Study suggests a single point mutation facilitated increase in human brain size

(This thread previously had a title that erroneously stated that brain size tripled).


Pretty damn amazing study.

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Yep. I wonder if it is possible to detect evidence of positive selection acting on these mutations?

Checked out the original publication, to see how the marmosets fared with their newly customized brains.

No data, and here’s why:

“We confined our analyses to marmoset fetuses, because we anticipated that expression of this human-specific gene would affect neocortex development in the marmoset. In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite – and mandatory from an ethical point of view – to first determine the effects of ARHGAP11B expression on the development of fetal marmoset neocortex.” (emphasis added)

“Potential unforeseeable consequences.” Yup. For an evolutionary transformation to occur, it must be stably heritable. The marmosets never had a chance to show that their customized brains actually worked.

Does anyone understand what they are getting at when they discuss the ethical aspects of the study?

Wieland Huttner, who led the study, concludes: “We confined our analyses to marmoset fetuses, because we anticipated that the expression of this human-specific gene would affect the neocortex development in the marmoset. In light of potential unforeseeable consequences with regard to postnatal brain function, we considered it a prerequisite – and mandatory from an ethical point of view – to first determine the effects of ARHGAP11B on the development of fetal marmoset neocortex.”

@pnelson and @Faizal_Ali, they are concerned that these marmosets will have much higher functioning brains, which might alter the ethical calculus of their experiments. That’s the unforeseen consequences they fear. There are ethical guidelines specifically on humanizing the brains of animals for this reason.

Of course, a point mutation is going to be stability heritable. That has nothing to do with this.

Their concern is the opposite of @pnelson, that this mutation might be more effective (not less) than they imagine. Perhaps they are wrong but this isn’t evidence for @pnelson’s objection.


Of course, that isn’t the hypothesis these scientists were testing.


Yeah I wondered about the same thing. I suppose they are trying to avoid criticisms from animal rights groups.

I hope they’re just trying to do the right thing.


But that is the relevant evolutionary question. Would a point mutation which induced massive expansion in brain size, within a single generation, nonetheless be functional in the juvenile and adult primate?

What needs to be “stably heritable,” Josh, isn’t the point mutation (alone) – it’s the resulting phenotype.

Is there any evidence that mutations of this sort, natural or induced, produce “much higher functioning brains”? I’m guessing none.

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I was writing about this story a few years ago when they first found this GAP and its role. It’s a great story because there is new genetic information, basically a weirdly new protein, involved. Because I’m an atheist and not smart enough to work at the Discovery Institute, I take this to be evidence of new information affecting evolution.

Please just let me rest peacefully in my godless delusions. It’s hard enough to ignore the compelling arguments of the ID scholars and their monster slide decks without having to decide whether a permanent genetic alteration is “stably heritable.”


“Change the frame” is a great maxim. I like that wording. (I can even imagine it printed on T-shirts.) Sometimes a tiny change in coding can produce enormous changes. It’s hard to overstate that fact.

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The paper is in Science and linked at bottom.

The effect of the new protein seems at first glance to involve two very different processes: 1) expansion of progenitors that generate cortical neurons, resulting in more cortical neurons (specifically in the upper layers of the cortex); and 2) increased gyrification, which means folding of the cortex and the resulting wrinkles. It’s fun to think about how the new protein could do both of those things. One possibility is that it separately exerts effects on both of those processes. A more likely possibility, in my view, is that one (gyrification) occurs as a result of the other (expansion). That might seem trivial, but I don’t think it is, and in fact the causes of gyrification are still not well understood. In short: we can’t assert casually that of course the wrinkling is just a passive result of the addition of cortex to a confined space, but it does seem likely that at least in mammalian brains, the expansion of cortical cell populations somehow induced gyrification.

What we do know from work a few months ago is that the new protein acts in mitochondria, where it induces a specific metabolic change that almost certainly explains the effect on expansion of progenitors. That work is in Neuron, abstract and link below. PDF happily provided on request.

Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis

The human-specific gene ARHGAP11B is preferentially expressed in neural progenitors of fetal human neocortex and increases abundance and proliferation of basal progenitors (BPs), which have a key role in neocortex expansion. ARHGAP11B has therefore been implicated in the evolutionary expansion of the human neocortex, but its mode of action has been unknown. Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. Searching for the underlying metabolic basis, we find that BP expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the tricarboxylic acid (TCA) cycle. Hence, an ARHGAP11B-induced, mitochondria-based effect on BP metabolism that is a hallmark of highly mitotically active cells appears to underlie its role in neocortex expansion.


Why wouldn’t it?

And since the point mutation is stably heritable, and causes the phenotype, the phenotype is stably heritable. You can’t separate one from the other, come on.

Curious. Are you saying there is no relationship between genetics, brain size and architecture, and intelligence, at all? The human brain is generally more densely populated by cells, more interconnected, and more folded, than in any of our primate cousins. Am I to understand your question to imply that you think these physiological facts have zero influence on our cognitive capacities?


That’s the part that is so amazing to me. That means there is a latent capacity for forming gyrations (which seemed to be a complex change) in an organism which has never had gyrations in its history.

My guess is that it’s an unexpected effect tied up in biophysics.

And why should it matter?

We observe that humans have higher numbers of neurons and gyrations, during fetal development. This mutation tripled the number of neurons and induces gyrations during fetal development. Put another way, this mutation makes marmoset brain development look much more like human brain development.

Does that point mutation or gene need to be functional in adults? No reason to think a gene altering development must remain active into adulthood. Rather it needs to be active during development, and it is.


Nearly all dramatic morphological mutations in animals (certain losses, such as eyeless phenotypes in cave fauna, are the noteworthy exception) are not stably heritable. The experiment cited in this thread provided no evidence that the mutants would survive to reproductive capability.

This is conflating two issues. Whether or not these animals survive to adulthood is a distinct question from whether or not this is a stably inherited trait.

You are hypothesizing that these guys are going to nonviable. That’s a prediction that’s testable of course. I’m sure also it will be tested.


That’s exactly where my thoughts go first, but I strongly suspect it’s also tied up in some cell biology:

I recommend a quick read of the last 3 paragraphs of the paper. Biophysics (indeed really basic volume-space stuff) is certainly part of the explanation but other things are at work.

No matter what, it’s very interesting.


Sorry, but “survive to adulthood and reproduce” is what “stably heritable” means.


What would it mean if your hypothesis is false, and in fact they do survive into adulthood and reproduce? What if they really are smarter?

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