Our own genetic blueprint is not a static library of instructions. Within our DNA are mobile genetic sequences known as retroelements, or “jumping genes,” which can move from one location in the genome to another. These elements are a major feature of our genetic landscape, making up nearly half of all our DNA.
The “Copy and Paste” Mechanism
Retroelements propagate using a “copy and paste” mechanism called retrotransposition. The process begins when a cell transcribes the retroelement’s DNA into an RNA molecule. This RNA copy then serves as a template for the enzyme reverse transcriptase, which synthesizes a new DNA copy from the RNA.
Another enzyme, an integrase, then cuts the host DNA at a new target site and pastes the new retroelement copy into the break. Because the original retroelement remains in its initial position, this mechanism leads to an accumulation of these sequences over evolutionary time.
A Rogue’s Gallery of Retroelements
Retroelements are classified into categories based on their structure. The primary division is between LTR and non-LTR retrotransposons, distinguished by the presence of Long Terminal Repeats (LTRs) at their ends. LTR retrotransposons resemble retroviruses and are often called endogenous retroviruses (ERVs). These elements contain the LTRs and genes needed to drive their own mobility.
The most active retroelements in humans are non-LTR retrotransposons, divided into two types: Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). LINEs, such as the LINE-1 (L1) family, are autonomous. A full-length L1 element is about 6,000 base pairs long and contains the genetic code for the proteins required to copy and paste itself.
SINEs are shorter and non-autonomous, meaning they must borrow the enzymes made by LINEs to move. The most abundant SINE in the human genome is the Alu element. At only 300 base pairs long, over one million copies of Alu are scattered throughout our DNA, making up roughly 11% of the entire human genome.
The Evolutionary Impact
The activity of retroelements over millions of years has had a major impact on the evolution of genomes. Far from being simple “junk DNA,” their insertions serve as a source of genetic novelty for natural selection to act upon. Each time a retroelement copies itself, it has the potential to alter the genetic landscape, creating variation that drives genomic restructuring.
Retroelement insertions can reshape genomes in several ways. They can land within a gene’s regulatory region, introducing new promoter or enhancer sequences that change how, when, or where a gene is turned on or off. In other instances, retroelements can be “exapted,” meaning their sequences are co-opted by the host to perform a new function, sometimes even contributing to the creation of entirely new genes.
Another mechanism is transduction, where a retroelement carries a piece of neighboring genomic DNA along with it when it moves. This can lead to the duplication and shuffling of exons, the protein-coding parts of genes. This process has been shown to create new gene families, actively contributing to genetic complexity.
The Link to Human Health and Disease
While retroelements drive evolution, their movement can also have detrimental consequences for an individual’s health. When a retroelement inserts itself into a new location, it can disrupt a gene’s normal function, a phenomenon known as insertional mutagenesis. If this insertion occurs within a gene important for health, it can lead to genetic disorders.
This process is documented in a range of human diseases. For example, some cases of hemophilia A are caused by a LINE-1 (L1) element inserting into and inactivating the Factor VIII gene. Similarly, insertions of L1 elements into the dystrophin gene have been identified as the cause of Duchenne muscular dystrophy in some patients. These insertions break the gene, preventing the production of a functional protein.
The smaller Alu elements are also responsible for many genetic conditions. A new, or de novo, insertion of an Alu element into the NF1 gene is a known cause of neurofibromatosis type 1, a disorder characterized by tumor growth along nerves. It is estimated that retroelement insertions may account for approximately 1 in every 250 disease-causing mutations.
Harnessing Retroelements for Science
Our growing knowledge of retroelements has opened up avenues for their use as tools in scientific research and biotechnology. Their unique properties, once viewed solely as a threat to genome stability, are now being harnessed for applications. Scientists can leverage the history of retroelement insertions recorded in our DNA to unravel evolutionary relationships and are exploring their potential in the field of medicine.
Because retroelement insertions are random events that become fixed in a population’s germline, they serve as excellent evolutionary markers. If two different species share the same retroelement at the exact same location in their respective genomes, it is almost certain they inherited it from a common ancestor. This principle has been instrumental in clarifying the evolutionary tree of primates, including the relationships between humans and other great apes.
Beyond tracing ancestry, the machinery of retroelements is being adapted for use in gene therapy. The ability of these elements to insert DNA into the genome is being explored as a method to deliver therapeutic genes to correct genetic defects. Researchers are working to engineer non-LTR retrotransposons to insert specific DNA sequences into safe, predetermined locations within the human genome. While significant challenges remain, these “jumping genes” offer a promising platform for developing new strategies to treat a wide range of genetic diseases.