An international team of medical researchers and anthropologists has determined that a gene mutation found only in humans and not in our evolutionary cousins, the apes, occurred more than two million years ago, just prior to human brain expansion but after human 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 human ancestors stood uprightabout six to seven million years agobut before their brains began to expand in size, about 2.2 million years ago.
Published in the September 2, 2002 issue of Proceedings of the National Academy of Science and previewed online, the study combined the investigative efforts of University of California, San Diego 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, 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 cannot 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 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 (including cave bear, dugong, and mammoth) from recognized dealers, and obtained Georgian Neanderthal and Java Man fossils via the Paabo group [researchers led by Svante Pääbo of the Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany].
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 to 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.