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The HAR-1 Gene - most intriguing mysteries of biology
Tue Apr 27, 2010 16:11

The HAR-1 Gene

One of the most intriguing mysteries of biology is why humans are the only species with a brain smart enough to ponder their own existence.

Researchers at the University of California at Santa Cruz believe they have discovered a possible answer: a gene that has undergone powerful mutational changes in the last 5 million years that may partly account for the accelerated evolution of the human brain.

Reporting Wednesday in the online version of the British medical journal Nature, the scientists said they do not know exactly what the gene does but that it is active at a key time and place in embryonic development when the brain is growing at its fastest pace.

"The properties of this gene are that it's turned on at about week seven of embryonic development in the same cells that help build the cerebral cortex," said David Haussler, director of the university's Center for Biomolecular Science and Engineering and a Howard Hughes Medical Institute investigator.

"And then it's turned off at about week 19 when the process is finished. It suggests that the gene is probably involved in this process of building the cerebral cortex because it's turned on in the right place at the right time and turned off in the right place at the right time."

Bruce Lahn, whose University of Chicago team reported earlier this year the discovery of two genes indicating the human brain is still evolving and perhaps becoming smarter, said the Nature report is a potentially important advance in uncovering the brain's genetic building blocks.

"Eventually all this information is going to come together and play a role in better human health and a better understanding of human evolution," he said.

Haussler's group found a gene called HAR1 that appears to exist in the brains of all animals. For most animals, from chickens to chimpanzees, the gene underwent little change for hundreds of millions of years, suggesting it performs a vital function.

But sometime in the last 5 to 7 million years, after the human lineage diverged from its last common ancestor with the chimpanzee, HAR1 began to change substantially. Today, approximately 10 percent of the human HAR1 gene is different than that of the chimpanzee, Haussler said, adding that the genetic changes may contribute to the human brain becoming three times larger than that of a chimp.

HAR1 belongs to a newly discovered type of gene made out of RNA instead of the usual DNA. RNA genes are made from DNA genes, but then they go on to act as genes in their own right. One of their jobs, it is thought, is to regulate other genes.

The HAR1 gene is active early in embryonic development when certain neurons produce a protein called reelin that guides the growth of brain cells and the formation of connections among them. The neurons orchestrate the layered structure of the human cerebral cortex, the brain's intelligence and command center. After this period of rapid development, HAR1 is turned off.

Scientists generally believe the complex human brain evolved over time because it provided a survival advantage to the vulnerable ancestors of humans.

"Why aren't there more species that have achieved the level of intellectual capability of humans? Why doesn't everybody want a big brain?" Haussler asked. "Well, the brain uses a lot of energy, about 20 percent of the energy in the body. It's definitely a costly organ to maintain from an energy perspective. I suppose if you're just out grazing on the grass all day, it's a waste of effort."

The tiny brain of the primitive sea squirt, for example, shrinks even smaller after birth, yet it gets along in its niche very well, pumping water in one hole and out another.

"Sea squirts have evolved a way of essentially getting rid of its brain," Haussler said. "It finds a rock, sits down on it, eats its own brain and becomes a kind of vegetable sitting on the rock, filter feeding.

"They have been very successful. They're happy. They don't need their brain," he said. Early humans, on the other hand, "got by by the skin of our teeth. It was our cunning that sculpted us as a species."

To help define the role of HAR1 in brain size, neuroscientist Pierre Vanderhaeghen of the University of Brussels, an author of the Nature paper, is developing a mouse strain that lacks the HAR1 gene. The purpose is to determine if the animals without the gene are born with smaller brains.

"If they delete the gene in a mouse and the mouse has a smaller brain, then one can argue that the changes in this gene might have contributed to a larger human brain," said the U. of C.'s Lahn.



Google: The HAR-1 Gene

What Makes Chimps And Humans Different?‎
NPR (blog) - Ursula Goodenough - Apr 1, 2010

HAR1 proves to mark a genetic region that is expressed early in the development of the neocortex; HAR152 is near the gene encoding a protein called ...

by Ursula Goodenough

When the protein-encoding genes of the human are compared with the protein-encoding genes of the chimpanzee, they are about 99 percent the same. Moreover, the one percent that are distinctive aren't obviously interesting, being involved with such traits as sperm surface proteins and immune responses.

So, given this, what's the genetic basis for the many ways, notably the cognitive ways, that humans and chimps are different from one another?

A most ingenious approach to this question is being developed in the lab of Katherine Pollard at the University of California in San Francisco. To understand their experiments, we first need a crash course in genes and embryos. I'll try to make it quick.

Our single-celled ancestors who lived more than 1.5 billion years ago were already impressively gene-rich and sophisticated, as per last week's blog. Notably, their genomes encoded a rich toolkit of regulatory molecules that turn on or off the expression of genes as appropriate to the occasion. For example, in the presence of bacterial food, the ancient ancestors turned on the expression of genes that allowed them to crawl around and engulf their prey. When things got lean, they instead turned on genes that allowed them to swim off to find new food sources.

The way these switches work is pretty straightforward to explain, albeit exquisitely intricate in detail. Basically, proteins are encoded by sectors of DNA called genes. Contiguous to each gene is DNA that doesn't code for protein; instead, it functions as the gene's on-off switch. When regulatory molecules bind to this switch DNA, the contiguous gene is either expressed or prevented from being expressed. So, very crudely, the thing on the wall is the switch DNA, your finger is the regulator, and gene expression is the light turning on or turning off.

The common-ancestral selves were unicellular, whereas the animal lineage has elected to construct multicellular selves. In making this transition, animals hung on to the same switch arrangement and the same sets of regulators used by the ancestors, but they added a splendid additional idea. In addition to being responsive to signals from the environment, they also became responsive to signals coming from their very own cells. So, to highly oversimplify the situation, after a fertilized egg has divided into two and then four, then eight, then 16 cells (where the human has, gulp, ten trillion cells), cell #16 makes a regulator that acts to switch on a set of unique genes in cell #10, the outcome being that cell #10 and its progeny eventually give rise to nervous tissue. Meanwhile, cell #11 expresses a different suite of genes, poising its progeny to influence yet other cells to differentiate into muscle.

As animals, and hence animal embryos, complexified over time, these cell-to-cell interactions have become increasingly impressive. In the developing mammalian brain, for example, neurons migrate up into the cranium, using much the same kind of amoeboid movement that our deep ancestor employed to capture bacteria. Neurons that reach a particular destination switch on genes that allow them to secrete a nerve growth hormone. As the next phalanx of neurons migrates into the region, they follow the hormone gradient, akin to male moths moving up pheromone gradients to find females, avidly competing for hormones that will enable their proliferation. The first to arrive at the pulsating source proceed to form synaptic connections with their targets; any laggards, by contrast, fail to proliferate and instead degenerate.

Granted that this is an absurdly simplified account of brain development, it suffices to make a key point, which is that brains build themselves. Bottom up. When A happens, that allows B and C to happen; B allows D and E to happen; and so on.

Because brain development is so contingent on what has gone on before, it's pretty easy to alter what happens. For example, if the pioneer neurons in our example carried a switch mutation that prevented them from secreting the nerve growth hormone at the appropriate time, the next phalanx of neurons wouldn't move towards them and might, instead, pick up on a more distant hormonal signal from another brain region and move in that direction, forming synapses with a new set of neurons altogether. A brain is still constructed, but it will have different kinds of neural pathways and connections and hence, perhaps, different ways of doing things.

So now we can return to the chimp-human question. If the chimp and human protein-encoding genes are virtually all the same, then are there any interesting differences in their switch regions? Given the bottom-up nature of development, mutant switches could have large-scale consequences.

The identification of switch sequences is much more computationally challenging than the identification of genes, but the Pollard lab is leading the charge.

Basically, they compare the DNA sequences adjacent to genes that are found not only in humans and chimps but also in mice and rats, where the most recent common ancestor of these four mammals roamed the planet some 60 million years ago.

The Pollard logic is this:

1) If a given set of sequences isn't doing anything important, which is usually the case, then the rat, mouse, human, and chimp versions are expected to be very different from one another. That's because they aren't under selection, so they tend to accumulate mutations. In genomic lingo, the sequences are said to "drift."

2) By contrast, if the sequences function as switches, then they are expected to be very similar because they are under selection to maintain their gene-regulating function.

3) Of particular interest are cases where the mouse, rat, and chimp sequences are all identical, indicating intense selection to maintain them, whereas the human sequence is markedly different from the other three. The Pollard lab has thus far identified 202 such cases, where each is called a human accelerated regions or HAR.

Now the fun begins. A researcher picks out a HAR (e.g. HAR34), figures out what gene it's contiguous to, and then asks: Where and when is that gene switched on/off during embryological development? And then: Is its expression pattern different in the human than in mouse, rat, or chimp? If it is, then the novel pattern may prove to be relevant to an understanding of how humans are distinctive creatures.

Thus far there are three preliminary stories relevant to the brain. HAR1 proves to mark a genetic region that is expressed early in the development of the neocortex; HAR152 is near the gene encoding a protein called neurogenin-2 that is expressed in a region of the hippocampus with a central role in learning and memory; and HAR2 is near a gene with strong expression in the hand, perhaps playing some role in human-specific hand coordination.

The knee-jerk response to this account is to think "Aha -- maybe some of those novel HAR sequences are running some new human-specific brain module or widget! Like my consciousness!"

But if we circle back to our core notion, that brains build themselves, and think about the HARs in this context, then we realize that we're not likely to be talking about new modules or widgets. Just as in our hypothetical example, where a group of neurons failed to secrete a hormone and the second phalanx of neurons wandered off to find new targets, a mutant HAR is more likely to result in some human-specific pattern of regional brain differentiation. Indeed, going back to the finch-song domesticated-ape story told here and here, some of the mutant HARs may have the effect of releasing constraints on ape-brain organization, opening things up to greater novelty and plasticity.

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