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EMBARGOED BY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES FOR AUGUST 19, 2002; note: article published online Aug. 21 and in print Sept. 2.

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An international team of medical researchers and world-renowned anthropologists has determined that a gene mutation found only in humans and not in our evolutionary cousins, the apes, occurred more than 2 million years ago, just prior to human brain expansion but after our ancestors stood upright.

Using advanced molecular techniques to analyze powdered bone fragments from fossilized remains of Neandertals and other species, and comparing the genomes of humans and apes, the researchers concluded that the mutation occurred after the time when our ancestors stood upright - about 6-7 million years ago - but before their brains began to expand in size, about 2.2 million years ago.

Published Sept. 2, 2002 in Proceedings of the National Academy of Science and previewed online beginning August 21, 2002, the study combined the investigative efforts of UCSD faculty with a team of international researchers that included anthropologists Meave Leakey of Kenya and Etty Indriati of Indonesia, and molecular scientists Svante Paabo of Germany and Naoyuki Takahata of Japan.

The study's senior author, Ajit Varki, M.D., director of the UCSD Glycobiology Research and Training Center and professor of medicine and cellular and molecular medicine, noted that "contrary to the implication of 'Jurassic Park,' intact DNA can not be recovered from fossils that are more than 100,000 years old. Since our own species is older than that, we had to use three alternative approaches to predict the timing of the genetic mutation we had found in humans."

The investigative work by the Varki team began several years ago. In 1998, Varki and UCSD's Elaine Muchmore, M.D., announced that they had identified the first major biochemical and genetic difference between humans and their closest evolutionary cousins, the great apes. The gene, a sialic acid which codes for the production of a cell-surface sugar called N-glycolylneuramine Acid (Neu5Gc), was mutated (knocked out) in humans in comparison with the normal, intact gene in apes. Continuing research by the Varki team has sought to determine when in human evolution that the mutation occurred.

In the PNAS paper, the scientists provide an estimated divergence date and describe three molecular techniques they used to determine that date:
First, the team obtained contemporary primate bone samples from the Natural History Museum in San Diego, purchased faunal fossil samples (cave bear, dugong, mammoth, etc.) from recognized dealers, and obtained Georgian Neanderthal and Java Man fossils via the Paabo group.

The team developed a new method to extract and identify Neu5Gc and other sialic acids from bones and bony fossils; previously, scientists have only been able to extract sialic acids from soft tissues. To obtain the samples, the scientists filed off the surface of the bone or fossil, drilled into the center to collect a powdered bone sample, then prepared it for detailed analysis to determine the biochemical signature (absence of Neu5Gc) of the mutated gene.

"This allowed us to say that Neandertals, who shared a common ancestor with us 500,000-600,000 years ago, were like us," Varki said. "Because they had biochemical evidence for the mutated gene, this indicated that the mutation occurred prior to their common ancestor with us."

The second approach took advantage of what Varki called "jumping parasitic DNA," that is found scattered throughout the human genome, a copy of which seems to have been the culprit in inactivating the Neu5Gc-producing human gene. Previously not well understood by researchers, these bits of rogue DNA now appear to offer clues to human evolution. The Varki and Takahata teams used complex mathematics and detailed data analysis to predict the timeframe in which the particular copy of parasitic DNA landed and caused the human mutation, about 2.8 million years ago.

Third, the researchers took advantage of the fact that when the Neu5Gc-producing gene mutated in apes, it lost its functional ability in the new human lineage, but continued that ability in apes. Utilizing accepted techniques to measure mutation rates, the researchers calculated that the mutation occurred approximately the same time indicated in the second approach above.

Currently, the Varki team is studying the potential role that this gene mutation could have played in actual brain expansion, as well as other later steps in human evolution that occurred during the last 2 million years.

"Of course, we only have a hypothesis right now to test. And, the expansion of the brain during human evolution occurred in multiple steps and is very likely to have involved multiple genetic changes," Varki said.

The lead authors are members of the UCSD Glycobiology Research and Training Center. The paper's first author is Hsun-Hua Chou, a UCSD graduate student who recently finished her Ph.D. with Varki. Additional authors are Toshiyuki Hayakawa, Ph.D., Sandra Diaz, Matthias Krings, Ph.D., Yoko Satta, Ph.D., Naoyuki Takahata, Ph.D., Etty Indriati, Ph.D., Meave Leakey, Ph.D., and Svante Paabo, Ph.D. Hayakawa, Satta and Takahata are affiliated with the Graduate University for Advanced Studies, Hayama, Kanagawa, Japan; Indriati is with Gadjah Mada University, Java, Indonesia; Leakey, a member of the famed Leakey family of anthropologists, represents the Kenya National Museums and the Leakey Foundation, Nairobi, Kenya; and Paabo and Krings are with the Max Planck Institute for Evolutionary Anthropology, Liepzig, Germany.

The study was funded by the U.S. Public Health Service and the G. Harold and Leila Y. Mathers Charitable Foundation.

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