Mobile DNA molecules that jump from one location in the genome to another may contribute to neurological diseases and could have subtle influences on normal brain function and behavior, according to a study published October 30 in Nature. (Scientific American is part of Nature Publishing Group.)

Retrotransposons are mobile genetic elements that use a copy-and-paste mechanism to insert extra copies of themselves throughout the genome. First discovered in plants about 60 years ago, they are now known to make up more than 40 percent of the entire human genome and may play an important role in genome evolution (pdf).

Researchers from the Roslin Institute in Edinburgh, Scotland, have now comprehensively mapped retrotransposon insertion sites in the genomes of normal human brain cells for the first time.

They used state-of-the-art DNA sequencing technology to screen for retrotransposons in tissue samples taken postmortem from three individuals who were healthy when alive and had no neurological disease or signs of abnormality in their brain tissue. Focusing on two brain regions—the hippocampus and caudate nucleus—they identified nearly 25,000 different sites for the three main retrotransposon families.

Their analyses identified more than 7,700 insertion sites for L1, the best-characterized retrotransposon family that was already known to be active in brain cells. They also found nearly 14,000 insertion sites for the Alu family, which has not been reported in the brain until now.

"Each sample had its own set of unique retrotransposition events," senior author Geoffrey Faulkner says. "The retrotransposons preferentially integrated in genes that were expressed in the brain. We think these genes are more susceptible because their DNA is packaged in an accessible way."

Many of the insertion sites were located within genes that play key roles in normal brain function. These include genes encoding receptors for the neurotransmitter dopamine and membrane transporters that mop up neurotransmitter molecules from the spaces between neurons after their signaling is complete. Some were located in tumor-suppressor genes, which are known to be deleted in several different types of brain cancer. Others were found in genes encoding regulatory proteins that are linked to psychiatric illnesses such as schizophrenia and the developmental disorder Smith–Magenis syndrome.

The researchers also found that there was far more jumping-gene activity in the hippocampus than in the caudate nucleus. This is interesting, because the hippocampus is known to be critical for learning and memory, and is widely thought to be one of the few parts of the brain that continues to produce new cells throughout life. "It is tempting to speculate that genetic differences between individual neurons could impact memory," Faulkner says, "but we have no evidence yet that this is the case."

Retrotransposons are normally silenced to prevent harmful mutations from occurring in egg and sperm cells, but are mobilized during certain stages of brain development, when neurons are being produced from dividing stem cells. Retrotransposons then take the opportunity to jump at random into parts of the chromosome that have been opened up for DNA replication.

As well as generating mutations by inserting themselves into and disrupting genes, retrotransposons can alter gene activity if inserted into adjacent regulatory regions of DNA. But Faulkner says that their effects are not necessarily harmful: "It is entirely possible that retrotransposition is generally a good thing but sometimes contributes to disease."

Once thought to be rare, these events actually take place surprisingly often. According to one recent estimate, they occur in many or most brain cells, perhaps several hundred times within each cell. Each neuron is likely subjected to a unique combination of insertions, leading to a genetic variability within populations of cells.

The full significance of this "genomic plasticity" is still not clear, but the authors suggest that it could influence brain development and behavior. It may, for example, partly account for the differences in brain structure and behavior between identical twins, and could even affect thought processes by subtly influencing the changes in nerve cell connections that occur with experience.

Faulkner and his colleagues are now planning another study with a larger sample size. "We want to see how much variability there is in this phenomenon in the healthy human population, to evaluate if there is a correlation between retrotransposition frequency and brain tumor formation, and to see whether it is increased or reduced in Alzheimer's disease."