June 15, 2005
Jumping Genes Create Brain Neuron Diversity?

Genetic elements in rat brains (and probably in human brains) jump around in early embryonic development to generate neural diversity.

LA JOLLA Brains are marvels of diversity: no two look 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 organization 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 result might explain why humans differ in their intellectual abilities and behavioral tendencies in ways that are not accounted for by genetic inheritance or environment. Humans may end up being even more controlled by their genes than twins studies would suggest because some of the genetic patterns that control them are generated during fetal development.

"This mobility adds an element of variety and flexibility to neurons in a real Darwinian sense of randomness and selection," says Fred H. Gage, Professor and co-head of the Laboratory of Genetics at the Salk Institute and the lead author of the study published in this week's 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, 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.

The researchers were aware that the immune system rather systematically reshuffles antibody genes to produce a large variety of immune cells that make many different antibodies for different antigens it might encounter.

In the immune system, the genes coding for antibodies are shuffled to create a wide variety of antibodies capable of recognizing 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 [WHY?]. "We were very excited when we saw green cells all over the brain in our mice," says research fellow and co-author M. Carolina N. Marchetto, "because then we knew it happened in vivo and couldn't be dismissed as a tissue culture artifact."

Transposable L1 elements, or "jumping genes" as they are often called, make up 17 percent 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 testis 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 germ line cells," says Gage.

Apart from their activity in testis and ovaries, jumping L1 elements are not only unique to the adult brain but appear to happen also 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 R. 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," he adds.

However, it is too early to tell how often endogenous L1 elements move in human neurons and how tightly this process is regulated or what happens when this process 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.

Maybe some mental illnesses are caused by L1 elements inserting in places where they mess up the functioning of some brain neurons.

If I'm right in my suspicion that this result shows how we could be even more genetically determined than twins studies suggest then we are genetically determined in ways that introduce randomness at an early stage of brain development. This leaves even less room for social environment to influence development. Eventually biotechnological means will be found to reduce the degree of randomness in the L1 insertions so that outcomes of the development of offspring will become more predictable. See my post Children Of The Future May Be More Genetically Determined for further elaboration of that argument.

The idea of jumping genes in our brains triggers a memory of Mark Twain's The Notorious Jumping Frog of Calaveras County. Seems faintly related because the genes jumping around in our brains seem whimsical. Oh, and for some reason unknown to me the story is also known as The Celebrated Jumping Frog of Calaveras County. So which title was the original?

Share |      Randall Parker, 2005 June 15 04:20 PM  Brain Genetics

Garson Poole said at June 16, 2005 1:07 AM:

The neuronal jumping genes are fascinating, but here I will address your question about the name of the Mark Twain story. The Columbia Encyclopedia, Sixth Edition (2001) has a profile of Twain here that states the following:

He first won fame with the comic masterpiece "The Celebrated Jumping Frog of Calaveras County," first published in 1865 in the New York Saturday Press and later (1867) used as the title piece for a volume of stories and sketches.

The story title with the word "celebrated" appears in "The Harvard Classics Shelf of Fiction" (1917) here and "The Cambridge History of English and American Literature" (1907-21) here. After obtaining this information I visited the Project Gutenberg website to download a version of the story and found something somewhat surprising. The collection "Sketches New and Old" by Mark Twain (1882) contains the story, so I downloaded the illustrated HTML version here. In this collection the actual name of the story is "The Jumping Frog". Twain writes a literary framing device around his basic story that contains a joke about translating the story into French and then back into a "civilized language". The embedded story is titled "The Notorious Jumping Frog of Calaveras County". So now we have three names for the story. But wait. There is a fourth possible story title. This webpage states the following:

"Jim Smiley and His Jumping Frog" --[This was the original title.]-- appeared in the Saturday Press of November 18, 1865, and was immediately copied and quoted far and near.

Science fiction author Vernor Vinge once extrapolated a galaxy spanning future version of the net. Its users called it the "Net of a Million Lies". We are already there.

A reader said at June 16, 2005 3:53 PM:

Thanks for posting the article about the jumping genes. (I really like your blog, btw.) As a sociologist-without-the-degree, this is really interesting.

It reminds me of the "thrill-seeking" gene. That mutation looks like a transposable element to me, too.

Below are links to research papers for this "novelty-seeking" gene -- this gene has been correlated to ADHD. I believe it has also been correlated with antisocial personality.

The gene is "dopamine receptor 4" -- encoding where dopamine binds to a brain cell and gives a "feel good" signal. (There are a bunch of dopamine receptors, all of them interesting).

Thrill seekers have extra DNA in a dopamine receptor -- the place on a brain cell where dopamine would attach, and give you a good feeling. "Thrill-seeking" has extra DNA in that gene -- 7 repeats of the same little segment. The "7R" mutation. Sort of like a lock and key (receptor + dopamine). My guess is that with extra DNA, the receptor encoded is a little crooked. Just like with a rusty lock and jiggling the key, you really have to push to get the dopamine to fit. (Oversimplifying, apologies to the science folks). So, if you don't feel good, you have to keep generating more dopamine (more thrills) until something clicks.

The extra DNA looks to me like a transposable element -- its a little bitty piece of DNA repeated 7 times. (Other dopamine receptor mutants have fewer copies, but none more).

The suprising thing is that this mutation is highly conserved in select populations all over the world.

The authors propose that this mutation arose during human migration 40,000-50,000 years ago, and then there was "positive selection." That's science language for: if you didn't have this you'd be dead.

Modern Asian populations don't normally carry this allele (mutation). Some European populations do (I think Russian/nordic), some African, some native North American, some native South American.

Think: Human migration and fierce tribal warfare. Visigoths.
Not applicable: Nice, agrarian, large scale agriculture, Mr. Roger's neighborhood.

As an aside, this reminds me of a difference between plants and animals. In response to a threat, the animal can get up and run away. A plant has to have a very plastic genome to adapt it's way out, say, in a generation or less. At least until its propagation material can get fly, float or go dormant.

((This was first discovered by Barbara McClintock (who later won the Nobel Prize in 1984, I think). She looked at Indian Corn (need a new PC name for that. . .) and determined that the pigments were due to transposable-element like DNA's jumping around in the genome in response to environmental stress.))

So, the transposable elements in people is really interesting. It makes sense that it would arise during times of human migration -- increase the plasticity of the genome while your getting the heck outta Dodge.

But, I don't see a way to "freeze" the genome so nothing jumps around, except maybe antisense DNA/RNA. So, maybe the "thrill-seekers" will just have to evolve out as couch-potatoes take over.

Below are two links to articles and the more recent abstract:

Henry Harpending and Gregory Cochran, PNAS (2002).

Wang et al, Am. J. Hum. Genet. 74:931944, 2004

Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the
VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals
(including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (∼40,00050,000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for
selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between receptor variants.

Bob McGrew said at June 16, 2005 9:46 PM:

It's been a long time since I took biology, but I'd guess that the cells glowed green because they added the DNA required to produce the firefly protein into the mobile segment in order to label the cells.

Randall Parker said at June 16, 2005 10:09 PM:

Bob McGrew,

I realize it looks like I asked that question. But the Why? in the square brackets was in the original press release. I suspect the press release writer meant to come back and fill in an answer there and forgot to do so.

Yes, I suspect you are right.

Mervyn Vogt said at July 13, 2005 2:02 AM:

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Anonymous said at August 6, 2009 8:28 PM:

I don't understand, is the L1 gene just one jump, just one time, for each fetus when the first neural stem cell begins to split? This would give us all just one dumb mutation to diversify everyone. Our children would not inherit the better mutations (no darwinian progress).

On the other hand, if the brain cells truely works like the immune cells, the L1 would jump repeatedly making it much more sophisticated and progressive. In the immune system, only the stem cell, which partialy succeeds at combating an invader, will mutiply. In turn, these daugter cells inherit the succesfull traits in addition to a mutation from a JUMPING GENE. As in darwinian selection, the unsuccessful daughters will die while the daughters, wich are marginaly better at combating the the invader, will multiply. The third generation daughter inherit the original good traits, the good mutations, and a new round of jumping genes. As in nature, each generation gets better adapted, exept this occures repeatedly inside each individual with each infection. All because the jumping gene jumps REPEATEDLY!!!

If true, our brains would be like a complex ecosystem, with diverse family linages competing (and cooperating) with each other. New borns are renowned for creating and killing millioins of brain cells. The 'darwinian struggle' may not be just a metaphore.

PLEASE PLEASE PLEASE clarify whether the jumps repeat or not!!!!!!

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