Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Ratchet-like genetic mutations make evolution irreversible

25.09.2009
By resurrecting ancient proteins, University of Oregon researchers find that evolution can only go forward

A University of Oregon research team has found that evolution can never go backwards, because the paths to the genes once present in our ancestors are forever blocked. The findings -- the result of the first rigorous study of reverse evolution at the molecular level -- appear in the Sept. 24 issue of Nature.

The team used computational reconstruction of ancestral gene sequences, DNA synthesis, protein engineering and X-ray crystallography to resurrect and manipulate the gene for a key hormone receptor as it existed in our earliest vertebrate ancestors more than 400 million years ago. They found that over a rapid period of time, five random mutations made subtle modifications in the protein's structure that were utterly incompatible with the receptor's primordial form.

The discovery of evolutionary bridge burning implies that today's versions of life on Earth may be neither ideal nor inevitable, said Joe Thornton, a professor in the UO's Center for Ecology and Evolutionary Biology and the Howard Hughes Medical Institute.

"Evolutionary biologists have long been fascinated by whether evolution can go backwards," Thornton said, "but the issue has remained unresolved because we seldom know exactly what features our ancestors had, or the mechanisms by which they evolved into their modern forms. We solved those problems by studying the problem at the molecular level, where we can resurrect ancestral proteins as they existed long ago and use molecular manipulations to dissect the evolutionary process in both forward and reverse directions."

Thornton's team, which included UO research scientist Jamie Bridgham and collaborator Eric A. Ortlund, a biochemist at Atlanta's Emory University, focused on the evolution of a protein called the glucocorticoid receptor (GR), which binds the hormone cortisol and regulates the stress response, immunity, metabolism and behavior in humans and other vertebrates.

"This fascinating study highlights the value of studying evolutionary processes," said Irene Eckstrand, who oversees evolution grants at the National Institutes of Health's National Institute of General Medical Sciences. "By showing how molecular structures are finely tuned by evolution, Dr. Thornton's research will have a broad impact on basic and applied sciences, including the design of drugs that target specific proteins."

In previous work, Thornton's group showed that the first GR evolved more than 400 millions ago from an ancestral protein that was also sensitive to the hormone aldosterone. They then identified seven ancient mutations that together caused the receptor to evolve its new specificity for cortisol.

Once Thornton's team knew how the GR's modern function evolved, they wondered if it could be returned to its ancestral function. So they resurrected the GR as it existed soon after cortisol specificity first evolved -- in the common ancestor of humans and all other vertebrates with bones -- and then reversed the seven key mutations by manipulating its DNA sequence.

'We expected to get a promiscuous receptor just like the GR's ancestor, but instead we got a completely dead, non-functional protein," Thornton said. "Apparently other mutations that occurred during early GR evolution acted as a sort of evolutionary ratchet, rendering the protein unable to tolerate the ancestral features that had existed just a short time earlier."

To identify the mutations, Thornton's team prepared crystals of resurrected ancient GR proteins and took them to the particle accelerator at the Advanced Photon Source outside Chicago, where they used powerful X-rays to determine the protein's atomic structure before and after the shift in function. By comparing the precise atomic maps of each protein, they identified five specific mutations in the later version of the GR that clashed with the architecture of the earlier protein.

"Suppose you're redecorating your bedroom -- first you move the bed, then you put the dresser where the bed used to be," Thornton said. "If you decide you want to move the bed back, you can't do it unless you get that dresser out of the way first. The restrictive mutations in the GR prevented evolutionary reversal in the same way."

When Thornton's group set the five mutations back to their ancestral state, the protein could now tolerate having the seven key changes reversed, which then transformed it into a promiscuous receptor just like the its ancestor.

Despite their powerful role as a ratchet preventing reversal, the five restrictive mutations had little or no direct effect on the protein's function when they occurred. And although they must be reversed before the protein can tolerate the ancestral state, reversing them first does absolutely nothing to enhance the ancestral function. "This means that even if the ancestral function were suddenly to become optimal again, there's no way natural selection could drive the protein directly back to its ancestral form," Thornton said.

GR's evolutionary irreversibility suggests that the molecules that drive our biology today may not be inevitable products of the evolutionary process. "In the GR's case, restrictive mutations erased the conditions that previously opened up the ancestral form as an evolutionary possibility. It's likely that throughout history other kinds of restrictive mutations have taken place, closing off innumerable trajectories that evolution might otherwise have taken," Thornton speculated.

"If we could wind back the clock and allow history to unfold again, different sets of mutations, apparently inconsequential at the time, would almost certainly occur, opening up some potential paths and blocking others -- including the one that leads to the present that actually evolved in our world," he said. "If what we observed in GR evolution is a general phenomenon, then the biology we have is just one of many possible rolls of the evolutionary dice."

The National Institutes of Health, the National Science Foundation and the Howard Hughes Medical Institute supported the research.

About the University of Oregon

The University of Oregon is a world-class teaching and research institution and Oregon's flagship public university. The UO is a member of the Association of American Universities (AAU), an organization made up of the 62 leading public and private research institutions in the United States and Canada. The UO is one of only two AAU members in the Pacific Northwest.

Source: Joe Thornton, associate professor of biology, 541-346-0328, joet@uoregon.edu

Links: Thornton faculty page: http://www.uoregon.edu/~joet/; UO Center for Ecology and Evolution: http://evolution.uoregon.edu/; biology department: http://biology.uoregon.edu/; Howard Hughes Medical Institute: http://www.hhmi.org/

Jim Barlow | EurekAlert!
Further information:
http://www.uoregon.edu

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>