Mutations Triggered Evolutionary Leap 500 Million Years Ago

Two Mutations Triggered an Evolutionary Leap 500 Million Years Ago:

Two Mutations Triggered an Evolutionary Leap 500 Million Years Ago

Two Mutations Triggered an Evolutionary Leap 500 Million Years Ago

A research team led by a University of Chicago scientist has discovered two key mutations that sparked a hormonal revolution 500 million years ago.

In a feat of “molecular time travel,” the researchers 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.

“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, who led the study.

“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.

Understanding how the genetic code of a protein determines its functions would allow biochemists to better design drugs and predict the effects of mutations on disease. Thornton said the discovery shows how evolutionary analysis of proteins’ histories can advance this goal, Before the group’s work, it was not previously known how the various steroid receptors in modern species distinguish estrogens from other hormones.

The team, which included researchers from the University of Oregon, Emory University and the Scripps Research Institute, studied the evolution of a family of proteins called steroid hormone receptors, which mediate the effects of hormones on reproduction, development and physiology. Without receptor proteins, these hormones cannot affect the body’s cells.

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.

“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 that, 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 on the body to evolve.

Earth’s evolutionary ancestor is a planet-spanning organism

The ancestor of all life on Earth might have been a gigantic planetary super-organism:

The ancestor of all life on Earth might have been a gigantic planetary super-organism

The ancestor of all life on Earth might have been a gigantic planetary super-organism

All life on Earth is related, which means we all must share a single common evolutionary ancestor. And now it appears that this ancestor might have been a single, planet-spanning organism that lived in a time that predates the development of survival of the fittest. That’s the idea put forward by researchers at the University of Illinois, who believe the last universal common ancestor, or LUCA, was actually a single organism that lived about three billion years ago. This organism was unlike anything we’ve ever seen, and was basically an amorphous conglomeration of cells. Instead of competing for resources and developing into separate lifeforms, cells spent hundreds of millions of years freely exchanging genetic material with each other, which allowed species to obtain the tools to survive without ever having to compete for anything. That’s maybe not an organism as we would comprehend it today, but that’s the closest term we have for this cooperative arrangement. All that we know about LUCA is based on conjecture, and the most promising recent research has been in figuring out what proteins and other structures are shared across all three domains of life: the unicellular bacteria and archaea and the multi-celled eukaryotes, which are where all plants and animals evolved from. This isn’t a foolproof method — it’s possible that two extremely similar but not identical structures could evolve independently after LUCA split into the three domains — but it’s a good starting point. Illinois researcher Gustavo Caetano-Anollés says about five to eleven percent of modern proteins could be traced back to LUCA. Based on the function of these particular proteins, it appears LUCA had the enzymes needed to break down nutrients and get energy from them, and it could also make proteins, but it probably didn’t have the tools necessary to make DNA. This fits with other research that suggests LUCA fed upon many different food sources, and that it had internal structures in its cells known as organelles. The big difference between LUCA and everything that came after, of course, is DNA. Because LUCA didn’t have the tools to deal with DNA, it probably used RNA instead, and it likely had very little control over the proteins that it made. The research suggests the ability to precisely control protein manufacture only came long after LUCA split apart, which means that protein-making was probably always a big crapshoot. That’s why LUCA had to be cooperative, with any cells that produced useful proteins able to pass them on throughout the world without competition. This was a weird variation on what we know as natural selections — helpful proteins could go from a single cell to global distribution, while harmful or useless proteins were quickly weeded out and discarded. The result was the equivalent of a planet-spanning organism. So why did this paradise of cellular cooperation give way to the last three billion years of cutthroat competition? The simple answer is that some cells probably outgrew this arrangement, as they had finally developed all the structures needed to survive without help. We don’t know quite why that happened, but it appears to coincide with the sharp increase of oxygen in the atmosphere. Whatever the cause, cells began eking out their own independent existences, ending the reign of LUCA that had lasted hundreds of millions of years… while beginning a new order that is still going strong 2.9 billion years later.