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 Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>