ARTICLE IN BRIEF
Investigators have identified a mechanism — mobile pieces of DNA — that might account for neural diversity and neurodegenerative disease.
Ever wonder how the human brain is so adaptive to the environment over the ever-changing experiences of a lifetime? Scientists at the Salk Institute for Biological Studies have discovered active jumping elements that change the genome and are specifically jumping in the human brain. These so-called jumping genes seem to change 50 percent of the DNA sequence in the brain, according to a new study published Aug. 5 online in advance of the print edition of Nature.
“This is a potential mechanism to create the neural diversity that makes each person unique,” said the senior study author Fred H. Gage, PhD, a professor in the Salk Laboratory of Genetics and an endowed chair for research on age-related neurodegenerative diseases. “The brain has 100 billion neurons with 100 trillion connections, but mobile pieces of DNA could give individual neurons a slightly different capacity from each other.”
Identification of jumping genes in the human brain may lead to new ways of understanding brain development and an individual's unique way of thinking and behaving, he said. It could also help understand neurodegenerative disease.
DEFINING JUMPING GENES
Jumping genes are mobile pieces of DNA that insert extra copies of themselves throughout the genome. This “copy and paste” genetic mechanism alters particular strings of letters, words, paragraphs, and even chapters in the DNA that drives the brain. Other investigators have identified different mechanisms that induce genomic diversity in sperm and the immune system — two organ systems that may need more diversity throughout evolution to survive. These actively mobile pieces of DNA are called LINE-1 (long interspersed nuclear element-1) elements.
In 2005, Dr. Gage and his colleagues found the first hints of LINE-1 elements in the brains of mice and rats. “During neurogenesis, when new cells are being born, these elements become active,” Dr. Gage explained. “They insert randomly in the genome of every new neuron.”
“As the brain matures, the newly inserted pieces of DNA in brain cells provide a little something extra to allow the organism to adapt to different changes in the environment,” he added.
LEARNING MORE THROUGH NEUROGENESIS
Dr. Gage's work in adult neurogenesis led him to the current finding. He has spent years working on the molecular mechanism that drives the birth of new neurons in the adult brain. The scientists isolated fetal neuronal and embryonic stem cells and let them mature. Along each step in the developmental process he would put the neurons on a gene chip and try to figure out which genes were more active at each point in the developmental journey to adulthood.
The first nine chips were these retrotransposition LINE-1 elements. These are strips of DNA that make protein that can “copy” DNA and reinsert the copied piece somewhere else in the genome. The proteins are LINE-1 elements. The structure of these elements looks like a virus and Dr. Gage said that it could actually be a retrovirus that originally infected the genome and survived by replicating itself.
“We co-evolved with viruses in our genome,” explained Dr. Gage. The scientists painstakingly counted the number of base pairs and found that 50 percent of the DNA sequence in the human genome was made up of these inserted jumping genes.
Figure. DR. FRED H. ...Image Tools
Previously, he said, no one thought these LINE-1 elements were active in somatic cells. But Dr. Gage, Nicole Coufal, PhD, and their colleagues showed that the LINE-1 elements were active in stem cells that become neurons.
In the present study, they biopsied tissue from 10 people, including cells from the heart, skin, liver, and brain. If their hypothesis were correct, DNA sequences in the brain would outnumber those found in the other tissues. They did find more DNA sequences in virtually every region of the brain where they looked. Most robust was the hippocampus. The brain had about 100 more LINE-1 elements per cell than tissue found outside of the brain.
“This is more new insertions per cell than I would have anticipated,” Dr. Gage said. “An important issue is whether there is a mechanism for genetic diversity — and here is the evidence that there is such a mechanism in the brain,” he added.
“This was proof that these elements really are jumping in neurons,” added Dr. Coufal.
A THEORY TO BE TESTED
Dr. Gage said that these findings have raised a lot of issues and right now the idea that this phenomenon is designed for genetic diversity is simply a theory. “But it is one that needs careful testing.”
The next step is to take these LINE-1 elements and start knocking them out to see what happens during development. He is reviewing work that is already being carried out in the immune system, where it's been shown that somatic recombination events allow for genetic diversity. “This somatic diversity in neurons might contribute to which neurons survive and which ones don't,” the scientist explained. “This may also provide diversity to an individual going through an unknown environmental experience so that we can build a nervous system for any known experience.”
Some retrotranspositions have been found to cause disease. The Salk scientists believe that their findings will have implications for understanding neurological diseases. “Dysregulated jumping could be contributing to the problems seen in these conditions,” Dr. Coufal said.
“It is quite striking,” said Robert Martienssen, PhD, a professor at Cold Spring Harbor Laboratory who studies epigenetics in plants and yeast. “The high rate of transposon activity found in the brain proves that this is a programmed change and not just an accidental occurrence.”
The question is why. “There are a variety of ideas floating about,” Dr. Martienssen said. “Imagine millions of neurons differentiating in the brain: if transposons jump around randomly each neuron would have a different set of transposons providing variability to the function of the neurons.” He suspects that transposons may be targeted for genes important for neuronal variability.
“The Salk team found about 80 new transposition events per neuron. We have no idea what happens as a result of these new genetic changes,” Dr. Martienssen continued. He added that there are many examples of diseases caused by such transposition events. “It is possible that if they insert in the wrong gene it can cause a problem,” he said.
Haig H. Kazazian Jr., MD, professor of genetics at the University of Pennsylvania School of Medicine, studies the nature of these so-called retrotransposable elements in humans. He said that there are half a million inactive copies and as many as 100 active copies in the average human genome.
The Salk findings, he said, are “very interesting and our work backs it up.” He said that his group published a paper in June in Genes and Development showing that most retrotransposition takes place in early development and “that many of these new insertions are not inherited in the next generation.”
Figure. DR. ROBERT M...Image Tools
His group has also shown that in most but not all of a small number of transgenic mice tested, the insertion number is higher in the brain than in other organs. “All of our observations correlate well with the Salk findings,” he added.
• Coufal NG, Garcia-Perez JL, Gage FH, et al. L1 retrotransposition in human neural progenitor cells. Nature 2009; E-pub 2009 Aug 5.
• Kano H, Godoy I, Kazazian HH Jr., et al. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev