Just 2 genetic mutations sparked evolutionary jump 500 million years ago

A research team has found that the stage for the evolution of modern hormonal signalling was set by just 2 mutations about 500 million years ago.

Washington: A research team has found that the stage for the evolution of modern hormonal signalling was set by just 2 mutations about 500 million years ago.

In a feat of "molecular time travel," the researchers led by Joe Thornton, PhD, professor of human genetics and ecology and evolution at the University of Chicago, who led the study resurrected and analyzed the functions of the ancestors of genes that play key roles in modern human reproduction, development, immunity and cancer.

By re-creating the same DNA changes that occurred during those genes` ancient history, the team showed that two mutations set the stage for hormones like estrogen, testosterone and cortisol to take on their crucial present-day roles.

Thornton said that 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.

He said that 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`s group traced how the ancestor of the entire receptor family-which recognized only estrogens-evolved into descendant proteins capable of recognizing other steroid hormones, such as testosterone, progesterone and the stress hormone cortisol.

To do so, the group used a gene "resurrection" strategy. They first inferred the genetic sequences of ancient receptor proteins, using computational methods to work their way back up the tree of life from a database of hundreds of present-day receptor sequences.

They then biochemically synthesized these ancient DNA sequences and used molecular assays to determine the receptors` sensitivity to various hormones.

Thornton`s team narrowed down the time range during which the capacity to recognize non-estrogen steroids evolved, to a period about 500 million years ago, before the dawn of vertebrate animals on Earth.

They then identified the most important mutations that occurred during that interval by introducing them into the reconstructed ancestral proteins. By measuring how the mutations affected the receptor`s structure and function, the team could re-create ancient molecular evolution in the laboratory.

They found that just two changes in the ancient receptor`s gene sequence caused a 70,000-fold shift in preference away from estrogens toward other steroid hormones.

The researchers also used biophysical techniques to identify the precise atomic-level mechanisms by which the mutations affected the protein`s functions. Although only a few atoms in the protein were changed, this radically rewired the network of interactions between the receptor and the hormone, leading to a massive change in function.

The findings have been published in the Proceedings of the National Academy of Sciences.

ANI

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