NEW KEY FITS OLD LOCK
03 June 2006 - National Science Foundation

Writing in the April 7 issue of the journal Science, a team led by Oregon biologist Joseph Thornton trace the stepwise genetic changes that allowed a single ancient ancestor molecule to produce two different modern receptors: one for the hormone aldosterone, which regulates kidney, colon and brain function, and the other for the hormone cortisol, which regulates the body's long-term response to stress.

To achieve this reconstruction, Thornton's group first characterized the receptors of several ancient vertebrate species, including lampreys, hagfish, and skates. Then, by applying standard statistical methods, the researchers showed that the two receptors found in most present-day vertebrates likely originated from a gene duplication that occurred about 450 million years ago. Finally, they inferred the gene sequence of the ancient receptor, synthesized it in the laboratory, and characterized its functions.

Their experiments showed that this synthesized receptor bound to an ancient hormone called deoxycorticosterone, as well as to the similarly shaped aldosterone and cortisol molecules. Thornton was surprised by the result, as aldosterone and cortisol did not exist until millions of years later. In effect, the new keys fit the old lock, opening the door to novel functions.

Thornton's group also identified two mutations, which presumably occurred millions of years after the duplication event, that enhanced the specificity of the modern-day receptor for cortisol.

Thornton said, "New techniques allowed us to see how ancient genes and their functions evolved hundreds of millions of years ago. We found that complexity evolved piecemeal with old genes being recruited to participate in new interactions and functions."

Thornton's research was supported in part by the National Science Foundation. William Zamer, the NSF program director who oversees the project commented, "Thornton's work is important scientifically because it shows how computational approaches can be used to infer the structure of ancient molecules, providing us with a window on how evolution has worked. Furthermore, it provided evidence that even highly specific receptor-hormone systems are not irreducibly complex and can come into existence through processes of Darwinian evolution."

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