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Two Small Mutations Led To Huge Leap In Hormone Evolution

Sometimes, evolution takes huge leaps instead of tiny steps. An example came to light this week in a paper published online in the Proceedings of the National Academy of Sciences (PNAS) where US researchers describe how they resurrected ancient proteins in the lab, replicated the gene changes that took place in them 500 million years ago, and found two key mutations triggered a leap in protein evolution that set the stage for hormones like estrogen, testosterone and cortisol to take on their vital present-day roles.

Study leader Joe Thornton, professor of human genetics and ecology & evolution at the University of Chicago, and colleagues, resurrected and tweaked ancestral genes of hormones that are important for human reproduction, development, immunity and cancer today.

"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," Thornton explains in a statement.

If evolution had taken a different course to that set by these two mutations, then human bodies would be using very different biological mechanisms to deal with stress, inflammation, libido, pregnancy, and the development of male and female differences in puberty, says Thornton.

He and his colleagues believe that by better understanding how proteins and the genes that code for them have evolved, we can design better drugs and anticipate how mutations might cause disease.

For instance, he and his team chose to study a set of proteins called steroid hormone receptors, without which hormones that control reproduction and development can't regulate cell behavior (the receptors are like docking stations for the hormones, without an appropriate docking station, the hormone cannot attach to a cell and affect how it behaves).

Before this study, scientist's didn't know how the different steroid receptors distinguished estrogens from other types of hormone.

Thornton and colleagues worked backwards to a common link connecting all the hormone receptors and found an ancient protein that only recognized estrogen, then traced the steps it underwent to evolve into proteins that recognise testosterone, progesterone and the stress hormone cortisol.

They built a computer model to help them work back up the tree of life that produced the genetic code in today's receptors. From this they inferred the genetic sequences of the ancient receptor proteins. They then made these ancient DNA sequences in the lab, and used molecular assays to find out how sensitive they were to different hormones.

They narrowed the window during which the ability to recognize non-estrogen hormones emerged to a period that occurred about 500 million years ago. This would be before the emergence of vertebrates (species with backbones).

By identifying the window, they could then look at the mutations that had occurred over that time, introduce them one by one into the resurrected proteins, and measure how they affected the structure and function of the receptor.

It was during this search that they found just two changes in the sequence of the receptor gene caused a 70,000-fold shift in preference: away from estrogens to other steroid hormones.

Using other techniques the team found that even though only a few atoms had moved in the protein, the change radically altered the pattern of signaling between receptor and hormone. The change in signaling pattern fundamentally altered the course of human reproduction, development, immunity and even cancer.

Thornton says their findings show that tiny changes in genetic code can trigger huge evolutionary leaps that lead to new molecular functions.

He also notes that a number of other mutations, as well as the two small changes in the receptor genetic code, were necessary to produce the radical shift in the pattern of hormone signaling.

Grants from the National Institutes of Health, National Science Foundation and the Howard Hughes Medical Institute helped finance the study.

These organizations also helped finance another intriguing study published in 2011, where researchers revealed that plant and animal receptor signaling pathways converged during evolution. They discovered that although plants took an evolutionary path different from their animal cousins, they arrived at similar solutions to a common problem: how to reliably receive and process incoming signals.

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