An RNA gene may help unlock the mystery of the evolution of the human brain, according to a report in Nature. By comparing the human genome with the genome of the chimpanzee, the study's authors identified a region that showed the most dramatic shift from chimps to humans, and is expressed by cells that play a role in cortical development -- suggesting that it may help explain what makes the human brain unique.
Because the chimpanzee brain is about a third of the size of the human brain, changes in brain development could be key to understanding the evolution of humans. There is a "tantalizing possibility" that this pinpointed gene is involved in that process, study author David Haussler from the University of California, Santa Cruz, told The Scientist.
"One of the great mysteries is how did we come to be so different from our ancestors," Haussler added. "Certainly there are molecular changes in our DNA that have evolved to make our species unique."
The human genome has undergone an estimated 15 million changes since evolving from our common ancestor with chimpanzees, and researchers are sifting through these changes to understand which are fundamental for human evolution. Many people have focused their search on the protein-coding regions of the human genome to identify important changes. But the great majority of genome alterations -- approximately 99% -- fall within areas that don't code for proteins.
As a result, Haussler and his team chose to look at the entire human genome, using an advanced computational screen to search for areas of the genome which experienced few changes between other species, but dramatic differences between chimps and humans. But with approximately three billion bases in the human genome, random drift was a problem, said Haussler. "We had to have something that was more extreme than what you would get in billions of random tries."
It was a long shot, he said, but the technique identified 49 regions of the human genome that experienced a significant increase in genetic alterations, relative to chimpanzees. Of those regions, HAR1 (human accelerated region 1) showed the most dramatic shift, experiencing 18 changes between humans and chimpanzees, but only two changes between chimpanzees and chickens -- a possible sign that the gene evolved a special function in humans.
The team went on to characterize HAR1 and found that it was part of an RNA gene. In situ hybridization experiments on human embryonic brain sections revealed that this gene is expressed in Cajal Retzius neurons, which previous studies have found play a role in cortical development by regulating expression of the protein, reelin. When the team looked at reelin localization, they found that reelin and the HAR1 RNA are co-expressed in very specific regions of the brain at particular gestation times.
Sean Hill, a genetics researcher at Children's Hospital, Boston, who was not involved in the study, called the new research "very promising." However, he cautioned that "any new approach has to be taken with a grain of salt," adding that "the ultimate test is the functional analysis of the gene."
The intrinsic challenge with this type of experiment is that, because there is only one form of this RNA gene in the human population, the researchers can't compare it to other forms of the gene to determine exactly what it does, according to Michael Zody, based at the Broad Institute, also not a co-author. But, he added, "Within the limitation of the experiments that can be done, this is a very solid piece of work."
"We wish we could say more about the exact molecular function of the gene," agreed Haussler. The team is ramping up for RNA binding studies, transgenic mouse experiments, and biochemical assays to get a better understanding of how the gene is involved in cortical development. "It's fascinating," he said, "to speculate that these changes might be important for our evolution into humans."
Juhi Yajnik
mail@the-scientist.com
Links within this article:
M.L. Phillips, "The evolving human brain," The Scientist, September 9, 2005.
http://www.the-scientist.com/article/display/22766/
K. Pollard et al. "An RNA gene expressed during corical development evolved rapidly in humans." Nature, August 2006.
http://www.nature.com
Chimpanzee Genome Resources
http://www.ncbi.nlm.nih.gov/projects/genome/guide/chimp/
M. Phillips, "Enhancing the hominoid brain," The Scientist, September 9, 2004.
http://www.the-scientist.com/article/display/22408/
The Haussler lab
http://www.cbse.ucsc.edu/staff/hausslerlab.shtml
C. Holding, "Chimps are not like humans," The Scientist, May 27, 2004.
http://www.the-scientist.com/article/display/22203/
G. Meyer, "Prenatal development of reelin-immunoreactive neurons in the human neocortex," Journal of Comparative Neurology, July 1998.
PM_ID: 9671277
Sean Hill, Member of the Walsh Group
http://www.childrenshospital.org/research/mrrc/investigators/walsh/index.html
M.C. Zody et al, "DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage," Nature, April 20, 2006.
PM_ID: 16625196