The Dynamic Genome: Transposable Elements

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A boy is born with a disease that makes his immune system ineffective. Diagnostic testing determines that he has a recessive genetic disorder called SCID (severe combined immunodeficiency disease), more commonly known as bubble-boy disease. This disease is caused by a mutation in the gene encoding the blood enzyme adenosine deaminase (ADA). As a result of the loss of this enzyme, the precursor cells that give rise to one of the cell types of the immune system are missing. Because this boy has no ability to fight infection, he has to live in a completely isolated and sterile environment—that is, a bubble in which the air is filtered for sterility (Figure 15-1). No pharmaceutical or other conventional therapy is available to treat this disease. Giving the boy a tissue transplant containing the precursor cells from another person would not work in the vast majority of cases because a precise tissue match between donor and patient is extremely rare. Consequently, the donor cells would end up creating an immune response against the boy’s own tissues (graft-versus-host disease).

In the past two decades, techniques have been developed that offer the possibility of a different kind of transplantation therapy—gene therapy—that could help people with SCID and other incurable genetic diseases. In regard to SCID, a normal ADA gene is “transplanted” into cells of a patient’s immune system, thereby permitting these cells to survive and function normally. In the earliest human gene-therapy trials, scientists modified a type of virus called a retrovirus in the laboratory (“engineered”) so that it could insert itself and a normal ADA gene into chromosomes of the immune cells taken from patients with SCID. In this chapter, you will see that retroviruses have many biological properties in common with a type of mobile element called a retrotransposon, which is present in our genome and the genomes of most eukaryotes. Lessons learned about the behavior of retrotransposons and other mobile elements from model organisms such as yeast are sources of valuable insights into the design of a new generation of biological vectors for human gene therapy.

Starting in the 1930s, genetic studies of maize yielded results that greatly upset the classical genetic picture of genes residing only at fixed loci on chromosomes. The research literature began to carry reports suggesting that certain genetic elements present in the main chromosomes can somehow move from one location to another. These findings were viewed with skepticism for many years, but it is now clear that such mobile elements are widespread in nature.

A variety of colorful names (some of which help to describe their respective properties) have been applied to these genetic elements: controlling elements, jumping genes, mobile genes, mobile elements, and transposons. Here we use the terms transposable elements and mobile elements, which embrace the entire family of types. Transposable elements can move to new positions within the same chromosome or even to a different chromosome. They have been detected genetically in model organisms such as E. coli, maize, yeast, C. elegans, and Drosophila through the mutations that they produce when they insert into and inactivate genes.

DNA sequencing of genomes from a variety of microbes, plants, and animals indicates that transposable elements exist in virtually all organisms. Surprisingly, they are by far the largest component of the human genome, accounting for almost 50 percent of our chromosomes. Despite their abundance, the normal genetic role of these elements is not known with certainty.

In their studies, scientists are able to exploit the ability of transposable elements to insert into new sites in the genome. Transposable elements engineered in the test tube are valuable tools, both in prokaryotes and in eukaryotes, for genetic mapping, creating mutants, cloning genes, and even producing transgenic organisms.

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Let us reconstruct some of the steps in the evolution of our present understanding of transposable elements. In doing so, we will uncover the principles guiding these fascinating genetic units.