The humanity switch: How one gene made us

brainier

09 May 2012 by Sara Reardon

Magazine issue 2864. e
For similar stories, visit the Genetics and Human Evolution

One gene made brains more complex (Image: Natural History Museum/Science Photo
Library)
Editorial: "We are the improbable ape"
THE stage was set. Around 2.5 million years ago, the erroneous duplication of a
single gene changed the course of our brains' evolution forever. Suddenly, our
ancestors' neurons developed complex shapes that made them capable of exchanging
information with a larger number of neighbouring cells. At the same time, infant
skulls became more flexible, allowing them to accommodate larger brains.
Three new studies reveal this remarkable sequence of events. Crucially, they also
show that the changes happened precisely at the same time as our own Homo
genussplit from the australopithecines (see evolutionary tree).
Gene duplications are rare in human history. Only about 30 genes have copied
themselves since we split from chimps between 4 and 6 million years ago. The few
that have been studied encode genes that are very exciting, says human geneticist
Evan Eichler of the University of Washington in Seattle. Many are involved in brain
development.
Eichler and Franck Polleux of the Scripps Institute in La Jolla, California, focused on
SRGAP2. This gene helps drive development of the neocortex, which in humans

controls higher-order brain functions such as language and conscious thought.

Humans with mutations in SRGAP2 are prone to epileptic seizures, as are mice that
have been engineered to lack it.
Eichler noted that the official sequence of the human genome featured unaccountedfor genetic material next to SRGAP2. His team found that this was because the gene
had duplicated itself twice and the copies were so similar to the original that no one
had distinguished between them.
Further analysis revealed that the first duplication happened 3.4 million years ago,
producingSRGAP2b. Around 1 million years later, this "daughter" of the original gene
underwent its own duplication, producing a "granddaughter" copy: SRGAP2c. All
three coexist in modern humans (Cell, DOI: 10.1016/j.cell.2012.03.033).
But just like a photograph of a photograph, each new copy decreased in quality. The
daughter and granddaughter genes were shorter than the original. And when Polleux
replaced the originalSRGAP2a gene in mice with either SRGAP2b or 2c, their brains
didn't mature normally.
When he inserted human versions of all three genes into mice, the proteins produced
by the 2band 2c genes bound to the original 2a proteins and hindered their ability to
do their job. The net effect of this genetic sabotage was to give the mouse brains more
time to develop.
Although the modified brains didn't grow larger, the neurons in its neocortex changed
to look like human brain cells. The spines that neurons use to exchange information
with other cells grew thicker, longer and in greater numbers than in normal mouse
neurons. This, say the researchers, would be likely to increase the brain's processing
power. Finally, the neurons migrated to their final positions more quickly than in
unmodified mice, suggesting they could have travelled greater distances before
maturity in a larger brain (Cell, DOI: 10.1016/j.cell.2012.03.034).
"It all makes sense in an elegant way," says James Noonan of Yale University. To
really pin down the effects of the gene, he says, the researchers have to show that a
mouse with a full triplet ofSRGAP2 genes has a more connected neocortex and that
its behaviour changes.
Polleux's lab are now testing whether this is the case. His team also plans to put the
human genes into a marmoset - a much closer human relative. Eichler's group is
searching for people with mutations in the granddaughter copy of SRGAP2. They
want to know if this causes cognitive disorders.

The timing of the duplications is significant. The first happened 3.4 million years ago,
which corresponds with when Australopithecus afarensis first began using tools, says
Dean Falk of Florida State University in Tallahassee. Better still, the second
duplication was 2.5 million years ago - when our genus, Homo, began separating from
the now-extinct Australopithecus.
"I'm really excited about this," Falk says, in part because it suggests human
intelligence has as much to do with brain connectivity as size. It is likely that the
changes 2.5 million years ago were instrumental in allowing our brains to go through
their unique growth spurt. Or as Falk puts it: "As other mutations pile on, the
machinery allows for further increases in brain size."
Falk herself has recently found evidence that while SRGAP2 was changing our
brains, our ancestors' skulls were shifting too. A 2.5-million-year-old A. africanus
toddler had the same gaps in its skull as a modern baby, allowing the head to
compress and fit through the birth canal. That suggests hominin brains - especially the
frontal cortex - were already expanding by this time (see "The scars of size").
What's interesting about the SRGAP2 duplication, Eichler says, is that it would have
changed brain development immediately and dramatically. Human ancestors with
two, three or even more copies of the gene - and consequently stark differences in
their cognitive abilities - could have coexisted at one point. "That's fun to think
about," he says.
The researchers suspect other gene duplications will hold even more secrets about
how our brains evolved. "We still have a few hundred gaps in the human genome and
that's precisely where those duplicated genes are mapping," says Eichler. It may be
that genes we share with our closest primate relatives are far more important than
those that are different, and may explain why our cognitive abilities are so much
greater.
The scars of size
The 2.5-million-year-old Taung Child skull is small enough to fit in the palm of a
hand. All that's left of it are a face, jaw and an internal cast of the braincase that
formed when sediment replaced its rotting brain. The cast gives us an idea of what the
brain of a youngAustralopithecus africanus looked like.
Dean Falk at Florida State University in Tallahassee and colleagues at the University
of Zurich, Switzerland, noticed a faint ridge running from the top of the brain cast
down towards the face. They say it shows that the two bones of the forehead had not
fused together when the child died, between its 3rd and 4th birthday. As a result,

sediment was able to push into the gap between the bones (Proceedings of the
National Academy of Sciences, DOI: 10.1073/pnas.1119752109).
That's unusual. In most primates, and other hominins around at the same time as A.
africanus, those bones fuse before or shortly after birth. Only in our genus, Homo, do
the bones take longer to fuse, to allow the brain extra room to grow during the first
years of life.
Adult A. africanus had a small brain, but the new finding suggests it might already
have adopted some of the characteristics of the bigger-brained Homo genus. "We
could be seeing fossil evidence for the kind of genetic reorganisation identified in the
studies [by Eichler and Polleux]," says Falk (see main story).
"One thing that is becoming clear from both genome evolution and palaeontology is
that this time period of 2 to 3 million years ago was one of remarkable genetic and
fossil changes," says Eichler. Colin Barras

From issue 2864 of New Scientist magazine, page 10-11.

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