A Blog by Ed Yong

Humans Restrain Jumping DNA That Chimps Allow To Run Free

Our genome isn’t static; some of it can move about. We’re loaded with stretches of DNA that can copy themselves and paste their duplicates into new locations, increasing their numbers as they go. These sequences, known as retrotransposons, have become so abundant that they make up more than 40 percent of our genome. They’ve probably been a major force in our evolution. Depending on where they land, they could either disrupt genes in debilitating ways, or act as building material for new adaptations.

The majority of our retrotransposons can no longer jump. They’re genetic fossils, which have mutated so much that their days of wanderlust are behind them. But one group of sequences—the L1 or LINE-1 elements—includes a small number that are still on the move. They’re still copying and pasting themselves, still creating variation between people, still causing disease.

It seems that our genome takes a particularly conservative attitude to L1 elements. By comparing our cells to those of our closest relatives, chimpanzees and bonobos, Carol Marchetto and Inigo Narvaiza from the Salk Institute for Biological studies have shown that we keep these slippery bits of DNA under a particularly tight leash. By contrast, the other two apes allow L1s to move with much greater abandon—a trait that might help to explain why their genetic diversity is far greater than ours.

Marchetto and Narvaiza began by reprogramming skin cells from four humans, two chimps and two bonobos into a state where they’re almost like stem cells. Rather than being stuck down the skin path, these stemmy cells (or iPSCs) can produce all the various types of cell in their host bodies.

The iPSCs from all three species were very similar in the genes that they switched on, but the differences were revealing. When the team looked at genes that were more strongly activated in the human cells than the chimp or bonobo ones, they saw that two of the top 50 were involved in restraining L1 elements.

If L1s were allowed to run roughshod across the genome, they could destabilise important genes and lead to disease. So, cells have evolved ways of keeping them in line. Two of these guardians—A3B and PIWIL2—are especially vigilant in our genomes. A3B is 30 times more active in human cells than chimp or bonobo cells, and PIWIL2 is 15 times more active.

It’s no surprise, then, that chimp and bonobo L1s jump about 8 to 10 times more frequently than those in humans. And the team managed to tweak that difference by changing the levels of A3B in their reprogrammed cells. By making it less active, they sent the human L1s into a jumping flurry. By making it more active, they forced the chimp and bonobo L1s to stay put.

This might help to explain why humans have such low genetic diversity. We might think that people from different corners of the world look very different, but our genomes tell a story of unusual uniformity. You can find are more genetic differences between chimps living in the same troop, than among all living humans.

It’s clear that humans passed through one or more genetic bottlenecks at some point in our evolutionary past. Something happened to whittle our population down to a small group, from whom everyone alive today descends. Perhaps that bottleneck was some sort of climatic change. Maybe it was a viral pandemic.

Fred Gage, who led the new study, quite likes the virus idea. Both PIWIL2 and AB3 also help to suppress viral infections. He wonders if, in response to an ancient pandemic, these genes allows certain groups of early humans to survive, and only later took up the task of suppressing the L1 elements. By holding down these jumping sequences, the genes exacerbated the loss of variation in the human genome even further.

And here’s another idea that Gage is pondering. Keeping a tight grip on L1 elements makes for less varied genomes. Less varied genomes mean that people (and children or neighbours in particular) become more similar, in both their physical traits and behaviour. In a population like that, “a cultural innovation like art or language might be more likely to persist,” says Gage. “If you have a unique event, like say a Picasso invents cubism, and you introduce it into the pack, it has a greater chance of being assimilated into the culture. “

This is all speculation for now. “The work is interesting, but I’m unclear at this point whether it says that L1 retrotransposition is important in speciation or in genome adaptation,” says Haig Kazazian, who studies mobile DNA at Johns Hopkins University School of Medicine. “I think that much more needs to be done to show that, and I’m sure the authors would agree.”

They do, and in producing iPSCs from chimps and bonobos, Gage’s team now have the tools to start answering more complicated questions about our evolutionary history. Kathleen Burns, who also studies mobile DNA, says that we have learned a lot about these invasive sequences by comparing the genomes of different animals. But with the iPSCs, scientists can now do a broader range of experiments to understand how L1s and other mobile elements are controlled.  “Understanding this has implications not only for normal human physiology, but also a wide variety of pathologies where mobile DNAs are de-repressed,” says Burns.

Reference: Marchetto, Narvaiza, Denil, Benner, Lazzirini, Nathanson, Paquola, Desai, Herai, Weitzman, Yeo, Muotri & Gage. 2013. Differential L1 regulation in pluripotent stem cells of humans and apes. Nature http://dx.doi.org/10.1038/nature12686

8 thoughts on “Humans Restrain Jumping DNA That Chimps Allow To Run Free

  1. Doesn’t this study indicate that chimps and bonobos are still evolving, and homo sapiens are”ät the end of our line”and thus more subject to potential mass extinction due to some catasrophic event?

    [Carol, jumping DNA is just one agent of evolution. Humans are still accumulating mutations in the usual way. – Ed]

  2. ignoring technology and culture’s effects, humans are still evolving. Its just that the number of base variants is less. Mutation unrelated to jumping genes is still a factor

    even stone age humans are less prone to mass extinction because they, unlike the apes, live in widely different places of the earth

  3. Nice write-up of an interesting study, Ed. It does make me wonder how representative of ‘normal’ tissue the iPSCs are. In plants, rates of transposon transcription varies with levels of stress etc. This is obviously not the same as the ‘jumping’ that you have written about here, but I wonder whether the particular culture conditions etc have an impact on some of the silencing mechanisms involved. In any case, an intriguing study of how genomes handle the ever-lasting battle with their resident parasites.

    [Good question. I asked Gage if the cell cultures might affect the transposition rates. He said: “Yes, but we find the same changes in hESs as we do in hiPS cells and importantly we find the same changes in all the cells we examined. Finally the predicted decrease in New L1 insertions in humans is found in the openly available genomes of humans and Chimps.” -Ed]”

  4. vince, the total variation in humans is less than in other great apes not because of our culture and technology, but because our ancestors went through a severe genetic bottleneck in the recent past, while their ancestors apparently did not. (The other great apes may be undergoing a severe genetic bottleneck right now, however, largely due to us destroying their habitats and killing them).

    Culture and technology may have reduced (not eliminated) some selection pressures on our populations (while simultaneously creating new ones) but the effect of that, if any, would actually be to increase the rate at which variations would accumulate in our populations, as fewer new mutations would be winnowed out by purifying selection, and will instead persist (ie more mutations are now neutral instead of deleterious).

  5. Nice writeup, but it seems very unlikely that a transposable element invasion can explain the reduction in the effective population size of humans.
    1) The reduction in human effective population size is a long term pattern, and so is unlikely due to some plague-like phenomenon.
    2) The fitness of a TE is very tied to that of its host, unlikely a typical virus, so TEs are strongly selected to avoid too high a fitness cost to host. [At least that is my imperfect understanding of TE dynamics].

  6. Rereading this again, I see I have misunderstood the causality of authors’ speculative hypothesis, in part because it jumps around between ideas (but mostly because I read it too quickly). They are speculating that a virus spread and the human population size crashed, and then adapted by changing their suppression mechanisms. However, point 1 stands as the low level of human diversity is a long term pattern, likely not due to a single plague.

    I note that the subsequent discussion about levels of diversity and culture is almost surely incorrect. Diversity levels in human populations are not that much lower than in other great apes, and there is no evidence that genetic diversity is a barrier to the establishment or spread of cultural ideas.

  7. Another recent paper looked at 83 genomes of great apes and concluded that L1 insertion rates have been relatively constant in great ape and human evolution, while Alu insertion rates have been much more variable. Not sure how that will fit with the results of the Nature paper.
    Rates and patterns of great ape retrotransposition.

  8. Bit of a tangent…but this seems to indicate that humans were always significantly more closely related to each other than chimps are to each other now, and I am wondering if this might not have significant implications for calculations related to the evolution of altruism. If genetic variation in a group is lower, then R value is higher for two human brothers than for two chimp brothers, right?

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