National Geographic

Under three layers of junk, the secret to a fatal brain disease

Writers often compare the human genome to a collection of recipes for making a person. Each gene contains the instructions for building a protein, and our thousands of proteins work together to build and maintain our bodies.

But if the genome is a recipe book, it’s one that was written without a good editor. It is riddled with typos, unnecessary repetitions and meaningless drivel. A miniscule proportion actually codes for proteins. The rest looks like a scrapyard. It contains the remnants of dead genes that are no longer used and have degenerated into nonsense. It contains jumping genes that hop around the genome under their own power, sometimes leaving copies of themselves behind. And it contains the remains of these jumping genes, which have lost their hopping ability and stayed in place.

These “non-coding sequences” are often called junk DNA, and for good reason. It seems that they’re largely useless… but not entirely so. Ever since these non-coding sequences were first discussed, scientists have suspected that some of them play fruitful roles in the body. Many examples have since come to light, and Francois Cartault and his colleagues have found the latest one. He has shown that one piece of supposed “junk” might explain why some people from a tiny French island die from a bizarre brain disease.

Réunion Island is technically part of France, although it lies in the Indian Ocean, between Madagascar and Mauritius. The French first settled there since 1665, and white people still make up a quarter of the island’s population. Those in the south have been particularly isolated because of the large ravines that scar the land. And as a result, they’ve experienced a history of heavy inbreeding. We know this because Réunion has rigorous family records dating back to its first settlements, and because an unusually high number of its people are born with genetic diseases.

Recently, Cartault’s team spotted the signs of a previously unnoticed disease. Babies who have it start suffering from extreme anorexia before their first birthday. They refuse to eat and they vomit uncontrollably. The white matter that connects different parts of their brain gradually vanish. Their brainstems, which control automatic processes like breathing and heartbeats, start to wither. It’s an understandably fatal condition, and some Réunion parents have lost several children to it.

The team named the disease Ravine encephalopathy, after the region it’s most common in. It’s rare, affecting around one in every 10,000 to 15,000 people. But when it appears, it tends to run in families. “It became obvious that it was an inherited disease,” says Alexandra Henrion-Caude, who led the study.

To find the gene responsible, the team scoured the genomes of nine families, including 15 people with the disease and 17 siblings without it. Their search revealed a single genetic change that was found in everyone with the disease, and no one else. It lay within a gene SLC7A2, which is deployed in the developing brain. In the affected babies, a single DNA ‘letter’ within this gene had changed from an A into a G. This mutation – the equivalent of a lone typo in a book – seemed to be responsible for the debilitating symptoms. If people inherited one copy of the G version, they were fine. No disease. If they inherited the double whammy, one from each parent, they developed Ravine encephalopathy.

There’s a similar story behind many genetic diseases, but this one had a twist: the mutation was nestled within three layers of junk. Cartault found that it lay inside a jumping gene called a LINE element. These bits of DNA can copy themselves and paste the duplicates elsewhere in the genome. They’re so good at multiplying that they make up around 17 per cent of our genome. This particular LINE element was stranded. It had degenerated to the point where it could no longer jump.

But that wasn’t all. The LINE element was embedded within another stranded jumping gene called a SINE element. These are similar in character but shorter. They make up 11 per cent of our genome.

And the SINE element, in turn, lay inside an intron – the part of a gene that’s eventually thrown away. When genes are activated, their DNA is converted into a related molecule called RNA. At this point, several introns are snipped out. The remaining segments – the exons – are glued together, and they’re the ones that contain instructions for making proteins.

So, here was a mutation that caused a fatal brain disease, lying in the genetic equivalent of Russian nesting dolls. Clearly, these sequences aren’t junk. If they were, changing that A to a G would have no effect. So what are they doing?

It turns out that the brain retains most of the discarded intron as a piece of “non-coding RNA”, which never goes on to produce a protein. It is, however, still important. When the team neutralised this RNA in laboratory cells, those cells started to die.

They now think that the RNA somehow helps to keep neurons stable. The mutation means that a baby’s brain produces less of the RNA, and its neurons start to self-destruct. That fits with the vanishing white matter and disappearing brainstems of babies with Ravine encephalopathy. Indeed, compared to these ill-fated infants, normal people have 8 times more of this precious RNA in their brains.

The details still need to be worked out, but Cartault’s study shows that this piece of “junk” plays an important part in the growing brain. It’s one of many such studies. “I think that examples like this will become more and more apparent as we sequence more people,” says Alysson Muotri from University of California San Diego.

Muotri was involved in a similar example herself, which I wrote about last year. He found that a fault in the MECP2 gene unleashes a wave of LINE elements, which coincides with another genetic brain disorder called Rett syndrome. Others have suggested that non-coding RNAs can broadly affect the odds of various diseases, or that some of them might have spurred the rise of our vaunted intelligence.

The big question now is: how much of the supposed junk is actually useful? Some says it’s a “large fraction”. Others point out that the onion has five times more of this non-coding DNA than we do. If it’s all useful, why does the onion need that much more of it?

Reference: Cartault, Muniera, Benkoc, Desguerred, Haneinb, Boddaerte, Bandiera, Vellayoudoma, Krejbich-Trotot, Bintner, Hoarau, Girard, Génin, de Lonlay, Fourmaintraux, Naville, Rodriguez, Feingold, Renouil, Munnich, Westhof, Fähling, Lyonnet, and Henrion-Caude. 2012. Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy. PNAS http://dx.doi.org/10.1073/pnas.1111596109

Image by James Jordan

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There are 8 Comments. Add Yours.

  1. Arvin
    March 12, 2012

    Cool!! You mentioned Mauritius!! That’s one of the very rate times I see this mention on such websites/blogs

    And what’s better… we are celebrating Independence Day today… How cool!!

    Happy 44th Independence Day to Us :)

  2. Cathy
    March 12, 2012

    I don’t think of it so much as junk as I do “background details.” Think of a beautiful landscape painting – there’s a small subject in one of the lower thirds (think of a swan), and then the rest is all background paint. The background is clearly not as important as the subject, but if the canvas is damaged or the paint is chipped, some critical details might be gone from the painting, rendering it incomplete and unfinished. What if, for example, the missing portion of the painting held the hunter that was about to shoot the swan?

  3. Clausentum
    March 13, 2012

    The reference to the onion is good, but it misses the point (explained in the link) that onions from the same genus can also have about 5x variation in the size of their genomes (due to “junk” DNA).

    This is perhaps more significant that the difference between onions and humans.

  4. amphiox
    March 13, 2012

    One can think of the “junk” DNA as a Tinker’s backyard junk-pile. Some of the junk is repurposed into things with uses, but most of the time one can still tell by looking at it that it is still (or was) made from junk, and not manufactured de novo.

  5. Jessica
    March 13, 2012

    Just wanted to help keep things correct here– “herself” in the second to last paragraph should be “himself.”

  6. JW
    March 13, 2012

    I find this kind of stuff fascinating (junk DNA, jumping genes, viral genes that have been incorporated into our genomes, etc.) Can anyone recommend a good recent book on these topics, aimed at a semi-layman? (I am a scientist, but work far outside this field)

  7. TR Gregory
    March 14, 2012

    Excellent job, as usual. It is refreshing to read a piece about an interesting study that eschews the standard cliches (“it’s not junk after all!”) in favour of a much more interesting treatment of the complex nature of the genome.

    @JW — I don’t think there’s any one book that focuses primarily on these topics in an accessible way. Maybe Ed and I should collaborate on one. :-)

  8. cicely
    March 16, 2012

    i’m confused about the use of “anorexia” here

    refusing to eat doesn’t qualify for a diagnosis of anorexia without the attendant body image issues. children under 1 wouldn’t have a developed sense of body

    neither does vomiting, which when self induced, falls under the umbrella of bulemia

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