CLEVELAND -- Researchers at Case Western Reserve University's School of Medicine and University Hospitals of Cleveland may have made an important discovery in the study of what makes chimpanzees and humans different.

In the October 4 issue of the science journal Nature, researchers in the CWRU and UHC Department of Genetics and Center for Human Genetics published a paper explaining that gene duplication followed by adaptive evolution is one of the primary forces for the emergence of new gene function. The title of their research is "Positive Selection of a Gene Family During the Emergence of Humans and African Apes."

The team under Evan Eichler, assistant professor, was comprised of lead author Matthew Johnson, a second-year graduate student; Jeffrey Bailey, a student in the Medical Scientist Training Program; Luigi Viggiano and Marlano Rocchl, both of Sezione di Genetica in Italy; and Munah Abdul-Rauf and Graham Goodwin, both of the Section of Molecular Carcinogenesis, Institute of Cancer Research, Haddow Laboratories in the United Kingdom.

Eichler said the team's goal was to study the origin and evolution of a gene family -- morpheus -- that was carried as part of a duplication on human chromosome 16. One of the important discoveries is that this duplication occurred recently during evolution -- 5 to 10 million years ago.

The duplication moved quickly throughout the genome and was characterized by mutations resulting in amino acid changes at 50 to 100 times the normal rate. There are various mechanisms that facilitate duplication, or the copying of a given gene. In this case, Eichler said, the mechanism is largely unknown.

"The unusual thing about it is the duplication itself spreads specifically on a given chromosome. It's not localized to one specific region," Eichler said. "It jumped from one location to another."

He added that the gene carried in this segment "changed like wildfire," and may be important for the adaptation of humans or chimpanzees. The most important observation about the duplication, Eichler said, is that the vast majority of the changes that occurred in the gene resulted in amino acid changes. It usually is the other way around.

"Usually, changing amino acids is a bad thing, destroying the function of a protein -- as a result they are selected against and don't occur as often as mutations that don't alter amino acids," Eichler said. "In this specific gene family, the amino acid changes appear advantageous. They were selected for at a very high rate. The role of these changes may be adaptive -- enhancing the immune system, for example, or playing a role in speciation or species adaptation."

Either a molecular mechanism or the level of positive selection favored the amino acids to change at a high frequency after the separation of human and great ape lineages from the orangutan. Positive selection continued to alter the amino acid composition after the divergence of human and chimpanzee lineages.

The data clearly indicate, Eichler said, that duplication is one of the most creative forces in the organization of any genome. There is the potential to create new genes very rapidly over short periods of time.

"This raises the possibility that a small subset of genes between us and chimps are doing completely different things," Eichler said. "In the past, scientists have suggested that all genes between us and chimps do the same thing, they just do things at different times and places during development. These findings suggest genes that rapidly change may have had enough time to be performing different functions in man and chimps."

At this point, scientists don't know how many of the estimated 15 copies of this gene family are involved. But Eichler said it opens up another way of thinking about the evolution and organization of our genome.

He added that the Human Genome Project led to this and other studies. Eichler and his fellow researchers were part of the Human Genome Project before they completed the duplication study. Although they actually began their study before working on the Human Genome Project, Eichler said having access to the entire human genome sequence facilitated this discovery, taking a year and a half off the time to complete this research.

Eichler said some scientists didn't believe duplication events that occurred 5 to 10 million years could have been an important force in shaping our genomes. The thought was that it could not have contributed a large amount to our complexity so recently. But that was before the Human Genome Project which suggested that more than 5 percent of our sequence is made up of recently duplicated material.

From here, Eichler's team intends to investigate the function of the gene. Johnson is working on understanding where the protein is expressed, which copies are expressed and the potential functions of the protein family.

Another sequel to the duplication study is assessing how much diversity there is within the human population, with respect to this gene family. Eichler said there might be more variation than previously thought. And he wonders if there are amino acid changes still occurring at an accelerated rate among different humans.

"We all wave our hands at this point of what could be doing this," Eichler said. "Finding a gene of this type has been a "Holy Grail" of human molecular evolution. It's nice to know there is an example."

Eichler said scientists have always been interested in knowing what makes us different from chimps. This duplication, he said, has several unusual features that may make it important in determining that distinction.

"The gorilla and chimp have as much sequence divergence as a human and chimp," Eichler said. "We're clearly different at several levels. Yet genetic evidence says we're all closely related. Finding regions of our genome that have changed radically may be a foray into that area."

This study was supported by grants from the National Institutes of Health and the U.S. Department of Energy, as well as grants from the private foundations PRIN, CE, MURST and Telethon. Eichler and Bailey are also members of CWRU's Center for Computational Genomics.