Human Gene for Big Brain

Dr. Swamidass, this seems like a big discovery. What do you think?


I’ll have to read up on that soon. Though, the work on DUF1220 is very compelling too. Copy number increases in DUF1220 seem to be very important driver in brain evolution.

For the above reasons and because DUF1220 sequences at 1q21.1 have undergone a dramatic and evolutionarily rapid increase in copy number in humans, a model [9][14] has been developed that proposes that:

  1. increasing DUF1220 domain dosage is a driving force behind the evolutionary expansion of the primate (and human) brain,

  2. the instability of the 1q21.1 region has facilitated the rapid increase in DUF1220 copy number in humans, and

  3. the evolutionary advantage of rapidly increasing DUF1220 copy number in the human genome has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. These include autism and schizophrenia (as discussed below) and other disorders resulting from 1q21.1 duplication syndrome and 1q21.1 deletion syndrome.[9]

From this perspective, disease-associated 1q21.1 CNVs may be the price the human species paid, and continues to pay, for the adaptive benefit of having large numbers of DUF1220 copies in its genome.[9][14]
Olduvai domain - Wikipedia

This is all pretty interesting and compelling work.

It is worth explaining that brain size is not correlated with intelligence, rather it is the number of neurons that is important. The only order where brain size is correlated with number of neurons is primates. In all other orders (as far as I know), brains size varies, but the number of neurons does not increase with bigger brains.

Lest this be misinterpreted, I’m talking about variance between species, not within species. Humans with different size brains can all be equally intelligent (within species variance).

Any how, I’ll circle back once I get a chance to read the new paper.

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And look at this:

NOTCH2NL’s location on the genome, incorrectly mapped until recently, is further support for its role in human brain size. Duplications or deletions at a genome region known as 1q21.1 are known to cause macrocephaly or microcephaly, respectively, and are associated with a range of neurodevelopmental disorders, including ADHD, autism spectrum disorder, and intellectual disability. Haussler’s team looked at 11 patients with errors at this locus and found that NOTCH2NL was indeed being duplicated and deleted in the rearrangement events associated with larger and smaller brain size that resulted. “We really wanted the gene to be in the 1q21.1 disease interval, because it made logical sense, but in the incorrect reference genome, it wasn’t. And then we found new data, and we realized that it was a mistake in the reference genome! It seldom happens that when you want something that appears to be false to be true, it turns out to actually be true. I don’t think something of that level will ever happen again in my career,” says Haussler.

Turns out that NOTCH2NL is associated with DUF1220 proteins (same location of the genome).

I feel like an encyclopedia =). Any how, I’ll still have to read that paper to see why it merits a Cell paper. It is already known that DUF1220 proteins (thought I am not sure precisely if NOTCH2NL is one) are important in the evolution of brain size. It is not clear what the advance here was yet. I’ll read the paper and get back to you later.

For reference, here it is:

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" they also didn’t see it in orangutans and found only truncated, inactive versions in our closest relatives, gorillas and chimpanzees."

This is not a mere duplication. This is a crucial gene which does not exist except in chimps and gorillas, and then only in a truncated and inactive form. They said it somehow got “repaired” somewhere in the hominid line. You would think an inactive gene that was already truncated would collect more and more mutations until it was a real mess. But in this case when it gets turned back on it increases brain size?

And check this quote out: "“What’s amazing is that there are many signaling pathways that control the development of the embryo and are completely conserved between species. The Notch signaling pathway is the oldest one. You can find it in every animal you look at. It has been used by developing embryos for as long as animals have existed. And yet, there is a very recent innovation in this pathway specifically in the human lineage, through NOTCH2NL,”

So the pathway is conserved in every animal species for hundreds of millions of years yet this quantum leap forward happened so far as we know just this once 3 million years ago? Is it not astounding that a path can be stable and essential for so long and then a game-changing improvement comes about via a repair to a long-deactivated and truncated gene?

And that happening once is astounding enough, but did you catch this one?..

“The Vanderhaeghen team developed a tailored RNA sequencing analysis for specific and sensitive detection of human-specific genes in human fetal cerebral cortex. This allowed them to identify a repertoire of 35 genes unique to humans that are active during development of the cerebral cortex in humans, including NOTCH2NL genes.”

35 functional genes unique to humans just on the development of cerebral cortex. That they know of.


Are you sure you know what “unique” means in this context?

What exactly is a “mere” duplication? There are gene variants formed all the time by segmental duplications. Keep in mind that “duplication” is not in reference to the gene per se, but of a segment of DNA, which can alter genes. It does look like this is a structural variant that had value.

Though, I have not had a chance to read the paper in detail yet. I’ll get around to it eventually.

I think it means that nothing else alive has them. Am I wrong?

A mere duplication would be a copy of an existing gene. For example “Chimps have one of these, but humans have two, therefore humans have more brain connections”. That is not what happened here. Not all of what happened. This was something that was inactive, truncated, and according to everything we know about how genes work it was piling up random mutations all the time. Yet not only did it get re-activated (they use that term even though there was no evidence it was ever active in chimps and gorillas or their ancestors) when it did it made hominids smarter.

It had better function than the other cortex genes that were working in chimp ancestors all along and presumably under evolutionary pressure. If being smarter is a plus, why didn’t natural selection work on existing functional genes to make them better until the breed was smarter? Why did nature resort to using some truncated inactivated gene for which selection pressure was non-existent in order to make this great leap forward?

You don’t find that the least bit eye-brow raising? Well, you have seen a lot more of this stuff than I have. Maybe you could cite a half-dozen examples of something similar happening right off the top of your head?


Someone could ask why feathers, which were happily used by dinosaurs for insulation and camouflage or mate selection, became the center piece of avian evolution.

Ultimately, the answer is at the molecular level where proteins answer the questions of survival.

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16 posts were split to a new topic: Are Birds Dinosaurs?

Yes that is right.

Because it was not a perfect copy. It acquired mutations that make it beneficial.

Because this worked better. It was easier to modify an existing gene with an imperfect copy, than to make one from scratch.

Definitely amazing. Definitely not anything that challenges evolutionary science.

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Thanks very much, Joshua, for closing the loop on this one!

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