Jumping genes mobilise in the brains of people with Rett syndrome

By Ed Yong | November 17, 2010 1:00 pm

MECP2_L1In the brain of a baby, developing in her mother’s womb, a horde of DNA is on the move. They copy themselves and paste the duplicates into different parts of the genome. They are legion. They have been released from the shackles that normally bind them. And in a year’s time, the baby that they’re running amok in will develop the classic symptoms of the debilitating brain disorder known as Rett syndrome.

Children with Rett syndrome – they’re almost all girls – appear normal for about a year before their development is spectacularly derailed. The neurons in their brain fail to develop properly. They lose control of their hands. Most will never speak and at least half cannot walk on their own. Digestive problems, breathing difficulties and seizure are common. They will depend on their loved ones for the rest of their lives.

In most cases, this panoply of problems are all caused by faults in a single gene called MECP2, nestled within the X chromosome. MECP2 is a genetic gag – it silences other genes in a way that’s essential for producing healthy, mature neurons. But Alysson Muotri and Maria Carol Marchetto – a husband and wife team – have found that MECP2 also has another role. It acts like a warden, restraining a mafia of mobile genes called LINE-1 sequences or L1.

L1 sequences are stretches of DNA with no obvious function, beyond making more copies of themselves. Using the proteins that they encode, they can copy and paste themselves into new locations throughout the genome, and potentially interfering with the genes that they jump into. And they’re very, very good at it. The human genome contains a staggering 500,000 L1 sequences, meaning that they account for a fifth of our DNA. For understandable reasons, they’ve been sometimes described as genetic parasites.

Most of the L1 copies have been neutered in some way, but some can still mobilise. These restless DNA strands are held in check by genes such as MECP2 and if MECP2 if faulty, L1 is unleashed upon the rest of the genome. It’s very unlikely that these sequences are actually causing the symptoms of the disease (more on this later), but they are certainly involved somehow.

Every potentially active copy of LINE-1 has a promoter – a stretch of DNA that ‘switches it on’. Muotri and Marchetto found that MECP2 sticks to the promoter, particularly in the stem cells that produce neurons and other cells of the brain. The presence of MECP2 interferes with the promoter, which disables the switch that activates L1. The mobile legion is kept in check.

Muotri and Marchetto demonstrated this by creating cells where the L1 promoter had been attached to a glow-in-the-dark gene. Without MECP2, the cells lit up like a beacon, pulsing with tiny dots that gave away the presence of roving L1 copies. With MECP2 around, they stayed dark. The same thing happened in the brains of mice that had been engineered in the same way. If the mice didn’t have any copies of MECP2 at all, the amount of glowing active L1 went up by two to six times, depending on the part of the brain (in the two images at the top, compare the number of green dots in the one on the right with the one on the left). With the warden gone, the mobile genes escaped and spread.

The results were fascinating, but Muotri and Marchetto wanted more direct evidence that these differences in L1 activity are actually relevant to Rett syndrome. To do that, they took cells from girls with the condition (who had busted versions of MECP2) and those without it. They transformed them back into a stem cell-like state (using a technique described last week), added their glowing version of the L1 promoter, and allowed the cells to produce fresh neurons. The telltale fireflies revealed that the neurons from the girls with Rett syndrome had twice as much active L1 as those from the other children.

The results are fascinating – here is a sequence of microscopic events that links the faulty gene behind Rett syndrome to the wanton spread of a mobile gene in the brain. But this doesn’t mean that the L1 sequences are actually causing the symptoms of Rett syndrome.  In fact, that’s very unlikely for three reasons.

First, L1 is hopping about the place when Rett children are still developing in the womb, and if that’s the case, it’s not clear why the symptoms of the condition should only show up after a year or so. Second, the parasitic sequences also jump into random places, so it’s very unlikely that they would produce the many consistent symptoms that Rett children show.  And finally, mice with broken copies of MECP2 also show Rett symptoms, but they make a partial recovery if they are given working copies of the gene, something that happens long after L1 has multiplied throughout the genome.

All in all, the spread of L1 might just as easily be a consequence of the events that produce Rett symptoms, rather than their cause. However, its chaotic jumping no doubt influences the development of neurons later on in life. It may well contribute to the differences between Rett children, who share many consistent symptoms as well as great variation.

Indeed, L1 and other similar jumping genes may have stuck around in the human genome precisely because they create genetic variation when they infiltrate new places. It’s telling that L1 is mobilised even in normal cells that are unaffected by MECP2 faults, although presumably in a more restricted way. Back in 2005, Muotri and Marchetto showed that L1 is active in normal neural stem cells, released as part of the normal course of development.

The result is variety. In thousands of bounds, these jumping genes produce neurons whose genes are all slightly different, fashioning tremendous variety from a single starting genome. Muotri and Marchetto have suggested that this process could help to create the infinite diversity that separates the billions of neurons within a brain and the billions of brains in the world. If that’s true (and it’s still open to debate), then L1 sequences aren’t quite the useless, parasitic ‘junk’ that they’re often billed as. They might even be necessary.

Reference: Nature http://dx.doi.org/10.1038/nature09544

More on jumping genes:

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Comments (5)

  1. ” MECP2 is a genetic gag – it silences other genes in a way that’s essential for producing healthy, mature neurons.”

    A ‘genetic gag’ is such an apt description of a transcriptional repressor! You have a magical way with words, Ed Yong :)

    I would also like to point out that MECP2 is also necessary for normal astrocyte development, which may explain at least some of the symptoms of Rett. The neurons always seem to get all the attention, but glia matters too!

  2. Fascinating and well written as usual.

    I was wondering if people with Rett syndrome tend to have more brain tumours than general population. All these roaming DNA elements could disrupt important genes such as tumour suppressor genes.

  3. Possibly, but it’d be very hard to tell. Brain cancer is more common in older people and most people with Rett syndrome don’t live long enough (although with care, life expectancy can apparently reach as high as 40-50). Also, Rett syndrome is very rare, and brain cancer is fairly rare. So it would be very hard for an epidemiologist to study the frequency of one among the other.

    However, it’s possible for a brain tumour to cause Rett-like symptoms: http://www.ncbi.nlm.nih.gov/pubmed/9881680

  4. Magnificent site. Lots of helpful info here. I’m sending it to a few pals ans also sharing in delicious. And naturally, thanks in your sweat!

  5. Helena

    Thanks for an interesting and easy-to-read-article and for the link to the article about brain stem tumour. On life expectancy, we recently met a very alert woman with RTT well over 60.

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