Mobile elements, evolution and human disease

March 23, 2000

Contact: Margaret G. Kidwell, 520-621-1784, kidwell@u.arizona.edu

WASHINGTON, D.C. -- New biological evidence challenges the idea that transposable elements are only "junk" genes or "selfish" genes that are at best worthless and primarily harmful to their host organisms, a respected evolutionary geneticist said yesterday. Margaret G. Kidwell of the University of Arizona spoke at the symposium, "Mobile elements, evolution and human disease," at the American Association for the Advancement of Science meeting in Washington, D.C.

New research suggests that transposable elements sometimes play a useful role in evolution, including human evolution. And there is growing evidence that transposable elements may be a major source of genetic diversity, which is nature's gift to organisms and species struggling to cope with changing environments.

Transposable elements are sequences of DNA that have the ability to replicate and move from one location in the genome to another. The ability of a bit of DNA to produce a copy of itself and hop to another location in the chromosome is the trait-defining property of several varieties of DNA sequences popularly called "jumping" genes. Nobel laureate Barbara McClintock first recognized this genetic phenomenon in the 1940s, though few believed her interpretation at that time.

Since, biologists have discovered that transposable elements (TEs) are very abundant and ubiquitous in all living organisms, said Kidwell, Regents Professor of ecology and evolutionary biology at the UA and a member of the National Academy of Sciences. She has been studying transposable elements for more than 25 years, specializing in those found in Drosophila fruit flies.

Few people might know that transposable elements make up a huge part of the human genome -- more than 35 percent of it, Kidwell said. Fewer apparently realize a particular point "that seems very astonishing to me," she added: While transposable elements make up more than a third of the human genome, according to recent estimate, they account for only one-sixth of one percent of mutations documented in the human genome database.

That is in striking contrast to the smaller mouse genome and the fruit fly genomes that contain far fewer transposable elements. However, transposable elements may account for up to 10 percent of the mutations in mice and perhaps more than 50 percent of the mutations in fruit flies. These comparisons are based on very skimply evidence, however, Kidwell noted, and "should not be considered the last word on this topic."

"It looks like we may be really lucky that transposable elements are not doing us too much harm despite their being so prevalent," Kidwell said.

One reason certainly is that most of the transposable elements in the human genome "are not jumping at all -- they're fossil elements, dead in the water," Kidwell said. Many mobile elements initially are "autonomous elements" that carry the coding sequences that enable them to move. Some replicate only a few times, but others make thousands to millions of copies in their host genome. Most mobile element families degrade over time into "non-autonomous elements," ones that have lost the ability to produce the enzymes to transpose - the leftover fossils at the end of the natural life cycle, she explained.

Another reason that transposable elements don't wreak greater havoc in the human genome is that the small percentage of the transposable elements that do "jump" to new locations often avoid active genes, thus reducing the damage that is done, she noted.

There's a way out for mobile elements that are seemingly doomed for fossilization, Kidwell added, and she is among the biologists who find the maneuver fascinating. Some transposable elements behave like some pathogens do and jump while still active and healthy from one host lineage to another, a process called "horizontal transfer." The process is like a bacterium infecting a new host organism. But for transposable elements this process is far rarer than for organisms that have a life stage when they can survive independently of their hosts.

Transposable elements can produce a wide variety of mutations by inserting themselves into genes or intergenic regions, by deleting genetic material or by rearranging chromosomes. Host organisms respond with a battery of strategies to mitigate the harmful effects of TE invasion. To name a few of more that Kidwell will present in her talk --

One strategy already mentioned is a bias for some transposable elements to land in non-coding regions of the genome, where they are less like to do damage. A good example is a clever strategy adopted by some yeast transposons which jump into the host chromosome on top of each other, piggybacking for a common point of entry into the genome.

Another tremendously clever strategy is for transposons to avoid a host's somatic cells -- the body cells that constitute the organs and tissues -- and target the host's germ cells. Germ cells are the cells that develop into ovaries and testes that are the "germ line" that gives rise to the next generation. Not only do these TE invaders not wreak damage in their host's body cells, but by targeting germ cells they ensure their own survival in the host's progeny. A good example of this strategy is the P element Kidwell has long studied in fruit flies. This element only jumps in germline cells..

Harmful mutations cause disfunction and disease in host organisms. A type of muscular dystrophy in humans is one example. But in terms of populations and species, deleterious mutations are usually eliminated by natural selection, Kidwell said. Or mutations can be benign or neutral, as in the case of speckled and striped varieties of the Japanese morning glory, for example.

New studies also show that mutations in the long-term can be positive and contribute to the evolution and survival of species. A fundamental part of the vertebrate immune system apparently resulted from a transposable element called RAG that played a critical role early in vertebrate evolution, Kidwell said. "It may be very rare that a beneficial mutation will arise, but that mutation could be so significant that it is out of all proportion to its frequency,"

So what is the relationship between transposable elements and their host genomes? Are they junk DNA of no use at all to the host organism? Can they be seen as selfish DNA with only deleterious consequences to their host? Are they ultimately beneficial to the rise and evolution of important species - including, probably, our own? All of the above, Kidwell says. "The selfish, junk and beneficial DNA hypotheses are by no means mutually exclusive. A single label for these relationships is inappropriate and potentially misleading.

"I would argue that transposon-host relationships can be viewed as a continuum, ranging between extreme parasitism at one end to mutualistic interactions at the other. Perhaps only a small proportion of transposon-host relationships evolve to become mutually beneficial over the long term. But a few of them will. Many relationships will not last long enough to make a difference.

"But there is a strong possibility that over evolutionary time, the nature of this relationship itself evolves. These elements might be selfish genes at one point in time, then they may coevolve with their hosts to the point where the two are indistinguishable from each other. In the end, mutations are the raw material of evolution."