Transposable Elements
Transposable elements are one of the few natural phenomena with a name that simply describes what it is and does. Transposable means something that moves around, and element means DNA. These “Jumping Genes” are pieces of DNA that exist inside the genome of an organism that can move from one location to another and copy themselves independent of the rest of the genome. These Transposable Elements, despite existing in the DNA of an organism, give no benefit. They merely jump around and replicate to continue themselves. Researchers refer to this as a “Selfish Gene”. All the other genes in an organism encode for something useful. Some genes make muscle proteins, components of the cell wall, but all of them serve the organism to survive and replicate. But not Transposable Elements. They bounce around the genome, inserting and copying maybe a hundred times over. They can prove harmful to the host; by inserting into specific sights in genes, causing disease. These transposable elements have been found throughout the tree of life: plants, animals, bacteria, and fungi. They were first discovered in corn by Dr. Barbara McClintock, for which she received the Nobel Prize. These ubiquitous genetic parasites are not merely silent passengers. They are found highly expressed in many cancers and are instrumental in bacteria becoming resistant to antibiotics.
To understand Transposable Elements and their potential for harm, it is important to know how DNA begets proteins. DNA is the recipe of life, but before it is interpreted into proteins and functional parts of the cell it has to be transcribed to RNA. RNA unlike DNA is single stranded and is read by a piece of biological machinery called the Ribosome. The Ribosome takes the information from the RNA and makes a polypeptide chain called a protein. This is the Central Dogma of biology, and everything that’s alive does it. Transposable Elements, TE for short, are segments of DNA. All TEs have to carry the genes they need to replicate and jump, in addition to that they often carry other genes with them.
In bacteria, which are prokaryotes, there are two types of TE: short insertion sequence elements and transposons. Prokaryotes unlike eukaryotes (you, me, the trees and the bees) have circular chromosomes. In addition, they have smaller circular pieces of DNA called plasmids. TEs in prokaryotes have two ways of getting around. The first is conservative, the enzymes encoded by the TE cut the gene out and stick it somewhere new. The second process, replicative, is a bit more complicated and involves copying the TE while inserting the copy into a new location. The first kind of TEs, short insertion sequence elements, only carry what they need to bounce from one part of the bacterial chromosome to another. The harm they cause is when they jump into the middle of a gene. Imagine you’re baking a cake and, all of a sudden, the recipe for meatloaf is inserted halfway in, it’s not going be a tasty. Transposons, the other kind of TE, carry not only the genes they need to replicate, but also other genes. These genes could be for a certain enzyme to breakdown food, a toxin to compete with other bacteria, or importantly to us, Antibiotic resistance. This is where the plasmid comes in, bacteria often trade plasmids in a process called conjugation. The plasmids are the carriers of the genes for all the things that could help a bacterium. The R factor, the bit that contains resistance, along with the rest of the transposon is replicated and inserted into the bacterial chromosome. After that it can be expressed and give the cells certain advantages. This is how bacteria can rapidly become impervious to so many different types of antibiotics.
In eukaryotes there are two types of Transposable elements: Class 1 Retrotransposons and Class 2 DNA transposons. DNA transposons utilize an enzyme called transposase to jump around using the “cut and paste” mechanism. This can interrupt the recipe of functional genes and halt expression. There is a very simple type of DNA Transposon called a P Element that contain only the genes they need to relocate. They can be used to find out exactly where genes might be in a genome. A researcher will randomly insert P elements into the genome of an organism. This will be done with thousands of individuals all at different sites in the genome. The researcher then looks for which one has a mutation in the gene they are studying. They then sequence the genome of the mutant and look for the code that makes the P Element, which the researcher already knows, to locate the target gene. In invertebrates, researchers have been even able to insert new DNA into target chromosomes. If we gain a better understanding of transposons in vertebrates, we might be able to use DNA Transposons to treat some genetic diseases by interrupting them with transposable elements.
Class II Retrotransposons are a bit more complicated. The Central Dogma of biology we referred to is generally a one-way street: DNA to RNA, RNA to protein. But special little viruses known as retroviruses play with the Central Dogma. Retroviruses are RNA encapsulated in a protein coat. The retrovirus injects its RNA chromosome into the host. The viral RNA highjacks a piece of the hosts cellular machinery called reverse transcriptase. Reverse transcriptase copies RNA into DNA. The new DNA copy of the viral chromosome is then inserted into the host chromosome, where it is copied and copied until the host’s destruction. Retrotransposon behave in a similar, though less deadly, way. A retrotransposon already exists in the hosts genome, unlike a retrovirus, and induces the cells to copy it from DNA to RNA. This new RNA copy of the Retrotransposon is then copied back to DNA by reverse transcriptase. The DNA is then inserted back into the chromosome. Each time this happens a new copy of the Retrotransposon is generated. With each new copy there is a new chance for interruption of host genes. An overabundance of Retrotransposon activity is shown to correlate with many different types of cancer. It can hardly be surprising that something that randomly copies and inserts itself into the human genome would be associated with so many cancers. It would be foolish to say that retrotransposons cause these cancers, rather they occur simultaneously. It does indicate that further study and understanding of Retrotransposons can only help in the battle against these cancers.
Something that Transposable elements likely do explain is the C-Value paradox. The C-Value paradox is when the size of a species genome, how much genetic material it has, doesn’t correlate with the complexity of an organism. A human being’s genome is about three billion base pairs long, only about 20% of that plays a role in the expressions of genes. About 3% of the human genome actually encodes for proteins, though that number may fluctuate based on current research. The genome of amphibians can be 3-30 times as large. But a frog is hardly more complex than a human being. The amount of genetic material might not correlate with complexity, but it does correlate with number of transposable elements. However, the TEs that make up vast swatches of DNA are inactive, mutated beyond the ability of copying and translocating themselves.
Still, it raises an interesting question: how much of you is you. When one says that something is “in your DNA” it means that it’s a part of you that can’t be altered, its simply who you are. Afterall a great deal is determined by genetics: intelligence, disposition, and health. The genome sequencing industry is worth billions of dollars. People are obsessed with finding out who they are based on the contents of their nucleus. But nearly half of our DNA is made up of selfish, opportunistic transposable elements. Just waiting in your body, being copied each time your chromosomes are copied, are millions of transposable elements, genetic deadweight. Luckily our bodies possess mechanism of repressing the activity of transposable elements like Dicer and RISC. Dicer will locate errant strands of potentially harmful RNA and RISC will chop them up, negating the ability of TE to jump about. Interestingly in the germline, cells specifically designated for reproduction like sperm and egg cells, Transposable Elements are repressed. This is so the genetic material we pass on to further generations won’t be corrupted and the human genome will remain intact through the generations.
Transposable elements demonstrate the flexibility of biology. Just when we think we fully grasp a field like genetics a new exciting facet will be discovered. Further understanding of this phenomenon in humans and other species will help in the treatment of a vast number of diseases. With each step closer to understanding life new discoveries will challenge our ideas and show us just how far we have to go.
References:
Griffiths, Wessler, Carroll, and Doebley, Introduction to Genetic Analysis, 11th edition 2015
Feschotte C., Transposable Elements and the Evolution of Regulatory Networks, Nature Review Genetics, 2008
Burns K.H., Transposable Elements in Cancer, Nature Review Cancer, 2017
Berger-Bchi, B., Insertional Inactivation of Staphylococcal Methicillin Resistance by Tn551, Journal of Bacteriology, 2006
Yant et Al, Somatic Integration and Long-Term Transgene Expression in Normal and Haemophilic Mice using a DNA Transposon System, Nature Review Genetics, 2000
Davies, J., Inactivation of Antibiotics and the Dissemination of Resistance Genes, Science, 1994