Hormone Revolution Two Ancient Mutations
June 25, 2013

Hormone Revolution Triggered By Two Mutations 500 Billion Years Ago

April Flowers for redOrbit.com - Your Universe Online

We tend to think of evolution as a very slow, crawling process. Sometimes, however, as a team of researchers led by the University of Chicago have recently discovered, evolution leaps. The new study, published in Proceedings of the National Academy of Sciences, revealed two key mutations that sparked a hormonal revolution about 500 million years ago.

The research team, which included members from the University of Oregon, Emory University and the Scripps Research Institute, performed a feat of “molecular time travel” by resurrecting and analyzing the functions of the ancestors of genes that play key roles in modern human reproduction, development, immunity and cancer. They recreated the same DNA changes that occurred during the ancient history of those genes, showing how two mutations set the stage for the critical modern day roles of hormones such as estrogen, testosterone and cortisol.

"Changes in just two letters of the genetic code in our deep evolutionary past caused a massive shift in the function of one protein and set in motion the evolution of our present-day hormonal and reproductive systems," said Joe Thornton, PhD, professor of human genetics and ecology & evolution at the University of Chicago.

"If those two mutations had not happened, our bodies today would have to use different mechanisms to regulate pregnancy, libido, the response to stress, kidney function, inflammation, and the development of male and female characteristics at puberty," Thornton said.

Armed with an understanding of how the genes coding for a protein determines its function, biochemists would be better able to design drugs and predict the effects of mutation on disease. This discovery, according to Thornton, shows how the evolutionary analysis of proteins' histories can advance this goal. Before this study, scientists had not known how the various steroid receptors in modern species distinguish estrogens from other hormones.

The team examined the evolution of a family of proteins called steroid hormone receptors. These receptors mediate the effects of hormones on reproduction, development and physiology. In the absence of receptor proteins, these hormones cannot affect the body’s cells.

The researchers traced the evolution of the entire receptor family – from recognizing only estrogen to proteins capable of recognizing other steroid hormones like testosterone, progesterone and the stress hormone cortisol.

To accomplish this, the team used a gene “resurrection” strategy. The genetic sequences of ancient receptor proteins were inferred using computational methods to work their way back up the tree of life from a database of hundreds of present-day receptor sequences. Then, the team biochemically synthesized the ancient DNA sequences and used molecular assays to determine the receptors' sensitivity to various hormones.

The researchers were able to narrow down the time range during which the capacity to recognize non-estrogen steroids evolved, approximately 500 million years ago before the dawn of vertebrate animals on Earth. The most important mutations that occurred during that time were identified by introducing them into the reconstructed ancestral proteins. The team re-created ancient molecular evolution in the laboratory by measuring how the mutations affected the receptor's structure and function.

Just two changes in the ancient receptor’s gene sequence caused a 70,000-fold shift away from a preference for estrogen to other steroid hormones. Biophysical techniques were also used to identify the precise atomic-level mechanisms by which the mutations affected the protein's functions. The network of interactions between the receptor and the hormone were radically rewired by a change in just a few atoms in the protein, leading to a massive change in function.

"Our findings show that new molecular functions can evolve by sudden large leaps due to a few tiny changes in the genetic code," Thornton said. He pointed out, along with the two key changes in the receptor, additional mutations, the precise effects of which are not yet known, were necessary for the full effects of hormone signaling in the body to evolve.