Thanks to Ken Bromberg for the link.

Reposted from:
http://www.nytimes.com/2007/08/21/science/21prot.html

Offering insight into how evolution progresses inside a gene, scientists have pinpointed mutations in an ancient protein that transformed its shape and function more than 400 million years ago.

Scientists at the University of Oregon and the University of North Carolina used modern technologies to conduct an archaeology of genes and help answer a longstanding question about how proteins change over time and develop new roles.

"We have now seen the mechanisms by which a new function evolves at the atomic level, how evolution sculpted the protein structure to produce a new function," said Joseph W. Thornton, a biology professor at Oregon who led the research.

The findings were published last week on the Web site of the journal Science.

A few mutations in a gene, which is a section of DNA that provides the blueprint for a specific protein, can result in a protein that no longer folds properly. That makes the protein useless, because it is the shape of a protein that largely determines which molecules it can bind to, and hence, its function.

The probability that subsequent mutations could reshape the unfolded protein into a form with a new function is essentially zero, and that is an evolutionary cul de sac.

Supporters of intelligent design, who question evolution, have argued that mutations, occurring one by one, could not refold a protein into a new function, because the mutations would first unravel the protein into a useless, unfolded configuration.

The new study refutes that assertion, at least in this instance. Dr. Thornton's research focuses on proteins known as hormone receptors that act as locks in a key-and-lock mechanism. When a hormone fits into a receptor, the receptor sends a signal to another part of the cell.

In work published last year, Dr. Thornton reported how his group reconstructed an ancestral protein of two hormone receptors found in humans. The two, once identical, diverged along different evolutionary paths. One is now part of the stress response system; the other is involved in different biological processes, including kidney function in many animals.

In the new study, the researchers determined the exact positions of more than 2,000 atoms in the ancestral hormone receptor. The receptor existed in animals that lived more than 440 million years ago, before the last common ancestor of people and sharks. Then the researchers examined what occurred during the next 20 million years — before another split of the evolutionary tree that led to bony fish. "That's the ancestor of you and a salmon," Dr. Thornton said.

In that time, one hormone receptor changed so that it bound most strongly to cortisol, a stress hormone. Bony fish and people have this version, called a glucocorticoid receptor. Sharks do not.

Of the glucocorticoid receptors that have been looked at in different species, five specific mutations are always present and distinguish them from the ancestral receptor. When the scientists introduced the five changes into the ancestral protein, they expected that it would be transformed into a glucocorticoid receptor.

Instead, the protein broke, unable to bind to any hormone.

On further investigation, the scientists found that two other mutations, which had negligible effects by themselves, strengthened some of the protein's folds so it could withstand the other five mutations. The researchers were also able to show several sequences in which the seven mutations could have occurred without the protein's functionality ever deteriorating.

Biologists often point out that evolution does not proceed through random chance. Rather, the process of natural selection — survival of the fittest — ruthlessly weeds out mutations detrimental to the survival of a species.

But the findings of Dr. Thornton and his colleagues show that some aspects of evolution do occur solely by chance. The two mutations that reinforced the protein did not directly help the organism. So natural selection did not particularly favor them. It was only by chance that they occurred and persisted to set the groundwork for the other mutations.

Other seemingly innocuous mutations might have led evolution down another path. "These very exquisitely adapted bodies we have represent a role of the dice," Dr. Thornton said. "And they could have turned out very differently."