Transposable elements – Definition, Types, Examples, Application

Barbara McClintock discovered the first transgenic elements in maize (Zea mays) at New York’s Cold Spring Harbor Laboratory. McClintock was conducting experiments on maize seedlings with broken chromosomes.

McClintock planted self-pollinating corn kernels during the winter of 1944–1945, indicating that the silk (style) of the flower received pollen from its own anther.These kernels originated from a lengthy line of self-pollinating plants, resulting in broken arms at the end of their ninth chromosomes.McClintock observed peculiar color patterns on the leaves as the maize plants began to mature.On a single leaf, for instance, there were two nearly identically sized albino regions located side-by-side.McClintock hypothesized that during cell division, some cells would lose genetic material while others would acquire it.Comparing the chromosomes of the current generation of plants with those of the progenitor generation, she discovered that certain chromosomal segments had switched positions. This disproved the prevalent genetic theory of the time, which held that genes’ positions on chromosomes were immutable. McClintock discovered that genes could not only move, but also be activated or inactivated in response to environmental conditions or at various phases of cell development.

McClintock also demonstrated that gene mutations are reversible.[9] She presented a report on her findings in 1951 and published an article titled “Induction of Instability at Selected Loci in Maize” in Genetics in November 1953.

At the 1951 Cold Spring Harbor Symposium, where she first presented her findings, there was complete stillness during her presentation.In the late 1960s and early 1970s, when transposable elements were discovered in bacteria, her work was rediscovered.More than thirty years after her initial investigation, she was awarded the Nobel Prize in Physiology or Medicine in 1983 for her discovery of transposable elements.

What are transposable elements?

Transposable elements, also known as transposons or jumping genes, are small DNA sequences that have the ability to change their position within a genome. They are mobile genetic elements that can move around chromosomes without the requirement of homology. The insertion of transposable elements can lead to various genetic alterations, such as deletions, inversions, chromosomal fusions, and complex rearrangements.

These elements are found in both prokaryotic and eukaryotic organisms. In bacteria, transposable elements can move from plasmids to the chromosome and vice versa. They can also be transferred from one bacterium to another through processes like conjugation, transformation, or transduction. This ability to transfer genetic material between bacteria plays a role in the spread of antimicrobial resistance genes.

Transposable elements constitute a significant portion of the genome and contribute to the overall mass of DNA in a eukaryotic cell. They were first discovered by Barbara McClintock in 1965 during her analysis of genetic instability in maize (corn). Her groundbreaking work on transposable elements earned her a Nobel Prize in 1983.

The impact of transposable elements extends beyond their selfish nature as genetic elements. Many of them have important functions in genome regulation, evolution, and genome organization. Some transposons are utilized by researchers as tools to manipulate DNA within living organisms for experimental purposes.

There are two main classes of transposable elements. Class I transposable elements, also known as retrotransposons, generally utilize a reverse transcription process during their movement. These elements are transcribed into RNA, which is then reverse transcribed back into DNA and inserted at a different location within the genome. Class II transposable elements, or DNA transposons, encode a protein called transposase, which is necessary for their insertion and excision from the genome. Some DNA transposons also encode additional proteins aside from transposase.

The study of transposable elements is gaining increasing importance in personalized medicine, as their presence and activity can contribute to genetic variations associated with diseases. Furthermore, the analysis of transposable elements poses challenges in data analytics due to the complex and high-dimensional nature of their interactions within genomes. Nonetheless, understanding the biology and behavior of transposable elements is crucial for comprehending the dynamics of genomes and their evolution.

Definition of Transposable elements

Transposable elements, also known as transposons, are DNA sequences that can change their position within the genome of an organism. They are mobile genetic elements that have the ability to “transpose” or move to different locations within the genome. Transposable elements can be found in the genomes of various organisms, including bacteria, plants, and animals. They play a significant role in genome evolution and can have both positive and negative effects on the host organism. Transposable elements can cause genetic mutations, rearrangements, and alterations in gene expression, and they are considered an important source of genetic diversity.

Characteristics of transposable elements

Transposable elements, also known as transposons, possess several characteristic features:

• Self-Duplication and Insertion: Transposable elements contain DNA sequences that encode enzymes responsible for their self-duplication and insertion into new sites within the DNA. This process is known as transposition.
• Transposition Events: Transposons are involved in transposition events that involve both recombination and replication. These events typically result in the generation of two copies of the original transposable element. One copy remains at the original or parent site, while the other copy is inserted into a new target site on the host chromosome.
• Disruption of Target Genes: The presence of transposable elements often disrupts the integrity of the target genes. When a transposon inserts itself into a gene, it can cause mutations or alterations in the gene’s function.
• Activation of Dormant Genes: Transposons carry genes responsible for initiating RNA synthesis. As a result, the insertion of a transposable element can activate previously dormant genes. This activation can lead to changes in gene expression and potentially influence the phenotype of the host organism.
• Dependence on Host Chromosome: Transposable elements do not possess a site for the origin of replication. Consequently, they rely on the host chromosome as plasmids or phages for replication. Transposons cannot replicate independently and require the host chromosome for their replication and transmission.
• Non-Homologous Insertion: There is generally no sequence homology between the transposable element and its target site for insertion. Transposons can insert themselves at various positions within the host chromosome or plasmid. Although certain transposons may prefer specific insertion sites (known as hot spots), they do not have strict base-specific target sites for insertion.

Types of Transposable elements

There are two main types of transposable elements:

1. Class I Transposable Elements (Retrotransposons)

Retrotransposons transpose via an RNA intermediate and utilize a “copy and paste” mechanism. They have the following subclasses:

• Long Terminal Repeat (LTR) Retrotransposons: These elements possess long terminal repeats, which are identical or nearly identical sequences found at both ends of the element. LTR retrotransposons are similar to retroviruses and use a reverse transcriptase enzyme to convert their RNA into DNA, which is then integrated back into the genome. Examples include Ty elements in yeast and the copia and gypsy elements in Drosophila.
• Non-LTR Retrotransposons: These elements lack long terminal repeats but still transpose through an RNA intermediate. They are further classified into two subclasses:
  • Long Interspersed Nuclear Elements (LINEs): LINEs are autonomous retrotransposons that encode their reverse transcriptase enzyme. They transpose by reverse transcribing their RNA into DNA, which is then inserted into a new genomic location. Human L1 elements are examples of LINEs.
  • Short Interspersed Nuclear Elements (SINEs): SINEs are non-autonomous retrotransposons that lack their reverse transcriptase enzyme. Instead, they rely on the reverse transcriptase provided by LINEs for their transposition. Alu elements are the most abundant SINEs in the human genome.

2. Class II Transposable Elements (DNA Transposons)

DNA transposons move directly as DNA segments without the need for an RNA intermediate. They typically encode a transposase enzyme that catalyzes the excision and insertion of the element. Class II transposable elements are further categorized into several types based on their transposition mechanism:

• Insertion Sequences (IS Elements): IS elements are simple transposons that consist of inverted terminal repeats (ITRs) flanking a transposase gene. They transpose via a “cut-and-paste” mechanism, where the transposase recognizes the ITRs, excises the element, and inserts it into a new location. Tn5 in bacteria is an example of an IS element.
• Transposons with Terminal Inverted Repeats (TIRs): These elements have terminal inverted repeats similar to IS elements but carry additional genes unrelated to transposition. The transposase recognizes the TIRs and catalyzes the movement of the entire transposon. The P element in Drosophila is an example of a TIR transposon.
• c. Helitrons: Helitrons are characterized by having hairpin-like structures at both ends and transpose through a rolling-circle replication mechanism. They are found in a wide range of organisms.
• Maverick/Polinton Transposons: These transposons are large and carry diverse genes unrelated to transposition. They have unique structural features and are found in various eukaryotes.

These are the major types of transposable elements found in genomes. Each type has its own specific features and mechanisms of transposition, contributing to genome plasticity and evolution.

There are also Class III Transposable Elements

Class III Transposable Elements: There are researchers who recognize the existence of a third category of transposable elements. This group is often referred to as a miscellaneous collection of transposons that do not neatly fall into the other two established categories. Some examples of these transposable elements include the Foldback (FB) elements found in Drosophila melanogaster, the TU elements in Strongylocentrotus purpuratus, and the Miniature Inverted-repeat Transposable Elements.

Mechanism of Transposition

The mechanism of transposition can vary depending on the type of transposable element involved, but I’ll provide a general overview of two common types:

1. Insertion Sequences (IS) Transposition:
   • Insertion sequences are the simplest type of transposable elements found in prokaryotes. They typically consist of a gene encoding a transposase enzyme flanked by short inverted repeat sequences.
   • The transposase enzyme recognizes the inverted repeat sequences and binds to them, forming a complex.
   • The transposase then cleaves the DNA at the boundaries of the transposable element.
   • The cleaved transposable element is then ligated into a new target site in the genome.
   • The process can result in the duplication of the target site sequence if the transposable element is inserted into a site that has a copy of the same sequence.
   • This mechanism allows insertion sequences to move around within the genome, potentially disrupting genes or altering regulatory sequences.
2. Retrotransposition:
   • Retrotransposons are transposable elements that are found in both prokaryotes and eukaryotes. They are characterized by their ability to move via an RNA intermediate.
   • Retrotransposons are usually flanked by long terminal repeat (LTR) sequences.
   • The retrotransposon is initially transcribed into RNA by the host cell’s RNA polymerase.
   • The RNA is then reverse transcribed into a DNA copy by the enzyme reverse transcriptase, which is encoded by the retrotransposon.
   • The newly synthesized DNA, called a cDNA (complementary DNA), is then integrated back into the genome at a new location.
   • This process can result in the duplication of LTR sequences if the retrotransposon inserts between two LTR sequences.
   • Retrotransposition can lead to the expansion of repetitive DNA sequences and has played a significant role in shaping the genomes of many organisms.

Methods for Transposable elements (TE) detection

Transposable elements (TEs) are mobile DNA sequences that can move within a genome or between genomes. Detecting TEs is important for understanding their impact on genome structure and function. Here are some common methods for TE detection:

1. Sequence similarity-based methods: These methods compare DNA or RNA sequences against a database of known TE sequences using tools such as BLAST or RepeatMasker. If a significant similarity is found, it suggests the presence of a TE in the sequence.
2. De novo assembly: In this method, raw sequencing reads are assembled into contigs or longer sequences. TEs can be identified by analyzing the repetitive nature of the assembled sequences using tools like RepeatModeler or RepeatScout.
3. Structural variant analysis: TEs can cause structural variations in the genome, such as insertions, deletions, or rearrangements. Various tools, such as BreakSeq, Delly, or Manta, can be used to detect these structural variants and infer the presence of TEs.
4. Read mapping-based methods: Short sequencing reads are aligned to a reference genome, and TE insertions can be detected by identifying reads that span the junction between a TE and the adjacent genomic region. Tools like TEPIC, RetroSeq, or TEMP can be used for this purpose.
5. Transposon display: This method involves PCR amplification of genomic DNA using primers specific to TE sequences. The resulting PCR products are separated by gel electrophoresis, and the presence or absence of specific TE bands can indicate the presence of TEs.
6. Transcriptome analysis: TEs can be transcribed into RNA, and their presence can be detected by analyzing RNA-seq data. Tools like TEtranscripts or TEtools can be used to identify TE-derived transcripts.
7. Long-read sequencing: Technologies like PacBio or Oxford Nanopore sequencing can generate long sequencing reads that span entire TE insertions. These long reads can provide direct evidence of TE presence and facilitate the identification of TE boundaries.

It’s worth noting that TE detection often requires a combination of these methods to achieve more accurate and comprehensive results. Additionally, specialized bioinformatics pipelines or software tools that integrate multiple approaches may be used for TE analysis.

Examples of Transposable elements

Here are a few examples of transposable elements:

1. Maize (Zea mays): The first TEs were discovered in maize by Barbara McClintock. She observed chromosomal insertions, deletions, and translocations caused by these elements, leading to changes in the genome and traits such as the color of corn kernels. Approximately 64% of the maize genome consists of TEs.
2. Oxytricha: TEs play a critical role in the development of the pond microorganism Oxytricha. When these elements are removed, the organism fails to develop.
3. Fruit fly (Drosophila melanogaster): The fruit fly contains a family of TEs called P elements. They appeared in the species during the mid-twentieth century and have since spread throughout every population. Researchers like Gerald M. Rubin and Allan C. Spradling developed technology to use artificial P elements for gene insertion in Drosophila.
4. Bacteria: In bacteria, TEs often carry additional genes, including those for antibiotic resistance. They can move between chromosomal DNA and plasmid DNA, facilitating the transfer and incorporation of genes like antibiotic resistance genes. Bacterial transposons of this type are classified as Tn family transposons.
5. Humans: The most common TE in humans is the Alu sequence. It is a relatively short sequence, around 300 bases long, and can be found in large numbers within the human genome. The Alu sequence alone accounts for approximately 15-17% of the human genome.
6. Mariner-like elements: Mariner is a class II transposable element found in various species, including humans. It was first discovered in Drosophila. Mariner elements can be horizontally transmitted across species. In the human genome, there are estimated to be around 14,000 copies of Mariner, covering approximately 2.6 million base pairs.
7. Mu phage: Mu phage transposition is a well-known example of replicative transposition. The Mu phage is a type of bacteriophage that can integrate into and replicate within the host genome.
8. Yeast (Saccharomyces cerevisiae): Yeast genomes contain several distinct retrotransposon families, including Ty1, Ty2, Ty3, Ty4, and Ty5. These retrotransposons are capable of replicating via a copy-and-paste mechanism involving reverse transcription.
9. Helitron: Helitrons are transposable elements found in eukaryotes, and they replicate using a rolling-circle mechanism.
10. Human embryos: In human embryos, two types of transposons combine to form noncoding RNA that plays a role in catalyzing the development of stem cells. These stem cells later differentiate and give rise to various cell types in the body.
11. Peppered moths: In peppered moths, a transposon located in a gene called cortex caused the moths’ wings to turn completely black. This color change helped the moths blend in with ash and soot-covered areas during the Industrial Revolution.
12. Aedes aegypti: Aedes aegypti, the mosquito species responsible for transmitting diseases like dengue and Zika, carries a large and diverse number of TEs. This characteristic is believed to be common among mosquitoes in general.

Diseases Caused by transposable elements

Transposable elements (TEs) have been implicated in various diseases, demonstrating their potential to disrupt normal cellular processes and contribute to pathological conditions. Here are some examples of diseases caused by TEs:

1. Hemophilia A and B: Hemophilia is a bleeding disorder characterized by deficiencies in clotting factors. In some cases, LINE1 (L1) TEs can insert themselves into the human Factor VIII gene, leading to the disruption of its normal function and causing hemophilia.
2. Severe combined immunodeficiency (SCID): SCID is a group of inherited disorders characterized by a severely compromised immune system. The insertion of L1 into the APC gene has been identified as a cause of colon cancer, indicating the role of TEs in disease development.
3. Porphyria: Porphyria refers to a group of rare disorders that affect the production of heme, a component of hemoglobin. The insertion of an Alu element into the PBGD gene interferes with its coding region, leading to acute intermittent porphyria (AIP).
4. Predisposition to cancer: TEs, particularly LINE1 (L1) and other retrotransposons, have been associated with cancer development. Their insertion can cause genomic instability, which is a hallmark of cancer progression.
5. Duchenne muscular dystrophy: Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. It has been linked to the insertion of the SVA transposable element in the fukutin (FKTN) gene, rendering the gene inactive and contributing to the development of DMD.
6. Alzheimer’s Disease and other Tauopathies: Dysregulation of transposable elements can lead to neuronal death, which is a key characteristic of neurodegenerative disorders like Alzheimer’s disease. The involvement of TEs in disrupting normal neuronal function contributes to the development of these conditions.

Negative effects of transposable elements

While transposable elements (TEs) have coexisted with eukaryotes for a long time and have positive effects in their host genomes, there are also negative effects associated with these “jumping genes.” TEs can lead to mutagenic effects, resulting in diseases and malignant genetic alterations.

One mechanism of mutagenesis is the formation of new cis-regulatory DNA elements connected to transcription factors in living cells. TEs can undergo evolutionary mutations and alterations, which can cause genetic diseases and potentially lethal effects through ectopic expression.

TEs can damage the genome of their host cells in several ways. For example:

1. Disabling functional genes: When a transposon or retrotransposon inserts itself into a functional gene, it can disable that gene, disrupting its normal function.
2. Incorrect repair: After a DNA transposon leaves a gene, the resulting gap may not be repaired correctly, leading to structural abnormalities in the genome.
3. Chromosomal pairing issues: Multiple copies of the same TE sequence, such as Alu sequences, can interfere with precise chromosomal pairing during mitosis and meiosis. This interference can result in unequal crossovers, leading to chromosome duplications, deletions, or rearrangements.

TEs use various mechanisms to cause genetic instability and disease in their host genomes, including:

1. Expression of damaging proteins: Some TEs contain sequences that encode proteins harmful to normal cellular function. The expression of these proteins can disrupt vital cellular processes and contribute to disease development.
2. Aberrant gene expression: Many TEs possess promoters that drive transcription of their own transposase, the enzyme responsible for their mobility. The activity of these promoters can lead to aberrant expression of linked genes, causing diseases or mutant phenotypes.

It is important to note that while TEs can have negative effects on genomes, they have also played a significant role in shaping genetic diversity and evolution. The impact of TEs can vary depending on their location within the genome and the specific genes they interact with. Researchers continue to investigate the complex interplay between TEs and their host genomes to better understand their effects on genetic stability and disease development.

Applications of transposable elements

Transposable elements (TEs) have found various applications in laboratory and research settings, enabling the study of genomes and the engineering of genetic sequences. The applications of TEs can be broadly categorized into genetic engineering and as genetic tools.

Genetic Engineering:

1. Insertional mutagenesis: TEs can be utilized to insert or disrupt specific DNA sequences. This technique is often employed to remove a DNA segment or induce a frameshift mutation, altering gene expression or function.
2. Reversible gene disruption: The insertion of a TE into a gene can temporarily disrupt its function. By utilizing transposase-mediated excision of the DNA transposon, the gene function can be restored, enabling the study of gene function reversibility.
3. Generation of mosaic organisms: TEs can generate plants or organisms with neighboring cells having different genotypes. This feature aids in distinguishing between cell-autonomous genes (whose function is restricted to the expressing cell) and genes with observable effects in other cells.

Genetic Tool:

Apart from genetic engineering, TEs serve as valuable tools in various analyses and research techniques.

1. Analysis of gene expression and protein functioning: TEs, particularly in signature-tagging mutagenesis, allow researchers to analyze gene expression patterns and study the function of specific genes by inducing mutations and comparing the phenotypic effects of the original and mutated genes.

Specific Applications:

1. Sleeping Beauty transposon system: The Sleeping Beauty transposon, a member of the Tc1/mariner class of TEs, has been extensively used as an insertional tag for identifying cancer genes. It is active in mammalian cells and shows potential for use in human gene therapy.
2. Reconstruction of phylogenies: TEs have been employed for the reconstruction of evolutionary relationships through presence/absence analyses, aiding in understanding the evolutionary history of organisms.
3. Transposons as mutagens: TEs can act as mutagens in bacteria, facilitating genetic studies and the introduction of genetic variations.

Commonly Studied Organisms:

Several model organisms have been well-developed for the use of transposons in research, including Drosophila (fruit flies), Arabidopsis thaliana (a plant model), and Escherichia coli (a bacterial model).

These applications highlight the versatility of transposable elements in genetic research, providing valuable tools for understanding gene function, engineering genomes, and exploring evolutionary relationships. Continued research and development in this field hold promise for advancements in genetic engineering, gene therapy, and other areas of biological sciences.

Mindmap on Transposable elements

FAQ

References

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