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The Human Genome Is In Stalemate in the War Against Itself

A moth evolves ears that can hear the sonar of bats, and bats adapt by hushing their calls to whispers. A newt evolves powerful poisons that can kill would-be predators, and a snake evolves immunity to those poisons. A gazelle becomes faster to outrun its hunter, and a cheetah becomes faster still. The natural world is full of these evolutionary arms races—endless battles where one party’s adaptations are met by counter-adaptations from its opponent. Both sides move in and out of check, changing all the time but locked in a perpetual stalemate.

The human genome is engaged in a similar evolutionary arms race… against itself.

The opponents are jumping genes called retrotransposons that can hop around the genome. They increase in number by copying themselves and pasting the duplicates into new locations. This mobile lifestyle is so successful that retrotransposons make up more than 40 percent of the human genome. Some have settled down, and are now static shadows of their once-active selves. Others are still on the move.

If the copies land in the right place, they could act as clay for building new adaptations. If they land in the wrong place, which is perhaps more likely, they could cause diseases by disrupting important genes. So genomes have ways of keeping these wandering sequences under control. One involves a gene called KAP1. It’s a kind of tranquiliser—it sticks to retrotransposons and stops them from activating.

KAP1 works differently in different species, targeting those retrotransposons that are active in that owner’s genome. Our KAP1 won’t keep a mouse’s jumping genes in line, and vice versa. Some scientists believe that this specificity is caused by another group of genes called KZNFs. They tell KAP1 where to go by searching for, and sticking to, specific retrotransposons. They’re like beat cops that patrol a neighbourhood, look for crime, and radio for back-up. Each KZNF targets a different type of retrotransposon and different species have their own set.

At least, that’s what happens in theory. In reality, it has been hard to confirm this idea,  partly because these cops do such a good job that it’s hard to see jumping genes in action.

Frank Jacobs and David Greenberg from the University of California, Santa Cruz solved this problem by sticking the retrotransposons in mouse cells—a less policed environment. They filled the mouse stem cells with a single human chromosome. Mice are adapted to control their own retrotransposons, so they’re oblivious to ours. The jumping genes on the human chromosome, freed from their usual restraints, started spreading, much like an invasive species running amok on an island with no native predators. Now, the team could pit different human KZNFs against these restless genes to see if any could bring them to heel.

They found two that could—ZNF91 and ZNF93. Each of these represses a major class of retrotransposons—SVAs and L1s, respectively—that are still jumping about in the human genome today.

ZNF91 and ZNF93 are only found in primates, but they have changed a lot even without our narrow lineage. For example, the human version of ZNF91 has deluxe features that are shared by gorillas but not by monkeys. To understand the value of these changes, Ngan Nguyen and Benedict Paten took the modern genes and worked backwards, reconstructing their ancestral versions at different stages of their evolution.

They found that between 8 and 12 million years ago, ZNF91 gained features that dramatically improved its ability to keep retrotransposons in line. That’s the point in primate evolution before humans diverged from gorillas and chimps. ZNF93 went through similarly dramatic changes between 12 and 18 million years ago, before the we (and the other great apes) diverged from orang-utans.

These results suggest that ape KZNFs have rapidly evolved to keep jumping genes in check. Indeed, the KZNFs are one of the fastest growing families of primate genes. We have around 400 of them, and some 170 of these are primate-only innovations. This expanded police force reflects our ongoing genomic arms race.

And the jumping genes are starting to fight back. For example, the team found that ZNF93 represses L1 genes by recognising a short signature sequence that most of them have. But some L1s, especially the most recently evolved ones, have lost this signature entirely. They can jump unnoticed.

The missing sequence would normally makes the jumping genes better at jumping. But this booster rocket ended up as a wheel clamp, since ZNF93 evolved to recognise it. So some of the L1s lost the rocket. They jumped less effectively, but at least they could still jump.

anchorman-well-that-escalated-quicklyThis is a classic evolutionary arms race. The hosts thrusts, the parasite parries, and the duel continues. But unlike more familiar battles between snakes and toads, or hosts and viruses, this is a case where we’re waging war against our own DNA.

There’s a sense of futility about this. Much of our genome seems to be engaged in an ultimately pointless duel whether neither side can give or gain any ground. But these battles aren’t quite as fruitless as they might seem.

The team found that KZNFs partly suppress the genes around a retrotransposon too. When the cops finds their target, they tell all the bystanders to the lie on the ground too. This is important because it seriously affects the activity of many human genes, beyond retrotransposons. It means that KZNFs can eventually be used to control the activity of genes that jumping genes land next to. (“Excuse me, officer, but while you’re manhandling your suspect, would you mind also rescuing my cat?”) This arms race could have given rise to more complicated networks of genes, and perhaps more complicated bodies or behaviours.

Reference: Jacobs, Greenberg, Nguyen, Haeussler, Ewing, Katzman, Paten, Salama & Haussler. 2014. An evolutionary arms race betweenKRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature http://dx.doi.org/10.1038/nature13760

More on jumping genes

Humans Restrain Jumping DNA That Chimps Allow To Run Free

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

How a quarter of the cow genome came from snakes

Flesh-Eating Plant Cleaned Junk From Its Minimalist Genome


5 thoughts on “The Human Genome Is In Stalemate in the War Against Itself

  1. While I agree this is a fantastic study, I think its erroneous to say that “no one had matched any one of them to a specific target”. Indeed, the KZNFs were partially discovered to have specific activity due to seminal studies by Daniel Wolf in Steve Goff’s lab against the MLV provirus (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676211/) which really set the stage for this direct antagonism model (also see beautiful correlation work by Jim Thomas and his student http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676211/).

    [Thanks, Harmit. You’re quite right and I’ve redacted the clause in question. – Ed]

  2. very nice article! But I think the word “without” (below) should be “within”.

    ZNF91 and ZNF93 are only found in primates, but they have changed a lot even without our narrow lineage.

    [Nope, I meant within. – Ed]

  3. I’m not a scientist and I’m not ashamed to admit that much of this is “over my head”. My take from this is that basically much of the genetic activity that’s been responsible for our evolutionary changes for millions of years basically continues? Again… my very limited understanding is that most of this “genetic activity” has been somehow “instinctive” and it’s purpose is the carriers “survival”? But…my question is this. What is “it” that is ultimately controlling all this genetic activity? Since I don’t believe there is some sort of “divine power” that controls everything and even “instinct” is something “learned”…then what is “it”? I know the “brain” controls our bodily functions but does it control our genetic activity?

    [Hi, David. There isn’t a controller as such. It’s an automatic, self-sustaining system. It runs by itself, but can receive inputs from the world around it. So, for example, the time of day, or sights and smells, or interactions with other people, will affect the activity of your genes. If you’ve ever played a computer game like SimCity, it’s a bit like that. It’s an automatic system that will run on its own until such time as you nudge it. – Ed]

  4. I have some basic questions about the retrotransposons in relation to total DNA. The article states that retrotransposons constitute at least 40% of the total DNA in humans. I want to know where they came from–acknowledging that they have a long evolutionary history with predecessors of humans as the article says, were these retrotransposons part of the original DNA of the organisms in which they were later discovered to be jumping around? Were they leftovers from viral infections where the virus integrates its DNA into the host’s? Is there some other origin suspected or known to be the case? (e.g. are they essentially life forms of their own that are now symbiotic or parasitic in other organisms, in much the same way that viruses and prions are not “alive” but can be considered their own separate entity?)

    Second, the article talks a little about the consequences of retrotransposons jumping around and accidentally interrupting other genes, or the KZNF’s halting expression of nearby genes too (which could be good or bad). I wonder if the retrotransposons can ever, as a consequence of jumping in the right way at the right time, end up duplicating themselves, increasing the total amount of DNA (either in one chromosome or in one cell). And if such a thing is possible, could it slightly extend the Hayflick Limit of the cells in which this happens (without the need for telomerase activity)? I know that some genetic disorders are the result of excess DNA in the form of additional chromosomes and that it usually doesn’t turn out well, but this seems a little different, not in the least because if 40% of our DNA is already made of retrotransposons, have we always had this much DNA or did we start out with significantly less?

    Thanks for your time, and any insights you have into these matters.

  5. I’m a shrink with not much more than a high school biology background. Do these transposons “jump” only at the moment of conception, and/or at the point in time when sperm and/or egg is/are being manufactured, and/or over the life span of the individual? I assume the third option wouldn’t be so relevant from an evolutionary perspective. If I understand correctly, the retrotransposons would serve as evolutionary accelerators, and the ZNFs, KZNFs, and KAP1s would serve as evolutionary brakes?

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