In the 1940s, geneticist Barbara McClintock performed a series of maize breeding experiments that yielded some surprising results. McClintock found that the inheritance of kernel and leaf coloration was highly unpredictable, and was associated with chromosome segments that appeared to change location.
McClintock attributed her findings to certain genes that can jump from one position in the genome to another. This conclusion was initially met with scepticism by the scientific community, but the findings were subsequently confirmed, and she was awarded the 1983 Nobel Prize in Physiology for her discoveries.
The "jumping genes" McClintock had discovered come from viruses, and were regarded as hitchhikers that parasitize the genome of their host organism and serve no function. In 1988, however, came the discovery that a mutation caused by insertion of a jumping gene causes a form of hemophilia. This was followed by the publication of the human genome draft sequence in 2001, which showed that approximately 40 percent of it consists of jumping genes. Several years later, Fred Gage of the Salk Institute of Biological Sciences and his colleagues published a paper showing that jumping genes are present and active in the human brain, and that they produce genetic variations in immature brain cells during embryonic development.
Also known as mobile, or "transposable," genetic elements, jumping genes are repetitive DNA sequences that use a cut-and-paste mechanism to excise themselves from the genome and insert themselves into other locations, apparently at random. When inserted into protein-coding regions of the genome, they can cause mutations that lead to protein dysfunction, and when inserted into regulatory regions, they can alter genetic activity.
Researchers discussed the implications of this for brain health and disease in a symposium held at the annual meeting of the Society for Neuroscience in San Diego this past month.
Gage described a diagnostic method developed in his lab for measuring transposition events in human brain cells and comparing them with those in chimps and bonobos, our closest living evolutionary relatives. His group has found that jumping gene sequences are far more abundant and active in the non-human primates than in humans, and believes that the differences between the species provide clues about evolution of the human brain.
"Many in the human evolution field believe that something happened to early humans as they diversified and emerged out of Africa, perhaps a viral infection," said Gage. "We speculate that a sub-group [of early modern humans] survived with elevated mechanisms for supressing this virus, and propose that this led to less genomic diversity in the human population, which may have led to a commonality that facilitated cultural evolution."
Geoff Faulkner of the Mater Medical Research Institute in Brisbane, Australia, described a potential role of jumping genes in human neurological diseases.
Faulkner and his colleagues use new DNA technology to map jumping gene insertion sites in the human brain. In 2011, they published a study performed on post-mortem brain tissue taken from three healthy people. They focused on two brain regions-the hippocampus, which is critical for learning and memory, and the caudate nucleus, which is involved in voluntary movement-and identified nearly 25,000 insertion sites for three different "families" of jumping genes. They also found that each brain tissue sample had a unique combination of insertion sites, and Faulkner suggests that the genetic variation produced by jumping genes may contribute to individual differences in brain function and behavior, as well as to neurological disease.
"We've analyzed brain tissue from patients with about ten different diseases, including Alzheimer's, schizophrenia, Parkinson's, and Rett Syndrome," he says. "In some cases, jumping gene activity is up-regulated, but we still lack evidence that these events are actually driving the disease process."
Joshua Dubnau of the Cold Spring Harbor Laboratory and his colleagues have turned to the fruit fly Drosophila melanogaster to better understand the link between jumping genes and neurodegeneration. Their latest research shows that age-related neuronal death is associated with increased jumping gene activity, such that jumping gene DNA sequences accumulate with age in the nervous tissue.
"There are many possible detrimental effects of jumping gene activation," says Dubnau. "If the level of insertion is massive enough we can essentially have an unstable genome that could have catastrophic effects on cell biology." The DNA damage caused by multiple insertions might contribute to age-related neuronal cell death; Dunbau described preliminary results showing that genetically engineered fruit flies in which jumping gene activity is suppressed live significantly longer than their normal counterparts.
"One possible reason that jumping genes might become activated with age is that the animals stop expressing machinery that normally silences them," he said.
Dubnau's group has also shown that a protein called TDP-43, mutated forms of which aggregate in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, normally supresses jumping gene activity. This suggests that TD-43 mutations lead to jumping gene dysregulation, which in turn may contribute to neurodegeneration. "The $225,000 question is whether jumping genes are a cause of neurodegeneration, or a consequence of it."
Finally, Igor Ponomarev of the University of Texas described research into the possible role of jumping genes in post-traumatic stress disorder (PTSD) and alcoholism.
Using large-scale gene profiling methods, Ponomarev and his colleagues have found that jumping genes are more active in the brains of mice subjected to stress-induced fear learning, an established animal model of human PTSD. Their findings suggest that these events are associated with stress-induced neuronal plasticity in the amygdala, a brain region known to be involved in fear learning, and that they may occur because of the inhibition of epigenetic mechanisms that normally suppress jumping gene mobilization. [See: Teasing Out the Effects of Environment on the Brain.]
More recently, the researchers have applied the same technique to post-mortem brain tissue samples from alcoholics. Here, too, they found that several different types of jumping genes are far more abundant in the brains of alcoholics than in those of healthy controls, also likely as a result of epigenetic modifications.
"Our working hypothesis is that stress and chronic alcohol abuse can lead to activation of jumping genes as a result of the down-regulation of epigenetic enzymes," said Ponomarev. A better understanding of these processes could eventually lead to treatments that target epigenetic mechanisms to block the potentially damaging effects of jumping genes on the brain.