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April 11, 2002
A team of international researchers from Germany, the Netherlands and San Diego may have shed light on why chimps and humans are so genetically similar (nearly 99 percent of shared DNA sequences), and yet so mentally different.
In a study published in the April 12, 2002 issue of the journal Science, the scientists noted that the striking difference between these primate cousins is most evident in their brains. The disparity appears to be the result of evolutionary differences in gene and protein expression, the manner in which coded information in genes is activated in the brain, then converted into proteins that carry out many cellular functions.
The brain differences are more a matter of quantity than quality. Differences in the amount of gene and protein expression, rather than differences in the structure of the genes or proteins themselves, distinguish the two species.
In addition, the researchers noted that the manner in which genes are expressed from the brain shows more differences than other parts of the two primates' bodies, such as the liver and white blood cells. Why these evolutionary differences occurred is still unknown.
The researchers first compared blood and liver samples for levels of messenger RNA, an intermediary step between DNA and protein production. As expected, they found humans were closer to chimps in these measures than chimps were to macaque monkeys.
In striking contrast, the human brain showed more messenger RNA differences when compared to the chimp brain, indicating a far greater rate of evolutionary change in gene expression. Moreover, chimpanzee and macaque gene expression patterns were more similar to each other than to the human pattern. The researchers also found unique differences in expression of proteins in the human brain. Thus, humans seem to have sped up the rate of change of gene expression selectively in their brains, accumulating expression differences at least five times faster than chimpanzees.
The study was a collaborative effort of investigators in Europe with two researchers from the University of California, San Diego (UCSD) School of Medicine and the VA San Diego Healthcare System. Senior author Svante Paabo and first authors Wolfgang Enard and Philipp Khaltovich are with the Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
"With an understanding of the differences between humans and chimpanzees, we may be able to learn more about the genetics underlying diseases that seem to harm humans but not chimpanzees," said Ajit Varki, M.D., UCSD professor of medicine and cellular and molecular medicine, director of the UCSD Glycobiology Research and Training Center, and one of the paper's authors.
He noted that several diseases seem to differ in frequency and severity between chimps and humans, including AIDS, Alzheimer's, cancer and malaria. For example, chimps get infected with HIV, but almost never get AIDS and get only a mild form of malaria, even when injected with an often deadly form of the human parasite.
Varki's colleague, Elaine Muchmore, M.D., a hematologist and genetic researcher with VA San Diego Healthcare System and a UCSD professor of medicine, said the study also points out that the differences between humans and chimps are a lot more complicated and extensive than some researchers had previously thought.
"There are many people who have spoken out about the differences, but they have really oversimplified things," she said. "The human brain is a very, very complicated organ and this study validates that."
In landmark papers published in 1998 by Varki and Muchmore, the two reported on the first known biochemical and genetic difference between people and chimps ? a missing oxygen atom in humans, in a cell-surface carbohydrate molecule called sialic acid. Since then, the Varki group has published discovery of a second genetic difference and have found additional, as yet unpublished, variances involving sialic acid biology.
For the current study published in Science, Varki and Muchmore provided and analyzed RNA samples from white blood cells and from liver and brain tissue of chimps and other primates that had died of natural causes at the Yerkes Primate Center in Atlanta.
Their European colleagues searched for human vs. chimp differences by using gene chips carrying tiny dabs of DNA derived from about 18,000 human genes. The chip DNA interacted with genetic material purified from brain and liver tissue collected from humans and non-human primates (including chimpanzees and macaque monkeys), allowing the researchers to measure and compare the levels of expression of each of the genes in each of the species.
The comparative data suggest that during the evolutionary process, humans somehow altered the process of gene expression in their brains, accumulating expression differences at least five times faster than chimpanzees and distancing themselves from their nearest cousin. A similar trend appeared when the scientists examined differences in brain protein levels.
To determine if the differences between humans and chimps were indeed more than expected between such closely related species, the researchers also analyzed gene and protein expression in two mouse species that are about as genetically different from to each other as humans are to chimps. They found fewer differences in gene expression levels among the mice, further suggesting that the human/chimp discrepancy marks a special evolutionary process.
"I have now been asked by the German group to help them sort out the large number of differences they found in this study," Varki said. "Using my medical background, I hope to provide some insight into which of these differences might be best for further study. These results also provide support for my efforts to encourage the initiation of a chimpanzee genome project."
Other members of the research team include Sebastian Zollner, Florian Heissig and Philipp Khaitovich, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany; Joachim Klose, Institut fuer Humangenetik Charite, Berlin, Germany; Patrick Giavalisco, Max-Planck-Institute for Molecular Genetics, Berlin, Germany; Kay Nieselt-Struwe, Mas-Planck-Institute of Biophysical Chemistry, Gottingen, Germany; Rivka Ravid, The Netherlands Brain Bank, Amsterdam; and Gaby M. Doxiadis and Ronald E. Bontrop, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Most funding came from the Bundesministerium fur Bildung und Forschung and the Max Planck Gesellschaft. The work at UCSD and the VA was supported by a grant from the G. Harold and Leila Y. Mathers Charitable Foundation of New York.
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