A Blog by Ed Yong

Same gene linked to bigger brains of dolphins and primates

Every whale and dolphin evolved from a deer-like animal with slender, hoofed legs, which lived between 53 and 56 million years ago. Over time, these ancestral creatures became more streamlined, and their tails widened into flukes. They lost their hind limbs, and their front ones became paddles. And they became smarter. Today, whales and dolphins – collectively known as cetaceans – are among the most intelligent of mammals, with smarts that rival our own primate relatives.

Now, Shixia Xu from Nanjing Normal University has found that a gene called ASPM seems to have played an important role in the evolution of cetacean brains. The gene shows clear signatures of adaptive change at two points in history, when the brains of some cetaceans ballooned in size. But ASPM has also been linked to the evolution of bigger brains in another branch of the mammal family tree – ours. It went through similar bursts of accelerated evolution in the great apes, and especially in our own ancestors after they split away from chimpanzees.

It seems that both primates and cetaceans—the intellectual heavyweights of the animal world—could owe our bulging brains to changes in the same gene. “It’s a significant result,” says Michael McGowen, who studies the genetic evolution of whales at Wayne State University. “The work on ASPM shows clear evidence of adaptive evolution, and adds to the growing evidence of convergence between primates and cetaceans from a molecular perspective.”

For decades, we’ve known that similarities between primate and cetacean intelligence run deep. For a start, both groups have members with unusually big brains. We humans have brains that are 7 times bigger than you’d expect for an animal of their size. The equivalent number is 2-3 for chimps and some monkeys, and 4-5 for some dolphins.

Over the last decade, scientists have identified seven genes that are linked to primate brain size. They’re called MCPH1 to MCPH7 (ASPM is the fifth in the line). Faults in these genes can lead to microcephaly – a developmental disorder characterised by a debilitatingly small brain.

McGowen had already shown that, unlike in humans, MCPH1 doesn’t neatly correlate with brain size in cetaceans. Xu wanted to see if ASPM would be more interesting. He sequenced the gene in fourteen species of cetaceans, from the bottlenose dolphin to the minke whale. He then compared these to known sequences from 18 other mammals, including several primates and the hippopotamus (the closest living relative to cetaceans).

Xu found that ASPM went through two periods of strong positive selection – where beneficial new versions of the gene spread through a population. The first coincides with the point when toothed whales (like sperm whale and dolphins) split away from the baleen whales (like blue, fin and humpback whales). Their brains got bigger. The second period marks the split of the toothed whales into the delphinoids (including all oceanic dolphins and porpoises) and all the others. The delphinoids’ already big brains got bigger still.

Xu also found signatures of positive selection within the ASPM genes of primates, but not in any other mammal groups. During their history, both groups must have experienced some evolutionary pressures that meant bigger brains suddenly became advantageous. We can only speculate what these might have been. For cetaceans, the toothed whales evolved to navigate with echolocation, and may have needed a larger brain to process the information from all the returning echoes. The delphinoids may owe their larger brains to the mental demands of living in large, complex social groups. (Both hypotheses have been on the cards for some time, and Xu’s ASPM discovery doesn’t provide a smoking gun for either.)

What does ASPM actually do? The gene is activated in neuroblasts, the embryonic cells that eventually divide into neurons. It helps to create structures in dividing cells that send a full complement of DNA into each daughter. If ASPM isn’t working properly, the neuroblasts cannot divide evenly, and brains get smaller. It’s not clear how the reverse happens – how changes in ASPM lead to bigger brains, but it’s now clear that this has happened in at least two mammal groups.

Xu found certain mutations that were associated with the bigger brains of toothed whales, and others that are associated with the even bigger brains of delphinoids. What these mutations did is anyone’s guess, and something that will take a lot of experimental work to uncover.

Here’s one critical nugget, though: they’re different to the changes you see in primates. The same gene may have enlarged the brains of both groups, but it did so in different ways. And undoubtedly, other genes were also involved.

(To close, here’s possibly my favourite ever example of convergent evolution, which also involves cetaceans. Toothed whales and some bats both use echolocation, and their abilities depend on the same changes to the same gene – Prestin. This was discovered at the same time by two independent groups of researchers, one led by Yang Liu and the other by Ying Li!)

Reference: Xu, Chen, Cheng, Yang, Zhou, Xu, Zhou & Yang. 2012. Positive selection at ASPM gene coincides with brain size enlargements in cetaceans. Proc Roy Soc B.

Photo: Common dolphins by NOAA

More on brain convergence:

More on cetacean intelligence:

11 thoughts on “Same gene linked to bigger brains of dolphins and primates

  1. I really enjoyed this post, Ed.
    This is a topic that I find fascinating and in a general sense my lab also is studying it not only from the normal brain growth and microcephaly perspectives, but also from the cancer side.
    We have identified a number of genes related to brain growth that operate basically the same way in mice and in humans. We are not so sure about whales, but I suspect there are parallels.
    One element to add to your piece is the cancer connection.
    When these genes including ASPM (and some that I study including one called Myc) are present at levels that are too high the end result is brain cancer. Thus, somehow these genes together form a brain growth machinery that must exquisitely regulate brain grown. Too much = brain cancer. Too little = microcephaly. Just right = the right sized brain for that organism.
    So now I’m wondering if whales get brain cancer as frequently as humans…don’t see a literature on that offhand.

  2. Ed, following up on our conversation on twitter.
    While interesting, the story is definitely just correlative.
    The question is how many genes in genome would show this pattern, and even if it is just a small number of genes do we really know what the phenotypic effects of substitutions at ASPM are?
    It’s too easy to tell adaptive stories about rapid protein evolution for almost any gene in the genome, I’ve certainly done it before.
    The mutant phenotype of ASPM is interesting, but I’d hazard a guess that the most obvious KO phenotype of a gene is rarely the target of adaptive protein evolution [especially with a complex trait like brain size]. As Vincent Lynch (https://twitter.com/@VinJLynch) pointed out the gene also plays a role in the testes and germline (http://m.pnas.org/content/107/38/16595.full). If I had to bet on the adaptive phenotype of a high dN/dS gene testes beats brains every time.

  3. “What does ASPM actually do?” now that is the interesting question. ASPM was first identified as a “brain size” gene because homozygous null humans have microcephaly so it was generally assumed that the selection event seen in humans (and found in many other primate lineages as well) was related to enlargement of the brain in the human lineage. But ASPM plays an essential role in cell proliferation in tissues other than the brain. Most interestingly (at least I think so), ASPM plays similar roles in the brain and the testis.

    This brain-testis connection was described by Svante Pääbo’s lab in a recent PNAS paper (http://m.pnas.org/content/107/38/16595.full). They swapped the mouse and human ASPM genes, I assume hoping to breed a super-intelligent strain of mice, and surprisingly found that nothing happened. Bummer. It would have been ground breaking to show that the human ASPM gene (which presumably accumulated changes under positive selection for increased brain size) when placed into mouse led to a huge mouse brain perhaps even an Acme labs-like “The Brain”. But rather than uncovering a role for ASPM as a casual agent of increased brain size in the human lineage, these authors found ASPM was required for male fertility (yes, the jokes are obvious) and suggested that the signal of selection observed in humans and other primates is likely related to role in testis.

    It is on old observation that many testis expressed genes evolve rapidly, many under some form of positive selection. So while ASPM may be related to changes in brain size in primates and cetaceans, it is more parsimonious to conclude that positive selection is related to the role in testis.

  4. I think I would tend to agree with Graham Coop. But I haven’t really followed the Asp literature much in recent years (I cloned the first Asp, in Drosophila). But as I recall, it could be that ASPM plays a role in asymmetric division, and this role might be important in a variety of developmental processes, including the development of the brain.
    Asp is named after the phenotype first recognised in mutants – abnormal spindle, the gene was first identified as a mitotic mutant in Pedro Ripoll’s lab. So a relationship to overgrowth and undergrowth depending on mutational status of ASPM would be consistent.

  5. Love this comment thread. Thanks for the valuable contributions + critiques, folks. I’ve changed the hed from “involved in” to “linked to”, and toned down the causality of the language in a couple of places. Still a cool discovery, though.

  6. These findings make a seductive story, but one that is built on inference more than evidence. The signatures of positive selection on the ASPM gene in the primate and cetacean lineages are intriguing but, first, do not prove that changes in the gene were definitely positively selected for, and second, do not imply anything about what functional effects they might have been selected for. While mutations impairing ASPM function in humans lead to microcephaly (reduced brain size), it does not follow that other mutations in the gene would lead to a bigger brain. It is far easier to disrupt the function of a protein than to change it in a beneficial way. The story is certainly plausible and could be true – ASPM plays a role in aligning the polarity of cell division in early neural progenitors and ensuring expansion of the progenitor pool at early stages – perhaps changes in the timing of its expression over evolution helped drive this expansion. For now, however, this remains an intriguing but speculative hypothesis.

  7. @Vincent Well, we only tried to see whether mice with human ASPM would have bigger brains than wild-type mice, we reserved the intelligence effect-jokes for the humanized FOXP2 mice :-). A previous study from Wieland Huttner’s group (Fish J et al, PNAS) showed that in utero knockdown of mouse endogenous ASPM results in more asymmetric divisions, which should lead to a smaller brain (you can’t check the end phenotype in these studies). But Pulvers J et al showed (I am the second author on that paper) that this is indeed the case – mice with Aspm ko have smaller brains, but much larger effect is in testis.

    Unfortunately it doesn’t work the other way – neither mice with human ASPM (or CENPJ, another human microcephaly gene, or both simultaneously that we tried) have brains larger than wild-type mice. Which of course does not imply that human Aspm doesn’t enlarge brains – there could be zillion reasons why it didn’t work in our case. Our experiment showed only that human ASPM in mice functions just as well as mouse ASPM, and that the major effect of ASPM in our system is in testis. Regarding this effect, it would be very interesting to see whether there are any sperm/testis phenotypes in the microcephalic people.

    I should also point out Jianzi Zhang’s paper from 2003 (and there was another one in PLoS Biol in 2005 by Kouprina I think), where they showed that selection on ASPM and big brains do not always go together, ie. there are mammalian and primate lineages with relatively big brains that do not show any positive selection on ASPM. And there is the whole issue of whether bigger brain is actually better in anything compared to smaller brains… Assuming changes in ASPM and their effects we saw in mice are true also for other organisms and that they indeed may confer some advantage, it may well be that larger brains are a side-effect of whatever goes on in testis.

    Also, @Kevin is exactly right.

  8. For whatever it is worth, the same genes seem to control brain growth in humans, mice, and many other organisms. Perhaps the genes are turned up or down or have longer or shorter periods of expression in different animals with different brain sizes at maturity, but the machinery is so similar it is striking. Also, the same machinery controls growth of other organs as well.

    I had one of my most startling moments as a scientist after years of studying N-myc in mice (finding its mutation causes microcephaly and other phenotypes) seeing a paper showing that mutation of N-myc in humans also causes microcephaly along with many of the same “other” phenotypes seen in mice. Too much N-myc also causes the same brain tumors in both mice and humans too. I’d love to study N-myc in whales with their amazing brains…..

  9. Just want to express a layman’s appreciation for the consistently enlightening comments on this blog. This thread is the perfect example.

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