strand is longer than the ...
, cuts out the DNA transposon and ligates it into the target site. A
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
fills in the resulting gaps from the sticky ends and
DNA ligase
DNA ligase is a specific type of enzyme, a ligase, () that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living organ ...
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 An inverted repeat (or IR) is a single stranded sequence of nucleotides followed downstream by its reverse complement. The intervening sequence of nucleotides between the initial sequence and the reverse complement can be any length including zero. ...
(which are important for the TE
excision by
transposase).
Cut-and-paste TEs may be duplicated if their transposition takes place during
S phase
S phase (Synthesis Phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during ...
of the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
, when a donor site has already been replicated but a target site has not yet been replicated. Such duplications at the target site can result in
gene duplication
Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. ...
, which plays an important role in genomic
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
.
Not all DNA transposons transpose through the cut-and-paste mechanism. In some cases, a
replicative transposition is observed in which a transposon replicates itself to a new target site (e.g.
helitron
Helitron is a mixed choir operating in Tallinn and originally set up to cater to employees of Tondi Elektroonika. Of the employment-related choirs established during Soviet occupation of Estonia, Helitron was one of the most famous ones, and is ...
).
Class II TEs comprise less than 2% of the human genome, making the rest Class I.
Autonomous and non-autonomous
Transposition can be classified as either "autonomous" or "non-autonomous" in both Class I and Class II TEs. Autonomous TEs can move by themselves, whereas non-autonomous TEs require the presence of another TE to move. This is often because dependent TEs lack transposase (for Class II) or reverse transcriptase (for Class I).
Activator element (''Ac'') is an example of an autonomous TE, and dissociation elements (''Ds'') is an example of a non-autonomous TE. Without ''Ac,'' ''Ds'' is not able to transpose.
Class III
Some researchers also identify a third class of transposable elements, which has been described as "a grab-bag consisting of transposons that don't clearly fit into the other two categories". Examples of such TEs are the Foldback (FB) elements of ''Drosophila melanogaster'', the TU elements of ''
Strongylocentrotus purpuratus'', and
Miniature Inverted-repeat Transposable Elements Miniature Inverted-repeat Transposable Elements (MITEs) are a group of non-autonomous Class II transposable elements (DNA sequences). Being non-autonomous, MITEs cannot code for their own transposase. They exist within the genomes of animals, plants ...
.
Distribution
Approximately 64% of the maize genome is made up of TEs,
as is 44% of the human genome, and almost half of
murine
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
genomes.
New discoveries of transposable elements have shown the exact distribution of TEs with respect to their transcription start sites (TSSs) and enhancers. A recent study found that a promoter contains 25% of regions that harbor TEs. It is known that older TEs are not found in TSS locations because TEs frequency starts as a function once there is a distance from the TSS. A possible theory for this is that TEs might interfere with the transcription pausing or the first-intro splicing.
Also as mentioned before, the presence of TEs closed by the TSS locations is correlated to their evolutionary age (number of different mutations that TEs can develop during the time).
Examples
* The first TEs were discovered in
maize
Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
(''Zea mays'') by
Barbara McClintock
Barbara McClintock (June 16, 1902 – September 2, 1992) was an American scientist and cytogeneticist who was awarded the 1983 Nobel Prize in Physiology or Medicine. McClintock received her PhD in botany from Cornell University in 1927. There s ...
in 1948, for which she was later awarded a
Nobel Prize
The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
. She noticed chromosomal
insertions,
deletions, and
translocations
In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...
caused by these elements. These changes in the genome could, for example, lead to a change in the color of corn kernels. About 64% of the maize genome consists of TEs.
The
Ac/Ds system described by McClintock are Class II TEs. Transposition of Ac in tobacco has been demonstrated by B. Baker.
* In the pond microorganism, ''
Oxytricha
''Oxytricha'' is a genus of ciliates in the family Oxytrichidae.
Genomics
The draft macronuclear genome of ''Oxytricha trifallax'' was published in 2013.
Species
References
Spirotrichea
Ciliate genera
{{Ciliate-stub ...
'', TEs play such a critical role that when removed, the organism fails to develop.
[
*]
* One family of TEs in the fruit fly ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
'' are called ''
P element
''P'' elements are transposable elements that were discovered in ''Drosophila'' as the causative agents of genetic traits called hybrid dysgenesis. The transposon is responsible for the ''P'' trait of the ''P'' element and it is found only in wil ...
s''. They seem to have first appeared in the species only in the middle of the twentieth century; within the last 50 years, they spread through every population of the species.
Gerald M. Rubin
Gerald Mayer Rubin (born 1950) is an American biologist, notable for pioneering the use of transposable P elements in genetics, and for leading the public project to sequence the ''Drosophila melanogaster'' genome. Related to his genomics wo ...
and
Allan C. Spradling
Allan C. Spradling is an American scientist and principal investigator at the Carnegie Institution for Science and the Howard Hughes Medical Institute who studies egg development in the model organism, ''Drosophila melanogaster'', a fruit fly. H ...
pioneered technology to use artificial P elements to insert genes into ''Drosophila'' by injecting the
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
.
* In
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, TEs usually carry an additional gene for functions other than transposition, often for
antibiotic resistance
Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. ...
. In bacteria, transposons can jump from
chromosomal
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
DNA to
plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
DNA and back, allowing for the transfer and permanent addition of genes such as those encoding antibiotic resistance (
multi-antibiotic resistant bacterial strains can be generated in this way). Bacterial transposons of this type belong to the Tn family. When the transposable elements lack additional genes, they are known as
insertion sequences.
* In
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s, the most common TE is the
Alu sequence. It is approximately 300 bases long and can be found between 300,000 and one million times in the
human genome. Alu alone is estimated to make up 15–17% of the human genome.
*
Mariner-like elements
Tc1/mariner is a class and superfamily of interspersed repeats DNA (Class II) transposons. The elements of this class are found in all animals, including humans. They can also be found in protists and bacteria.
The class is named after its two b ...
are another prominent class of transposons found in multiple species, including humans. The Mariner transposon was first discovered by Jacobson and Hartl in ''Drosophila''. This Class II transposable element is known for its uncanny ability to be transmitted horizontally in many species. There are an estimated 14,000 copies of Mariner in the human genome comprising 2.6 million base pairs. The first mariner-element transposons outside of
animals were found in ''
Trichomonas vaginalis
''Trichomonas vaginalis'' is an anaerobic, flagellated protozoan parasite and the causative agent of a sexually transmitted disease called trichomoniasis. It is the most common pathogenic protozoan that infects humans in industrialized countries ...
''.
*
Mu phage
Bacteriophage Mu, also known as mu phage or mu bacteriophage, is a muvirus (the first of its kind to be identified) of the family ''Myoviridae'' which has been shown to cause genetic transposition. It is of particular importance as its discover ...
transposition is the best-known example of
replicative transposition.
* In Yeast genomes (''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'') there are five distinct retrotransposon families:
Ty1,
Ty2,
Ty3,
Ty4 and
Ty5.
* A
helitron
Helitron is a mixed choir operating in Tallinn and originally set up to cater to employees of Tondi Elektroonika. Of the employment-related choirs established during Soviet occupation of Estonia, Helitron was one of the most famous ones, and is ...
is a TE found in eukaryotes that is thought to replicate by a
rolling-circle mechanism.
* In
human embryos
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm c ...
, two types of transposons combined to form noncoding RNA that catalyzes the development of stem cells. During the early stages of a fetus's growth, the embryo's inner cell mass expands as these stem cells enumerate. The increase of this type of cells is crucial, since stem cells later change form and give rise to all the cells in the body.
* In
peppered moths, a transposon in a gene called cortex caused the moths' wings to turn completely black. This change in coloration helped moths to blend in with ash and soot-covered areas during the Industrial Revolution.
* ''
Aedes aegypti
''Aedes aegypti'', the yellow fever mosquito, is a mosquito that can spread dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its legs ...
'' carries a large and diverse number of TEs. This analysis by Matthews et al. 2018 also suggests this is common to all mosquitoes.
Negative effects
Transposons have coexisted with eukaryotes for thousands of years and through their coexistence have become integrated in many organisms' genomes. Colloquially known as 'jumping genes', transposons can move within and between genomes allowing for this integration.
While there are many positive effects of transposons in their host eukaryotic genomes, there are some instances of mutagenic effects that TEs have on genomes leading to disease and malignant genetic alterations.
[Belancio VP, Hedges DJ, Deininger P (March 2008). "Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health". ''Genome Research''. 18 (3): 343–58. doi:10.1101/gr.5558208. PMID 18256243.]
Mechanisms of mutagenesis
TEs are
mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
s and due to the contribution to the formation of new cis-regulatory DNA elements that are connected to many transcription factors that are found in living cells; TEs can undergo many evolutionary mutations and alterations. These are often the causes of genetic disease, and gives the potential lethal effects of ectopic expression.
TEs can damage the genome of their host cell in different ways:
* A transposon or a retrotransposon that inserts itself into a functional gene can disable that gene.
* After a DNA transposon leaves a gene, the resulting gap may not be repaired correctly.
* Multiple copies of the same sequence, such as
Alu sequences, can hinder precise
chromosomal
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
pairing during
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
and
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately resu ...
, resulting in unequal
crossovers
Crossover may refer to:
Entertainment
Albums and songs
* ''Cross Over'' (Dan Peek album)
* ''Crossover'' (Dirty Rotten Imbeciles album), 1987
* ''Crossover'' (Intrigue album)
* ''Crossover'' (Hitomi Shimatani album)
* ''Crossover'' (Yoshino ...
, one of the main reasons for chromosome duplication.
TEs use a number of different mechanisms to cause genetic instability and disease in their host genomes.
* Expression of disease-causing, damaging proteins that inhibit normal cellular function.
** Many TEs contain
promoters which drive
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of their own
transposase. These promoters can cause aberrant expression of linked genes, causing disease or
mutant
In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
phenotypes
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
.
Diseases
Diseases often caused by TEs include
*
Hemophilia
Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...
A and B
** LINE1 (L1) TEs that land on the human Factor VIII have been shown to cause haemophilia
[Kazazian HH, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE (March 1988). "Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man". ''Nature''. 332 (6160): 164–6. Bibcode:1988Natur.332..164K. doi:10.1038/332164a0. PMID 2831458.]
*
Severe combined immunodeficiency
** Insertion of L1 into the APC gene causes colon cancer, confirming that TEs play an important role in disease development.
*
Porphyria
**Insertion of Alu element into the PBGD gene leads to interference with the coding region and leads to acute intermittent porphyria (AIP).
* Predisposition to
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
**LINE1(L1) TE's and other retrotransposons have been linked to cancer because they cause genomic instability.
*
Duchenne muscular dystrophy.
**Caused by SVA transposable element insertion in the fukutin (FKTN) gene which renders the gene inactive.
* Alzheimer's Disease and other Tauopathies
** Transposable element dysregulation can cause neuronal death, leading to neurodegenerative disorders
Rate of transposition, induction and defense
One study estimated the rate of transposition of a particular retrotransposon, the
Ty1 element in ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
''. 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. Some TEs contain
heat-shock like promoters and their rate of transposition increases if the cell is subjected to stress, thus increasing the mutation rate under these conditions, which might be beneficial to the cell.
Cells defend against the proliferation of TEs in a number of ways. These include
piRNAs and
siRNAs, which
silence TEs after they have been transcribed.
If organisms are mostly composed of TEs, one might assume that disease caused by misplaced TEs is very common, but in most cases TEs are silenced through
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
mechanisms like
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
, chromatin remodeling and piRNA, such that little to no phenotypic effects nor movements of TEs occur as in some wild-type plant TEs. Certain mutated plants have been found to have defects in methylation-related enzymes (methyl transferase) which cause the transcription of TEs, thus affecting the phenotype.
One hypothesis suggests that only approximately 100 LINE1 related sequences are active, despite their sequences making up 17% of the human genome. In human cells, silencing of LINE1 sequences is triggered by an
RNA interference (RNAi) mechanism. Surprisingly, the RNAi sequences are derived from the 5′ untranslated region (UTR) of the LINE1, a long terminal which repeats itself. Supposedly, the 5′ LINE1 UTR that codes for the sense promoter for LINE1 transcription also encodes the antisense promoter for the miRNA that becomes the substrate for siRNA production. Inhibition of the RNAi silencing mechanism in this region showed an increase in LINE1 transcription.
Evolution
TEs are found in almost all life forms, and the scientific community is still exploring their evolution and their effect on genome evolution. It is unclear whether TEs originated in the
last universal common ancestor, arose independently multiple times, or arose once and then spread to other kingdoms by
horizontal gene transfer. While some TEs confer benefits on their hosts, most are regarded as
selfish DNA
Selfish genetic elements (historically also referred to as selfish genes, ultra-selfish genes, selfish DNA, parasitic DNA and genomic outlaws) are genetic segments that can enhance their own transmission at the expense of other genes in the genome, ...
parasite
Parasitism is a close relationship between species, where one organism, the parasite, lives on or inside another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has ...
s. In this way, they are similar to
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es. Various viruses and TEs also share features in their genome structures and biochemical abilities, leading to speculation that they share a common ancestor.
Because excessive TE activity can damage
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s, many organisms have acquired mechanisms to inhibit their activity. Bacteria may undergo high rates of
gene deletion
In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...
as part of a mechanism to remove TEs and viruses from their genomes, while
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
organisms typically use
RNA interference to inhibit TE activity. Nevertheless, some TEs generate large families often associated with
speciation
Speciation is the evolutionary process by which populations evolve to become distinct species. The biologist Orator F. Cook coined the term in 1906 for cladogenesis, the splitting of lineages, as opposed to anagenesis, phyletic evolution within ...
events. Evolution often deactivates DNA transposons, leaving them as
intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s (inactive gene sequences). In vertebrate animal cells, nearly all 100,000+ DNA transposons per genome have genes that encode inactive transposase polypeptides. The first synthetic transposon designed for use in vertebrate (including human) cells, the
Sleeping Beauty transposon system
The ''Sleeping Beauty'' transposon system is a synthetic DNA transposon designed to introduce precisely defined DNA sequences into the chromosomes of vertebrate animals for the purposes of introducing new traits and to discover new genes and thei ...
, is a Tc1/mariner-like transposon. Its dead ("fossil") versions are spread widely in the salmonid genome and a functional version was engineered by comparing those versions. Human Tc1-like transposons are divided into Hsmar1 and Hsmar2 subfamilies. Although both types are inactive, one copy of Hsmar1 found in the
SETMAR
Histone-lysine N-methyltransferase SETMAR is an enzyme that in humans is encoded by the ''SETMAR'' gene.
Function
SETMAR contains a SET domain that confers its histone methyltransferase activity, on Lys-4 and Lys-36 of Histone H3, both of which ...
gene is under selection as it provides DNA-binding for the histone-modifying protein. Many other human genes are similarly derived from transposons. Hsmar2 has been reconstructed multiple times from the fossil sequences.
Large quantities of TEs within genomes may still present evolutionary advantages, however.
Interspersed repeat Interspersed repetitive DNA is found in all eukaryotic genomes. They differ from tandem repeat DNA in that rather than the repeat sequences coming right after one another, they are dispersed throughout the genome and nonadjacent. The sequence that r ...
s within genomes are created by transposition events accumulating over evolutionary time. Because interspersed repeats block
gene conversion
Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. Gene conversion can be either allelic, meaning that one allele of the same gene replaces a ...
, they protect novel gene sequences from being overwritten by similar gene sequences and thereby facilitate the development of new genes. TEs may also have been co-opted by the
vertebrate immune system as a means of producing antibody diversity. The
V(D)J recombination
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell rece ...
system operates by a mechanism similar to that of some TEs. TEs also serve to generate repeating sequences that can form dsRNA to act as a substrate for the action of
ADAR
Adar ( he, אֲדָר ; from Akkadian ''adaru'') is the sixth month of the civil year and the twelfth month of the religious year on the Hebrew calendar, roughly corresponding to the month of March in the Gregorian calendar. It is a month of 29 d ...
in RNA editing.
TEs can contain many types of genes, including those conferring antibiotic resistance and the ability to transpose to conjugative plasmids. Some TEs also contain
integrons, genetic elements that can capture and express genes from other sources. These contain
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
, which can integrate
gene cassettes. There are over 40 antibiotic resistance genes identified on cassettes, as well as virulence genes.
Transposons do not always excise their elements precisely, sometimes removing the adjacent base pairs; this phenomenon is called
exon shuffling
Exon shuffling is a molecular mechanism for the formation of new genes. It is a process through which two or more exons from different genes can be brought together ectopic recombination, ectopically, or the same exon can be duplicated, to create ...
. Shuffling two unrelated exons can create a novel gene product or, more likely, an intron.
Some non-autonomous DNA TEs found in plants can capture coding DNA from genes and shuffle them across the genome. This process can duplicate genes in the genome (a phenomenon called transduplication), and can contribute to generate novel genes by exon shuffling.
Evolutionary drive for TEs on the genomic context
There is a hypothesis that states that TEs might provide a ready source of DNA that could be co-opted by the cell to help regulate gene expression. Research showed that many diverse modes of TEs co-evolution along with some transcription factors targeting TE-associated genomic elements and chromatin are evolving from TE sequences. Most of the time, these particular modes do not follow the simple model of TEs and regulating host gene expression.
Applications
Transposable elements can be harnessed in laboratory and research settings to study genomes of organisms and even engineer genetic sequences. The use of transposable elements can be split into two categories: for genetic engineering and as a genetic tool.
Genetic engineering
* Insertional mutagenesis uses the features of a TE to insert a sequence. In most cases, this is used to remove a DNA sequence or cause a frameshift mutation.
** In some cases the insertion of a TE into a gene can disrupt that gene's function in a reversible manner where transposase-mediated excision of the DNA transposon restores gene function.
** This produces plants in which neighboring cells have different
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
s.
** 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.
Genetic tool
In addition to the qualities mentioned for Genetic engineering, a Genetic tool also:-
* Used for analysis of gene expression and protein functioning in
signature-tagging mutagenesis.
** This analytical tool allows researchers the ability to determine
phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
expression of gene sequences. Also, this analytic technique mutates the desired locus of interest so that the phenotypes of the original and the mutated gene can be compared.
Specific applications
* 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.
* The Tc1/mariner-class of TEs Sleeping Beauty transposon system, awarded Molecule of the Year in 2009,
is active in mammalian cells and is being investigated for use in human gene therapy.
* TEs are used for the reconstruction of phylogenies by the means of presence/absence analyses.
Transposons can act as biological mutagen in bacteria.
* Common organisms which the use of Transposons has been well developed are:
**''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
''
** ''
Arabidopsis thaliana
''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land.
A winter a ...
''
** ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
''
''De novo'' repeat identification
''De novo'' repeat identification is an initial scan of sequence data that seeks to find the repetitive regions of the genome, and to classify these repeats. Many computer programs exist to perform ''de novo'' repeat identification, all operating under the same general principles.
As short tandem repeats are generally 1–6 base pairs in length and are often consecutive, their identification is relatively simple.
Dispersed repetitive elements, on the other hand, are more challenging to identify, due to the fact that they are longer and have often acquired mutations. However, it is important to identify these repeats as they are often found to be transposable elements (TEs).
''De novo'' identification of transposons involves three steps: 1) find all repeats within the genome, 2) build a
consensus of each family of sequences, and 3) classify these repeats. There are three groups of algorithms for the first step. One group is referred to as the
k-mer approach, where a k-mer is a sequence of length k. In this approach, the genome is scanned for overrepresented k-mers; that is, k-mers that occur more often than is likely based on probability alone. The length k is determined by the type of transposon being searched for. The k-mer approach also allows mismatches, the number of which is determined by the analyst. Some k-mer approach programs use the k-mer as a base, and extend both ends of each repeated k-mer until there is no more similarity between them, indicating the ends of the repeats.
Another group of algorithms employs a method called sequence self-comparison. Sequence self-comparison programs use databases such as
AB-BLAST to conduct an initial
sequence alignment
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Alig ...
. As these programs find groups of elements that partially overlap, they are useful for finding highly diverged transposons, or transposons with only a small region copied into other parts of the genome.
Another group of algorithms follows the periodicity approach. These algorithms perform a
Fourier transformation on the sequence data, identifying periodicities, regions that are repeated periodically, and are able to use peaks in the resultant spectrum to find candidate repetitive elements. This method works best for tandem repeats, but can be used for dispersed repeats as well. However, it is a slow process, making it an unlikely choice for genome-scale analysis.
The second step of ''de novo'' repeat identification involves building a consensus of each family of sequences. A
consensus sequence
In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...
is a sequence that is created based on the repeats that comprise a TE family. A base pair in a consensus is the one that occurred most often in the sequences being compared to make the consensus. For example, in a family of 50 repeats where 42 have a T base pair in the same position, the consensus sequence would have a T at this position as well, as the base pair is representative of the family as a whole at that particular position, and is most likely the base pair found in the family's ancestor at that position.
Once a consensus sequence has been made for each family, it is then possible to move on to further analysis, such as TE classification and genome masking in order to quantify the overall TE content of the genome.
Adaptive TEs
Transposable elements have been recognized as good candidates for stimulating gene adaptation, through their ability to regulate the expression levels of nearby genes.
Combined with their "mobility", transposable elements can be relocated adjacent to their targeted genes, and control the expression levels of the gene, dependent upon the circumstances.
The study conducted in 2008, "High Rate of Recent Transposable Element–Induced Adaptation in Drosophila melanogaster", used ''D. melanogaster'' that had recently migrated from Africa to other parts of the world, as a basis for studying adaptations caused by transposable elements. Although most of the TEs were located on introns, the experiment showed a significant difference in gene expressions between the population in Africa and other parts of the world. The four TEs that caused the selective sweep were more prevalent in ''D. melanogaster'' from temperate climates, leading the researchers to conclude that the selective pressures of the climate prompted genetic adaptation.
From this experiment, it has been confirmed that adaptive TEs are prevalent in nature, by enabling organisms to adapt gene expression as a result of new selective pressures.
However, not all effects of adaptive TEs are beneficial to the population. In the research conducted in 2009, "A Recent Adaptive Transposable Element Insertion Near Highly Conserved Developmental Loci in Drosophila melanogaster", a TE, inserted between Jheh 2 and Jheh 3, revealed a downgrade in the expression level of both of the genes. Downregulation of such genes has caused ''Drosophila'' to exhibit extended developmental time and reduced egg to adult viability. Although this adaptation was observed in high frequency in all non-African populations, it was not fixed in any of them.
This is not hard to believe, since it is logical for a population to favor higher egg to adult viability, therefore trying to purge the trait caused by this specific TE adaptation.
At the same time, there have been several reports showing the advantageous adaptation caused by TEs. In the research done with silkworms, "An Adaptive Transposable Element insertion in the Regulatory Region of the EO Gene in the Domesticated Silkworm", a TE insertion was observed in the cis-regulatory region of the EO gene, which regulates molting hormone 20E, and enhanced expression was recorded. While populations without the TE insert are often unable to effectively regulate hormone 20E under starvation conditions, those with the insert had a more stable development, which resulted in higher developmental uniformity.
These three experiments all demonstrated different ways in which TE insertions can be advantageous or disadvantageous, through means of regulating the expression level of adjacent genes. The field of adaptive TE research is still under development and more findings can be expected in the future.
TEs participates in gene control networks
Recent studies have confirmed that TEs can contribute to the generation of transcription factors. However, how this process of contribution can have an impact on the participation of genome control networks. TEs are more common in many regions of the DNA and it makes up 45% of total human DNA. Also, TEs contributed to 16% of transcription factor binding sites. A larger number of motifs are also found in non-TE-derived DNA, and the number is larger than TE-derived DNA. All these factors correlate to the direct participation of TEs in many ways of gene control networks.
See also
Notes
*
*
*
References
External links
* – A possible connection between aberrant reinsertions and lymphoma.
Repbase– a database of transposable element sequences
Dfam- a database of transposable element families, multiple sequence alignments, and sequence models
RepeatMasker– a computer program used by computational biologists to
annotate
An annotation is extra information associated with a particular point in a document or other piece of information. It can be a note that includes a comment or explanation. Annotations are sometimes presented in the margin of book pages. For anno ...
transposons in DNA sequences
Use of the Sleeping Beauty Transposon System for Stable Gene Expression in Mouse Embryonic Stem CellsIntroduction to Transposons, 2018 YouTube video
{{Authority control
Modification of genetic information
Mobile genetic elements
Molecular biology
Non-coding DNA