There are many aspects of biology that should inspire wonder in believers and non-believers alike. One of them, in my humble opinion, is the form of genetic recombination known as ‘crossing over.’ You can read a bit more about it elsewhere, but the gist is that in sexually-reproducing creatures, the formation of sperm and eggs involves a mixing-up of genetic material that ensures that the billions of individual sperm or eggs are genetically unique. The process involves the deliberate cutting of DNA, followed by a repair process that often stitches pieces together that weren’t together before. It is an amazing thing, almost audacious in its apparently deliberate drive to create genetic variation, via means that are elsewhere associated with chaos and catastrophe. (Such as cancer, to complete a nice alliterative triplet of horrors.)
Crossing over between chromosomes creates new chromosomes that are chimeras of the originals, hence creating new genetic combinations and diversity. The DNA breaks can happen almost anywhere on a chromosome, but they are not uniformly distributed. Instead, the breaks that begin the recombination process tend to occur commonly in specific spots called hotspots. And just a few years ago, we learned why: a protein called PRDM8 (in mammals) binds to those hotspots and encourages breakage there.
But looking at related species (such as various mammals) reveals something odd. The hotspots are different between species. This is remarkable, because mammalian genomes are very similar. Specifically two very closely-related species, humans and chimps, have different hotspots despite having genomes that are statistically nearly indistinguishable. This means that hotspots evolve very quickly, and it raises several interesting questions. One of those questions—how?—has been answered. PRDM8 evolves rapidly, changing its preferred binding site(s) regularly during evolution. When the binding sites change, the hotspot sites change, and this doesn’t have to involve large-scale change in the genome. But another question is harder: why? Why does PRDM8 change, leading to the shifting of hotspots?
Several years ago, some biologists proposed an answer: Red Queen dynamics. The Red Queen hypothesis is a delightfully-named theory to explain why some crazy things exist in biology. Sex, in fact, is crazy, and biologists often wonder why it exists. (Marketers don’t.) The Red Queen hypothesis proposes that sexual reproduction (and the genetic recombination that comes with it) exists because organisms are in a mad evolutionary arms race with parasites and pathogens. Everyone is racing to create diversity, to get evolutionary opportunity and flexibility, to stay abreast of the enemy. Everyone is running, but no one is winning. As U2 put it in a somewhat different context, running to stand still. Broadly speaking, “Red Queen dynamics” refers to a situation in which two things are changing in tandem and in a mutually antagonistic way. In the case of PRDM8 and hotspots, we know that PRDM8 evolves rapidly, and in a Red Queen scenario this implies that the hotspots are shifting or disappearing, thereby forcing PRDM8 to “adapt” by picking new binding sites. That explanation is fraught with teleological talk and anthropomorphism. But the key point is that Red Queen dynamics could account for the strangely rapid changes.
In this proposal, scientists theorized that hotspots are regularly destroyed, necessitating the need for PRDM8 evolution. And they proposed that the hotspots self-destruct. The details are fascinating but can be summarized like this:
- A hotspot is a place where crossing over happens regularly.
- Crossing over creates opportunities for new combinations, because the DNA isn’t always reattached the way it was before the break. (This is why crossing over creates genetic diversity, as we saw above.)
- These new combinations often replace the hotspot sequence with a slightly different sequence, that was present on the other DNA strand.
- In other words, hotspots are highly prone to a mutational process that erases them from existence. They tend to self-destruct.
The Red Queen dynamics idea predicts that hotspots should come and go quickly, and that PRDM8 should change in lockstep with them. It was already clear that both hotspots and PRDM8 differ between chimps and humans. But can this mad race drive even faster evolution? Can we see it happening on shorter time scales? (Chimps and humans diverged around 6 million years ago.)
Some new data shows that hotspots can evolve even faster than was previously thought. A new paper in PLoS Genetics, “The Red Queen Model of Recombination Hotspots Evolution in the Light of Archaic and Modern Human Genomes” by Laurent Duret and colleagues at the University of Lyon, looked at some ancient human DNA, from a Denisovan, one of those very interesting relatives of ours. Denisovans appear to have diverged from modern humans no more than 800,000 years ago. They found that human hotspots are different from Denisovan hotspots, implying a very fast rate of evolutionary change. They also saw tell-tale signs of hotspot self-destruction. And interestingly, their evidence suggests that the partnership between the currently most-popular version of human PRDM8 and the currently most-popular hotspot signature was formed just before the split between humans and Denisovans. Consistent with this, both the Neanderthal and Denisovan versions of PRDM8 (more accurately, the major versions) were different from those of us sophisticated modern humans.
Recombination by crossing over is a crazy business, and there are Red Queens everywhere. Sex seems a race to go nowhere (rather than to oblivion), and the elaborate and risky undertaking of recombination is itself a Red Queen mess. One lesson is this: evolution can move very quickly, just to stand still.