Complexity from evolutionary tweaks

U. OREGON (US) — By reconstructing an ancient protein and tracing subtle changes over time, scientists have shown that novelty and complexity are the result of small evolutionary adjustments.

Human and other animal cells contain thousands of proteins with functions so diverse and complex that it is often difficult to see how they could have evolved from a few ancestral proteins, says biologist Joseph Thornton of the University of Oregon and the Howard Hughes Medical Institute, who led the research.

The team’s findings appear in the October issue of the open-access journal PLoS Biology.

Thornton’s team, which included researchers from Emory University and the University of Queensland in Australia, studied a large family of related proteins called nuclear receptors. These regulate development, reproduction, metabolism and cancer by triggering the expression of specific genes in response to hormones, nutrients, and other chemical signals.

A handful of nuclear receptors, however, do not have to be activated by a chemical signal: They are stable enough to trigger gene expression on their own.

Scientists have long thought that the ancestral protein was of this simpler type, implying that the complex capacity to bind and be regulated by chemical signals evolved independently in many lineages.

Using a database of the molecular sequences, functions, and atomic structures of hundreds of modern-day receptor proteins, the researchers reconstructed the biochemical characteristics of the ancestral nuclear receptor, which existed before the last common ancestor of all animals on earth—as much as a billion years ago.


Researchers were able to accurately reconstruct the ancestral receptor protein by gathering extensive new data about its descendants in species that diverged very early from other animals, including sponges such as the Amphimedon queenslandica, a sponge from the Great Barrier Reef. (Credit: Wikimedia Commons)

They found that the ancestral receptor in fact required activation by a chemical signal—most likely a fatty acid, a class of substances commonly found in animal diets.

They also found that the underlying atomic mechanisms that allowed the ancestral protein to be activated by chemical signals were conserved in virtually all present-day descendants.

The researchers then traced how evolution tinkered with ancestral structure over time. They found that in various lineages, receptors evolved partnerships with new hormones or other signals, because a few mutations subtly changed the size and shape of the cavity where the signaling compound binds.

Other members of the receptor family became independent of chemical signals; these proteins, like switches stuck in the “on” position, evolved when simple mutations increased the proteins’ intrinsic stability, removing the need for it to interact with a chemical signal to activate gene expression.

“If you just compare the receptors in modern humans, the evolutionary events by which they could have evolved are not obvious. It may look as if the complex functions of each protein evolved independently,” says Thornton.

“But when we traced these proteins from their ancestor through time, we saw how evolution tinkered with the ancestral form, producing an incredible diversity of protein functions and the ability to interact with many different chemical signals.

Thornton’s group was able to accurately reconstruct the ancestral receptor protein by gathering extensive new data about its descendants in species that diverged very early from other animals.

They first scanned the genomes of sponges, sea anemones, and a host of other animal species to collect the sequences of their nuclear receptors. Sponges, they found, had just two such proteins, while humans have 48.

By reconstructing the evolutionary tree of the entire receptor family, they found that the two sponge proteins branched off closest to the root, providing insights into the likely state of the ancestor.

The scientists then extracted the receptors from Amphimedon queenslandica, a sponge from the Great Barrier Reef, and showed that these receptors, like some of the other early-evolving receptors, bind fatty acids. They used computational methods to predict the three-dimensional atomic structure of the sponge proteins to show that they bound the fatty acid in a cavity very similar to that in some receptors in mammals.

“Nuclear receptors are a great case-study in protein evolution,” Thornton says. “It’s likely that other protein families, when studied in similar detail, will turn out to have diversified by a similar kind of tinkering. What looks like novelty turns out to have evolved by making subtle changes to something very old.”

The National Science Foundation, National Institutes of Health, Australian Research Council and Howard Hughes Medical Institute supported the research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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