23 January 2017

Does it take special genes to make a special human?

We humans think we're pretty special. Here's Hamlet, in the speech that gave this blog its name:

What a piece of work is a man! How noble in reason! how infinite in faculty! in form, in moving, how express and admirable! in action how like an angel! in apprehension how like a god! the beauty of the world! the paragon of animals!

Hamlet, Act II, Scene II, The Oxford Shakespeare
It is common, at least in the West, to consider humans "the paragon of animals," typically making reference to the ancient idea of "God's image." I won't address here whether humanity is a paragon, but here's a more tractable question: what are the facets that distinguish humans from other animals? Biologically speaking, what is special about humans that sets them apart from other apes?

Anatomically, we're pretty unremarkable apes. We have enlarged gluteal muscles and other adaptations that make us good distance runners. We have fancy thumbs that make us good tool users. We have a tweaked larynx that facilitates speech. We have spineless penises that facilitate other things. And of course we have what Hamlet was talking about: big brains and associated cognitive abilities.

These biological specializations do make us human, and that makes them interesting and important. But biologically, I have always thought of them — all of them — as incremental changes to an ape blueprint. I have never thought of human biology as something extraordinary. And for that reason, I have always been skeptical of attempts to find human-specific genes or proteins or cell types that would explain human specialness.

Now, I don't mean that I don't think there are human-specific changes in the genome. Every species has species-specific genetic components, essentially by definition. But I never expected that we would find extraordinary new genetic components in the human genome, since I never thought our biology was extraordinary. Same goes for special cell types: some really smart biologists have looked for human-specific nerve cells in the brain. The human brain is big and complex, but it has always seemed to me to be built of the same stuff, in the same basic ways, as all the other brains I studied in my career.

Here is an example that illustrates my point. FoxP2 is a control protein involved in brain development, and because mutations in the FoxP2 gene lead to loss of language in humans, its roles and evolution are of intense interest. It was first thought perhaps to be a human-specific gene, indeed perhaps "the language gene," given its strong link to such a special human trait. But no: FoxP2 is an ancient gene found throughout the animal kingdom. The human version is different from the chimp version by just two amino acids. This is pretty much the opposite of a "human-specific gene." It's an animal-specific gene with some tiny human-specific edits.

But lately we've been learning that there are a lot of human-specific genes that are not so easily dismissed. The ongoing annotation of the human genome has revealed a somewhat surprising number of genes that are not found in other apes or mammals. Ed Yong has nicely explained why many of these genes were missed for so many years. And he highlights two of the more striking examples of human-specific genes: HYDIN2 and ARHGAP11b. (I'm so very sorry about our naming conventions. I wasn't consulted.) While both of these new genes are known to have arisen from copies of existing genes, both have been modified significantly. So they both seem (to me) to be "new genes." And, remarkably, they are both centrally involved in human brain development.

That last part is an especially interesting twist, since brain overgrowth is one of the most attention-getting human specializations. I think it raises the possibility that the human brain is not just a big ape brain, but a peculiar ape brain. In other words, if we found some weird new genes in the human genome and showed that they do weird new things to brain development, I might start to take more seriously the suggestion that the human brain is a distinctive evolutionary innovation.

I know that these dichotomies (merely big vs. peculiar, different vs. distinctive) are not very well defined. But I hope the basic questions seem interesting to you:
1) Are there unique human genes that underlie human specializations? Specifically is ARHGAP11b an example of this?
2) If so, what do these genes do and how did they arise in evolution?

Ed Yong has told the HYDIN2 story so far. But what about this ARHGAP11b? We now know how this gene acts on the brain and — this is really cool — we know how the gene was born. Both are up in the next post.

Image credits:
Top, Kemble as Hamlet, Wellcome Images
Bottom, Variation of brain size and external topography, Figure 7 from "The evolution of the brain, the human nature of cortical circuits, and intellectual creativity" by J. DeFelipe, Frontiers in Neuroanatomy, 2011.

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