UChicago scientists create alternate evolutionary histories in a test tubeSeptember 13, 2017
Scientists at the University of Chicago studied a massive set of genetic variants of an ancient protein, discovering a myriad of other ways that evolution could have turned out and revealing a central role for chance in evolutionary history.
The study, published this week in Nature by University of Chicago graduate student Tyler Starr and his advisor Professor Joseph Thornton, is the first to subject reconstructed ancestral proteins to deep mutational scanning -- a state-of-the-art technique for characterizing massive libraries of protein variants. The authors' strategy allowed them to compare the path that evolution actually took in the deep past to the millions of alternative routes that could have been taken, but were not.
Starting with a resurrected version of an ancient protein that evolved a new function some 500 million years ago - a function critical to human biology today -- the researchers synthesized a massive library of genetic variants and used deep mutational scanning to analyze their functions. They found more than 800 different ways that the protein could have evolved to carry out the new function as well, or better than, the one that evolved historically.
The researchers showed that chance mutations early in the protein's history played a key role in determining which ones could occur later. As a result, the specific outcome of evolution depended critically on the way a serial chain of chance events unfolded.
"By comparing what happened in history to all the other paths that could have produced the same result, we saw how idiosyncratic evolution is," said Tyler Starr, a graduate student in biochemistry and molecular biology at UChicago, who performed the paper's experiments. "People often assume that everything in biology is perfectly adapted for its function. We found that what evolved was just one possibility out of many that were just as good, or even better, functionally than what we happened to end up with today."
Molecular time travel
Over the last 15 years, Joe Thornton, PhD, senior author on the new study and a professor of ecology and evolution and human genetics at UChicago, led research that pioneered "molecular time travel" using ancestral protein reconstruction. In 2013, his team resurrected and analyzed the functions of the ancestors of a family of proteins called steroid hormone receptors, which mediate the effects of hormones like testosterone and estrogen on sexual reproduction, development, physiology, and cancer. The body's various receptors recognize different hormones and, in turn, activate the expression of different target genes, which they accomplish by binding specifically to DNA sequences called response elements near those targets.
Thornton's group inferred the genetic sequences of ancient receptor proteins by statistically working their way back down the tree of life from a database of hundreds of present-day receptor sequences. They synthesized genes corresponding to these ancient proteins, expressed them in the lab, and measured their functions.
They found that the ancestor of the family behaved like an estrogen receptor - recognizing only estrogens and binding to estrogen response elements - but during one specific interval of history, they evolved into a descendant group capable of recognizing other steroid hormones and binding to a new class of response elements. The researchers found that three key mutations before the emergence of vertebrate animals caused the ancestral receptor to evolve its ability to bind to the new target sequences.
That work set the stage for the current study. Knowing precisely how evolution played out in the past, Thornton's group asked: Was this the only evolutionary path to evolving the new function? Was it the most effective one, or the easiest to achieve? Or was it simply one of many possibilities?
Starr began working on the project during his first year as a graduate student, developing the technique to assess massive numbers of variants of the ancestral receptor for their ability to bind the new response element. First, he engineered strains of yeast in which the ancestral or new response elements drive expression of a fluorescent reporter gene. He then synthesized a library of ancestral proteins containing all possible combinations of amino acids at the four key sites in the receptor that recognize DNA - 160,000 in all, comprising all possible evolutionary paths that this critical part of the protein could have followed - and introduced this library into the engineered yeast. He sorted hundreds of millions of yeast cells by their fluorescence using a laser-driven device, and then used high-throughput sequencing to associate each receptor variant with its ability to carry out the ancestral function and the new function.
Most of the variants failed to function at all, and some maintained the ancestral function. But Starr found 828 new versions of the protein that could carry out the new function as well, or better than, the one that evolved during history. Remarkably, evolution could have accessed many of these even more easily than the historical "solution," but it happened not to, apparently wandering around the space of possible mutations until it arrived at the version of the protein in our bodies today.
"We all share the same gene sequence for this protein, so it might seem like evolutionary destiny, as if we've arrived at the best possible version. But there are hundreds of other directions that evolution could just as well have taken," Thornton said. "There's nothing special about the history that happened, except that a few chance steps brought us to this singular chance outcome."
Thornton said that deep mutational scanning will be a powerful tool for evolutionary biologists, geneticists and biochemists, and he looks forward to using the approach on successive ancestors at different points in history to see how the set of possible outcomes changed through time.
"We have a molecular time machine to go back to the past, and once we're there, we can simultaneously follow every alternate history that could possibly have played out," Thornton said. "It's a molecular version of every evolutionary biologist's dream."
The study, "Alternate evolutionary histories in the sequence space of an ancient protein," was supported by the National Institutes of Health and the National Science Foundation. Lora Picton, a former research scientist in Thornton's lab at the University of Chicago, was also co-author.
The University of Chicago Medicine & Biological Sciences is one of the nation's leading academic medical institutions. It comprises the Pritzker School of Medicine, a top 10 medical school in the nation; the University of Chicago Biological Sciences Division; and the University of Chicago Medical Center, which recently opened the Center for Care and Discovery, a $700 million specialty medical facility. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine.
Visit our research blog at sciencelife.uchospitals.edu and our newsroom at uchospitals.edu/news.
Twitter @UChicagoMed, @ScienceLife
University of Chicago Medical Center
Related Evolution Articles:
The evolution of cells and organisms is thought to have been preceded by a phase in which informational molecules like DNA could be replicated selectively.
A new study by University of Arizona biologists helps explain why different groups of animals differ dramatically in their number of species, and how this is related to differences in their body forms and ways of life.
A genome project, comprising six evolutionary biologists from Professor Axel Meyer's research team from Konstanz and researchers from China and Singapore, sequenced and analyzed the genome of the tiger tail seahorse.
Rapid evolution of other species happens all around us all the time -- and many of the most extreme examples are associated with human influences.
Landscapes are formed by a combination of uplift and erosion.
How enzymes -- the biological proteins that act as catalysts and help complex reactions occur -- are 'tuned' to work at a particular temperature is described in new research from groups in New Zealand and the UK, including the University of Bristol.
On Nov. 11, 1954, Syuiti Mori turned out the lights on a small group of fruit flies.
A team of researchers, among them a zoologist from the University of Cologne, has succeeded in reconstructing a 160 million year old compound eye of a fossil crustacean found in southeastern France visible.
Evolution may be more intelligent than we thought, according to a University of Southampton professor.
Organized opposition to the teaching of evolution in public schoolsin the United States began in the 1920s, leading to the famous Scopes Monkey trial.
Related Evolution Reading:
by Douglas J. Futuyma (Author), Mark Kirkpatrick (Author)
Extensively rewritten and reorganized, this new edition of Evolution--featuring a new coauthor: Mark Kirkpatrick (The University of Texas at Austin)--offers additional expertise in evolutionary genetics and genomics, the fastest-developing area of evolutionary biology. Directed toward an undergraduate audience, the text emphasizes the interplay between theory and empirical tests of hypotheses, thus acquainting students with the process of science. It addresses major themes--including the history of evolution, evolutionary processes, adaptation, and evolution as an explanatory... View Details
Why Evolution Is True
by Jerry A. Coyne (Author)
"Coyne's knowledge of evolutionary biology is prodigious, his deployment of it as masterful as his touch is light." -Richard Dawkins
In the current debate about creationism and intelligent design, there is an element of the controversy that is rarely mentioned-the evidence. Yet the proof of evolution by natural selection is vast, varied, and magnificent. In this succinct and accessible summary of the facts supporting the theory of natural selection, Jerry A. Coyne dispels common misunderstandings and fears about evolution and clearly confirms the scientific truth that... View Details
Evolution: A Visual Record
by Robert Clark (Author)
Stunning images to reawaken us to the scientific process that drives the amazing diversity of life on earth
Evidence of evolution is everywhere. Through 200 revelatory images, award-winning photographer Robert Clark makes one of the most important foundations of science clear and exciting to everyone. Evolution: A Visual Record transports readers from the near-mystical(human ancestors) to the historic (the famous 'finches' Darwin collected on the Galapagos Islands that spurred his theory); the recently understood (the link between dinosaurs and modern birds)... View Details
Evolution: The Cutting-Edge Guide to Breaking Down Mental Walls and Building the Body You've Always Wanted
by Joe Manganiello (Author)
Joe Manganiello first gained recognition around the world for his incredible, sculpted body while winning both popular and critical praise as the star of HBO's True Blood. Now, from the man that Magic Mike director Steven Soderbergh called “walking CGI,” comes the cutting-edge guide to achieving the perfect body and therefore enhancing your overall quality of life.
With a build that men envy and women adore, Joe Manganiello is more than qualified to write the end-all guide to sculpting the perfect body. His fit physique catapulted him to the top of the list of... View Details
Improbable Destinies: Fate, Chance, and the Future of Evolution
by Jonathan B. Losos (Author)
A major new book overturning our assumptions about how evolution works
Earth’s natural history is full of fascinating instances of convergence: phenomena like eyes and wings and tree-climbing lizards that have evolved independently, multiple times. But evolutionary biologists also point out many examples of contingency, cases where the tiniest change—a random mutation or an ancient butterfly sneeze—caused evolution to take a completely different course. What role does each force really play in the constantly changing natural world? Are the plants and animals that... View Details
Grandmother Fish: A Child's First Book of Evolution
by Jonathan Tweet (Author), Karen Lewis (Illustrator)
Where did we come from?
It's a simple question, but not so simple an answer to explain―especially to young children. Charles Darwin's theory of common descent no longer needs to be a scientific mystery to inquisitive young readers. Meet Grandmother Fish.
Told in an engaging call and response text where a child can wiggle like a fish or hoot like an ape and brought to life by vibrant artwork, Grandmother Fish takes children and adults through the history of life on our planet and explains how we are all connected.
Get your students thinking critically about evolution.Evolution presents foundational concepts through a contemporary framework of population genetics and phylogenetics that is enriched by current research and stunning art. In every chapter, new critical thinking questions and expanded end-of-chapter problems emphasizing data interpretation reinforce the Second Edition’s focus on helping students think like evolutionary biologists. View Details
Evolution: Making Sense of Life
by Carl Zimmer (Author), Douglas Emlen (Author)
Science writer Carl Zimmer and evolutionary biologist Douglas Emlen have produced a thoroughly revised new edition of their widely praised evolution textbook. Emlen, an award-winning evolutionary biologist at the University of Montana, has infused Evolution: Making Sense of Life with the technical rigor and conceptual depth that today’s biology majors require. Zimmer, an award-winning New York Times columnist, brings compelling storytelling to the book, bringing evolutionary research to life. Students will learn the fundamental concepts of evolutionary theory, such as natural... View Details
Four Views on Creation, Evolution, and Intelligent Design (Counterpoints: Bible and Theology)
by J.B. Stump (Editor), Stanley N. Gundry (Editor), Ken Ham (Editor), Hugh Ross (Editor), Deborah Haarsma (Editor), Stephen C. Meyer (Editor)
Four Views on Creation, Evolution, and Intelligent Design presents the current "state of the conversation" about origins among evangelicals representing four key positions:Young Earth Creationism - Ken Ham (Answers in Genesis)Old Earth (Progressive) Creationism - Hugh Ross (Reasons to Believe)Evolutionary Creation - Deborah B. Haarsma (BioLogos)Intelligent Design - Stephen C. Meyer (The Discovery Institute)
The contributors offer their best defense of their position addressing questions such as: What is your position on origins - understood broadly to include the... View Details Evolution: The Whole Story provides an in-depth and up-to-the- minute account of evolution, one of the ultimate keystone theories in modern science. Ten esteemed experts thoroughly survey how each of Earth's major groups of living things diversified and evolved through time and using visual features that make the story comprehensible, the book gives readers, even those with no previous knowledge of the topic, a clear understanding of evolution and how it brought us to the present day. Each of seven chapters takes one of Earth's major living groups and describes the... View Details
Evolution: The Whole Story
by Steve Parker (Editor), Alice Roberts (Editor)
Evolution: The Whole Story provides an in-depth and up-to-the- minute account of evolution, one of the ultimate keystone theories in modern science. Ten esteemed experts thoroughly survey how each of Earth's major groups of living things diversified and evolved through time and using visual features that make the story comprehensible, the book gives readers, even those with no previous knowledge of the topic, a clear understanding of evolution and how it brought us to the present day.
Each of seven chapters takes one of Earth's major living groups and describes the... View Details