"We've discovered a striking phenomenon that challenges a paradigm of molecular evolution that has been around for several decades," said lead author Bruce Lahn, PhD, assistant professor of genetics at the University of Chicago and Howard Hughes Medical Institute investigator. "As such, it may cause a significant shift in the field."

The researchers report their findings in the July 2005, issue of the journal Trends in Genetics. Other authors are Gerald Wyckoff, PhD, previously a postdoctoral fellow in Lahn's lab and now an assistant professor at the University of Missouri-Kansas City, and Christine Malcom and Eric Vallender, both graduate students in Lahn's lab.

For more than three decades, molecular evolutionists have thought that no matter how many genetic mutations show up on a specific gene, whether or not those mutations become fixed in the species is determined primarily by natural selection. The new study shows that the speed at which these new mutations arrive also affects whether the mutations become fixed.

Lahn's team looked at nearly 6,000 genes in their study. For each gene, they compared sequences between two mammalian species. This enabled them to measure the mutation rate of the gene “ specifically, the rate of those mutations that do not affect the protein's structure, called synonymous mutation (Ks). These mutations are functionally neutral, which means natural selection is not a factor in whether they are accepted during evolution.

Lahn's team also looked at the mutation rate of nonsynonymous changes (Ka)--the rate of those mutations that do affect protein structure. These mutations are typically subject to natural selection. A nonsynonymous mutation will get accepted into or bounced out of the population based upon how the change alters protein function.

The researchers then studied the Ka/Ks ratio. A low Ka/Ks ratio indicates strong selection; conversely, a high ratio, weak selection. Some genes have a ratio of 0, which means protein changes are not accepted. It is, in a sense, "perfect."

For a pseudogene--a stretch of DNA sequence that resembles a gene but has no function--its Ka/Ks ratio is approximately 1.0, which means that synonymous and nonsynonymous mutations are accepted at the same rate since the gene is functionally irrelevant.

For a gene that is highly functional and important for the organism, its Ka/Ks ratio is typically low. For example, if a gene has a Ka/Ks ratio of 0.1, it means that it's highly selective and is only accepting 10 percent of the nonsynonymous mutations.

Regardless of the rate of new mutations at a particular gene, scientists have always presumed the percentage of nonsynonymous mutations accepted during evolution remains constant.

"This theory has been the workhorse of molecular evolution," Lahn said. "Thousands of scientific papers have been published based directly or indirectly on this notion."

The new data show that if more mutations show up at a gene, that gene tends to accept a higher percentage of those mutations.

"A gene under strong mutational pressure succumbs to that pressure," Lahn said. "For genes that have a high mutation rate, somehow selection appears to become less stringent."

Lahn cannot explain the mechanism of his findings and expects many will question this novel finding. "It's too radical," he said. "People just don't want to believe it, but the data are there."

"Lahn and his associates have found a most striking result, one that is totally unexpected," said geneticist James Crow, professor emeritus of genetics and zoology at the University of Wisconsin-Madison. "If this result is indeed confirmed it would cast doubt on use of this ratio [Ka/Ks] as an indicator of selection."

Sudhir Kumar, an associate professor of molecular evolution at Arizona State University, agreed. "It goes against strict theory, but evolutionary biologists know that nothing's clean cut. There's always distortion because we're looking at longtime history.

"The novelty of this work is that he [Lahn] used a large amount of data," Kumar said. "It's a perfect example of the power of the genome project."

"I hope that further work will provide an explanation of what now is a major puzzle," Crow added.

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