By: Leslie A. Pray, Ph.D. © 2008 Nature Education
Transposable elements (TEs), also known as “jumping genes,” are DNA sequences that move from one location on the genome to another. These elements were first identified more than 50 years ago by geneticist Barbara McClintock of Cold Spring Harbor Laboratory in New York. Biologists were initially skeptical of McClintock’s discovery. Over the next several decades, however, it became apparent that not only do TEs “jump,” but they are also found in almost all organisms (both prokaryotes and eukaryotes) and typically in large numbers. For example, TEs make up approximately 50% of the human genome and up to 90% of the maize genome (SanMiguel, 1996).
Types of Transposons
Today, scientists know that there are many different types of TEs, as well as a number of ways to categorize them. One of the more common divisions is between those TEs that require reverse transcription (i.e., the transcription of RNA into DNA) in order to transpose and those that do not. The former elements are known as retrotransposons or class 1 TEs, whereas the latter are known as DNA transposons or class 2 TEs. The Ac/Ds system that McClintock discovered falls in the latter category. Different classes of transposable elements are found in the genomes of different eukaryotic organisms (Figure 1).
Autonomous and Nonautonomous Transposons
Both class 1 and class 2 TEs can be either autonomous or nonautonomous. Autonomous TEs can move on their own, while nonautonomous elements require the presence of other TEs in order to move. This is because nonautonomous elements lack the gene for the transposase or reverse transcriptase that is needed for their transposition, so they must “borrow” these proteins from another element in order to move. Ac elements, for example, are autonomous because they can move on their own, whereas Ds elements are nonautonomous because they require the presence of Ac in order to transpose.
What Jumping Genes Do (Besides Jump)
The fact that roughly half of the human genome is made up of TEs, with a significant portion of them being L1 and Alu retrotransposons, raises an important question: What do all these jumping genes do, besides jump? Much of what a transposon does depends on where it lands. Landing inside a gene can result in a mutation, as was discovered when insertions of L1 into the factor VIII gene caused hemophilia (Kazazian et al., 1988). Similarly, a few years later, researchers found L1 in the APC genes in colon cancer cells but not in the APC genes in healthy cells in the same individuals. This confirms that L1 transposes in somatic cells in mammals, and that this element might play a causal role in disease development (Miki et al., 1992).
Silencing and Transposons
As opposed to L1, most TEs appear to be silent—in other words, these elements do not produce a phenotypic effect, nor do they actively move around the genome. At least that has been the general scientific consensus. Some silenced TEs are inactive because they have mutations that affect their ability to move from one chromosomal location to another; others are perfectly intact and capable of moving but are kept inactive by epigenetic defense mechanisms such as DNA methylation, chromatin remodeling, and miRNAs. In chromatin remodeling, for example, chemical modifications to the chromatin proteins cause chromatin to become so constricted in certain areas of the genome that the genes and TEs in those areas are silenced because transcription enzymes simply cannot access them.
Another example of transposon silencing involves plants in the genus Arabidopsis. Researchers who study these plants have found they contain more than 20 different mutator transposon sequences (a type of transposon identified in maize). In wild-type plants, these sequences are methylated, or silenced. However, in plants that are defective for one of the enzymes responsible for methylation, these transposons are transcribed. Moreover, several different mutant phenotypes have been explored in the methylation-deficient plants, and these phenotypes have been linked to transposon insertions (Miura et al., 2001).
Based on studies such as these, scientists know that some TEs are epigenetically silenced; in recent years, however, researchers have begun to wonder whether certain TEs might themselves have a role in epigenetic silencing. Interestingly, it was Barbara McClintock who first speculated that TEs might play this kind of regulatory role (McClintock, 1951). It has taken decades for scientists to collect enough evidence to consider that maybe McClintock’s speculation had a kernel of truth to it.
Transposons Can Encode siRNAs That Mediate Their Own Silencing
Because transposon movement can be destructive, it is not surprising that most of the transposon sequences in the human genome are silent, thus allowing this genome to remain relatively stable, despite the prevalence of TEs. In fact, investigators think that of the 17% of the human genome that is encoded by L1-related sequences, only about 100 active L1 elements remain. Moreover, research suggests that even these few remaining active transposons are inhibited from jumping in a variety of ways that go beyond epigenetic silencing.
For instance, in human cells, small interfering RNAs (siRNAs), also known as RNAi, can prevent transposition. RNAi is a naturally occurring mechanism that eukaryotes often use to regulate gene expression. What is especially interesting about this situation is that the siRNAs that interfere with L1 activity are derived from the 5′ untranslated region (5′ UTR) of L1 LTRs. Specifically, the 5′ UTR of the L1 promoter encodes a sense promoter that transcribes the L1 genes, as well as an antisense promoter that transcribes an antisense RNA. Yang and Kazazian (2006) demonstrated that this results in homologous sequences that can hybridize, thereby forming a double-stranded RNA molecule that can serve as a substrate for RNAi. Furthermore, when the investigators inhibited endogenous siRNA silencing mechanisms, they saw an increase in L1 transcripts, suggesting that transcription from L1 is indeed inhibited by siRNA.
Transposons Are Not Always Destructive
Not all transposon jumping results in deleterious effects. In fact, transposons can drive the evolution of genomes by facilitating the translocation of genomic sequences, the shuffling of exons, and the repair of double-stranded breaks. Insertions and transposition can also alter gene regulatory regions and phenotypes. In the case of medaka fish, for instance, the Tol2 DNA transposon is directly linked to pigmentation. One highly inbred line of these fish was shown to have a variety of pigmentation patterns. In the members of this line in which the Tol2 transposon hopped out “cleanly” (i.e., without removing other parts of the genomic sequence), the fish were albino. But when Tol2 did not cleanly hop from the regulatory region, the result was a wide range of heritable pigmentation patterns (Figure 4; Koga et al., 2006).
The fact that transposable elements do not always excise perfectly and can take genomic sequences along for the ride has also resulted in a phenomenon scientists call exon shuffling. Exon shuffling results in the juxtaposition of two previously unrelated exons, usually by transposition, thereby potentially creating novel gene products (Moran et al., 1999).
The ability of transposons to increase genetic diversity, together with the ability of the genome to inhibit most TE activity, results in a balance that makes transposable elements an important part of evolution and gene regulation in all organisms that carry these sequences.