Neuroscience - why do brains differ from each other? / Fred H. Gage and Allison R. Mottery

How is it possible for identical twins to develop different personalities? Those responsible for this are "jumping genes" that change their location in nerve cells and change the way the cells work 

Your brain is special. So do both of us, the authors of the article. The differences are found at every level in the incredibly complex architecture of this organ. The human brain contains 100 billion nerve cells, which appear in thousands of types and create between them, according to estimates, more than 100 trillion interconnections. The differences in the organization of these components, in turn, affect the way we think, learn and behave and our tendency to get mental illnesses.

How is the difference in wiring and brain function created? Variation in the level of genes we inherit from our parents plays a role in this. But even identical twins raised by the same parents can differ considerably in mental functioning, behavioral traits, and risk of mental illness or neurodegenerative diseases. In fact, even genetically identical mice that receive the same treatment in the laboratory, show differences in learning ability, responses to fear and stress even when their age, sex and treatment conditions are identical to each other. Something else must therefore be going on in the brain.

Undoubtedly, our life circumstances play a role. They can, for example, affect the strength of connections between groups of nerve cells. But researchers are discovering more and more intriguing findings that indicate that other factors also have a hand in creating variation, such as processes that cause genetic mutations or processes that affect the behavior of genes during embryonic development or in later stages of life. These phenomena include alternative splicing, where one gene can code for the production of two or more different proteins. Proteins perform most of the actions in cells, therefore the types of proteins that each cell produces affect the function of the tissues made from these cells. Many researchers also examine the role of epigenetic changes, that is, external changes in the DNA structure that change the activity of genes (and are expressed in increasing or decreasing the production of certain proteins) without changing the information encoded in the genes [see: The Hidden Switches of the Mind, by Eric Nestler, Scientific American Israel, April 2012].

Over the past few years, our colleagues and we have discovered particularly intriguing suspects that apparently work mainly in the brain and less in other tissues: the "jumping genes". These genes, found in every biological species tested so far, including humans, can insert copies of themselves into other parts of the genome (which is the total DNA found in the cell nucleus) and change the function of one particular cell and not the cells next to it, which are identical to it in any other respect. Inserting many such copies in different cells should cause minor or major changes in cognitive ability, personality traits and the risk of having neurological problems.

Our early finding regarding jumping genes in the brain led to another question: as we know, proper functioning of the brain is essential for survival, so why does evolution allow the existence of a process that disrupts the brain's genetic programming? Although we do not yet have a definite answer, the accumulating evidence suggests that jumping genes, which create differences between brain cells, provide the organism with flexibility that allows it to quickly adapt to environmental changes. Because of this, the jumping genes, formally called mobile elements, may survive during evolution because, from the point of view of the survival of the biological species, the benefits of rapid adaptation outweigh the risk.

ancient invaders

The idea that mobile elements exist and move from place to place in the genome is not new, but the surprise lies in the fact that they are so active in the brain. Jumping genes were first discovered in plants, even before James Watson and Francis Crick deciphered the double helix structure of DNA in 1953. In the 40s, Barbara McClintock of Cold Spring Harbor Laboratories noticed that "control elements" moved from place to place in the genetic material of the corn plant. She discovered that under stress, certain regions of the genome can migrate and activate or silence genes in their new location. The products of McClintock's experiments are the corn cobs with the famous colored kernels that demonstrate the genetic mosaic phenomenon, a phenomenon in which the activity pattern of genes in a certain cell differs from that of neighboring cells that are identical to it in every other respect.

McClintock's research, which was initially met with skepticism in the scientific community, eventually won her a Nobel Prize in 1983. Since then it has become clear that the genetic mosaic phenomenon does not distinguish plants but occurs in many organisms, including humans.

McClintock studied transposons, mobile elements that use a cut-and-paste mechanism to move a piece of DNA from place to place in the genome. More recent research on mobile elements in the brain has focused on retrotransposons, which use a copy-and-paste mechanism to copy themselves to new regions of the genome. Instead of jumping out of the DNA surrounding them, they replicate themselves and the new copy settles in a new position in the genome.

About half of the nucleotides (the building blocks of DNA) in the human genome originate from retro-transposons. This is a considerable rate if you take into account that the nucleotides that make up the 25,000 protein-coding genes in our genome are less than 2% of the DNA in mammals. The jumping genes are descendants of the first primitive replication systems that invaded the genome of eukaryotes (organisms whose cells contain a nucleus) a long time ago. A research group led by Haig H. Kazazian Jr. at the University of Pennsylvania showed in 1988 that retrotransposons - previously defined as inactive DNA known as junk DNA - are active in human tissues.

One type of retrotransposon, known as L1, is particularly well known as a key player in the human genome. It is able to jump with high frequency, probably because, unlike other mobile elements in humans, it itself encodes proteins necessary for its distribution throughout the genome. When you look at the behavior of L1 in cells, you find that when something causes it to start "jumping", first of all it copies itself into a single-stranded RNA molecule that leaves the nucleus to the cytoplasm, where it serves as a template for the creation of proteins encoded by certain parts of the DNA of L1. The proteins form a molecular conjugate (complex) with the still intact RNA, and the entire conjugate returns to the nucleus. In the nucleus, one of the proteins, an enzyme called endonuclease, cuts the DNA in certain places. It also uses the RNA as a template to make a double-stranded DNA copy of the original retrotransposon and inserts the copy into the genome at the point where the cut was made. Reverse transcription, from RNA to DNA, is known to many people today as a step in the pathway in which the HIV virus produces a DNA copy from its RNA genome for the purpose of locating itself in the genome of the cells it infects.

Many times the retrotransposon fails to complete the process completely and inactive truncated copies of the original L1 DNA are created. Sometimes these segments (or a full copy of L1) do not affect protein-coding genes. In other cases they can have a positive or negative effect on cell fate. They can, for example, drop into a gene in a protein-coding region and thus change it. Such an event can lead to the creation of a new version of the protein, which will benefit the organism or harm it. It is also possible that the insertion of the transposon will completely prevent the production of the protein. In other cases, the new piece of DNA may penetrate outside a certain gene and serve as a promoter (a switch that activates nearby genes) and change the level of expression, that is, the amount of protein the gene produces. And here too the consequences for the cell and the organism can be good or bad. As many copies of the L1 transposon penetrate many places in nerve cells or many cells in the brain, or both, the brain will be very different from the brain that would have formed without their influence. Such a genetic mosaic can affect behavior, thinking and a tendency to disease, and can also explain why one identical twin is healthy, while the other is diagnosed as schizophrenic, for example.

Where does the jump occur?

Until recently, most researchers who were aware of the action of L1 retrotransposon assumed that it jumps mainly in germ cells (ovaries or testes). Although several clues indicated that the L1 genes remain active in somatic tissues (ie, not in the germ cells) during the early stages of embryonic development and even later, researchers have generally ignored these clues. If the entire existence of genes is simply to propagate themselves, as one evolutionary theory claims, then the jumping genes have no reason to remain active in non-germ cells because these cells will not pass the new DNA to the next generation of the organism. After all, these cells will die when their "owner" dies.

Improved detection methods now reveal that retrotransposons can move in somatic tissues early during embryonic development and even later in life. These events occur in the brain with greater frequency than in the other tissues, a finding that poses a direct challenge to the conventional wisdom that the genetic code of brain cells in the adult human is the same and remains the same throughout the life of the cell.

For example, in our lab at the Salk Institute for Biological Studies in La Hoya, California, we tracked a gene pop in a mouse whose cells had been genetically engineered to glow green fluorescent light wherever the L1 element inserted itself into a cell's genome. We saw cells that glowed green only in germ cells and in special areas of the brain, including the hippocampus (an area important for memory and attention). This result suggests that L1 may jump more in the brain than in other somatic tissues. It is interesting to note that the jumps occurred in precursor cells (progenitor cells) that form the neurons in the hippocampus.

Various organs in a fully developed organism contain a small population of precursor cells capable of dividing and producing certain types of cells necessary to replace dead cells. The hippocampus is one of two areas in the brain that has neurogenesis, the creation of new nerve cells. Although L1 elements are mainly active in the early stages of embryonic development, when neurons are born, they can also move in the adult brain in areas where new neurons continue to form.

Even in mouse experiments, more evidence was needed that there really was retrotransposition in the brain. We decided to examine tissues from people after death and compare the number of L1 elements in the brain, heart and liver. We found that brain tissue contained much more L1 per cell nucleus than heart or liver tissue.

Most of the jumps probably occurred during brain development, because retrotransposition involves cell division, a process that does not occur in the brain after early childhood, except in two small areas. Analysis of the results revealed that each nerve cell in a person undergoes an average of 80 new penetrations of L1 into the genome, a rate that can certainly lead to a great level of variation between cells and in the general activity of the brain between different people.

A recent finding by researchers from the Roslin Institute near Edinburgh in Scotland and their colleagues provides further confirmation of the activity of L1 in the brain. In 2011, the researchers reported in the journal Nature on 7,743 somatic insertions of L1 in the hippocampus and the caudate nucleus (an area also involved in memory) that were counted in three people after their death. This study also suggests that the emerging picture of genetic variation in the brain will only become more complex as research progresses. The group from the Roslin Institute was surprised to discover about 15,000 copies of a group of shorter retrotransposons called SINEs. The most common SINE, which belongs to a group of elements called Alu, has never been observed before in the brain.

In light of our findings we wonder what triggers L1 activity. It is known that the hippocampus is also an area where neurogenesis takes place, the division of nerve cells, and that exposure to new situations or exercises stimulates neurogenesis in mice. Because of this, we decided to check if exercises also trigger gene jumping. We found that after our transgenic mice ran on a treadmill, the number of cells that glowed green doubled in the rodents' hippocampus. Because novelty and challenge accelerate neurogenesis, we consider the possibility that a new or unfamiliar environment can stimulate retrotransposition.

If indeed the number of L1 jumps increases as the nervous system learns and adapts to the outside world, the findings could indicate that different brains and the neural networks that make them up are constantly changing with each new experience, even in identical twins.

The origins of the disease

We continue to expand the base of support for the hypothesis that jumping genes contribute to human variation in brain processing ability by looking for evidence other than a simple count of L1 type elements in DNA. In our attempts to link the data with real events that have a positive or negative effect on living people, it is sometimes easier to order negative results from jumping a gene, if only because the consequences are so obvious.

In November 2010 our group reported in Nature that there was a mutation in the so-called gene MeCP2 Affects the transposition of L1 in the brain. Mutations in the gene MeCP2 can cause Rett syndrome, a serious disorder in brain development that almost exclusively affects girls. when it was discovered that MeCP2 Mutates in girls with the syndrome and in patients with other mental problems, many questions have arisen about the molecular and cellular mechanisms of the disease. Our study showed that the mutation in the brains of mice or people with Rett syndrome caused a marked increase in the number of L1 insertions in their neurons, a finding that suggests that jumping genes may explain at least some of the effects of the mutation in MeCP2.

Activity of L1 has also been discovered in other diseases. Scanning of areas in the frontal cortex of people with schizophrenia showed increased production of mobile element sequences compared to people without the disease. Circumstantial evidence suggests that L1 elements are an important component in various brain diseases, including autism. Understanding the role of mobile elements in the development of psychiatric diseases may lead to the development of new methods for diagnosis, treatment and prevention.

The research on jumping genes in the brain may challenge an entire academic field. Behavioral geneticists often follow sets of identical twins over long periods of time as a way to disentangle genetic influence and determine the contribution of the environment to diseases such as schizophrenia. The new findings showing that jumping genes actively change the genome after the formation of the embryo challenge the assumption that "identical" twins are indeed genetically identical. Indeed, the new discoveries make it even more difficult to separate the relative effects of heredity and the effects of the environment on mental processes.

The question remains: Why hasn't evolution destroyed these ancient virus strongholds in our cells, which have a high chance of causing fatal genetic defects? To answer the question, we need to recognize that humans have always been subject to attack by viral parasites and other invaders that expand our genome with the help of jumping DNA. The human body (and that of its ancestors) was probably not able to completely eliminate the interfering factors, but it adapted to coexist with the invaders by silencing them with a variety of sophisticated mechanisms that cause them to mutate and neutralize them. It appears that in some cases our genome even overrides the genetic machinery of L1 retroelements to increase our survivability. This is one reason why cells sometimes induce, and even encourage, genome-wide L1 hopping under well-controlled conditions.

One clue to the survival of jumping genes comes from a more rigorous analysis of findings showing that mice of the same genetic strain raised under well-controlled conditions respond very differently to stressful conditions. The observed behavioral differences are typically distributed in the population (bell curve), in a pattern indicating that the mechanisms creating the variation are random, as are, apparently, the insertion sites of the L1 retrotransposon.

The seemingly random nature of L1 movement from place to place in the genome suggests that natural selection is actually betting that the benefits of beneficial insertions will outweigh the negative effects of other insertions. It is possible that nature often bets on precursor neurons in the hippocampus to increase the chance that at least some of the new positions of L1 will allow the creation of mature neurons specially adapted to the tasks the brain is dealing with. A somewhat similar process occurs when the DNA in the cells of the immune system rearranges itself to form an array of antibodies. Then, only the most successful antibodies in fighting invaders are selected for mass production.

Such a scenario is not improbable. The effects of L1 do not need to be very large and do not need to occur in many cells to affect behavior. In rodents, a change in the firing pattern of a single neuron can be sufficient.

Another possible support for this idea is the discovery that the only lineage of L1 jumping elements currently active in the human genome evolved about 2.7 million years ago, after the evolutionary split from chimpanzees to bipedal humans, and at the time when our hominid ancestors first began using stone tools. This finding supports the notion that L1 elements helped produce brains that can quickly process information about the environment and are therefore able to cope more easily with the frequently changing environmental and climatic conditions. Jumping genes of the L1 type are probably partners in promoting the evolution of Homo sapiens.

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About the authors

Fred H. Gage (Gage) is a professor in the genetics laboratory at the Salk Institute for Biological Research in La Hoya, California, who specializes in the creation of nerve cells in the brain.

Alison R. Muotri is an associate professor in the Department of Pediatrics and Cellular and Molecular Medicine at the University of California, San Diego. He did his post-doctorate in Gage's lab in 2002-2008.

And more on the subject

L1 Retrotransposition in Human Neural Progenitor Cells. Nicole G. Coufal et al. in Nature, Vol. 460, pages 1127-1131; August 27, 2009.

LINE-1 Retrotransposons: Mediators of Somatic Variation in Neuronal Genomes? Tatjana Singer et al. in Trends in Neurosciences, Vol. 33, no. 8; August 2010. www.ncbi.nlm.nih.gov/pmc/articles/PMC2916067/?tool=pubmed

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