Duke University. US: The size of the human brain expanded dramatically during the course of
evolution, imparting us with unique capabilities to use abstract
language and do complex math. But how did the human brain get larger
than that of our closest living relative, the chimpanzee, if almost all
of our genes are the same?
Duke scientists have shown that it’s
possible to pick out key changes in the genetic code between chimpanzees
and humans and then visualize their respective contributions to early
brain development by using mouse embryos.
The team found that
humans are equipped with tiny differences in a particular regulator of
gene activity, dubbed HARE5, that when introduced into a mouse embryo,
led to a 12% bigger brain than in the embryos treated with the HARE5
sequence from chimpanzees.
The findings, appearing online Feb.
19, 2015, in Current Biology, may lend insight into not only what makes
the human brain special but also why people get some diseases, such as
autism and Alzheimer’s disease, whereas chimpanzees don’t.
“I
think we’ve just scratched the surface, in terms of what we can gain
from this sort of study,” said Debra Silver, an assistant professor of
molecular genetics and microbiology in the Duke University Medical
School. “There are some other really compelling candidates that we found
that may also lead us to a better understanding of the uniqueness of
the human brain.”
Every genome contains many thousands of short
bits of DNA called ‘enhancers,’ whose role is to control the activity of
genes. Some of these are unique to humans. Some are active in specific
tissues. But none of the human-specific enhancers previously had been
shown to influence brain anatomy directly.
In the new study,
researchers mined databases of genomic data from humans and chimpanzees,
to find enhancers expressed primarily in the brain tissue and early in
development. They prioritized enhancers that differed markedly between
the two species.
The group’s initial screen turned up 106
candidates, six of them near genes that are believed to be involved in
brain development. The group named these ‘human-accelerated regulatory
enhancers,’ HARE1 through HARE6.
The strongest candidate was
HARE5 for its chromosomal location near a gene called Frizzled 8, which
is part of a well-known molecular pathway implicated in brain
development and disease. The group decided to focus on HARE5 and then
showed that it was likely to be an enhancer for Frizzled8 because the
two DNA sequences made physical contact in brain tissue.
The
human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters
in their genetic code. Yet, in mouse embryos the researchers found that
the human enhancer was active earlier in development and more active in
general than the chimpanzee enhancer.
“What’s really exciting
about this was that the activity differences were detected at a critical
time in brain development: when neural progenitor cells are
proliferating and expanding in number, just prior to producing neurons,”
Silver said.
The researchers found that in the mouse embryos
equipped with Frizzled8 under control of human HARE5, progenitor cells
destined to become neurons proliferated faster compared with the chimp
HARE5 mice, ultimately leading to more neurons.
As the mouse
embryos neared the end of gestation, their brain size differences became
noticeable to the naked eye. Graduate student Lomax Boyd started
dissecting the brains and looking at them under a microscope.
“After
he started taking pictures, we took a ruler to the monitor. Although we
were blind to what the genotype was, we started noticing a trend,”
Silver said.
All told, human HARE5 mice had brains 12% larger in
area compared with chimpanzee HARE5 mice. The neocortex, involved in
higher-level function such as language and reasoning, was the region of
the brain affected.
Producing a short list of strong candidates
was in itself a feat, accomplished by applying the right filters to
analysis of human and chimpanzee genomes, said co-author Gregory Wray,
professor of biology and director of the Duke Center for Genomic and
Computational Biology.
“Many others have tried this and failed,"
Wray said. "We’ve known other people who have looked at genes involved
in brain size evolution, tested them out and done the same kinds of
experiments we’ve done and come up dry.”
The Duke team plans to
study the human HARE5 and chimp HARE5 mice into adulthood, for possible
differences in brain structure and behavior. The group also hopes to
explore the role of the other HARE sequences in brain development.
“What
we found is a piece of the genetic basis for why we have a bigger
brain,” Wray said. “It really shows in sharp relief just how complicated
those changes must have been. This is probably only one piece -- a
little piece.”
The work was supported by a research incubator
grant from the Duke Institute for Brain Sciences, the National
Institutes of Health (R01NS083897), and National Science Foundation
(HOMIND BCS-08-27552).
CITATION: “Human-Chimpanzee Differences
in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing
Neocortex,” J. Lomax Boyd, Stephanie L. Skove, Jeremy Rouanet, Louis-Jan
Pilaz, Tristan Bepler, Raluca Gordan, Gregory A. Wray, Debra L. Silver.
Current Biology, February 19, 2015. DOI: 10.1016/j.cub.2015.01.041. The
full journal article can be found here in DukeSpace, the open-access online repository of university research