'Jumping genes' contribute to the uniqueness of individual brains 15/6/05. By the Salk Institute for Biological Studies Brains are marvels of diversity: no two are the same, not even those of otherwise identical twins. Scientists at the Salk Institute for Biological Studies may have found one explanation for the puzzling variety in brain organisation and function: mobile elements, pieces of DNA that can jump from one place in the genome to another, randomly changing the genetic information in single brain cells. If enough of these jumps occur, they could allow individual brains to develop in distinctly different ways.

"This mobility adds an element of variety and flexibility to neurons in a real darwinian sense of randomness and selection," says Professor Fred Gage of the Salk Institute's Laboratory of Genetics and lead author of the study published in the 16 June issue of Nature. This process of creating diversity with the help of mobile elements and then selecting for the fittest is restricted to the brain and leaves other organs unaffected. "You wouldn't want that added element of individuality in your heart," he adds.

Precursor cells in the embryonic brain, which mature into neurons, all look and act more or less the same. Yet these precursors ultimately give rise to a panoply of nerve cells that are enormously diverse in form and function and together form the brain. Identifying the mechanisms that lead to this diversification has been a longstanding challenge. "People have speculated that there might be a mechanism to create diversity in brain like there is in the immune system, and the immune system's diversity is perhaps the closest analogy we have," says Gage.

In the immune system, the genes coding for antibodies are shuffled to create a wide variety of antibodies capable of recognising an infinite number of distinct antigens.

In their study, the researchers closely tracked a single human mobile genetic element, a so-called LINE-1 or L1 element, in cultured neuronal precursor cells from rats. Then they introduced it into mice. Every time the engineered L1 element jumped, the affected cell started glowing green.

Transposable L1 elements, or 'jumping genes' as they are often called, make up 17 per cent of our genomic DNA but very little is known about them. Almost all of them are marooned at a permanent spot by mutations rendering them dysfunctional, but in humans a hundred or so are free to move via a 'copy-and-paste' mechanism. Long dismissed as useless gibberish or 'junk' DNA, the transposable L1 elements were thought to be intracellular parasites or leftovers from our distant evolutionary past.

It has been known for a long time that L1 elements are active in testes and ovaries, which explains how they potentially play a role in evolution by passing on new insertions to future generations. "But nobody has ever demonstrated mobility convincingly in cells other than germline cells," says Gage.

Apart from their activity in testes and ovaries, jumping L1 elements not only are unique to the adult brain but also appear to be present during early stages of the development of nerve cells. The Salk team found insertions only in neuronal precursor cells that had already made their initial commitment to becoming a neuron. Other cell types found in the brain, such as oligodendrocytes and astrocytes, were unaffected.

At least in the germ line, copies of L1s appear to plug themselves more or less randomly into the genome of their host cell. "But in neuronal progenitor cells, these mobile elements seem to look for genes expressed in neurons. We think that's because when the cells start to differentiate, the cells start to open up genes and expose their DNA to insertions," explains co-author Alysson Muotri. "What we have shown for the first time is that a single insertion can mess up gene expression and influence the function of individual cells."

However, it is too early to tell how often endogenous L1 elements move in human neurons, how tightly this process is regulated or what happens when it goes awry, cautions Gage. "We only looked at one L1 element with a marker gene and can only say that motility is likely significantly more for endogenous L1 elements," he adds.

Adapted from a news release by the Salk Institute .

Further Reading

Professor Fred Gageresearch page

Muotri AR et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition Nature 2005; 435: 903–910. Abstract